冠脉微循环（微血管）功能障碍（CMVD）

目的 采用“一站式”心脏CT扫描〔冠状动脉CT血管造影（coronary computed tomography angiography, CCTA）联合动态CT心肌灌注成像（computed tomography myocardial perfusion imaging, CT-MPI）〕分析非阻塞性冠状动脉疾病（coronary artery disease, CAD）的2型糖尿病（type 2 diabetes mellitus, T2DM）与非糖尿病患者间CT心肌灌注参数的差异，并探讨糖尿病对发生冠状动脉微循环缺血的影响。 方法 经倾向性评分匹配均衡基线水平，最终纳入非阻塞性CAD的T2DM患者92例（T2DM组）及非糖尿病患者92例（非糖尿病组），比较两组患者的临床特征、CCTA及CT-MPI结果；采用有向无环图分析各变量之间的因果关系，筛选关键混杂因素，建立多因素回归模型，校正混杂因素后评估T2DM对发生冠状动脉微循环缺血的独立影响。 结果 T2DM组与非糖尿病组间患者的年龄、性别、高血压、高血脂、吸烟史、体质量指数、胸前区症状、钙化积分、CAD-RADS评分、辐射剂量差异均无统计学意义。T2DM组患者整体及心肌各节段（基底段、中间段、心尖段）的心肌血流量平均值与非糖尿病组相比降低（P<0.05）；T2DM患者冠状动脉微循环缺血的发生率高于非糖尿病患者〔21.7%（20/92） vs. 5.4%（5/92）〕，P=0.001〕。多因素logistic回归分析表明T2DM是冠状动脉微循环缺血的独立危险因素（比值比=5.095，95%置信区间：1.753～14.805）。 结论 CCTA联合动态CT-MPI的心脏“一站式”扫描显示，非阻塞性CAD的T2DM患者整体心肌血流灌注降低，更易发生冠状动脉微循环缺血；T2DM与冠状动脉微循环缺血独立相关。

目的 评估心脏康复对心肺运动试验阳性的高原非阻塞性冠状动脉疾病患者症状和生活质量的影响。 方法 通过随机对照方法，选取高原怀疑冠心病住院患者进行冠脉造影检查。根据检查结果，对非阻塞性冠状动脉疾病患者进行心肺运动试验评估，将结果为阳性的患者纳入。心肺运动试验阳性患者根据数字表、完全随机被分为两组：一组（试验组）接受心脏康复（个体化制定运动方案）+常规治疗，另一组（对照组）只接受常规治疗，在入组时和随访3个月时进行西雅图心绞痛量表（Seattle Angina Questionnaire, SAQ）和36条简明健康状况（36-item Short-Form Health Survey, SF-36）调查表评分。通过分析两组数据，评估心脏康复对心肺运动试验阳性的高原非阻塞性冠状动脉疾病患者症状和生活质量的影响。 结果 本研究共纳入100例患者，试验组和对照组各为50例。试验组平均年龄（55.0±6.8）岁，对照组平均年龄（56.6±9.1）岁。入组时，两组在SAQ各指标上的差异均无统计学意义。然而，在3个月随访时，试验组在躯体活动受限程度（75.6±5.0 vs. 72.1±5.9）、心绞痛稳定状态（69.6±6.4 vs. 62.5±9.6）、心绞痛发作情况（70.8±9.1 vs. 65.3±9.3）、治疗满意程度（79.5±5. 0vs. 76.3±4.7）和疾病认识程度（84.9±5.2 vs. 80.4±3.8）方面的评分高于对照组（P<0.05）。入组时，两组在SF-36各指标上的差异均无统计学意义。然而，在3个月随访时，试验组在生理功能（27.4±2.4 vs. 25.8±3.0）、生理职能（6.6±1.2 vs. 6.0±0.8）、躯体疼痛（4.7±1.3 vs. 4.1±1.0）、一般健康状况（20.2±2.2 vs. 19.0±1.8）、精力（15.8±2.1 vs. 14.5±2.1）、社会功能（7.2±1.3 vs. 6.4±1.1）、情感职能（5.2±1.1 vs. 4.7±1.2）和精神健康（22.9±2.7 vs. 20.8±2.1）评分方面均优于对照组（P<0.05）。 结论 心脏康复有利于改善心肺运动试验阳性的高原非阻塞性冠状动脉疾病患者症状和提高生活质量，康复期间患者均未发生不良心血管事件，其安全性和有效性得到初步验证。

目的 探讨miR-328-3p对氧化型低密度脂蛋白（oxidized low-density lipoprotein, ox-LDL）诱导的冠状动脉内皮细胞损伤的保护作用及可能相关的作用机制。 方法 用ox-LDL诱导人冠状动脉内皮细胞（human coronary artery endothelial cells, HCAECs），将细胞分为对照（control）组（正常培养细胞）、ox-LDL组（ox-LDL处理）、ox-LDL+miR-NC组（转染miR-NC，用ox-LDL处理）、ox-LDL+miR-328-3p组（转染miR-328-3p，用ox-LDL处理）、ox-LDL+miR-328-3p+pcDNA组（共转染miR-328-3p和pcDNA，用ox-LDL处理）、ox-LDL+miR-328-3p+胰岛素样生长因子2（insulin-like growth factor 2, IGF2）组（共转染miR-328-3p和IGF2，用ox-LDL处理）。RT-qPCR检测miR-328-3p表达水平；MTT以及流式细胞术检测细胞增殖和凋亡；Western blot法检测cleaved cas-3、IGF2、Bax、Bcl-2蛋白含量；ELISA法检测肿瘤坏死因子-α（tumor necrosis factor α, TNF-α）、白细胞介素（interleukin, IL）-6、IL-1β含量 ；应用双荧光素酶报告实验验证分子间靶向关系。 结果 与control组相比，ox-LDL组中miR-328-3p表达水平、细胞活性降低（P<0.05），凋亡率，cleaved cas-3、IGF2蛋白表达，TNF-α、IL-6、IL-1β水平增加（P<0.05）。与ox-LDL+miR-NC组相比，ox-LDL+miR-328-3p组miR-328-3p表达水平、细胞活性增加（P<0.05），凋亡率，cleaved cas-3、IGF2蛋白表达，TNF-α、IL-6、IL-1β水平降低（P<0.05）。IGF2是miR-328-3p的功能靶标。与共转染ox-LDL+miR-328-3p+pcDNA组比较，共转染ox-LDL+miR-328-3p+IGF2组IGF2蛋白水平升高（P<0.05），细胞活性降低（P<0.05），而凋亡率、cleaved cas-3蛋白水平以及TNF-α、IL-6、IL-1β含量升高（P<0.05）。 结论 miR-328-3p通过靶向负调控IGF2抑制ox-LDL诱导的冠状动脉内皮细胞凋亡和炎性损伤。

BACKGROUND AND AIMS Skeletal muscle (SM) fat infiltration, or intermuscular adipose tissue (IMAT), reflects muscle quality and is associated with inflammation, a key determinant in cardiometabolic disease. Coronary flow reserve (CFR), a marker of coronary microvascular dysfunction (CMD), is independently associated with body mass index (BMI), inflammation and risk of heart failure, myocardial infarction, and death. The relationship between SM quality, CMD, and cardiovascular outcomes is not known. METHODS Consecutive patients (n = 669) undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion and preserved left ventricular ejection fraction were followed over a median of 6 years for major adverse cardiovascular events (MACEs), including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve was calculated as stress/rest myocardial blood flow. Subcutaneous adipose tissue (SAT), SM, and IMAT areas (cm2) were obtained from simultaneous positron emission tomography attenuation correction computed tomography using semi-automated segmentation at the 12th thoracic vertebra level. RESULTS Median age was 63 years, 70% were female, and 46% were nonwhite. Nearly half of patients were obese (46%, BMI 30-61 kg/m2), and BMI correlated highly with SAT and IMAT (r = .84 and r = .71, respectively, P < .001) and moderately with SM (r = .52, P < .001). Decreased SM and increased IMAT, but not BMI or SAT, remained independently associated with decreased CFR (adjusted P = .03 and P = .04, respectively). In adjusted analyses, both lower CFR and higher IMAT were associated with increased MACE [hazard ratio 1.78 (95% confidence interval 1.23-2.58) per -1 U CFR and 1.53 (1.30-1.80) per +10 cm2 IMAT, adjusted P = .002 and P < .0001, respectively], while higher SM and SAT were protective [hazard ratio .89 (.81-.97) per +10 cm2 SM and .94 (.91-.98) per +10 cm2 SAT, adjusted P = .01 and .003, respectively]. Every 1% increase in fatty muscle fraction [IMAT/(SM + IMAT)] conferred an independent 2% increased odds of CMD [CFR <2, odds ratio 1.02 (1.01-1.04), adjusted P = .04] and a 7% increased risk of MACE [hazard ratio 1.07 (1.04-1.09), adjusted P < .001]. There was a significant interaction between CFR and IMAT, not BMI, such that patients with both CMD and fatty muscle demonstrated highest MACE risk (adjusted P = .02). CONCLUSIONS Increased intermuscular fat is associated with CMD and adverse cardiovascular outcomes independently of BMI and conventional risk factors. The presence of CMD and SM fat infiltration identified a novel at-risk cardiometabolic phenotype.

No abstract available

Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials.

BACKGROUND Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

Background Coronary microvascular dysfunction (CMD) is a common complication of ST‐segment–elevation myocardial infarction (STEMI) and can lead to adverse cardiovascular events. Whether CMD after STEMI is associated with functional left ventricular remodeling (FLVR) and diastolic dysfunction, has not been investigated. Methods and Results This is a nonrandomized, observational, prospective study of patients with STEMI with multivessel disease. Coronary flow reserve and index of microcirculatory resistance of the culprit vessel were measured at 3 months post‐STEMI. CMD was defined as index of microcirculatory resistance ≥25 or coronary flow reserve <2.0 with a normal fractional flow reserve. We examined the association between CMD, LV diastolic dysfunction, FLVR, and major adverse cardiac events at 12‐month follow‐up. A total of 210 patients were enrolled; 59.5% were men, with a median age of 65 (interquartile range, 58–76) years. At 3‐month follow‐up, 57 patients (27.14%) exhibited CMD. After 12 months, when compared with patients without CMD, patients with CMD had poorer LV systolic function recovery (−10.00% versus 8.00%; P<0.001), higher prevalence of grade 2 LV diastolic dysfunction (73.08% versus 1.32%; P<0.001), higher prevalence of group 3 or 4 FLVR (11.32% versus 7.28% and 22.64% versus 1.99%, respectively; P<0.001), and higher incidence of major adverse cardiac events (50.9% versus 9.8%; P<0.001). Index of microcirculatory resistance was independently associated with LV diastolic dysfunction and adverse FLVR. Conclusions CMD is present in ≈1 of 4 patients with STEMI during follow‐up. Patients with CMD have a higher prevalence of LV diastolic dysfunction, adverse FLVR, and major adverse cardiac events at 12 months compared with those without CMD. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05406297.

Coronary microvascular dysfunction (CMD) is a frequent complication of diabetes mellitus (DM) characterized by challenges in both diagnosis and intervention. Circulating levels of microRNAs are increasingly recognized as potential biomarkers for cardiovascular diseases. Serum exosomes from patients with DM, DM with coronary microvascular dysfunction (DM-CMD) or DM with coronary artery disease (DM-CAD) were extracted for miRNA sequencing. The expression of miR-16-2-3p was assessed in high glucose-treated human aortic endothelial cells and human cardiac microvascular endothelial cells. Fluorescence in situ hybridization (FISH) was used to detect miR-16-2-3p within the myocardium of db/db mice. Intramyocardial injection of lentivirus overexpressing miR-16-2-3p was used to explore the function of the resulting gene in vivo. Bioinformatic analysis and in vitro assays were carried out to explore the downstream function and mechanism of miR-16-2-3p. Wound healing and tube formation assays were used to explore the effect of miR-16-2-3p on endothelial cell function. miR-16-2-3p was upregulated in circulating exosomes from DM-CMD, high glucose-treated human cardiac microvascular endothelial cells and the hearts of db/db mice. Cardiac miR-16-2-3p overexpression improved cardiac systolic and diastolic function and coronary microvascular reperfusion. In vitro experiments revealed that miR-16-2-3p could regulate fatty acid degradation in endothelial cells, and ACADM was identified as a potential downstream target. MiR-16-2-3p increased cell migration and tube formation in microvascular endothelial cells. Our findings suggest that circulating miR-16-2-3p may serve as a biomarker for individuals with DM-CMD. Additionally, miR-16-2-3p appears to alleviate coronary microvascular dysfunction in diabetes by modulating ACADM-mediated fatty acid degradation in endothelial cells.

BACKGROUND Approximately half of the patients with angina and nonobstructive coronary artery disease (ANOCA) have evidence of coronary microvascular dysfunction (CMD). OBJECTIVES This study aims to characterize patients with ANOCA by measuring their minimal microvascular resistance and to examine the pattern of vascular remodeling associated with these measurements. METHODS The authors prospectively included patients with ANOCA undergoing continuous thermodilution assessment. Lumen volume and vessel-specific myocardial mass were quantified using coronary computed tomography angiography (CTA). CMD was defined as coronary flow reserve <2.5 and high minimal microvascular resistance as >470 WU. RESULTS A total of 153 patients were evaluated; 68 had CMD, and 22 of them showed high microvascular resistance. In patients with CMD, coronary flow reserve was 1.9 ± 0.38 vs 3.2 ± 0.81 in controls (P < 0.001). Lumen volume was significantly correlated with minimal microvascular resistance (r = -0.59 [95% CI: -0.45 to -0.71]; P < 0.001). In patients with CMD and high microvascular resistance, lumen volume was 40% smaller than in controls (512.8 ± 130.3 mm3 vs 853.2 ± 341.2 mm3; P < 0.001). Epicardial lumen volume assessed by coronary CTA was independently associated with minimal microvascular resistance (P < 0.001). The predictive capacity of lumen volume from coronary CTA for detecting high microvascular resistance showed an area under the curve of 0.79 (95% CI: 0.69-0.88). CONCLUSIONS Patients with CMD and high minimal microvascular resistance have smaller epicardial vessels than those without CMD. Coronary CTA detected high minimal microvascular resistance with very good diagnostic capacity. Coronary CTA could potentially aid in the diagnostic pathway for patients with ANOCA.

No abstract available

Coronary microvascular dysfunction (CMD) encompasses several pathogenetic mechanisms involving coronary microcirculation and plays a major role in determining myocardial ischemia in patients with angina without obstructive coronary artery disease, as well as in several other conditions, including obstructive coronary artery disease, nonischemic cardiomyopathies, takotsubo syndrome, and heart failure, especially the phenotype associated with preserved ejection fraction. Unfortunately, despite the identified pathophysiological and prognostic role of CMD in several conditions, to date, there is no specific treatment for CMD. Due to the emerging role of CMD as common denominator in different clinical phenotypes, additional research in this area is warranted to provide personalized treatments in this "garden variety" of patients. The purpose of this review is to describe the pathophysiological mechanisms of CMD and its mechanistic and prognostic role across different cardiovascular diseases. We will also discuss diagnostic modalities and the potential therapeutic strategies resulting from recent clinical studies.

The coronary microcirculation plays a cardinal role in regulating coronary blood flow to meet the changing metabolic demands of the myocardium. Coronary microvascular dysfunction (CMD) refers to structural and functional remodeling of the coronary microcirculation. CMD plays a role in the pathogenesis of obstructive and non-obstructive coronary syndromes as well as myocardial diseases, including heart failure with preserved ejection fraction (HFpEF). Despite recent diagnostic advancements, CMD is often under-appreciated in clinical practice, and may allow for the development of novel therapeutic targets. This review explores the diagnosis and pathogenic role of CMD across a range of cardiovascular diseases, its prognostic significance, and the current therapeutic landscape.

BACKGROUND Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown. OBJECTIVES The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease. METHODS Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm. RESULTS Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR, 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005). CONCLUSIONS In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

ST-segment elevation myocardial infarction (STEMI) treatment with primary percutaneous coronary intervention has dramatically impacted prognosis. However, despite satisfactory angiographic result, occurrence or persistence of coronary microvascular dysfunction after revascularization still affects long-term outcomes. The diagnostic and therapeutic value of understanding the status of coronary microcirculation is gaining attention in the cardiology community. However, current methods to assess microvascular function (namely, cardiac magnetic resonance and invasive wire-based coronary physiology) remain, at least in part, limited by technical and logistic aspects. On the other hand, angiography-based indices of microcirculatory resistance are emerging as valid and user-friendly tools with potential impact on prognostic stratification of patients with STEMI. This review provides an overview about conventional and novel methods to assess coronary microvascular dysfunction in patients with STEMI. The authors also provide a proposed procedural algorithm to facilitate optimal use of wire-based and angiography-based indices in the acute setting of STEMI.

BACKGROUND: Coronary microvascular dysfunction (CMD) is involved in heart failure (HF) onset and progression, independently of HF phenotype and obstructive coronary artery disease. Invasive assessment of CMD might provide insights into phenotyping and prognosis of patients with HF. We aimed to assess absolute coronary flow, absolute microvascular resistance, myocardial perfusion, coronary flow reserve, and microvascular resistance reserve in patients with HF with preserved ejection fraction and HF with reduced ejection fraction (HFrEF). METHODS: Single-center, prospective study of 56 consecutive patients with de novo HF with nonobstructive coronary artery disease divided into HF with preserved ejection fraction (n=21) and HFrEF (n=35). CMD was invasively assessed by continuous intracoronary thermodilution and defined as coronary flow reserve <2.5. Left ventricular and left anterior descending artery–related myocardial mass was quantified by echocardiography and coronary computed tomography angiography. Myocardial perfusion (mL/min per g) was calculated as the ratio between absolute coronary flow and left anterior descending artery–related mass. RESULTS: Patients with HFrEF showed a higher left ventricular and left anterior descending artery–related myocardial mass compared with HF with preserved ejection fraction (P<0.010). Overall, 52% of the study population had CMD, with a similar prevalence between the 2 groups. In HFrEF, CMD was characterized by lower absolute microvascular resistance and higher absolute coronary flow at rest (functional CMD; P=0.002). CMD was an independent predictor of a lower rate of left ventricular reverse remodeling at follow-up. In patients with HF with preserved ejection fraction, CMD was mainly due to higher absolute microvascular resistance and lower absolute coronary flow during hyperemia (structural CMD; P≤0.030). CONCLUSIONS: Continuous intracoronary thermodilution allows the definition and characterization of patterns with distinct CMD in patients with HF and could identify patients with HFrEF with a higher rate of left ventricular reverse remodeling at follow-up.

Importance Coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may contribute to the pathophysiologic characteristics of heart failure with preserved ejection fraction (HFpEF). However, the prevalence of CAD and CMD have not been systematically studied. Objective To examine the prevalence of CAD and CMD in hospitalized patients with HFpEF. Design, Setting, and Participants A total of 106 consecutive patients hospitalized with HFpEF were evaluated in this prospective, multicenter, cohort study conducted between January 2, 2017, and August 1, 2018; data analysis was performed from March 4 to September 6, 2019. Participants underwent coronary angiography with guidewire-based assessment of coronary flow reserve, index of microvascular resistance, and fractional flow reserve, followed by coronary vasoreactivity testing. Cardiac magnetic resonance imaging was performed with late gadolinium enhancement and assessment of extracellular volume. Myocardial perfusion was assessed qualitatively and semiquantitatively using the myocardial-perfusion reserve index. Main Outcomes and Measures The prevalence of obstructive epicardial CAD, CMD, and myocardial ischemia, infarction, and fibrosis. Results Of 106 participants enrolled (53 [50%] women; mean [SD] age, 72 [9] years), 75 had coronary angiography, 62 had assessment of coronary microvascular function, 41 underwent coronary vasoreactivity testing, and 52 received cardiac magnetic resonance imaging. Obstructive epicardial CAD was present in 38 of 75 participants (51%, 95% CI, 39%-62%); 19 of 38 (50%; 95% CI, 34%-66%) had no history of CAD. Endothelium-independent CMD (ie, coronary flow reserve <2.0 and/or index of microvascular resistance ≥25) was identified in 41 of 62 participants (66%; 95% CI, 53%-77%). Endothelium-dependent CMD (ie, abnormal coronary vasoreactivity) was identified in 10 of 41 participants (24%; 95% CI, 13%-40%). Overall, 45 of 53 participants (85%; 95% CI, 72%-92%) had evidence of CMD and 29 of 36 (81%; 95% CI, 64%-91%) of those without obstructive epicardial CAD had CMD. Cardiac magnetic resonance imaging findings included myocardial-perfusion reserve index less than or equal to 1.84 (ie, impaired global myocardial perfusion) in 29 of 41 patients (71%; 95% CI, 54%-83%), visual perfusion defect in 14 of 46 patients (30%; 95% CI, 19%-46%), ischemic late gadolinium enhancement (ie, myocardial infarction) in 14 of 52 patients (27%; 95% CI, 16%-41%), and extracellular volume greater than 30% (ie, diffuse myocardial fibrosis) in 20 of 48 patients (42%; 95% CI, 28%-56%). Patients with obstructive CAD had more adverse events during follow-up (28 [74%]) than those without obstructive CAD (17 [46%]). Conclusions and Relevance In this cohort study, 91% of patients with HFpEF had evidence of epicardial CAD, CMD, or both. Of those without obstructive CAD, 81% had CMD. Obstructive epicardial CAD and CMD appear to be common and often unrecognized in hospitalized patients with HFpEF and may be therapeutic targets.

Coronary microvascular dysfunction (CMD) is a high-risk factor for a variety of cardiovascular events. Due to its complex aetiology and concealability, knowledge of the pathophysiological mechanism of CMD is still limited at present, which greatly restricts its clinical diagnosis and treatment. Studies have shown that CMD is closely related to a variety of cardiovascular diseases, can aggravate the occurrence and development of cardiovascular diseases, and is closely related to a poor prognosis in patients with cardiovascular diseases. Improving coronary microvascular remodelling and increasing myocardial perfusion might be promising strategies for the treatment of cardiovascular diseases. In this paper, the pathogenesis and functional assessment of CMD are reviewed first, along with the relationship of CMD with cardiovascular diseases. Then, the latest strategies for the treatment of CMD and cardiovascular diseases are summarized. Finally, urgent scientific problems in CMD and cardiovascular diseases are highlighted and future research directions are proposed to provide prospective insights for the prevention and treatment of CMD and cardiovascular diseases in the future.

BACKGROUND Coronary microvascular dysfunction (CMD) is an important contributor to angina syndromes. Recently, two distinct endotypes were identified using combined assessment of coronary flow reserve (CFR) and minimal microvascular resistance (MR), termed structural and functional CMD. AIMS We aimed to assess the relevance of the combined assessment of CFR and MR in patients with angina and no obstructive coronary arteries. METHODS Patients with chronic coronary syndromes (CCS) and non-obstructive coronary artery disease (fractional flow reserve [FFR] ≥0.80) were selected (N=1,102). Functional CMD was defined as abnormal CFR in combination with normal MR and structural CMD as abnormal CFR with abnormal MR. Clinical endpoints were the incidence of major adverse cardiac events (MACE) and target vessel failure (TVF) at 5-year follow-up. RESULTS Abnormal CFR was associated with an increased risk of MACE and TVF at 5-year follow-up. Microvascular resistance parameters were not associated with MACE or TVF at 5-year follow-up. The risk of MACE and TVF at 5-year follow-up was similarly increased for patients with structural or functional CMD compared with patients with normal microvascular function. There were no differences between both endotypes (p=0.88 for MACE, and p=0.55 for TVF). CONCLUSIONS Coronary microvascular dysfunction, identified by an impaired CFR, was unequivocally associated with increased MACE and TVF rates over a 5-year follow-up period. In contrast, impaired MR was not associated with 5-year adverse clinical events. Moreover, there was no significant difference in the risk of MACE and TVF between a low CFR accompanied by pathologically increased MR (structural CMD) or not (functional CMD). CLINICALTRIALS gov: NCT04485234.

Purpose of Review Abnormal structure and function of the coronary microvasculature have been implicated in the pathophysiology of multiple cardiovascular disease processes. This article reviews recent research progress related to coronary microvascular dysfunction (CMD) and salient clinical takeaways. Recent Findings CMD is prevalent in patients with signs and symptoms of ischemia and no obstructive epicardial coronary artery disease (INOCA), particularly in women. CMD is associated with adverse outcomes, including most frequently the development of heart failure with preserved ejection fraction. It is also associated with adverse outcomes in patient populations including hypertrophic cardiomyopathy, dilated cardiomyopathy, and acute coronary syndromes. In patients with INOCA, stratified medical therapy guided by invasive coronary function testing to define the subtype of CMD leads to improved symptoms. Summary There are invasive and non-invasive methodologies to diagnose CMD that provide prognostic information and mechanistic information to direct treatment. Available treatments improve symptoms and myocardial blood flow; ongoing investigations aim to develop therapy to improve adverse outcomes related to CMD.

Background Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries. Objectives The authors sought to assess protein biomarker signature for CMD. Methods We quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson’s correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts. Results Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM. Conclusions CMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.

Severe psoriasis is associated with an increased cardiovascular risk, which may be independent of the traditional risk factors. Coronary microvascular dysfunction (CMD) has been shown to predict a poor cardiovascular prognosis in the general population and in patients with psoriasis. In this study, we assessed the prevalence and predictors of CMD in a large cohort of patients with psoriasis without clinical cardiovascular disease. A total of 503 patients with psoriasis were enrolled and underwent transthoracic Doppler echocardiography to evaluate coronary microcirculation. Of these, 55 patients were excluded from the analyses because of missing data. Of the 448 patients in this study, 31.5% showed CMD. Higher PASI, longer disease duration, the presence of psoriatic arthritis, and hypertension were independently associated with CMD. An increase of 1 point of PASI and 1 year of psoriasis duration were associated with a 5.8% and 4.6% increased risk of CMD, respectively. In our study, CMD was associated with the severity and duration of psoriasis. This supports the role of systemic inflammation in CMD and suggests that the coronary microcirculation may represent an extracutaneous site involved in the immune-mediated injury of psoriasis. We should diagnose and actively search for CMD in patients with severe psoriasis.

Background Coronary microvascular dysfunction (CMD) has differences in prevalence and presentation between women and men; however, we have limited understanding about underlying contributors to sex differences in CMD. Myocardial perfusion reserve index (MPRI), as semi-quantitative measure of myocardial perfusion derived from cardiac magnetic resonance (CMR) imaging has been validated as a measure of CMD. We sought to understand the sex differences in the relations between the MPRI and traditional measures of cardiovascular disease by CMR. Methods A retrospective analysis of a single-center cohort of patients receiving clinical stress CMR from 2015 to 2022 was performed. Patients with calculated MPRI and no visible perfusion defects consistent with obstructive epicardial coronary disease were included. We compared associations between MPRI versus traditional cardiovascular risk factors and markers of cardiac structure/function in sex-stratified populations using univariable and multivariable regression models. Results A total of 229 patients [193 female, 36 male, median age 57 (47–67) years] were included in the analysis. In the female population, no traditional cardiovascular risk factors were associated with MPRI, whereas in the male population, diabetes (β: −0.80, p = 0.03) and hyperlipidemia (β: −0.76, p = 0.006) were both associated with reduced MPRI in multivariable models. Multivariable models revealed significant associations between reduced MPRI and increased ascending aortic diameter (β: −0.42, p = 0.005) and T1 times (β: −0.0056, p = 0.03) in the male population, and increased T1 times (β: −0.0037, p = 0.006) and LVMI (β: −0.022, p = 0.0003) in the female population. Conclusion The findings suggest different underlying pathophysiology of CMD in men versus women, with lower MPRI in male patients fitting a more “traditional” atherosclerotic profile.

Background: Coronary microvascular dysfunction is a clinically significant component of ischemic heart disease. There can be heterogenous patterns of coronary microvascular dysfunction defined by invasive physiologic indexes such as coronary flow reserve (CFR) and index of microcirculatory resistance (IMR). We sought to compare the prognosis of coronary microvascular dysfunction according to different patterns of CFR and IMR. Methods: The current study included 375 consecutive patients undergoing invasive physiologic assessment for suspected stable ischemic heart disease and intermediate but functionally nonsignificant epicardial stenosis (fractional flow reserve, >0.80). According to cutoff values of invasive physiologic indexes reflecting microcirculatory function (CFR, <2.5; IMR, ≥25), patients were classified into 4 groups: (1) preserved CFR and low IMR (group 1), (2) preserved CFR and elevated IMR (group 2), (3) depressed CFR and low IMR (group 3), and (4) depressed CFR and elevated IMR (group 4). Primary outcome was a composite of cardiovascular death or admission for heart failure during the follow-up time. Results: Cumulative incidence of the primary outcome was significantly different among the 4 groups (group 1, 20.1%; group 2, 18.8%; group 3, 33.9%; and group 4, 45.0%; overall P<0.001). Depressed CFR had significantly higher risk of primary outcome than preserved CFR in both low (hazard ratio [HR], 1.894 [95% CI, 1.112–3.225]; P=0.019) and elevated IMR subgroups (HR, 3.307 [95% CI, 1.519–7.202]; P=0.003). Conversely, the risk of primary outcome was not significantly different between elevated and low IMR in preserved CFR subgroups (HR, 0.926 [95% CI, 0.428–2.005]; P=0.846). Furthermore, as continuous variables, IMR-adjusted CFR (adjusted HR, 0.644 [95% CI, 0.537–0.772]; P<0.001) was significantly associated with the risk of primary outcome but CFR-adjusted IMR (adjusted HR, 1.004 [95% CI, 0.992–1.016]; P=0.515) was not. Conclusions: Among patients with suspected stable ischemic heart disease who were found to have an intermediate but functionally nonsignificant epicardial stenosis, depressed CFR was associated with an increased risk of cardiovascular death and admission for heart failure. However, elevated IMR alone with preserved CFR showed limited prognostic value in this population. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05058833.

Background Coronary microvascular dysfunction (CMD) is a strong determinant of prognosis in patients with chronic coronary syndrome (CCS). The triglyceride-glucose index (TyG index), an alternative method to evaluate insulin resistance, is positively correlated with the incidence and adverse outcomes of cardiovascular diseases. However, the relationship between the TyG index and the presence and prognosis of CMD in CCS patients has not been investigated. Therefore, we aimed to evaluate the association between the TyG index and the presence and clinical outcomes of CMD among CCS patients. Methods CCS patients who underwent coronary angiography between June 2015 to June 2019 were included. The TyG index was calculated as Ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Coronary angiography‑derived index of microvascular resistance (caIMR) was used to measure microvascular function, and CMD was defined as caIMR ≥ 25U. Patients with CMD were divided into three groups (T1, T2, and T3 groups) according to TyG tertiles. The primary endpoint was major adverse cardiac event (MACE). Results Of 430 CCS patients, 221 patients had CMD. CMD patients had significantly higher TyG index than those without CMD. Sixty-three MACE was recorded during the follow-up duration among CMD patients, and the incidence rate of MACE was higher in the T3 group compared to T1/T2 groups (39.2% vs. 20.5% vs. 25.7%; P = 0.035). Multivariable logistic regression analysis showed that the TyG index was an independent predictor of CMD (OR, 1.436; 95% CI, 1.014–2.034; P = 0.042). Compared to the T1 group, the T3 group strongly correlated with the risk of MACE in CMD patients even after adjusting for additional confounding risk factors (HR, 2.132; 95%CI, 1.066–4.261; P = 0.032). Conclusion TyG index is significantly associated with the risk of CMD, and it is an independent predictor of MACE among CMD patients with CCS. This study suggests that the TyG index has important clinical significance for the early prevention and risk stratification of CMD.

Coronary microvascular dysfunction (CMD) has been proposed as an important pathophysiological mechanism in Takotsubo syndrome (TTS). Our aims were (i) to evaluate and compare levels of CMD in patients with TTS and patients with ischaemia and no obstructive coronary arteries (INOCA) and (ii) to investigate associations between CMD and clinical parameters, left ventricular function, and coronary atherosclerosis in TTS.

Background Type 2 diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mouse ( db/db ) and lean rat (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction. Methods The microRNA (miRNA) content of circulating extracellular vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in endothelial cells (ECs). Results We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation, while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium. Conclusions MiR-30d/e represent early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart.

Nearly half of all patients with angina have non-obstructive coronary artery disease (ANOCA); this is an umbrella term comprising heterogeneous vascular disorders, each with disparate pathophysiology and prognosis. Approximately two-thirds of patients with ANOCA have coronary microvascular disease (CMD). CMD can be secondary to architectural changes within the microcirculation or secondary to vasomotor dysfunction. An inability of the coronary vasculature to augment blood flow in response to heightened myocardial demand is defined as an impaired coronary flow reserve (CFR), which can be measured non-invasively, using imaging, or invasively during cardiac catheterisation. Impaired CFR is associated with myocardial ischaemia and adverse cardiovascular outcomes. The CMD workstream is part of the cardiovascular partnership between the British Heart Foundation and The National Institute for Health Research in the UK and comprises specialist cardiac centres with expertise in coronary physiology assessment. This document outlines the two main modalities (thermodilution and Doppler techniques) for estimation of coronary flow, vasomotor testing using acetylcholine, and outlines a standard operating procedure that could be considered for adoption by national networks. Accurate and timely disease characterisation of patients with ANOCA will enable clinicians to tailor therapy according to their patients’ coronary physiology. This has been shown to improve patients’ quality of life and may lead to improved cardiovascular outcomes in the long term.

Myocardial infarction without obstructive coronary artery disease (MINOCA) is a heterogeneous clinical condition presenting with myocardial necrosis not due to an obstruction of a major coronary artery. Recently, a relevant role of coronary microvascular dysfunction (CMD) in the pathogenesis of MINOCA has been suggested; however, data on this are scarce. Particularly, it is unclear if CMD is equally present in all subtypes of MINOCA or differentially identifies one or more of these conditions. Therefore, the aim of this study was to assess CMD in all three coronary vessels of MINOCA patients, relating it with the clinical subtype. We retrospectively assessed coronary microvascular function in all three coronary territories by means of angiography-based index of microvascular resistance (aIMR) in 92 patients (64 with working diagnosis of MINOCA, 28 control patients). To further assess the association of CMD with MINOCA subtypes, MINOCA patients were subdivided according to clinical data in coronary cause (n = 13), takotsubo (n = 13), infiltrative or inflammatory cardiomyopathy (n = 9) or unclear (n = 29). Patients with working diagnosis of MINOCA showed a significantly elevated average aIMR compared to control patients (30.5 ± 7.6 vs. 22.1 ± 5.9, p < 0.001) as a marker of a relevant CMD; these data were consistent in all vessels. Among MINOCA subtypes, no significant difference in average aIMR could be detected between patients with coronary cause (33.2 ± 6.6), takotsubo cardiomyopathy (29.2 ± 6.9), infiltrative or inflammatory cardiomyopathy (28.1 ± 6.8) or unclear cause (30.6 ± 8.5; p = 0.412). Interestingly, aIMR was significantly elevated in the coronary vessel supplying the diseased myocardium compared with other vessels (31.9 ± 11.4 vs. 27.8 ± 8.2, p = 0.049). Coronary microvascular dysfunction is a hallmark of all MINOCA subtypes. This study adds to the pathophysiological understanding of MINOCA and sheds light into the role of CMD in MINOCA.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/Eʹ ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

BACKGROUND: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. METHODS: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. RESULTS: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, −4.26 seconds [95% CI, −19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). CONCLUSIONS: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314.

No abstract available

Microvascular angina (MVA) is the most common cause of cardiac ischemic chest pain in patients without obstructive coronary artery disease (CAD) and lacks of effective treatment means. Medicine food homology (MFH) involves substances with both nutritional and medicinal qualities that have the potential to improve MVA symptoms as medicines, dietary supplements. However, research on MFH formula (MFHF) for MVA is not available. The study aims to generate a core MFHF for MVA through data mining and offer scientific backing for the utilization of edible medications in the prevention and alleviation of MVA. 11 databases were utilized to construct a database of MFH drugs, and the MFHF was generated through frequency analysis, association rule analysis, and clustering analysis. The composition of the formula is Codonopsis Radix, Astragali Radix, Platycodonis Radix, Persicae Semen, Glycyrrhizae Radix Et Rhizoma, Angelicae Sinensis Radix, and Allii Macrostemonis Bulbus. Through network pharmacology and molecular docking, we identified five major active components of MFHF: Adenosine, Nonanoic Acid, Lauric Acid, Caprylic Acid, and Enanthic Acid, along with nine core targets (NFKB1, ALB, AKT1, ACTB, TNF, IL6, ESR1, CASP3, and PTGS) for the improvement of MVA. These 5 active components have various biological activities, such as reducing oxidative stress, anti-inflammation, analgesia effect, inhibiting platelet aggregation, vasodilatation, vascular endothelial protection, and cardio-protection. GO and KEGG enrichment analyses revealed that MFHF mainly acted on the response to xenobiotic stimulus, integrative component of the plasma membrane, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, pathways in cancer, lipid and atherosclerosis, human cytomegalovirus infection, and the PI3K-Akt signaling pathway, which are the main pathogenesis of MVA.

Recent studies have highlighted that a significant proportion of patients (up to 47%) undergoing coronary angiography due to clinical indications do not exhibit significant stenosis in epicardial vessels. Among these patients, up to 50% may suffer from microvascular angina (MVA). Despite the absence of intramural coronary artery lesions typically associated with atherosclerosis, the occurrence of transient myocardial ischemia and cardiac pain syndrome raises interest due to the incomplete understanding of their underlying mechanisms. This study aims to comprehensively investigate sympathoadrenal system activity in patients with microvascular angina. A total of 40 patients diagnosed with MVA, aged 35-76 years, including 11 (27.5%) men and 29 (72.5%) women, were enrolled, along with 20 healthy individuals. Assessment of sympathoadrenal system (SAS) activity involved determining daily urinary excretion levels of free and conjugated catecholamine fractions (CA) using solid-phase enzyme immunoassay: adrenaline (A), noradrenaline (NA), dopamine (DA), and DOFA. Additionally, catecholamine deamination enzyme activity—monoamine oxidase (MAO)—was determined using solid-phase EIA. Patients with MVA exhibited a significant increase in the excretion of all CA fractions. Specifically, adrenaline (A) excretion increased by 56.7%, surpassing the control by 1.7 times (p<0.001). Noradrenaline (NA) levels were elevated by 59.5% in MVA patients, which was 1.6 times higher than the control group (p<0.001). Dopamine (DA) levels in MVA patients increased by 31.0%, surpassing control values by 1.36 times (p<0.001). Moderate elevation in DOFA levels by 19.7% was observed, which was 1.23 times higher than the control (p<0.01). Ratios of CA sulfocatecholamine formation processes indicated pronounced deviations from normal. Gender differences revealed marked changes in sympathoadrenal activity, particularly in women (p<0.001). Studies of MAO activity on the first day identified a moderate decrease in its activity in MVA patients—0.03±0.002 units/ext. (p<0.01), while healthy individuals exhibited an activity level of 0.07±0.001 units/ext. The findings underscore the crucial pathogenetic role of SAS in the development of MVA. The study demonstrates that the severity of ischemia correlates with disruptions in SAS components. Notably, these disruptions are pronounced in MVA, indicating an overload of the sympathoadrenal system—a critical component of organismal homeostasis. Under conditions of SAS overload, the pivotal enzyme in biogenic amine oxidation, MAO, undergoes significant transformation, leading to reduced activity towards monoamines. These findings were consistent with our clinical investigation.

No abstract available

This randomized clinical trial investigates the effect of coronary venous pressure on myocardial resistances in patients with microvascular disease.

Abstract Aims To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). Methods and results The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). Conclusions This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis.

Background: The aim of the study is to evaluate the subclinical alterations of cardiac mechanics detected using speckle-tracking echocardiography and compare these data with the coronary angiography indices used during coronary angiography in a population of patients diagnosed with ischemia with no obstructive coronary artery (INOCA) and microvascular angina (MVA). Methods: The study included 85 patients admitted to our center between November 2019 and January 2022 who were diagnosed with INOCA compared with a control group of 70 healthy patients. A collection of anamnestic data and a complete cardiovascular physical examination, and echocardiogram at rest with longitudinal strain were performed for all patients. Furthermore, the TIMI frame count (TFC) for the three coronary vessels was calculated according to Gibson’s indications. All parameters were compared with a control population with similar characteristics. Results: Patients with INOCA compared to the control population showed statistically significant changes in the parameters assessed on the longitudinal strain analysis. In particular, patients with INOCA showed statistically significant changes in GLS (−16.71) compared to the control population (−19.64) (p = 0.003). In patients with INOCA, the total TIMI frame count (tTFC) correlated with the GLS value with a correlation coefficient of 0.418 (p = 0.021). Conclusions: In patients with angina, documented myocardial ischemia, the absence of angiographically significant stenosis (INOCA) and LVEF > 50%, the prevalence of microvascular dysfunction documented by TFC was extremely represented. A statistically significant reduction in GLS was observed in these patients. TFC and longitudinal strain, therefore, appear to be two reliable, sensitive and easily accessible methods for the study of alterations in coronary microcirculation and the characterization of patients with INOCA and microvascular angina.

The Coronary Sinus Reducer (CSR) is an hourglass-shaped device approved for the treatment of refractory angina. Its percutaneous implantation in the coronary sinus leads to a retrograde increase in venous pressure, which is thought to improve capillary recruitment and perfusion to the ischemic myocardium. No data is however available on the use of the CSR to treat microvascular angina, an increasingly recognized but still poorly understood condition. In this preliminary study, we evaluated the efficacy of the CSR in a small cohort of patients with non-obstructive disease. We screened consecutive patients from the prospective COMPLEX registry that received a CSR for refractory angina between June 2018 and November 2022. Inclusion criteria were the absence of obstructive coronary artery disease (<50% narrowing in all coronary arteries, or a negative intracoronary fractional flow reserve test) and no prior history of revascularization. Endpoints were angina and dyspnea symptoms, evaluated with the Canadian Cardiovascular Society (CCS) and the New York Hearth Association (NYHA) scores respectively, procedural success rate, and major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, cardiovascular death, acute coronary syndromes (ACS) and heart failure (HF) hospitalizations. We ultimately enrolled 8 patients; 6 (75%) were females and mean age was 67.8±9.9 years. Their baseline characteristics are further depicted in table 1. Microvascular dysfunction was invasively confirmed in 5 (62.5%) patients; mean index of microvascular resistance (IMR) was 32.8±15.7 and mean coronary flow reserve (CFR) was 1.7±0.7. In one patient, reduced global CFR (1.4) was evident on cardiac magnetic resonance examination. At baseline, mean CCS class was 2.9±0.6, NYHA class 2±0.9, and number of antianginal drugs 2.6±1.6. Procedural success was 100%, with only one patient experiencing a procedure-related complication (sternocleidomastoid muscle hematoma requiring no intervention). At a median follow-up of 647.5 days (IQR 132-732), mean CCS class was 1.5±0.8, NYHA class 1.9±0.9 and number of antianginal drugs 1.9±1.1. All patients improved by ≥1 CCS class and 3 (37.5%) by ≥2 CCS classes. No MACE was observed. To the best of our knowledge, we present the first report of CSR implantation for the treatment of microvascular angina. Our positive results are particularly promising given the paucity of treatment options currently available for the condition, but larger studies are needed to confirm these findings.table 1figure 1

Background Postacute sequelae of SARS-CoV-2 infection (PASC) are a novel clinical syndrome characterized in part by endothelial dysfunction. Enhanced external counterpulsation (EECP) produces pulsatile shear stress, which has been associated with improvements in systemic endothelial function. Objective To explore the effects of EECP on symptom burden, physical capacity, mental health, and health-related quality of life (HRQoL) in patients with PASC-associated angina and microvascular dysfunction (MVD). Methods An interventional pilot study was performed, including 10 patients (male = 5, mean age 50.3 years) recruited from a tertiary specialized PASC clinic. Patients with angina and MVD, defined as index of microcirculatory resistance (IMR) ≥25 and/or diagnosed through stress perfusion cardiac magnetic resonance imaging, were included. Patients underwent one modified EECP course (15 one-hour sessions over five weeks). Symptom burden, six-minute walk test, and validated generic self-reported instruments for measuring psychological distress and HRQoL were assessed before and one month after treatment. Results At baseline, most commonly reported PASC symptoms were angina (100%), fatigue (80%), and dyspnea (80%). Other symptoms included palpitations (50%), concentration impairment (50%), muscle pain (30%), and brain fog (30%). Mean IMR was 63.6. After EECP, 6MWD increased (mean 29.5 m, median 21 m) and angina and fatigue improved. Mean depression scores showed reduced symptoms (−0.8). Mean HRQoL scores improved in seven out of eight subscales (+0.2 to 10.5). Conclusions Patients with PASC-associated angina and evidence of MVD experienced subjective and objective benefits from EECP. The treatment was well-tolerated. These findings warrant controlled studies in a larger cohort.

BACKGROUND Coronary microvascular dysfunction may cause myocardial ischemia with no obstructive coronary artery disease (INOCA). If functional testing is not performed INOCA may pass undetected. Stress perfusion cardiovascular MRI (CMR) quantifies myocardial blood flow (MBF) but the clinical utility of stress CMR in the management of patients with suspected angina with no obstructive coronary arteries (ANOCA) is uncertain. OBJECTIVES First, to undertake a diagnostic study using stress CMR in patients with ANOCA following invasive coronary angiography and, second, in a nested, double-blind, randomized, controlled trial to assess the effect of disclosure on the final diagnosis and health status in the longer term. DESIGN All-comers referred for clinically indicated coronary angiography for the investigation of suspected coronary artery disease will be screened in three regional centers in the United Kingdom. Following invasive coronary angiography, patients with ANOCA who provide informed consent will undergo noninvasive endotyping using stress CMR within 3 months of the angiogram. DIAGNOSTIC STUDY Stress perfusion CMR imaging to assess the prevalence of coronary microvascular dysfunction and clinically significant incidental findings in patients with ANOCA. The primary outcome is the between-group difference in the reclassification rate of the initial diagnosis based on invasive angiography versus the final diagnosis after CMR imaging. RANDOMIZED, CONTROLLED TRIAL Participants will be randomized to inclusion (intervention group) or exclusion (control group) of myocardial blood flow to inform the final diagnosis. The primary outcome of the clinical trial is the mean within-subject change in the Seattle Angina Questionnaire summary score (SAQSS) at 6 months. Secondary outcome assessments include the EUROQOL EQ-5D-5L questionnaire, the Brief Illness Perception Questionnaire (Brief-IPQ), the Treatment Satisfaction Questionnaire (TSQM-9), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI), the International Physical Activity Questionnaire- Short Form (IPAQ-SF), the Montreal Cognitive Assessment (MOCA) and the 8-item Productivity Cost Questionnaire (iPCQ). Health and economic outcomes will be assessed using electronic healthcare records. VALUE To clarify if routine stress perfusion CMR imaging reclassifies the final diagnosis in patients with ANOCA and whether this strategy improves symptoms, health-related quality of life and health economic outcomes. CLINICALTRIALS GOV: NCT04805814.

Background Microvascular angina (MVA) is a group of clinical manifestations of angina pectoris or angina-like chest pain, positive exercise test, and exclusion of epicardial coronary artery spasm, wherein coronary angiography (CAG) does not present obvious epicardial vascular stenosis. Shexiang Tongxin dropping pill (STDP) has the effect of benefiting the Qi and opening the blood vessels, activating blood circulation, and resolving blood stasis. We explored the mechanism of STDP against MVA by network pharmacology and molecular docking. Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), literature search, SwissTargetPrediction database, and high-throughput experiment- and reference-guided database of traditional Chinese medicine (HERB) were applied to identify the active ingredients and targets of STDP. The MVA targets were searched in the databases of GeneCards, Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), DisGeNET, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). The common targets of STDP and MVA were screened. The software RStudio 4.1.3 was used to analyze the enrichment of these targets using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein-protein interaction (PPI) network analysis of the common targets was performed using the Search Tool for the Retrieval of Interacting Genes/Genomes (STRING) database. The cytoHubba plug-in of Cytoscape 3.9.1 software was employed to analyze the PPI network and obtain the core targets. Molecular docking was performed to verify the relationship between the core compounds and proteins with AutoDock Tools 1.5.7 and Pymol 2.4.0. Results We identified 93 effective components of STDP, 310 potential targets, 981 MVA targets, and 138 intersectional targets. The potential anti-MVA mechanism of STDP may involve the advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications; lipids and atherosclerosis; fluid shear stress; atherosclerosis; the tumor necrosis factor (TNF), interleukin (IL)-17, hypoxia-inducible factor (HIF)-1, and C-type lectin receptor signaling pathways. Further, STDP mainly acts on its targets IL-6, AKT1, STAT3, JUN, and IL-1β to against MVA. Conclusions The STDP may exert its therapeutic effects through processes, such as anti-inflammation, promotion of smooth muscle cell proliferation and differentiation, lipid metabolism, immunomodulation, and regulation of cellular autophagy.

Patients diagnosed with ischemia without obstructive coronary artery disease (INOCA) comprise the group of patients with primary microvascular angina (MVA). The pathophysiology underlying ischemia and angina is multifaceted. Differences in vascular tone, collateralization, environmental and psychosocial factors, pain thresholds, and cardiac innervation seem to contribute to clinical manifestations. There is evidence suggesting potential interactions between the clinical manifestations of MVA and non-cardiac conditions such as abnormal function of the central autonomic network (CAN) in the central nervous system (CNS), pain modulation pathways, and psychological, psychiatric, and social conditions. A few unconventional non-pharmacological and pharmacological techniques targeting these psychosocial conditions and modulating the CNS pathways have been proposed to improve symptoms and quality of life. Most of these unconventional approaches have shown encouraging results. However, these results are overall characterized by low levels of evidence both in observational studies and interventional trials. Awareness of the importance of microvascular dysfunction and MVA is gradually growing in the scientific community. Nonetheless, therapeutic success remains frustratingly low in clinical practice so far. This should promote basic and clinical research in this relevant cardiovascular field investigating, both pharmacological and non-pharmacological interventions. Standardization of definitions, clear pathophysiological-directed inclusion criteria, crossover design, adequate sample size, and mid-term follow-up through multicenter randomized trials are mandatory for future study in this field.

BACKGROUND Endothelial dysfunction and oxidative stress were hypothesized to be involved in the pathogenesis of coronary microvascular angina (MVA). NADPH oxidase-2 (NOX2) activation could provoke increased oxidative stress and endothelial dysfunction but data in MVA have not been provided yet. AIMS The aim of this study was to evaluate the interaction among NOX2 activation, serum lipopolysaccharide (LPS) levels as well as oxidative stress production as potential causes of endothelial dysfunction in MVA patients. METHODS In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), H2O2 production, hydrogen peroxide breakdown activity (HBA), nitric oxide (NO) bioavailability, endothelin-1 (ET-1), serum zonulin (as intestinal permeability assay) and LPS in 80 consecutive subjects, including 40 MVA patients and 40 controls (CT) matched for age and gender. RESULTS Compared with CT, MVA patients had significant higher values of sNOX-2-dp, H2O2, ET-1, LPS and zonulin; conversely HBA and NO bioavailability was significantly lower in MVA patients. Simple linear regression analysis showed that sNOX2 was associated with serum LPS, serum zonulin, H2O2 and ET-1; furthermore, an inverse correlation between sNOX2 and HBA and nitric oxide bioavailability was observed. Multiple linear regression analysis showed that LPS and zonulin emerged as the only independent predictive variables associated with sNOX2. CONCLUSIONS this study provides the first report attesting that patients with MVA have high LPS levels, NOX-2 activation and an imbalance between pro-oxidant and antioxidant systems, in favor of the oxidizing molecules that could be potentially implicated in the endothelial dysfunction and vasoconstriction of this disease.

BACKGROUND Coronary microvascular dysfunction (CMD) is a common cause of angina with no obstructive coronary artery disease (ANOCA), and effective treatment options are limited. OBJECTIVES This study aims to assess the safety and efficacy of the coronary sinus (CS) Reducer (Neovasc, Inc/Shockwave Medical) for treatment of angina in patients with CMD. METHODS This Phase II trial enrolled 30 patients with ANOCA, invasively diagnosed CMD, and Canadian Cardiovascular Society (CCS) class 3 to 4 angina despite medical therapy. CMD was defined by coronary flow reserve (CFR) ≤2.5 and/or ≤50% increase in coronary blood flow (CBF) in response to intracoronary infusion of acetylcholine. Invasive coronary microvascular function testing was performed before and at 120 days postimplantation. The primary endpoint was change in microvascular function at 120 days. Secondary endpoints were changes in CCS angina class and Seattle Angina Questionnaire (SAQ) scores. RESULTS Mean age was 54.8 ± 11.0 years; 67% (20/30) were women. In patients with low baseline CFR (endothelium-independent CMD), CFR increased significantly from 2.1 (1.95-2.30) to 2.7 (2.45-2.95) (n = 19; P = 0.0011). Patients with abnormal CBF response to acetylcholine at baseline (endothelium-dependent CMD) had an increase in CBF response to acetylcholine: -11.0% (-20.15% to 5.85%) to 11.5% (-4.82% to 39.29%) (n = 11; P = 0.042). There was a significant improvement in CCS angina class from 4.0 (3.25-4.0) to 2.0 (2.0-3.0) (P < 0.001) and increase in each domain of the SAQ questionnaire (P < 0.006 for all). CONCLUSIONS This study demonstrates that the CS Reducer is associated with significant improvement in angina, quality of life, and coronary microvascular function in patients with CMD and may emerge as a novel therapy for patients with ANOCA.

Highlights • Microvascular angina is a common cause of ischemia with non-obstructive coronary arteries (INOCA).• Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of microvascular angina.• Zibotentan, an Endothelin Receptor Antagonist is being tested as a treatment for microvascular angina in the ‘PRIZE’ trial using a genetic ‘precision medicine’ approach.• The PRIZE ET Sub-study will provide a comprehensive genotype and phenotype bio-resource for microvascular angina patients.

Patients with chest pain may have normal coronary arteries and suffer from microvascular angina (MVA). The aim of this study was to determine if patients with suspected MVA have lower global myocardial perfusion (global MP) during adenosine stress compared with healthy controls and coronary artery disease (CAD) patients and to determine if there are sex differences in global MP.

BACKGROUND Coronary microvascular dysfunction (CMD) may cause symptoms of myocardial ischemia (microvascular angina, MVA), but recent studies suggested that it might also contribute to the syndrome of heart failure with preserved ejection fraction (HFpEF). In this study we assessed the relation of CMD with findings of HFpEF in MVA patients. METHODS We enrolled 36 consecutive patients with MVA, in whom we assessed: 1) coronary blood flow (CBF) response to adenosine and cold pressor test (CPT) by colour-Doppler echocardiography of the left anterior descending coronary artery; 2) complete echocardiographic examination; 3) N-terminal-pro-B-natriuretic peptide (NTproBNP); 4) grade of dyspnea by the modified Medical Research scale. RESULTS Among patients, 15 had definite HFpEF findings (group 1), 12 had equivocal HFpEF findings (group 2) and 9 had no evidence of HFpEF findings (group 3). Group 1 patients were older, had more cardiovascular risk factors and higher NT-proBNP levels (p=0.018), and showed a higher prevalence of diastolic dysfunction. Left ventricle dimensions and systolic function, however, did not differ among groups. Dyspnea was also not significantly different among groups (p=0.19). CBF to adenosine was 1.85±0.47, 1.78±0.40 1.49±0.32 in group 1, 2 and 3, respectively (p=0.13). Similarly, CBF response to CPT was 1.57±0.4, 1.49±0.2 and 1.45±0.3 in the 3 groups, respectively (p=0.74). Both CBF response to adenosine and CPT showed no relation with the severity of dyspnea symptoms. CONCLUSIONS Our data suggest that in patients with MVA there is no relation between the grade of impairment of coronary microvascular dilatation and findings of HFpEF.

Background: In patients with Ischemia and non-obstructive coronary artery stenosis (INOCA) wall motion is rarely abnormal during stress echocardiography (SE). Our aim was to determine if patients with INOCA and reduced coronary flow velocity reserve (CVFR) have altered cardiac mechanics using two-dimensional speckle-tracking echocardiography (2DSTE) during SE. Methods: In a prospective, multicenter, international study, we recruited 135 patients with INOCA. Overall, we performed high dose (0.84 mg/kg) dipyridamole SE with combined assessment of CVFR and 2DSTE. The population was divided in patients with normal CVFR (>2, group 1, n = 95) and abnormal CVFR (≤2, group 2, n = 35). Clinical and 2DSTE parameters were compared between groups. Results: Feasibility was high for CFVR (98%) and 2DSTE (97%). A total of 130 patients (mean age 63 ± 12 years, 67 women) had complete flow and strain data. The two groups showed similar 2DSTE values at rest. At peak SE, Group 1 patients showed lower global longitudinal strain (p < 0.007), higher mechanical dispersion (p < 0.0005), lower endocardial (p < 0.001), and epicardial (p < 0.0002) layer specific strain. Conclusions: In patients with INOCA, vasodilator SE with simultaneous assessment of CFVR and strain is highly feasible. Coronary microvascular dysfunction is accompanied by an impairment of global and layer-specific deformation indices during stress.

Background Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. Methods We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. Conclusion PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

ABSTRACT Purpose Physical activity is recommended for patients with coronary microvascular dysfunction, however, avoided due to fear about the heart. The aim is to achieve an understanding of the meaning of physical activity one year after participating in a high-intensity exercise training program. Method Twelve people were interviewed using a phenomenological hermeneutic approach. Results Four themes were formulated and revealed that one year after participating in high-intensity exercise training participants had an awareness of the meaning of the project, their chest pain and daily life: Being reassured, Daily life’s impact on chest pain and continuing doing high-intensity exercise training, A strengthened body and mind, Being part of a group of people with similar problems. Comprehensive understanding was formulated as “Being reassured according being physically active in a background of vulnerability”. Conclusion This study indicates that by going through the high-intensity exercise training program the person regains more unity with the lived body and an unfolding life. A person-centred approach is suggested including an underlying dimension of vulnerability. A lifeworld led care means meeting the patient in their way of relating to the world bodily and existentially. Taking this understanding into consideration will advance the requirements for establishing person-centred care.

Approximately half of all coronary angiograms performed for angina do not show obstructive coronary artery disease, and many of these patients have coronary microvascular dysfunction (CMD). Invasive testing for CMD has increased with the advent and wider availability of thermodilution systems. We review CMD pathophysiology and invasive diagnostic testing using the Doppler and thermodilution systems. We report the results of a PubMed search of invasive microvascular testing and discuss limitations of current diagnostic algorithms in the diagnosis of CMD, including controversies regarding the optimal cutoff value for abnormal coronary flow reserve, use of microvascular resistance indices, and options for increasing sensitivity of testing.

Background: Coronary microvascular dysfunction (CMD), characterised by a reduced coronary flow reserve (CFR) or an increased index of microcirculatory resistance (IMR), has received considerable attention as a cause of chest pain in recent years. However, the risks and causes of CMD remain unclear; therefore, effective treatment strategies have not yet been established. Heart failure or coronary artery disease (CAD) is a risk factor for CMD, with a higher prevalence among women. However, the other contributing factors remain unclear. In this study, we assessed the risk in patients with angina and non-obstructive coronary artery disease (ANOCA), excluding those with heart failure or organic stenosis of the coronary arteries. Furthermore, we analysed whether the risk of CMD differed according to component factors and sex. Methods: This study included 84 patients with ANOCA (36 men and 48 women; mean age, 63 years) who underwent coronary angiography and functional testing (CFT). The CFT included a spasm provocation test (SPT), followed by a coronary microvascular function test (CMVF). In the SPT, patients were mainly provoked by acetylcholine (ACh), and coronary spasm was defined as >90% transient coronary artery constriction on coronary angiography, accompanied by chest pain or ischaemic changes on electrocardiography. In 15 patients (18%) with negative ACh provocation, ergonovine maleate (EM) was administered as an additional provocative drug. In the CMVF, a pressure wire was inserted into the left anterior descending coronary artery using intravenous adenosine triphosphate, and the CFR and IMR were measured using previously described methods. A CFR < 2.0 or IMR ≥ 25 was indicative of CMD. The correlations between various laboratory indices and CMD and its components were investigated, and logistic regression analysis was performed, focusing on factors where p < 0.05. Results: Of the 84 patients, a CFR < 2.0 was found in 22 (26%) and an IMR ≥ 25 in 40 (48%) patients, with CMD identified in 46 (55%) patients. CMD was correlated with smoking (p = 0.020) and the use of EM (p = 0.020). The factors that correlated with a CFR < 2.0 included the echocardiograph index E/e′ (p = 0.013), which showed a weak but positive correlation with the CFR (r = 0.268, p = 0.013). Conversely, the factors correlated with an IMR ≥ 25 included RAS inhibitor usage (p = 0.018) and smoking (p = 0.042). Assessment of the risk of CMD according to sex revealed that smoking (p = 0.036) was the only factor associated with CMD in men, whereas the left ventricular mass index (p = 0.010) and low glycated haemoglobin levels (p = 0.012) were associated with CMD in women. Conclusions: Our results indicated that smoking status and EM use were associated with CMD. The risk of CMD differed between the two CMD components and sex. Although these factors should be considered when treating CMD, smoking cessation remains important. In addition, CMD assessment should be performed carefully when EM is used after ACh provocation. Further validation of our findings using prospective studies and large registries is warranted.

Abstract Background: Microvascular angina has become a clinical and frequent cardiovascular disease in recent years, which is complicated and there is no clear treatment. Today, Western medicine still deals with microvascular angina with standardized treatment based on the stable angina. Firstly, it is to control the risk factors of atherosclerosis, and the second is to reduce the oxygen consumption of the patient's heart muscle. In the previous randomized controlled clinical trials, it has shown that nicorandil can improve the symptoms of angina for the treatment of microvascular angina, but there is a lack of high-quality randomized controlled trials on the clinical effectiveness and safety of nicorandil in the treatment of microvascular angina, and the lack of evaluation of its effectiveness and safety. Therefore, this paper aims to understand whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug through the method of systematic evaluation. Methods: Retrieval of relevant network electronic databases by computer: SinoMed, CNKI, WanFang Data, VIP, PubMed, EMbase and The Cochrane Library, the retrieval time is from the establishment of each database to December 2017, to collect randomized controlled studies of nicorandil in the treatment of microvascular angina. At the same time, it is supplemented by manual search of the included literature references, as far as possible to increase the included literature imformation. Two researchers independently browse the topics and abstracts, and select, find, read the full text of the relevant literature, and screen the literature according to the criteria for inclusion and exclusion established in advance, then extract the data, and cross-check, and resolve the differences through multi-person discussion. Data analysis of collected information is performed by using RevMan 5.3 software. Results: The data of the included literature are statistically analyzed by meta-analysis, and the key outcome indicators are used to determine whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug. Conclusion: Through the method of evidence-based medicine, this study finds the existing problems and defects in the current research, which will provide high-quality evidence-based medical evidence for nicorandil's treatment of microvascular angina, and it help the clinical treatment and further research. OSF registration number: DOI 10.17605/OSF.IO/DSQG9.

Background In patients with angina and nonobstructive coronary artery disease (NOCAD), confirming symptoms due to coronary microvascular dysfunction (CMD) remains challenging. Cardiac magnetic resonance (CMR) assesses myocardial perfusion with high spatial resolution and is widely used for diagnosing obstructive coronary artery disease (CAD). Objectives The goal of this study was to validate CMR for diagnosing microvascular angina in patients with NOCAD, compared with patients with obstructive CAD and correlated to the index of microcirculatory resistance (IMR) during invasive coronary angiography. Methods Fifty patients with angina (65 ± 9 years of age) and 20 age-matched healthy control subjects underwent adenosine stress CMR (1.5- and 3-T) to assess left ventricular function, inducible ischemia (myocardial perfusion reserve index [MPRI]; myocardial blood flow [MBF]), and infarction (late gadolinium enhancement). During subsequent angiography within 7 days, 28 patients had obstructive CAD (fractional flow reserve [FFR] ≤0.8) and 22 patients had NOCAD (FFR >0.8) who underwent 3-vessel IMR measurements. Results In patients with NOCAD, myocardium with IMR <25 U had normal MPRI (1.9 ± 0.4 vs. controls 2.0 ± 0.3; p = 0.49); myocardium with IMR ≥25 U had significantly impaired MPRI, similar to ischemic myocardium downstream of obstructive CAD (1.2 ± 0.3 vs. 1.2 ± 0.4; p = 0.61). An MPRI of 1.4 accurately detected impaired perfusion related to CMD (IMR ≥25 U; FFR >0.8) (area under the curve: 0.90; specificity: 95%; sensitivity: 89%; p < 0.001). Impaired MPRI in patients with NOCAD was driven by impaired augmentation of MBF during stress, with normal resting MBF. Myocardium with FFR >0.8 and normal IMR (<25 U) still had blunted stress MBF, suggesting mild CMD, which was distinguishable from control subjects by using a stress MBF threshold of 2.3 ml/min/g with 100% positive predictive value. Conclusions In angina patients with NOCAD, CMR can objectively and noninvasively assess microvascular angina. A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation.

BACKGROUND The aim of this study was to evaluate and compare the subfoveal choroidal thickness (SFCT) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in patients with microvascular angina (MA), coronary slow flow phenomenon (CSFP) and healthy controls. METHODS Thirty-two consecutive patients with MA, 35 consecutive patients with CSFP and 40 age and sex-matched controls were enrolled. SFCT, average pRNFLT and four quadrants of pRNFLT were measured by spectral domain- optical coherence tomography (SD-OCT). RESULTS The mean SCFT in patients with CSFP (267.57 ± 30.61 µm) was significantly thinner than those of patients with MA (288.84 ± 28.25 µm) and control (291.21 ± 31.75 µm) (p = 0.002) while SFCT of patients with MA were similar with those of controls. Patients with CSFP had thinner superior and inferior pRNFLT compared to patients with MA and controls (p < 0.001 and p = 0.005, respectively) while there were no significant differences in average pRNFLT, nasal and temporal quadrant of pRNFLTs among three groups. In the multivariate linear regression analyses, the presence of CSFP was found negatively correlated with SFCT and superior pRNFLT. CONCLUSION Patients with CSFP had thinner SFCT, superior and inferior quadrants of pRNFLT proposing the presence of a generalized endothelial dysfunction and increased microvascular resistance in these patients.

Diabetes is a complex metabolic disease characterized by hyperglycemia. Its complications are various, often involving the heart, brain, kidney, and other essential organs. At present, the number of diabetic patients in the world is growing day by day. The cardiovascular disease caused by diabetes has dramatically affected the quality of life of diabetic patients. It is the leading cause of death of diabetic patients. Diabetic patients often suffer from microvascular angina pectoris without obstructive coronary artery disease. Still, there are typical ECG ischemia and angina pectoris, that is, chest pain and dyspnea under exercise. Unlike obstructive coronary diseases, nitrate does not affect chest pain caused by coronary microvascular angina in most cases. With the increasing emphasis on diabetic microvascular angina, the need for accurate diagnosis of the disease is also increasing. We can use SPECT, PET, CMR, MCE, and other methods to evaluate coronary microvascular function. SPECT is commonly used in clinical practice, and PET is considered the gold standard for non-invasive detection of myocardial blood flow. This article mainly introduces the research progress of these imaging methods in detecting microvascular angina in diabetic patients.

Background Myocardial bridges (MB) are prevalent but not universally associated with angina. The mechanisms linking MB and angina are poorly defined. The objective of this study was to determine the prevalence of epicardial spasm, microvascular spasm, and/or endothelium-independent coronary microvascular dysfunction (CMD) in patients with MB which might explain symptoms. Methods Patients with known MB and chest pain at the University of Chicago Medical Center between 2020-2023 were included. All patients underwent dobutamine testing with measurement of resting full-cycle ratio to determine hemodynamic significance (resting full-cycle ratio ≤0.76). Endothelium-independent CMD was defined as coronary flow reserve <2.0 or index of microvascular resistance ≥25 on adenosine testing. Microvascular spasm was defined as chest pain and electrocardiogram changes with nonischemic fractional flow reserve with acetylcholine. Epicardial spasm was defined as dynamic stenosis of >90% of the epicardial vessel or ischemic fractional flow reserve (≤0.8) with acetylcholine. Results A total of 30 patients (mean age, 47 ± 10 years; 60% female) with MB were studied. Endothelium-independent CMD, microvascular spasm, and epicardial spasm occurred commonly in 60%, 29%, and 37% of patients respectively, with 77% having at least one abnormality. The MB was hemodynamically significant in 47% of patients, and the prevalence of these coexisting conditions was not affected by hemodynamic significance. Conclusions Epicardial spasm, microvascular spasm, and endothelium-independent CMD are prevalent in patients presenting with known MB and chest pain irrespective of the hemodynamic significance of the bridge. Invasive coronary function testing may play an important role in uncovering alternative explanations for angina in patients with known MB.

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Background With the increase in cardiac PET/CT availability and utilization, the development of a PET/CT-based major adverse cardiovascular events, including death, myocardial infarction (MI), and revascularization (MACE-Revasc) risk assessment score is needed. Here we develop a highly predictive PET/CT-based risk score for 90-day and one-year MACE-Revasc. Methods and results 11,552 patients had a PET/CT from 2015 to 2017 and were studied for the training and development set. PET/CT from 2018 was used to validate the derived scores (n = 5049). Patients were on average 65 years old, half were male, and a quarter had a prior MI or revascularization. Baseline characteristics and PET/CT results were used to derive the MACE-Revasc risk models, resulting in models with 5 and 8 weighted factors. The PET/CT 90-day MACE-Revasc risk score trended toward outperforming ischemic burden alone [ P  = .07 with an area under the curve (AUC) 0.85 vs 0.83]. The PET/CT one-year MACE-Revasc score was better than the use of ischemic burden alone ( P  < .0001, AUC 0.80 vs 0.76). Both PET/CT MACE-Revasc risk scores outperformed risk prediction by cardiologists. Conclusion The derived PET/CT 90-day and one-year MACE-Revasc risk scores were highly predictive and outperformed ischemic burden and cardiologist assessment. These scores are easy to calculate, lending to straightforward clinical implementation and should be further tested for clinical usefulness. 摘要: 在40-70%有缺血症状的患者中, 有创冠状动脉造影检查未发现梗阻性冠状动脉疾病 (INOCA) 。当这一病变组接受冠状动脉功能学检查, 大约三分之二的人有明显的冠状动脉微血管功能障碍 (CMD), 这与不良预后独立相关。CMD有四种不同的表型或亚组, 每种表型都有独特的病理生理机制和对应的不同治疗策略。CMD临床表型包括微血管性心绞痛、血管痉挛性心绞痛、混合型 (微血管和血管痉挛) 和非心脏症状 (重新分类为非INOCA) 。冠状动脉血管运动障碍国际研究组 (COVADIS) 提出了标准化的诊断标准。临床医生和指南对这些疾病的认识也在不断提高。 CorMicA研究提倡 "功能性血管造影 "的概念以指导分层医学治疗。对CMD的检测可以采用侵入性或非侵入性的方式进行。治疗方法大致分为两类: 控制心血管风险和缓解心绞痛症状。患者治疗管理应个体化, 并定期重新评估疗效。基于表型的管理对患者和临床医生来说都是值得努力的, 这与 "精准医学 "以改善预后、症状改善和提高生活质量的概念相一致。在此, 我们对于INOCA患者提出了一种基于表型管理的现代方法。

BACKGROUND Coronary microvascular dysfunction is implicated in ∼2/3rd of INOCA cases and is significant due to its association with a higher risk of MACE. While invasive techniques are the gold standard for diagnosing CMD, PET offers a non-invasive approach to quantifying myocardial blood flow and detecting CMD. This study aimed to quantify MFR using PET in INOCA patients to identify CMD and to correlate it with TIMI and TMPG angiographic flow grades. METHODS Thirty INOCA patients with angiographic evidence of non-obstructive coronaries and slow flow were prospectively enrolled and underwent dynamic rest and stress cardiac 13N-NH3 PET with MBF and MFR quantification. Patients with MFR values below 2.3 were classified as having CMD. Angiographic flow grades (TIMI and TMPG) were correlated with MFR and MBF. RESULTS The mean global stress MBF and MFR for the study cohort were 2.54 ± 0.72 ml/min/gm and 2.91 ± 0.81, respectively. No significant correlation was found between MFR and TIMI (r=-0.140, p=0.108) or MFR and TMPG (r=-0.06, p=0.446). Among the participants, 8 (27%) had reduced global MFR <2.3 (mean 1.80 ± 0.36), indicating CMD. The remaining 22 patients (73%) had normal MFR values. Within the CMD group, 3 patients had functional CMD with elevated resting MBF, while 5 had classic CMD with blunted hyperemic response to vasodilator stress. CONCLUSION PET is an excellent non-invasive modality for diagnosing CMD. Coronary slow flow in angiographically normal arteries does not correlate with 13N-NH3 PET MFR values and is not a reliable marker for identifying CMD, as indicated by the study's findings.

Up to 70% of patients with angina undergoing invasive coronary angiography have Ischemia with Non-Obstructive Coronary Arteries (INOCA). Patients with endothelial dysfunction [EnD] and coronary microvascular dysfunction [CMD] have impaired myocardial blood flow and ischemia despite the absence of obstructive CAD, which is partially attributed to inflammation. Sodium Glucose Co-Transporter 2 inhibitors (SGLT2i’s) have remarkable cardiovascular benefits and reduce EnD. However, these effects have not been examined in an INOCA population with CMD. Phase II open label pilot trial was conducted in INOCA patients (n = 7) with CMD treated with the SGLT2i Empagliflozin (EMPA, 10mg/daily) for 90 days. CMD was diagnosed with the invasive thermodilution method using adenosine and acetylcholine, excluding patients with diabetes or heart failure. We investigated change in circulating levels of inflammatory cytokines, ROS markers (plasma 8-isoprostane, myeloperoxidase – MPO and total MPO activity), antioxidants (total antioxidant capacity) and circulating levels of CD34+ repair endothelial microvesicles (eEVs) and inflammatory VCAM+ eEVs at baseline and 45-days following treatment. We also compared baseline samples to INOCA with no-CMD controls (n = 4) from stored samples. In an all-female cohort, mean age was 60 + 12 years (Table 1). Through the 45-day visit, there were two reported UTI’s, one vaginal yeast infection and one non-clinically significant decrease in GFR. INOCA patients with CMD had significantly upregulated levels of 9 proinflammatory cytokines (CRP, TNFα, IL1β, IL-6, ICAM-1, VCAM-1, E-Selectin, Thrombomodulin, VEGF) compared to no-CMD controls; and these levels were reduced following EMPA treatment (Fig 1A – 1D; 1F – 1J); and anti-inflammatory IL-10 was downregulated compared to non-CMD controls and increased with treatment (Fig. 1E). INOCA patients with CMD had elevated ROS markers and reduced antioxidant capacity compared to no-CMD controls, and these improved with treatment (Fig 1K – 1N). INOCA patients with CMD had significantly elevated total concentration of inflammatory eEVs (VCAM+) and reduced repair eEVs (CD34+) at baseline that improved with EMPA treatment (Fig. 1O – 1P). In a cohort of INOCA patients, as compared to patients with no-CMD, patients with CMD had elevated circulating markers associated with EnD. This pilot study indicates that SGLT2i treatment is well-tolerated and has the potential to reduce inflammation, ROS, and eEVs in INOCA patients with CMD.  Figure 2

Ischemia with non-obstructive coronary artery disease (INOCA) is a clinically significant condition associated with adverse cardiovascular outcomes. Coronary microvascular dysfunction (CMD), a major contributor to myocardial ischemia in INOCA patients, remains underrecognized and poorly understood. The coronary endothelium modulates vascular tone through endothelium-derived relaxing factors (EDRFs), including vasodilator prostaglandins (PGs), nitric oxide (NO), and endothelium-dependent hyperpolarisation (EDH) factors, which act in a vessel size-dependent manner. While NO predominantly mediates vasodilation in large conduit arteries, EDH factors play a crucial role in regulating the tone of resistance arteries, and their dysfunctions are particularly relevant to CMD. Endothelial dysfunction, marked by diminished production or activity of EDRFs, is considered a key mechanism underlying CMD in INOCA. However, the specific contributions of individual EDRF components to CMD in INOCA remain unclear. This study aimed to elucidate the mechanism of microvascular dysfunction in INOCA patients, focusing on the relative contributions of EDRFs to endothelial function. Patients undergoing interventional diagnostic procedure (IDP) for invasive coronary functional testing and subcutaneous fat tissue biopsy were prospectively recruited. Resistance arteries were isolated from the femoral fat samples and evaluated using wire myography. EDRF components were analyzed by assessing the inhibitory effects of indomethacin (Indo) for vasodilator PGs, Nω-nitro-L-arginine (L-NNA) for NO, and a combination of charybdotoxin (CTx) and apamin (Apm) for EDH-mediated relaxation. Among 23 patients enrolled (male/female 7/16, mean age 63 ± 12 years), resistance arteries (mean diameter: 286 μm) were successfully isolated and analyzed in 21 patients. Based on IDP findings, patients were classified into the INOCA group (n=17; 16 with vasospastic angina, 1 with microvascular angina) and the control group (n=4; patients with normal coronary physiology and no inducible ischemia). Baseline demographics, cardiovascular risk factors, and physiological parameters were comparable between the groups (Table). Acetylcholine induced concentration-dependent relaxations in precontracted resistance arteries in both groups; however, endothelium-dependent relaxations were significantly impaired in the INOCA group (Figure A). Notably, EDH-mediated relaxation was markedly attenuated in INOCA patients (Figures B-D), while vascular smooth muscle responses to sodium nitroprusside remained preserved. Systemic microvascular dysfunction is prevalent in INOCA, with a substantial reduction in EDH-mediated relaxation, the primary EDRF component regulating microvascular tone. This finding provides new insights into CMD pathophysiology in INOCA and highlights the potential for endothelial function as a therapeutic target.  

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AIM To investigate whether there was an association between coronary microvascular dysfunction (CMD) and left ventricular (LV) diastolic function in patients with myocardial ischemia with non-obstructive coronary artery disease (INOCA). MATERIALS AND METHODS Our study included 115 subjects with suspected myocardial ischemia that underwent stress perfusion cardiac magnetic resonance (CMR). They were divided into non-CMD and CMD two groups. CMR-derived volume-time curves and CMR-FT parameters were used to assess LV diastolic function using CVI42 software. The latter included global/regional LV peak longitudinal, circumferential, radial diastolic strain rate (LDSR, CDSR, RDSR). Logistic regression analysis was performed with CMR-FT strain parameters as independent variables and CMD as dependent variables, and the effect value was expressed as an odds ratio (OR). RESULTS Of the 115 patients, we excluded data from 23 patients and 92 patients (56.5% male；52 ± 12 years) were finally included in the study. Of these, 19 patients were included in the non-CMD group (49 ± 11 years) and CMD group included 73patient (52 ± 12 years). The regional CDSR (P=0.019), and regional RDSR (P=0.006) were significantly lower in the CMD group than in non-CMD group. But, regional LDSR in CMD group was higher than non-CMD (P=0.003). In logistic regression analysis, regional LDSR (adjusted β= 0.1, 95%CI 0.077, 0.349, p=0.002) and RDSR (adjusted β= 0.1, 95 % CI 0.066, 0.356, p=0.004) were related to CMD. CONCLUSIONS LV myocardial perfusion parameter MPRI was negatively correlated with LV diastolic function (CDSR) which needs to take into account the degree of diastolic dysfunction.

Background Ischemia with non-obstructive coronary arteries (INOCA) is a major clinical entity that involves potentially 20%–30% of patients with chest pain. INOCA is typically attributed either to coronary microvascular disease and/or vasospasm, but is likely distinct from classical coronary artery disease (CAD). Objectives To gain insights into the etiology of INOCA and CAD, RNA sequencing of whole blood from patients undergoing both stress testing and elective invasive coronary angiography (ICA) was conducted. Methods Stress testing and ICA of 177 patients identified 40 patients (23%) with INOCA compared to 39 controls (stress-, ICA-). ICA+ patients divided into 38 stress- and 60 stress+. RNAseq was performed by Illumina with ribosomal RNA depletion. Transcriptome changes were analyzed by DeSeq2 and curated by manual and automated methods. Results Differentially expressed genes for INOCA were associated with elevated levels of transcripts related to mucosal-associated invariant T (MAIT) cells, plasmacytoid dendritic cells (pcDC), and memory B cells, and were associated with autoimmune diseases such as rheumatoid arthritis. Decreased transcripts were associated with neutrophils, but neutrophil transcripts, per se, were not less abundant in INOCA. CAD transcripts were more related to T cell functions. Conclusions Elevated transcripts related to pcDC, MAIT, and memory B cells suggest an autoimmune component to INOCA. Reduced neutrophil transcripts are likely attributed to chronic activation leading to increased translation and degradation. Thus, INOCA could result from stimulation of B cell, pcDC, invariant T cell, and neutrophil activation that compromises cardiac microvascular function.

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OBJECTIVES This study sought to better characterize the quality of life and economic impact in patients with symptoms of ischemia and no obstructive coronary disease (INOCA) and to identify the influence of coronary microvascular dysfunction (CMD). BACKGROUND Patients with INOCA have a high symptom burden and an increased incidence of major adverse cardiac events. CMD is a frequent cause of INOCA. The morbidity associated with INOCA and CMD has not been well-characterized. METHODS Sixty-six patients with INOCA underwent stress cardiac magnetic resonance with calculation of myocardial perfusion reserve (MPR); MPR 2.0 to 2.4 was considered borderline-reduced (possible CMD) and MPR <2.0 was defined as reduced (definite CMD). Subjects completed quality of life questionnaires to assess the morbidity and economic impact of INOCA. Questionnaire results were compared between INOCA patients with and without CMD. In addition, logistic regression was used to determine the predictors of CMD within the INOCA population. RESULTS The prevalence of definite CMD was 24%. Definite or borderline CMD was present in 59% (MPR ≤2.4). Patients with INOCA reported greater physical limitation, angina frequency, and reduced quality of life compared to referent stable coronary artery disease and acute myocardial infarction populations. In addition, Patients with INOCA reported frequent time missed from work and work limitations, suggesting a substantial economic impact. No difference was observed in reported symptoms between INOCA patients with and without CMD. Glomerular filtration rate and body-mass index were significant predictors of CMD in multivariable regression analysis. CONCLUSIONS INOCA is associated with high morbidity similar to other high-risk cardiac populations, and work limitations reported by Patients with INOCA suggest a substantial economic impact. CMD is a common cause of INOCA but is not associated with increased morbidity. These results suggest that there is significant symptom burden in the INOCA population regardless of etiology.

Introduction - Severe obesity is associated with cardiometabolic disease and coronary microvascular dysfunction, as reflected by impaired coronary flow reserve (CFR). Bariatric surgery promotes sustained weight loss and lower incidence of diabetic microvascular complications, but its effect on the coronary microcirculation is unclear. In this ongoing pilot study, we aimed to investigate the impact of bariatric surgery on CFR, endothelial function, and cardiorespiratory fitness in patients with severe obesity and INOCA. Methods - Consecutive patients (N=19) with severe obesity (BMI≥35 kg/m 2 ), exertional dyspnea and planned bariatric surgery were enrolled. Patients underwent cardiac stress positron emission tomography (PET), peripheral arterial tonometry (PAT), echocardiogram and cardiopulmonary exercise testing (CPET) at baseline and after a median of 6.2 months post-surgery (N=9 completed to date). CFR was quantified as stress/rest myocardial blood flow (MBF) from PET. Reactive hyperemia index (RHI), a marker of endothelial function, was calculated as the ratio between PAT signal post and pre-occlusion in the corresponding arm. Results - Median age was 50 (Q1-Q3 42-54) years and 63% were female. At baseline, median BMI was 43 (40-54), LVEF was 0.62, and %LV visual ischemia was 0. Higher BMI inversely correlated with CFR (r= -0.53, p=0.02). As compared to baseline, patients post-surgery (78% sleeve gastrectomy, 22% gastric bypass) had significantly decreased BMI (45.2 vs. 34.3, p=0.008) and improved stress MBF [1.8 (1.3-2.2) vs. 2.4 (1.8-2.8), p<0.02], CFR [2.3 (1.9-2.6) vs. 3.1 (2.4-3.6), p<0.02] and peripheral endothelial function [RHI 1.5 (1.4-1.8) vs. 2.4 (1.8-2.8) vs. p=0.04]. These changes were accompanied on CPET by significantly higher exercise workload [112 (84.2-146) vs. 124.5 (90.5-149) W, p=0.046] and relative peak VO 2 [12.5 (11.9-14) vs. 15.2 (12.6-17) mL/kg/min, p=0.028]. Higher stress MBF directly correlated with relative peak VO 2 (r=0.53, p=0.04). Conclusion - In this pilot clinical study, bariatric surgery was associated with significant improvements in coronary microvascular function, peripheral endothelial function, and cardiorespiratory fitness in symptomatic patients with severe obesity after six months.

Background Ischemia and no obstructive coronary artery disease (INOCA) patients who presented coronary microvascular dysfunction (CMD) demonstrate a poor prognosis, yet the risk factors for CMD remain unclear. Subtle changes in thyroid hormone levels within the normal range, especially the free thyroxine (FT4)/free triiodothyronine (FT3) ratio, have been shown to regulate the cardiovascular system. This prospective study investigated the correlation between FT4/FT3 ratio and CMD in euthyroid patients with INOCA. Methods This prospective study (www.chictr.org.cn/, ChiCTR2000037112) recruited patients with myocardial ischemia symptoms who underwent both coronary angiography (CAG) and myocardial perfusion imaging (MPI) with dynamic single-photon emission computed tomography (D-SPECT). INOCA was defined as coronary stenosis< 50% and CMD was defined as coronary flow reserve (CFR)<2.5. All patients were excluded from abnormal thyroid function and thyroid disease history. Results Among 71 INOCA patients (15 [21.1%] CMD), FT4 and FT4/FT3 ratio in CMD group were significantly higher and both showed significantly moderate correlation with CFR (r=-0.25, p=0.03; r=-0.34, p=0.003, respectively). The ROC curve revealed that FT4/FT3 ratio had the highest efficacy for predicting CMD with an optimized cutoff value>3.39 (AUC 0.78, p<0.001, sensitivity, 80.0%; specificity, 71.4%). Multivariate logistic regression showed that FT4/FT3 ratio was an independent predictor of CMD (OR 7.62, 95% CI 1.12-51.89, p=0.038, P for trend=0.006). Conclusion In euthyroid INOCA patients, increased FT4/FT3 ratio levels are associated with the occurrence of CMD, presenting a novel biomarker for improving the risk stratification.

Ischemic pain with no‐obstructive coronary artery (INOCA) is clinically significant and defined by nonobstructive coronary stenosis <50%. Coronary microvascular dysfunction (CMD) is a relevant cause associated with adverse outcomes.

Background/Objectives: Coronary artery disease (CAD) remains one of the leading cardiovascular diseases worldwide. While obstructive CAD is well characterized and managed, identification of patients with non-obstructive CAD (NOCAD) remains challenging. Unlike the coronary vasculature, the eye's microcirculation can be easily and non-invasively assessed. Therefore, this systematic review summarized the ophthalmological diagnostic methods used to assess microvascular alterations associated with coronary microvascular dysfunction (CMD), angina with non-obstructive coronary arteries (ANOCA), or ischemia with non-obstructive coronary arteries (INOCA). Methods: According to PRISMA guidelines, PubMed/MEDLINE and Embase databases were screened by two independent reviewers from inception to 25 November 2025. Original articles that examined ophthalmological microvascular changes by any method in adults with CMD or its subtypes were included. The quality of the studies was assessed using the JBI Critical Appraisal Checklist. Results: Of 101 identified articles, nine studies met the inclusion criteria, comprising 1894 patients. Optical coherence tomography angiography was the most frequently used imaging modality, followed by optical coherence tomography, slit-lamp smartphone imaging, and fundus photography. Five investigations employed blinded image analysis, three did not, and one study used it partially. Four studies used semi-automated measurements, four employed fully automated methods, and one study applied manual and automated measurements for different parameters. Conclusions: Despite a limited number of studies, retinal and conjunctival microvascular alterations helped differentiate CAD subtypes and may reflect systemic microcirculatory impairment among patients with ANOCA/INOCA. Ophthalmological imaging techniques have the potential to serve as non-invasive tools for detecting microvascular alterations associated with CMD in ANOCA and INOCA patients. PROSPERO Registration Number: CRD420251239875.

BACKGROUND: In patients with ischemia and no obstructive coronary artery disease (INOCA), coronary microvascular dysfunction is associated with higher rate of major adverse cardiovascular events. OBJECTIVE: To demonstrate if microvascular dysfunction present in coronary microcirculation of patients with INOCA may be detected noninvasively in their peripheral circulation. METHODS: 25 patients with INOCA and 25 apparently healthy individuals (controls) were subjected to nailfold videocapillaroscopy (NVC) and venous occlusion plethysmography (VOP) to evaluate peripheral microvascular function and blood collection for biomarkers analysis, including soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1) and C-reactive protein (CRP). RESULTS: Red blood cell velocity (RBCV) before and after ischemia (RBCVmax) were significantly lower in patients with INOCA (p = 0.0001). Time to reach maximal red blood cell velocity (TRBCVmax) was significantly longer in INOCA group (p = 0.0004). Concerning VOP, maximal blood flow (p = 0.004) and its relative increment were significantly lower in patients with INOCA (p = 0.0004). RBCVmax showed significant correlations with sVCAM-1 (r = –0.38, p < 0.05), ET-1 (r = –0.73, p < 0.05) and CRP (r = –0.33, p < 0.05). Relative increment of maximal post-ischemic blood flow was significantly correlated with sVCAM-1 (r = –0.42, p < 0.05) and ET-1 (r = –0.48, p < 0.05). CONCLUSIONS: The impairment of microvascular function present in coronary microcirculation of patients with INOCA can be also detected in peripheral microcirculation.

MINOCA is a syndrome characterized by symptoms suggesting normal ischemia and coronary arteries or with stenosis less than or equal to 50%, and INOCA by the presence of ischemia without obstructive coronary artery disease. It affects women more frequently, with a prevalence of 3.5 to 40%. It is multifactorial and may correspond to a) epicardial coronary abnormalities (atherosclerotic plaque rupture, ulceration, fissures, erosion or coronary dissection with non-obstructive coronary artery disease or without coronary heart disease): type 1 infarction; b) Imbalance between oxygen supply and demand (such as spasm and coronary embolism, type 2 infarction); c) Coronary endothelial dysfunction (epicardial coronary spasm or microvascular dysfunction, type 2 infarction), and d) Secondary to myocardial disorders without involvement of coronary arteries (myocarditis, cardiomyopathy, Takotsubo cardiomyopathy). Diagnosis is based on the clinical and ECG findings and elevated troponin values. Imaging has a determining role; thus, an angiography is necessary to start the diagnosis of accuracy and establish the cause, and to perform an evaluation of the coronary wall with IVUS or OCT, and when the lesions are moderate in many cases an FFR is necessary. PET provides a highly reliable evaluation of coronary microcirculation, myocardial perfusion, coronary blood flow and left ventricular function; but its high cost makes it not possible to use it routinely in our environment. Treatment should be aimed at correcting the cause; if there is ≤50% obstruction with evidence of atherosclerotic plaque rupture or erosion, the treatment will be that of an ACS.

BACKGROUND Ischemia with non-obstructive coronary arteries (INOCA) represents a diagnostic and therapeutic challenge, often related to coronary microvascular dysfunction (CMD). Identifying non-invasive electrocardiographic markers that predict ischemia in this population remains a clinical priority. P-wave peak time (PWPT), reflecting atrial conduction delay, has been linked to ischemic pathophysiology. METHODS This retrospective, observational study included 444 patients who underwent coronary angiography with normal epicardial arteries followed by SPECT myocardial perfusion imaging (MPI) due to persistent anginal symptoms. Patients were classified into three groups based on the percentage of reversible left ventricular ischemia: <5 %, 5-10 %, and > 10 %. P-wave indices-including PWPT in leads DII and V1-were measured digitally by two independent observers. Multivariate logistic regression identified independent predictors of >10 % ischemia. ROC analysis assessed the discriminative power of PWPT. RESULTS PWPT-DII and PWPT-V1 were significantly prolonged in patients with >10 % ischemia (63 ± 8 ms and 58 ± 9 ms, respectively) compared to patients with <5 % ischemia (55 ± 7 ms and 50 ± 8 ms; both p < 0.001). PWPT-DII yielded an AUC of 0.82 (95 % CI 0.77-0.86), outperforming PWPT-V1 (AUC 0.76). In multivariate models, PWPT-DII (OR 1.15, 95 % CI 1.08-1.23), PWPT-V1 (OR 1.10, 95 % CI 1.03-1.17), age, diabetes mellitus, and E/e' ratio emerged as independent predictors of significant ischemia. CONCLUSIONS Prolonged PWPT, particularly in lead DII, was observed to be independently associated with myocardial ischemia in INOCA. Incorporating PWPT into standard ECG interpretation may aid in risk stratification and early identification of CMD in patients with normal coronary angiograms but ongoing ischemic symptoms.

BACKGROUND Chronic coronary syndromes (CCS) occur commonly in the absence of flow-limiting epicardial coronary stenoses. Ischemia or angina with no obstructive coronary arteries (INOCA/ANOCA) may be caused by coronary microvascular disease, coronary artery spasm, myocardial bridging, diffuse atherosclerosis, or a combination of disorders. METHODS & RESULTS We highlight the new recommendations in the 2024 European Society of Cardiology (ESC) guidelines on CCS relevant to the diagnosis and management of INOCA/ANOCA. The guidelines place a new emphasis on consideration of INOCA/ANOCA early during cardiovascular risk stratification and the initial diagnostic workup for chest pain. There is a new class I recommendation for the availability of invasive coronary function testing (CFT) at the time of initial coronary angiography, when mechanisms of chest pain are uncertain after non-invasive testing, and in patients with established INOCA/ANOCA who have persistent symptoms and poor quality of life despite medical therapy. Once underlying disorders have been identified based on the results of invasive CFT, the ESC guidelines emphasize a patient-centered, mechanism-based approach to medical treatment of INOCA/ANOCA to improve symptoms and quality of life. CONCLUSIONS The 2024 ESC CCS guidelines provide a new vision for the diagnosis and management of ANOCA/INOCA, with an expanded role for invasive CFT and targeted medical therapy to improve symptoms and quality of life in patients with angina.

INOCA (ischemia with nonobstructive coronary arteries) is a general term for different types of coronary artery disease which excludes an obstruction of the coronary arteries: vasospastic angina, microvascular angina and muscular myocardial bridge. According to coronary angiography data, 37–39% of patients don’t have hemodynamically significant stenoses of the coronary arteries. INOCA is assigned with significant quality of life limitations, decreased working capacity, the risk of major cardiovascular events is higher and survival rate is lower than in a healthy population. Two main pathogenetic mechanisms were studied and differentiated based on scientific data: microcirculatory dysfunction and vasospasm. Myocardial bridge is classified as structural vasospasm endotype. Coronary blood flow examination and an acetylcholine provocation test are the main diagnostical procedures, which can help to determine the leading pathophysiological mechanism of INOCA. Microvascular disease treatment is pretty similar to an obstructive coronary disease therapy with the possible addition of metabolic therapy. In vasospastic angina front-line drugs are calcium antagonists.

Background/Objectives: Ischemia with non-obstructive coronary arteries (INOCA) remains an underdiagnosed and undertreated condition due to the extensive diagnostic testing required and heterogeneous pathophysiology of different endotypes, each of which require tailored treatment. This study aimed to explore the effect of intracoronary physiology testing-based endotype-specific medical therapy on quality of life in patients with INOCA. Methods: Intracoronary physiology testing was performed in patients presenting with cardiac symptoms, evidence of significant ischemia on non-invasive testing, and non-obstructive epicardial coronary arteries. Microvascular angina (MVA) was defined as coronary flow reserve ≤ 2.5 and an index of microvascular resistance ≥ 25. Vasospastic angina (VSA) was defined as a >90% vasoconstriction of an epicardial artery during acetylcholine provocation test in the presence of ischemic electrocardiogram changes and chest pain. Quality of life was evaluated using the Seattle Angina Questionnaire 7 (SAQ-7) before the start of new treatment and at the three months follow-up. Results: The total study population consisted of 35 patients (80% women), of whom MVA was observed in 19 (54.3%), VSA in 9 (25.7%), and the combination of MVA and VSA in 3 (8.6%) cases. Four patients (11.4%) had no pathology on intracoronary physiology testing detected. High rates of dyslipidemia (100%), arterial hypertension (85.7%), diabetes (17.1%), and depression and anxiety (34.3%) were documented. In the isolated MVA and VSA groups, adjustment of medical therapy resulted in an improvement in the SAQ-7 summary score at 3 months (p < 0.001 and p = 0.007, respectively). There was no change of SAQ-7 summary score in the mixed endotype group (p = 0.11). Conclusions: Adjustment of medical therapy according to intracoronary physiology testing-based phenotype resulted in improved quality of life as assessed by the SAQ-7. Our findings highlight the importance of invasive testing in patients with clinically suspected INOCA.

Angina and ischaemia with non-obstructive coronary arteries (ANOCA/INOCA) are manifestations of chronic nonobstructive coronary artery disease (CAD) and refer to anginal symptoms or evidence of myocardial ischaemia without flow‐limiting obstructive lesions in the epicardial coronary arteries. Both entities share common vascular dysfunction mechanisms, called endotypes: endothelial dysfunction, impaired vasodilation, epicardial vasospasm, microvascular vasospasm and their combinations, and carry clinical aggravated significance by refractory angina, increased risk of major adverse cardiovascular events (MACE) and important impairment of quality of life (QoL). The updated (2024) European Society of Cardiology (ESC) guidelines for the management of chronic coronary syndromes (CCS) pay increase attention to the subject of ANOCA/INOCA, providing diagnostic and therapeutic management recommendations. In order to achieve a personalized approach based on endotype and reliable evidence, the imperative for additional clinical research emerged, which would provide new effective diagnostic strategies and treatments for patients with ANOCA/INOCA syndrome.

Approximately 60% of patients with angina symptoms do not have obstructive coronary lesions, a condition known as ischemia with non-obstructive coronary arteries (INOCA). Among these patients, coronary microvascular dysfunction (CMD) is found in nearly half. The epicardial coronary arteries represent only a small portion of the heart’s vascular bed, with CMD increasingly recognized as a significant mechanism of myocardial ischemia in INOCA. Recent revisions in the Japanese and European guidelines emphasize the importance of a comprehensive functional evaluation through interventional diagnostic procedure (IDP) for diagnosing CMD and coronary vasospastic angina, two primary causes of ischemia in INOCA patients. IDP allows clinicians to identify the underlying endotype and implement tailored therapeutic strategies, moving beyond empirical therapy. Despite its clinical relevance, INOCA remains under-recognized due to a lack of awareness among healthcare providers as well as the general public, leading to diagnostic delays and undertreatment. Public education campaigns and clinician training are crucial for improving disease recognition and reducing diagnostic delay. Future directions for INOCA management include standardizing and simplifying IDP protocols, incorporating artificial intelligence for diagnostic support, and developing non-invasive alternatives for coronary functional testing. These efforts will enhance the accuracy and accessibility of IDP, facilitating its integration into routine clinical practice. Ultimately, the continued evolution of IDP will play a key role in advancing precision cardiovascular medicine, bridging the gap between symptoms, diagnosis, and meaningful care, and improving outcomes for INOCA patients.

Ischemia with non-obstructed coronary arteries (INOCA) is a common but under-treated condition due to limited diagnostic methods and complex pathophysiologic mechanisms involving microvascular (MVA) and vasospastic angina (VSA), which both require tailored medical therapy. To prove the crucial role of intracoronary physiology testing to determine an exact INOCA endotype, adjust specific medical therapy and achieve improvement of quality of life in symptomatic patients with INOCA. In the single centre study invasive testing was performed in 35 patients presented with cardiac symptoms, significant ischemia on non-invasive tests and non-obstructed epicardial coronary arteries during invasive or computed tomography coronary angiography (epicardial stenosis less than 50% and/or fractional flow reserve >0.80). MVA was defined as coronary flow reserve ≤ 2.5 and microvascular resistance index ≥ 25. The VSA was assessed if significant vasospasm (>90%) with subsequent ischemic signs in ECG and chest pain was present during acetylcholine provocation test. Medical treatment was adjusted according to the European Society of Cardiology Guidelines and compared before and after invasive testing. Patients’ quality of life was assessed by Seattle Angina Questionnaire 7 (SAQ-7) before and 3 months after treatment adjustment. Invasive functional testing was performed in 35 patients. 19 (54.3%) patients were diagnosed with MVA, 9 (25.7%) with VSA, the combination of MVA and VSA was observed in 3 (8.6%) cases. In 4 patients (11.4%) the cause of symptoms was non-cardiac. Comparing medical treatment before and after invasive physiology testing - in patients with MVA significant increase in prescription of calcium channel blockers (CCB) (26.3% vs 94.7%, p<0.001), antianginal treatment like ranolazine or trimetazidine (15.8% vs 94.7%, p<0.001) and beta-blockers (BB) (42.1% vs 73.7%, p=0.05) was observed. In contrast, in patients with VSA the prescription of BB decreased by 66.6% (p=0.015) but increased the usage of CCB (44.4% vs 100%, p=0.03) and long-acting nitrates (0% vs 77.8%, p=0.002). There were no changes in prescribed treatment of patients with mixed INOCA endotype. Medical treatment adjustment according to the INOCA endotype resulted in an improvement in the SAQ-7 physical limitation (p<0.001), angina frequency (p<0.001), quality of life (p<0.001) and summary score at 3 months (p<0.001). There were no complications during the testing. The intracoronary physiology testing is safe, and provides precise diagnosis in patients whose symptoms were previously attributed to non-cardiac causes, allowing to start early treatment suitable for exact INOCA endotype, which leads to a rapid improvement in patients quality of life.

Background Management of ischemia with nonobstructive coronary arteries (INOCA) remains insufficiently defined in current guidelines, particularly when complicated by symptomatic myocardial bridging, evolving nonobstructive atherosclerosis, and systemic inflammation. Such overlapping mechanisms create complex diagnostic and therapeutic challenges that require individualized care. Case Summary A 39-year-old man with recurrent chest discomfort, left anterior descending myocardial bridging, and suspected microvascular dysfunction was found to have progressive high-risk atherosclerosis and elevated systemic inflammatory burden, despite the absence of obstructive coronary disease. Multimodal imaging—including coronary computed tomography angiography with machine learning (ML)–based ischemia risk scoring and pericoronary adipose tissue analysis—enabled precise characterization of both functional and structural risk. A tailored, intensive regimen targeting lipid lowering, myocardial unloading, and inflammation control led to regression of high-risk plaque features, reduction in pericoronary adipose tissue attenuation, normalization of inflammatory markers, and complete resolution of symptoms over 15 months. Why Beyond the Guidelines No established guideline recommendations address INOCA with concurrent symptomatic myocardial bridging, subclinical plaque progression, and residual inflammatory risk. A multimodal, off-label pharmacologic strategy was required to stabilize disease activity and restore functional status. Discussion This case underscores the utility of phenotype-specific, imaging-guided therapy in complex INOCA presentations. Integration of ML-enhanced coronary computed tomography angiography and individualized prevention enabled both anatomic regression and physiologic recovery in a high-risk but nonobstructive phenotype. Take-Home Messages INOCA with symptomatic myocardial bridging and inflammation may require off-label, intensive therapy. ML-enhanced multimodal imaging facilitates dynamic risk stratification and tailored treatment adjustments.

Vascular aging contributes to structural and functional changes across various organs, including the heart. In patients with angina and no obstructive coronary artery disease (ANOCA/INOCA), coronary vasomotor disorders potentially causing angina pectoris may be attributed to coronary aging. However, the prevalence of these disorders across different age groups remains unclear. This study aims to investigate the prevalence of coronary vasomotor disorders across different age groups in patients with ANOCA/INOCA. We conducted coronary function testing (CFT) in 138 consecutive ANOCA/INOCA patients presenting with angina but without significant epicardial stenosis (<50%). The CFT included an intracoronary acetylcholine (ACh) coronary spasm test and an adenosine test to evaluate coronary microvascular dysfunction (CMD) by assessing coronary flow reserve (CFR) and hyperemic microvascular resistance (MR). We analyzed CFT outcomes in different age groups and between sexes. Categorical variables were compared using the Chi-square test, with statistical significance set at p < 0.05. Of the study cohort, 120 patients (87%) had a positive CFT result, with 109 (79%) exhibiting coronary spasm and 58 (42%) diagnosed with CMD (Table 1). There were no significant differences in the diagnostic yield of a positive CFT result across age groups (<55 years, 55–65 years, 66–75 years, >75 years) (p=0.9424), in the prevalence of coronary spasm (p=0.6361), or in CMD prevalence (p=0.5731). CMD subtypes also showed no significant age-related differences (CFR pathological/MR normal vs. CFR pathological/MR pathological vs. CFR normal/MR pathological; p=0.2824). Furthermore, no significant differences were observed in the distribution of CFT results between sexes across the age groups (p=0.4521). Coronary vasomotor disorders are present across all age groups with similar prevalence rates, and no sex differences between age groups were observed. These findings suggest that vascular aging does not significantly impact the occurrence of coronary spasm or CMD. As such, these conditions should be considered in patients across all age groups, as various triggers or underlying causes may contribute to their manifestation.Table 1

Despite increasing awareness, INOCA is underdiagnosed. Our study aims to assess the prevalence of INOCA in 3 centers in Northern, Central, and Southern Italy, stratifying patients based on coronary microvascular dysfunction (CMD), vasospastic angina (VSA), microvascular spasm (MSA), or non-cardiac origins (NCO), implementing tailored medical therapy and evaluating impact on angina severity, quality of life, and cardiac outcomes at 1 year. The INOCA IT Multicenter Registry is a prospective, multicenter, single-arm clinical study that included patients presenting with CCS symptoms and/or positive stress tests, and non-obstructive CAD on coronary angiography.Invasive coronary functional testing was performed, assessing Coronary Flow Reserve (CFR), Index of Microvascular Resistance (IMR). Acetylcholine (ACh) spasm provocation test was also conducted to identify abnormal vasoreactivity. Patients were consequently classified into different INOCA endotypes and received personalized medical therapy. Patients underwent 1-year clinical follow-up. A total of 212 patients were enrolled, the mean age was 61±11 years and 60.4% were female. Overall, 64.2% of patients suffered from hypertension, 15.6% had diabetes, the mean BMI was 26.8±4.7 and 72.6% suffered from dyslipidemia. Most patients presented with typical chest pain (86.8%), the median Canadian Cardiovascular Society (CCS) grade was 2(IQR 2-3) and the median New York Heart Association (NHYA) class median 2 (IQR 1-2). At invasive coronary functional testing (mean CFR: 3.25±1.78, mean IMR 22.1±15.0), 22.6% of patients were diagnosed with CMD, 22.2% with VSA, 14.2% with MSA, 16.0% were affected by both CMD and VSA, 3.8% had both CMD and MVA, 21.2% patients had NCO symptoms.The prevalence of INOCA endotypes showed geographical differences: the first endotype in northern Italy was VSA (27.5%), CMD was the first in central Italy (28.9%), whereas most patients from southern Italy had chest pain of NCO (32.1%) – p for overall comparisons =0.028. The latter also had the highest prevalence of hypertension (83.9%vs52.5% and 61.8% in the other areas, p<0.01) and dyslipidemia (85.7vs 65.0 and 71.1 in the other areas, p=0.026). Moreover, male patients were more frequently affected by VSA compared to other endotypes in northern Italy (37.5%, p for overall comparison=0.043). Finally, VSA was the most frequently misdiagnosed endotype upon non-invasive diagnostic work-up, with a false negative rate of 78.8%, whereas CMD was identified more frequently, with a true positive rate of 50%. The last patient was enrolled in March 2024, and 1-year follow will be available at the time of presentation. This real-world analysis highlights the importance of providing accurate diagnosis and subsequent tailored therapy to INOCA patients with a safe and systematical approach. We expect to detect improved QOL and angina symptoms following optimization of medical therapy.

Ischemia with Non-Obstructive Coronary Arteries (INOCA) is seen in up to 70% of patients with angina undergoing invasive coronary angiography. In INOCA patients, with coronary microvascular dysfunction (CMD) and underlying endothelial dysfunction (EnD)-induced inflammation and excessive reactive oxygen species (ROS) signaling leads to increased release of cytokines, upregulation of leucocyte adhesion molecules, the release of endothelial microvesicles (eEVs), and ultimately EC apoptosis. In vitro studies have found Sodium Glucose Co-Transporter 2 inhibitors (SGLT2i) reverse EnD. However, the effect of SGLT2i on EnD in an INOCA population with CMD has not been studied. Phase II open label pilot trial in INOCA patients with CMD treated with the SGLT2i Empagliflozin (EMPA, 10mg/daily) for 90 days. Blood samples were collected at baseline and after 45 days of treatment (n = 7), baseline samples were compared to no-CMD controls stored samples (n = 4). Cultured Human Coronary Artery Endothelial Cells (HCAECS) were exposed to sera from the 3 groups at various concentrations (5,10,20%); and cell viability, apoptosis, eEV release, VCAM-1 concentrations, and mitochondrial ROS staining were quantified. In an all-female cohort, the mean age was 60 years (SD 12) (Table 1). Compared to no-CMD controls HCAECs, incubated with sera from INOCA patients with CMD had significantly higher apoptosis (Fig. 1A) and lower viability (Fig. 1B) that significantly improved following EMPA treatment (Fig. 1A – 1B). Compared to no-CMD controls HCAECs incubated with 10% sera, INOCA patients with CMD induced significantly higher release of eEVs (concentration, Fig. 1C) with concomitant higher eEV median size (Fig. 1D); and EMPA treated sera significantly reduced the release of eEVs and eEV size (Fig. 1C – 1D). Compared to no-CMD controls, sera of INOCA patients with CMD induced significantly higher levels of VCAM-1 in the supernatant (Fig. 1E) and VCAM-1 protein in the cell lysate (Fig. 1F), which was significantly reduced following treatment (Fig. 1E – 1F). HCAECs incubated with 10% sera from INOCA patients with CMD had significantly elevated Mito-SOX staining compared to non-CMD controls, and this was significantly reduced following treatment (Fig. 1G). Sera from INOCA patients with CMD has an increased capacity to induce EnD compared to no-CMD controls and this capacity is reduced following SGLTi treatment. These results suggest SGLT2i’s may target the underlying mechanisms of disease (EnD and CMD) in INOCA patients.  

Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM.

Background Approximately 30% to 50% of patients who are referred for diagnostic coronary angiography are found to have no obstructive coronary artery disease (CAD). Ischemia and nonobstructive coronary arteries (INOCA) is increasingly recognized and encompasses coronary microvascular dysfunction, vasospastic angina, symptomatic myocardial bridging, and other vasomotor disorders. However, the prevalence of these disorders and whether underlying atherosclerotic plaque burden and morphology affect the long-term outcomes of each physiologic phenotype is unknown. Methods The DISCOVER INOCA registry is ongoing at 8 centers in the United States and plans to enroll 500 patients with ischemic heart disease referred for angiography undergoing coronary function testing (CFT). All participants will complete patient-reported outcome measures and undergo protocol-guided angiography, acetylcholine provocation, coronary thermodilution, and intravascular imaging. Follow-up assessments occur at 30 days, 6 months, 1 year, and annually for 5 years. The primary short-term end point is the prevalence of INOCA phenotypes based on physiology and the degree of atherosclerosis based on intravascular ultrasound or optical coherence tomography (intravascular imaging). The primary long-term end point is the incidence of major adverse cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, hospitalization for cardiovascular causes, or coronary revascularization at a follow-up of 5 years. At the time of this publication, 100 participants have been enrolled. Conclusions DISCOVER INOCA is the first prospective study of INOCA patients to integrate anatomic and physiologic measures of disease and correlate them with long-term outcomes. DISCOVER INOCA will report on the prevalence of INOCA phenotypes, the safety of comprehensive invasive CFT, and the impact of testing on diagnoses and medical therapy. Symptoms and cardiovascular adverse events at long-term follow-up will be determined in patients with no obstructive CAD undergoing angiography.

Ischemia and non-obstructive coronary artery disease (INOCA) might be due to coronary microvascular dysfunction (CMD), vasospastic angina (VSA) or both. We compared plasma concentration of various extracellular vesicles (EVs) in patients with different INOCA endotypes. Patients were divided into those with INOCA (CMD, VSA, mixed CMD + VSA) and non-anginal chest pain. Plasma concentrations of EVs were measured using flow cytometry. Out of 96 patients included, 34 had CMD (35%), 15 VSA (16%), 24 mixed endotype (25%) and 23 non-anginal chest pain (24%). Patients with INOCA had lower ratio of endothelial EVs (CD144 +) to total EVs, compared to patients with non-anginal pain (p = 0.027). Patients with mixed endotype had lower ratio of endothelial EVs (CD144 +) to total EVs, compared to CMD (p = 0.008), VSA (p = 0.014) and non-anginal pain (p < 0.001). Decreased ratio of endothelial EVs (CD144 +) to total EVs might serve as a "circulating footprint" of the mixed INOCA endotype. CCS – chronic coronary syndrome, CD – cluster of differentiation, CMD – coronary microvascular dysfunction, CFR – coronary flow reserve, EVs – extracellular vesicles, FFR – fractional flow reserve, INOCA - IMR – index of microvascular resistance, VSA – vasospastic angina

Patients with ischemia and nonobstructive coronary arteries (INOCA) suffer from a broad range of anginal symptoms that may differ depending on the biologic sex of the patient, the underlying coronary vasomotor disorder, or the type of presentation. We sought to characterize the symptom description and angina classification of patients referred for invasive coronary function testing (CFT) in the DISCOVER INOCA multicenter registry, stratified by type of presentation (stable vs unstable), biologic sex, and underlying diagnosis, including coronary microvascular dysfunction (CMD), vasospastic angina (VSA), or other disorders such as symptomatic myocardial bridging. DISCOVER INOCA is a prospective, multicenter registry in the United States that includes patients who are referred for clinically indicated coronary angiography and found to have INOCA. All patients underwent protocol-guided angiography, acetylcholine provocation, coronary thermodilution, and intravascular imaging. Symptom characteristics were compared between groups. From September 2022 until February 2024, 104 patients were enrolled, 78% were female, and mean age was 57 ± 11 years. The post-procedure diagnosis was CMD in 19%, VSA in 41%, a mixed syndrome in 15%, or other diagnosis in 26%. The average coronary flow reserve (CFR) was 2.9 ± 1.1 in the CMD group and 5.3 ± 3.0 in the VSA group, (p < 0.001). 53% of patients presented with stable angina and 47% with unstable or progressive symptoms. Symptoms included chest pain (89%), chest tightness (42%), chest pressure (39%), shortness of breath (53%), and fatigue (16%), and no significant differences were reported when stratified by diagnostic phenotype. Female patients were more likely to report arm/neck/back/jaw pain (25% vs 5% in men, p = 0.038). Symptom triggers included exertion/activity in 73%, emotional stress in 12%, and resting symptoms in 58%. In female patients 4% reported catamenial symptoms. Of patients with stable angina, the Canadian Cardiovascular Society (CCS) Angina Classification was Grade I in 25%, Grade II in 52%, Grade III in 21%, and Grade IV in 2%. In patients with unstable angina, the Braunwald Angina Classification was Class I in 9%, Class II in 73%, and Class III in 18%. Patients with INOCA referred for clinically indicated coronary angiography and CFT were predominantly female and most commonly reported chest pain as a presenting symptom. Female patients were more likely to report arm/neck/back/jaw pain than male patients. Over half of patients reported resting symptoms with no differences between the diagnostic phenotypes (CMD, VSA, or other). The CCS and Braunwald angina classification indicated that most patients had moderate intensity symptoms. Patient-reported outcome measures will be used to systematically categorize the symptom burden in these patients.

For diagnosis of exact INOCA endotype the invasive measurements of coronary flow reserve (CFR), index of microvascular resistance (IMR), which both represents the microvascular function, and acetylcholine (ACH) provocation test to diagnose vasospasm is mandatory. To perform the intracoronary physiological testing, including measurements of CFR, IMR and ACH provocation test for defining the INOCA endotypes – microvascular angina (MVA), vasospastic angina (VSA), microvascular spasm (MVS), or combination of them. The invasive examination was performed in a single University Hospital from March 2023 till December 2023 in patients presented with cardiac symptoms, significant ischemic signs at exercise ECG test and non-obstructed epicardial coronary arteries during invasive or computed tomography coronary angiography (epicardial stenosis less than 50% and/or fractional flow reserve (FFR) >0.80). The criteria for MVA were CFR ≤ 2.5 and IMR ≥ 25. The VSA was assessed if significant (>90%) vasospasm occurred during ACH provocation test with subsequent ischemic signs in ECG and chest pain during the test. In patients presented with the ischemic signs in ECG and chest pain during the ACH provocation test, without vasospasm – the MVS was defined. Invasive functional testing was performed for 20 patients. 15 patients (75.0%) were women. The mean age of the patients was 59.9 ± 9.4 years. The most common cardiac symptoms were chest pain (18, 90.0%), dyspnea (15, 75.0%), fatigue (14, 70.0%), headache (8, 40.0%) and excessive sweating (6, 30.0%). 3 (15.0%) patients were current or ex-smokers. Dyslipidemia was present in 20 (100.0%), arterial hypertension in 17 (85.0%) and type 2 Diabetes mellitus (T2DM) in 3 (15.0%) patients. In 8 (40.0%) patients the somatoform autonomic dysfunction was suggested as a primary diagnosis after the first tests. 3 patients (15.0%) showed normal values of all measurements. 8 (40.0%) patients were diagnosed with MVA, 6 (30.0%) with VSA, MVS was assessed in 1 (5.0%) patient and the combination of MVA and VSA was observed in 2 (10.0%) cases. The first clinical data of INOCA diagnostics of patients in Latvia are very promising since the amount of INOCA patients is high. The patients are underdiagnosed and remains symptomatic without tailored medical treatment, emphasizing that every INOCA endotype requires different treatment. More clinical evidence will be needed to routinely adapt coronary function testing during invasive management.

Ischemia with no obstructive coronary artery (INOCA) is a common cause of hospitalizations, resulting in poor outcomes and diminished quality of life. A key element in the pathophysiology of INOCA is endothelial dysfunction, which leads to myocardial ischemia despite the absence of significant coronary artery obstruction. Effective management of endothelial dysfunction is essential for alleviating symptoms and preventing cardiovascular events in INOCA patients. Recent studies have highlighted diabetes mellitus (DM) as a significant contributor to INOCA complications by exacerbating endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs), which are known to regulate gene expression, have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, there is a lack of research evaluating miRNA biomarkers specifically in INOCA patients. In our study, we examined a panel of circulating miRNAs associated with the regulation of endothelial function in INOCA patients with and without DM. Using RT-qPCR, we analyzed miRNA expression in a cohort of consecutive patients undergoing percutaneous coronary intervention (PCI) who were confirmed to have INOCA. We measured the expression levels of a previously validated panel of miRNAs in INOCA patients with DM compared to those without DM. Specifically, we observed an increased expression of several miRNAs previously associated with endothelial dysfunction and decreased expression of miRNAs known to protect endothelial function. Further analyses revealed that among these miRNAs, miR-363-5p was significantly downregulated (P<0.001) and miR-92a-3p was significantly upregulated (P<0.001) in INOCA patients with DM compared to those without DM, as illustrated in the volcano plot in Figure 1 . Taken together, our findings demonstrated significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their potential role as biomarkers for endothelial dysfunction in INOCA.

AIMS To investigate the influence of index of microcirculatory resistance (IMR) on fractional flow reserve (FFR) and adenosine-induced hyperemia (ΔPd/Pa-FFR) in patients with chronic (CCS) or stabilized acute coronary syndromes (ACS), utilizing various IMR threshold values. METHODS Data were extracted from two ongoing Italian registries involving patients with CCS or stabilized ACS who underwent a #FullPhysiology approach [Pd/Pa, FFR, IMR, coronary flow reserve (CFR)] by bolus thermodilution technique in the left anterior descending artery. Correlations between IMR and both FFR and ΔPd/Pa-FFR were analyzed both globally and within three IMR-defined groups: Group 1 (IMR <25), Group 2 (25 ≤ IMR <40), and Group 3 (IMR ≥40). A multiple linear regression was employed to adjust for confounding factors. RESULTS Of 275 patients, 163 were in Group 1, 60 in Group 2, and 52 in Group 3. Globally, a weak but significant correlation was observed between IMR and both FFR (r = 0.170, p < 0.01) and ΔPd/Pa-FFR (r = -0.159, p < 0.01). After stratification only patients in Group 3 exhibited a significant and more pronounced, though still weak, correlation between FFR and IMR (r = 0.387, p < 0.01) coupled with a reduction of ΔPd/Pa-FFR as IMR values increased (r = -0.411, p < 0.01). After adjustment, a significant increase of 0.01 in FFR values was observed for every 14-unit rise in IMR (p < 0.01) in Group 3. CONCLUSIONS FFR appears particularly influenced by elevated IMR values (≥40) highlighting the importance of the #FullPhysiology approach in understanding epicardial and microvascular contribution of myocardial ischemia.

Despite the plausible physiological connection between the index of microvascular resistance (IMR) and fractional flow reserve (FFR), a comprehensive understanding of their correlation is lacking. This study aims to elucidate the association between IMR and FFR in patients presenting with angina and non-obstructive coronary artery disease, employing various IMR threshold values. Consecutively enrolled patients with angina and non-obstructive coronary artery disease underwent a thorough functional assessment encompassing both epicardial (Pd/Pa, FFR) and microvascular (coronary flow reserve, CFR; IMR) domains by the thermodilution technique. The hyperemic response to adenosine (Δ) was quantified as the disparity between Pd/Pa and FFR. Correlations between FFR and IMR, as well as between Δ and IMR, were examined globally and categorized based on the presence of coronary microvascular dysfunction (CMD, CFR<2). Subsequently, patients were stratified into three groups based on IMR values: Group 1 (IMR<25), Group 2 (25≤IMR<40), and Group 3 (IMR ≥ 40). Further analyses of adenosine hyperemic response, IMR, and FFR correlations were conducted within each group. A total of 116 patients and lesions were evaluated, with 71 in Group 1, 32 in Group 2, and 13 in Group 3. Globally, FFR showed no correlation with IMR (r = 0.025, p = 0.788), regardless of CMD presence (CMD, r = 0.210, p = 0.325; no CMD r = -0.051, p = 0.631). Same results were observed for the relationship of hyperemic response to adenosine and IMR (r = -0.0398, p = 0.673). However, upon stratification by IMR values, only patients in Group 3 exhibited a positive correlation between FFR and IMR (r = 0.580, p = 0.037), with a notable reduction in the hyperemic response to adenosine as IMR values increased (r = -0.5485, p = 0.052). After adjusting for potential confounding factors, a significant increase of 0.01 in FFR values was observed for every 10-unit rise in IMR (p = 0.045) in this Group. FFR appears to be particularly influenced by elevated IMR values (≥40). Prudent interpretation of FFR values in such instances is imperative, especially in cases of functionally borderline epicardial stenosis.

Cardiovascular-kidney-metabolic (CKM) syndrome may predispose patients to coronary microvascular dysfunction (CMD) through systemic microvascular injury. We investigated the association between CKM risk factors and CMD, focusing on the diagnostic performance of accessible biomarkers. In this exploratory analysis, we retrospectively analyzed 65 patients who underwent invasive coronary physiological assessment with thermodilution-derived coronary flow reserve (CFR) and index of microcirculatory resistance (IMR). Clinical variables included casual blood glucose, B-type natriuretic peptide (BNP), and the urine albumin-to-creatinine ratio (ACR), along with echocardiographic indices of diastolic function. Among the 65 patients, 20 (31 %) had impaired CFR. BNP (AUC = 0.74; 95 % confidence interval, CI, 0.60–0.88) and casual blood glucose (area under the curve, AUC = 0.64; 95 % CI, 0.49–0.80) showed diagnostic accuracy for impaired CFR of <2.0, while ACR improved model performance when combined with BNP or E/e′. The combination of BNP and casual glucose significantly improved diagnostic performance compared with either marker alone (AUC = 0.83 vs. 0.75; 95 % CI, 0.73–0.93; p = 0.03). The elevated BNP (AUC = 0.77, 95 % CI: 0.59–0.95) and higher ACR (AUC = 0.71, 95 % CI: 0.52–0.90) were significantly associated with structural CMD defined as CFR < 2.0 and IMR ≥ 25, whereas casual blood glucose was not. From a CKM perspective, BNP and casual blood glucose were associated with impairment of CFR and may serve as simple, accessible biomarkers for its early detection and risk stratification.

Background/Objectives: Coronary microvascular dysfunction (CMD) is emerging as a critical factor in patients presenting with anginal symptoms without obstructive coronary artery disease (CAD). This study aims to investigate the relationship between invasive measurements of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) using thermodilution techniques, compared to non-invasive assessments of CFR with transthoracic Doppler echocardiography (TDE). Methods: In this observational prospective cross-sectional study, a total of 49 patients, clinically characterized as having angina with no obstructive CAD (ANOCA) or ischemia with no obstructive CAD (INOCA), underwent both TDE and invasive coronary angiography (ICA) followed by thermodilution assessment of CFR and IMR. Results: It was found that there is a statistically significant negative correlation between both non-invasive and invasive CFR measurements and IMR. Specifically, a negative moderate correlation was observed between non-invasive CFR and IMR (rs = −0.477, p < 0.01), as well as a high negative correlation between invasive CFR and IMR (r = −0.541, p < 0.01). Receiver operating characteristic (ROC) analysis indicated that both non-invasive and invasive CFRs are effective predictors of CMD, defined as IMR > 25. Conclusions: Both noninvasive and invasive CFR measurements are significant independent predictors of CMD. Our results indicate that noninvasive TDE CFR can be a reliable tool for assessing CMD in patients with ANOCA, potentially facilitating earlier diagnosis and management strategies for this patient population.

Background Angina and nonobstructive coronary arteries is increasingly recognized, but the impact of age and sex on coronary microvascular function in this population has received limited study. Methods In 206 consecutive patients with angina and nonobstructive coronary arteries, invasive coronary function testing was performed including vasoreactivity testing with acetylcholine provocation, guidewire–based assessment of coronary flow reserve (CFR) with bolus thermodilution, and index of microcirculatory resistance (IMR). Multivariable regression models assessed associations of age and sex with coronary physiologic indices, and subgroup analyses were conducted to examine age-related trends in microvascular function separately in men and women. Results Mean age was 57.1 ± 11.2 years (range, 27-81 years), and 149 (72.3%) were women. Increasing age was associated with progressive decrease in CFR (β = −0.05; P = .001) and increase in hyperemic mean transit time (Tmn; β = 0.009; P < .001) and IMR (β = 0.63; P < .001). Baseline Tmn was similar among the 3 age groups. Women had lower IMR (24.5 ± 13.5 vs 30.2 ± 18.1; P = .038), and shorter baseline and hyperemic Tmn, but similar CFR (3.43 ± 1.59 vs 3.73 ± 1.94; P = .315) compared with men. In sex-stratified analysis, age was associated with higher IMR in women (β = 0.51; P < .001), but not in men (β = 0.29; P = .154). CFR declined significantly with increasing age in both sexes, with a stronger association in women (β = −0.04; P < .001) than in men (β = −0.06; P = .011). Conclusions Increasing age was associated with a decrease in coronary microvascular function and increase in microcirculatory resistance, which was pronounced in women but not in men. There was no association of baseline Tmn with age, suggesting that age-related impairment in CFR was primarily driven by reduced hyperemic flow.

Bolus thermodilution is the most commonly used invasive assessment for coronary microvascular dysfunction (CMD). However, variability in thermodilution transit time measurements (TTM) affects calculated Coronary Flow Reserve (CFR) and Index of Microvascular Resistance (IMR) values. This study determined variables associated with transit time variability and quantified confidence intervals for the range of measured CFR and IMR values.

Coronary flow reserve (CFR) and the index of microvascular resistance (IMR) are commonly used for the diagnosis of coronary microvascular dysfunction, but the two indices can reveal discordance. The aim of this study was to investigate the mechanisms of the discordance between CFR and IMR. Haemodynamic data from patients who underwent invasive coronary functional assessment using a guidewire equipped with pressure and temperature sensors was analysed. We performed vessel-based analysis, and classified vessels with reference to the criteria of IMR ≥25 and CFR <2.0 as pathological into four groups: normal IMR/normal CFR (Group 1: G1), abnormal IMR/normal CFR (Group 2: G2), normal IMR/abnormal CFR (Group 3: G3), and abnormal IMR/abnormal CFR (Group 4: G4). Of 249 vessels form 176 patients, 82 (33%) were classified into G1, 28 (11%) into G2, 94 (38%) into G3, and 45 (18%) into G4. Median and interquartile ranges of IMR of the four groups were 14.3 [10.7–18.9], 34.2 [29.8–45.1], 16.9 [12.7–19.7], and 30.7 [28.4–43.5] (P <0.001), respectively, and those of CFR were 3.21 [2.48–4.29], 2.73 [2.34–3.03], 1.27 [1.06–1.55], and 1.28 [1.07–1.67] (P <0.001), respectively (Figure). In G2, hyperemic flow velocity was as low as G4 (1.97 [1.47–2.29] vs. 1.95 [1.41–2.50] sec-1, P=1.00), and the baseline flow velocity was lower than G4 (0.71 [0.49–0.85] vs. 1.44 [0.93–1.96] sec-1, P <0.001), leading to apparently normal CFR despite the diminished hyperemic flow. In G3, the hyperemic (3.60 [2.77–4.73] vs. 1.95 [1.41–2.50] sec-1, P <0.001) and the baseline flow velocity (2.85 [2.19–3.92] vs. 1.44 [0.93–1.96] sec-1, P <0.001) were higher than G4, leading to apparently decreased CFR despite the maintained hyperemic flow. The discordance between IMR and CFR can be explained by decreased coronary flow in abnormal IMR/normal CFR, and by increased baseline coronary flow in normal IMR/abnormal CFR.

Beyond the observation that patients with low CFR indicating presence of coronary microvascular dysfunction (CMD) have an unfavourable prognosis compared to patients with preserved CFR, recent large multicentre trials [1-2] have shown that increased minimal hyperaemic microvascular resistance (HMR or IMR) ,neither on top of the low CFR nor alone, does not play a role as a prognostic factor for ischemia in nonobstructive coronary artery disease (INOCA) patients. This study investigates the pathophysiological interactive processes in CMD and no-CMD groups with high and low HMR taking into account potential adaptive mechanisms that alter arterial reservoir function [3] associated with microvascular resistance and systemic vasomotor response in INOCA patients. Analysis was conducted on 312 unique unobstructed vessels (FFR>0.80) from 258 patients (73% male) enrolled in the DEFINE-FLOW [4] study. CFR and HMR were quantified using intracoronary Doppler and pressure measurements. Vessels were categorized into four groups based on high and low CFR and HMR using the best available cut-off values (2.5 for both). Arterial reservoir capacity (ARC) and related parameters [3] were quantified using reservoir-excess pressure (Preservoir and Pexcess) analysis of averaged aortic and distal coronary pressure waveforms in CMD (CFR<2.5) and no-CMD (CFR≥2.5) subgroups. (Figure 1-2) Compared to vessels without CMD, functional and structural CMD have increased Pexcess (p:0.007) and a rapid decline in diastolic pressure (DRCcoronary p<0.001, DRCaortic, p<0.05), indicating the ongoing systemic hemodynamic superfluous state despite locally suppressed resting blood flow in the structural CMD. Higher baseline microvascular resistance (BMR) was associated with increased reservoir pressure (r:0.302, p<0.001). The vessels with preserved CFR despite high HMR are characterised by uniquely increased ARC (p:0.014), effectively diminished Pexcess (p:0.010), which parallels the local (highest BMR p<0.001) and global (lowest DRCaortic, p<0.05) vasomotor response, that normalizes the systemic and local hyperperfusion, and ultimately regains an adequate flow reserve (CFR) (p<0.001). The high HMR in this group was mainly due to increased resting tonus unlike structural CMD, evident by the highest RRR (BMR/HMR).(p<0.001) (Figure 1-2) The high HMR despite preserved CFR vessels form a unique-adaptive group, characterised by substantially increased arterial reservoir capacity and effectively diminished Pexcess, by means of an adaptive vasomotor response which manifests locally in the coronary bed as pronouncedly augmented BMR & RRR, and globally as reduced DRC in the aortic pressure waveform. This adaptive myogenic response normalising resting flow and ongoing systemic and local hyperperfusion ultimately regains an adequate flow reserve (CFR).Figure 1.Methods and Main FindingsFigure 2.Visual Abstract

No abstract available

The progression of coronary artery disease (CAD) is influenced by multiple risk factors. While coronary microvascular dysfunction (CMD) is known to be associated with adverse cardiovascular outcomes, its role in CAD progression remains unclear. The angiography-derived index of microcirculatory resistance (angio-IMR) is a novel, non-invasive metric that estimates IMR without the need for guidewire insertion and hyperemia induction. However, reports on the relationship between angio-IMR and CAD progression are limited. This study aimed to investigate the association between angio-IMR and lesion progression, defined by fractional flow reserve (FFR) assessment over time. We retrospectively analyzed patients who underwent coronary angiography (CAG) and FFR measurements at our institution between 2016 and 2025. Among them, 105 patients who had undergone serial CAG and FFR assessments at an interval of more than one year were included. To ensure reliable measurement of angio-IMR, only lesions in the left anterior descending artery (LAD) were analyzed. Patients who underwent percutaneous coronary intervention (PCI) between the two evaluations, those without LAD-FFR assessment, or those with a history of coronary artery bypass grafting (CABG) were excluded. Angio-IMR was derived from angiography at the initial evaluation. The association between a change in FFR over time and A-IMR was assessed. The median age was 68.0 years (interquartile range (IQR): 65.0, 74.0), and 76.2% (80/105) of patients were male. The median time interval of the serial FFR assessments was 29.7 [IQR: 18.3, 48.5] months. The difference between the initial and following FFR was 0.01 [IQR: -0.01, 0.04]. Patients were divided into two groups based on the median value of the change in FFR (0.01). The progression group exhibited significantly higher initial angio-IMR values compared to the non-progression group (33.71 [IQR 22.03, 47.61] vs. 23.98 [IQR 17.39, 33.78], p=0.011). A significant correlation was observed between angio-IMR and the change in FFR over time (r=0.286, P=0.003). Multivariable linear regression analysis identified male gender, lower estimated glomerular filtration rate, and higher angio-IMR as independently associated factors with a change in FFR over time. Multivariable logistic regression analysis revealed that angio-IMR was an independent predictor of the progression after adjusting for confounding factors (adjusted odds ratio: 1.03 [95% confidence interval: 1.00, 1.05], P=0.04). Higher angio-IMR values were associated with CAD progression as assessed by serial FFR measurements. These findings suggest that microvascular dysfunction, as reflected by angio-IMR, may contribute to the identification of potentially progressive epicardial coronary lesions. Non-invasive assessment of microcirculatory function could provide valuable insights into CAD progression and aid in risk stratification.

Introduction: Ischemia and nonobstructive coronary artery disease (INOCA) may be caused by coronary microvascular dysfunction (CMD), but coronary function testing for CMD is not routinely performed. Consensus statements include coronary flow reserve (CFR), an index of microcirculatory resistance (IMR), or coronary slow flow by corrected TIMI frame count (cTFC) >25 as diagnostic for CMD. However, correlations between cTFC and invasive parameters of CMD are uncertain. Methods: Adults age ≥ 18 with INOCA (<50% stenosis by invasive coronary angiography in all major epicardial coronary arteries) were prospectively enrolled. cTFC was measured from baseline angiography of the left anterior descending artery. Invasive coronary function testing using thermodilution techniques was performed to identify CMD, defined by IMR≥25 and/or CFR<2.5. Relationships between cTFC and invasively derived CMD were evaluated. Results: Ninety-seven patients (mean age 60.4 ± 11 years; 80% female) underwent assessment; coronary slow flow was present in 46%. Coronary slow flow (cTFC>25) had a sensitivity of 50%, a specificity of 57%, a positive predictive value of 53%, and a negative predictive value of 54% to identify CMD defined by IMR and/or CFR. cTFC weakly correlated with IMR (r=0.40, p<0.001) and was not correlated with CFR (Pearson r=-0.03, p=0.73). Areas under the receiver operating characteristic curves were calculated for cTFC to identify abnormal IMR (AUC = 0.64), CFR (AUC = 0.55), CMD (AUC = 0.59), and CMD endotypes of abnormal IMR with normal CFR (AUC = 0.65), abnormal CFR with normal IMR (AUC = 0.58), abnormal IMR and CFR (AUC = 0.54). Conclusions: Coronary slow flow by angiography was not a reliable indicator of CMD defined by abnormal IMR and/or CFR. Correlations between cTFC and IMR were poor and no correlation with CFR was observed. These findings raise questions regarding the relevance of coronary slow flow at baseline to assess microvascular pathology causing INOCA.

Background Cardiac 15O-water PET is a noninvasive method to evaluate epicardial and microvascular dysfunction and further quantitate absolute myocardial blood flow (MBF). Aim: The aim of this study was to assess the impact of revascularization on MBF and myocardial flow reserve (MFR) assessed with 15O-water PET and invasive flow and pressure measurements. Methods In 21 patients with single-vessel disease referred for percutaneous coronary intervention (PCI), serial PET perfusion imaging and fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were performed during PCI and after 3 months. Results In the affected myocardium, stress MBF and MFR increased significantly from before revascularization to 3 months after revascularization: stress MBF 2.4 ± 0.8 vs. 3.2 ± 0.8; P < 0.001 and MFR 2.5 ± 0.8 vs. 3.4 ± 1.1; P = 0.004. FFR and CFR increased significantly from baseline to after revascularization and remained stable from after revascularization to 3-month follow-up: FFR 0.64 ± 0.20 vs. 0.91 ± 0.06 vs. 0.91 ± 0.07; P < 0.001; CFR 2.4 ± 1.2 vs. 3.6 ± 1.9 vs. 3.6 ± 1.9; P < 0.001, whereas IMR did not change significantly: 30.3 ± 22.9 vs. 30.1 ± 25.3 vs. 31.9 ± 25.2; P = ns. After revascularization, an increase in stress MBF was associated with an increase in FFR (r = 0.732; P < 0.001) and an increase in MFR (r = 0.499; P = 0.021). IMR measured before PCI was inversely associated with improvement in stress MBF, (r = −0.616; P = 0.004). Conclusion Recovery of myocardial perfusion after PCI was associated with an increase in FFR 3 months after revascularization. Microcirculatory dysfunction was associated with less improvement in myocardial perfusion.

Background: Coronary microvascular function can be distinctly quantified using the coronary flow reserve (CFR) and index of microvascular resistance (IMR). Patients with low CFR can present with low or high IMR, although the prevalence and clinical characteristics of these patient groups remain unclear. Methods: One hundred ninety-nine patients underwent coronary microvascular assessments using coronary thermodilution techniques. A pressure-temperature sensor-tipped guidewire measured proximal and distal coronary pressure, whereas the inverse of the mean transit time to room temperature saline was used to measure coronary blood flow. The CFR and IMR were quantified during adenosine and acetylcholine hyperemia. Results: Low adenosine and acetylcholine CFR was observed in 70 and 49 patients, respectively, whereas low CFR/low IMR to adenosine and acetylcholine was observed in 39(56%) and 19(39%) patients, respectively. Despite similar adenosine CFR, patients with low CFR/low IMR had increased resting (2.8±1.2 versus 1.3±0.4s-1) and hyperemic coronary blood flow (4.8±1.5 versus 2.1±0.5s-1) compared with patients with low CFR/high IMR (both P<0.01). The same pattern was observed in response to acetylcholine. Patients with low CFR/low IMR to adenosine were younger (56±12 versus 63±10 years), women (84% versus 66%), had fewer coronary risk factors (1.1±1.0 versus 1.6±1.1), lower hemoglobin A1c (5.8±0.7 versus 6.1±0.9 mmol/L), and thinner septal thickness (8.5±2.5 versus 9.9±1.6 mm) compared with patients with low CFR/high IMR to adenosine (all P<0.05). Conclusions: Low CFR/low IMR to adenosine and acetylcholine are associated with elevated resting coronary blood flow and preserved hyperemic coronary blood flow. These patients present with distinct phenotypic characteristics. Simultaneous CFR and IMR measures appear necessary to differentiate these endotypes.

Background Angio-based index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) have been developed, however, the differences between baseline and hyperemic data and their effects on their computation have not yet been discussed. This study aimed to compare the diagnostic performance of a novel method for calculating IMR and FFR from coronary angiography under baseline and hyperemic conditions. Methods We performed a retrospective study to investigate the diagnostic performance of angiography-derived IMR (AccuIMR) and FFR (AccuFFRangio) computed from the hyperemic condition (AccuIMRhyp, AccuFFRangiohyp) and baseline condition (AccuIMRbase, AccuFFRangiobase) in 101 consecutive patients with chronic coronary syndrome (CCS) who underwent measurements of IMR and FFR at a single center, using wire-based IMR and FFR as the reference standard. Results AccuIMRhyp showed much better correlation with IMR than AccuIMRbase (r=0.77 vs. 0.47, P<0.001). The diagnostic accuracy and area under the curve (AUC) for identifying significant microvascular dysfunction was higher for AccuIMRhyp than AccuIMRbase [92.1% (95% CI: 85.0–96.5%) vs. 83.2% (95% CI: 74.4–89.9%), P=0.012; 0.942 (95% CI: 0.877–0.979) vs. 0.815 (95% CI: 0.726–0.886), P=0.003]. The computed AccuFFRangio showed good correlations with FFR and good diagnostic performance under both hyperemic and baseline conditions [r=0.68 vs. 0.68, P>0.99; diagnostic accuracy =95.9% (95% CI: 89.8–98.9%) vs. 94.9% (95% CI: 88.4–98.3%), P=0.728; AUC =0.989 (95% CI: 0.942–1.000) vs. 0.973 (95% CI: 0.919–0.995), P=0.381]. The net reclassification index (NRI) demonstrated that hyperemic group had improved reclassification ability compared to the baseline group in identification of IMR >25 (NRI =0.20, P<0.001) and FFR ≤0.8 (NRI =0.11, P<0.001). Conclusions By comparing the calculated angio-derived IMR and FFR under the baseline and hyperemic conditions, this study demonstrates that AccuIMR calculation is more accurate using the hyperemic condition, while AccuFFRangio calculation is accurate under both conditions.

No abstract available

Background Type 2 diabetes (DM) is a common comorbidity associated with cardiovascular disease, especially when poor glucose control is present. Extracardiac microcirculatory complications prevalence is well documented, however coronary microcirculatory dysfunction (CMD) seem to be underreported in this group. Methods The present study analyzed coronary physiology measurements (coronary flow reserve [CFR], index of microcirculatory resistance [IMR], resistance reserve ratio [RRR]) in 47 diabetic patients (21 subjects with poor glycemia control defined as fasting glucose levels > 7.2 mmol/L and 26 with normal fasting glucose), and compared to 54 non-diabetic controls, who had undergone coronary angiography due to symptoms of chronic coronary syndrome. The median age of patients was 65.5 [59.0; 73.0] years old, 74% male, similar in terms of cardiovascular risk factors and prior myocardial infarction. Insulin was used by 19% of diabetic patients with poor glucose control and by 15% of those with DM and low fasting glucose. Results Prevalence of CMD was 38% in poor glycemia control patients, 27% in DM-patients with proper glucose control and 31% of non-diabetics. Median CFR values were the lowest in poor DM control patients compared to both, normal fasting glucose (1.75 [1.37; 2.32] vs. 2.30 [1.75; 2.85], p = 0.026) and to non-diabetics (1.75 [1.37; 2.32] vs. 2.15 [1.50; 2.95], p = 0.045). Levels of IMR, RRR and microvascular resistance reserve did not differ significantly between compared groups (p > 0.05 for all comparisons). Conclusions Poor glycemia control in type 2 DM might be associated with a higher prevalence of CMD driven by decreased coronary flow reserve, however, further research in larger groups of patients should be performed to confirm this observation.

No abstract available

Background Resting full-cycle ratio (RFR) is an alternative to fractional flow reserve (FFR) for the evaluation of borderline coronary artery lesions. Although FFR and RFR results are discordant in some cases, factors associated with the discordance remain unclear. The role of coronary microvascular dysfunction (CMD) is discussed as a potential mechanism to explain these discrepancies. Aim The study aimed to assess concordance between RFR and FFR in a real-life cohort from a high-volume center regarding the role of CMD. Methods Consecutive patients with borderline coronary lesions undergoing coronary functional testing for chronic coronary syndromes were included in the study. Measurements of RFR and FFR were performed alongside additional coronary flow reserve (CFR), resistance reserve ratio (RRR), and an index of microcirculatory resistance (IMR) measurements. CMD was defined according to the current guideline by either IMR ≥25 or CFR ≤2.0 in vessels with no significant stenosis. Results Measurements were performed in 157 coronary arteries, in 101 patients, with a median age of 66 y., 74% male, with prior history of arterial hypertension (96%), dyslipidaemia (91%), and diabetes (40%). The median value of vessel diameter stenosis was 45% according to QCA. Overall, FFR and RFR values were significantly correlated (r = 0.66, p < 0.001), where positive FFR/negative RFR and negative FFR/positive RFR were observed in 6 (3.8%) and 38 (24.2%) of 157 vessels. The RFR/FFR discrepancy was present in 44 (28%) of measurements. CMD was confirmed in 28 (64%) of vessels with discrepant RFR/FFR and in 46 (41%) of vessels with concordant results (p = 0.01). In discordant RFR/FFR vessels, as compared to concordant ones, significantly lower values of CFR [median 1.95 (IQR: 1.37, 2.30) vs. 2.10 (IQR: 1.50, 3.00), p = 0.030] and RRR [median 2.50 (IQR: 1.60, 3.10) vs. 2.90 IQR (1.90, 3.90), p = 0.048] were observed. Main predictors of RFR/FFR discrepancy in a univariate regression analysis were: higher age of patients [OR = 1.06 (1.01; 1.10), p = 0.010], presence of CMD [OR = 2.51 (1.23; 5.25), p = 0.012], lower CFR [OR = 1.64 (1.12; 2.56), p = 0.018], and lower RRR values [OR = 1.35 (95% CI: 1.03; 1.83), p = 0.038]. Conclusion In discrepant RFR/FFR vessels, CMD is more prevalent than in concordant RFR/FFR measurements, which can be driven by lower CFR or RRR values. Further research is needed to confirm this observation.

No abstract available

Background and Objectives Recent guideline recommends evaluation using of coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) in patients with functionally insignificant stenosis. We evaluated clinical implications of CFR and IMR in patients with high fractional flow reserve (FFR) and deferred revascularization. Methods A total of 867 patients (1,152 vessels) consigned to deferred revascularization who underwent comprehensive physiologic assessments were enrolled. Patients with high FFR (>0.80) were categorized by CFR (≤2) and IMR (≥23 U). Clinical outcome was assessed by patient-oriented composite outcome (POCO), a composite of any death, myocardial infarction (MI), and revascularization at 5 years. Results Patients with low CFR (≤2) showed significantly greater risk of POCO than those with high CFR (>2) in both high-FFR (p=0.024) and low-FFR (p=0.034) groups. In patients with high FFR, those with low CFR and high IMR (overt microvascular disease) displayed the greatest risk of POCO overall (p=0.015), surpassing those with high CFR and low IMR (HR, 2.873; 95% CI, 1.476–5.594; p=0.002) and showing significantly greater risk of cardiac death or MI (HR, 5.662; 95% CI, 1.984–16.154; p=0.001). Overt microvascular disease was independently associated with POCO in the high-FFR population (HR, 2.282; 95% CI, 1.176–4.429; p=0.015). Conclusion Among patients with deferred revascularization, those with low CFR showed significantly greater risk of POCO than those with high CFR, regardless of FFR. In patients with high FFR, those with overt microvascular disease showed significantly greater risk of POCO and cardiac death or MI at 5-year, compared with the others. Trial Registration ClinicalTrials.gov Identifier: NCT03690713

Background We sought to investigate prognostic implication of microvascular dysfunction as assessed by the index of microcirculatory index (IMR) in patients without residual obstructive CAD with non-flow limiting fractional flow reserve (FFR) (>0.80) following percutaneous coronary intervention (PCI). Methods A total of 570 patients who had both post-PCI FFR and IMR values were included in the present analysis; of these, 65 patients had FFR ≤ 0.80 and 505 had FFR > 0.80. Of the 505 patients with FFR > 0.80, 137 had high IMR and 368 had low IMR. The primary outcome of the present analysis is a composite of all-cause death, spontaneous myocardial infarction, or target-vessel revascularization. Impaired microvascular function was defined as IMR ≥ 25 (high IMR). Results During a median follow-up duration of 4.0 years, those with FFR > 0.80 and low IMR demonstrated lower rate or primary outcome event than those with FFR ≤ 0.80 (hazard ratio 0.49 [95% confidence interval 0.27–0.92], p = 0.026) and those with FFR > 0.80 and high IMR (hazard ratio 1.60 [0.99–2.16], p = 0.056). The patients with FFR > 0.80 and IMR ≥ 25 had similar rate of primary outcome event compared with those with FFR ≤ 0.80 (p = 0.49). Conclusion Microvascular dysfunction following PCI is not rare and is associated with adverse events even in the setting of a non-flow limiting FFR; these results suggest that when performing coronary physiologic assessment following PCI, interrogating not only the epicardial vessel, but also the microvasculature is useful for the risk stratification in patients undergoing PCI.

Acute myocardial infarction (AMI) is one of the most common causes of death in both the developed and developing world. It has high associated morbidity despite prompt institution of recommended therapy. The focus over the last few decades in ST-segment elevation AMI has been on timely reperfusion of the epicardial vessel. However, microvascular consequences after reperfusion, such as microvascular obstruction (MVO), are equally reliable predictors of outcome. The attention on the microcirculation has meant that traditional angiographic/anatomic methods are insufficient. We searched PubMed and the Cochrane database for English-language studies published between January 2000 and November 2019 that investigated the use of invasive physiologic tools in AMI. Based on these results, we provide a comprehensive review regarding the role for the invasive evaluation of the microcirculation in AMI, with specific emphasis on coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR).

No abstract available

BACKGROUND The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093).

Coronary microvascular dysfunction plays a major role in patients with cardiac ischemia without flow limiting epicardial coronary stenosis, takotsubo cardiomyopathy, aortic valve stenosis and heart failure with preserved ejection fraction. In clinical practice, the index of microvascular resistance (IMR) and coronary flow reserve (CFR), and more recently the absolute coronary blood flow (ABF), absolute coronary resistance (ACR) and the microvascular resistance reserve (MRR) are used as parameters to measure resistance and flow using continuous coronary thermodilution. Firstly, to validate ABF measured with continuous coronary thermodilution in vivo against epicardial doppler-measured flow. Secondly, to assess reliability and reproducibility in-vivo of different microvascular indices. For the purpose of this study coronary measurements were conducted in two large animal models and in patients, all with the appropriate ethical committee approval. For the first part of the study, fourteen sheep underwent repeated paired measurements of ABF and ACR (with use of continuous thermodilution) with different saline infusion speeds, as well as IMR, CFR and MRR in multiple coronary vessels. Seven additional sheep underwent these measurements while having simultaneous measurements with epicardial coronary flow probes (gold standard) in an open-chest model. The epicardial flow probes were placed on the proximal left anterior descending and circumflex artery. Maximal hyperemia was induced with adenosine (CFR and IMR) or infusion of saline at a rate of 30ml/min (ABF, ACR and MRR). For the second part of the study, in 41 patients receiving routine microvascular assessment, IMR and CFR measurements were duplicated by a single operator, after re-calibration, to assess the reproducibility of the measurement. The combined animal and human data resulted in the analysis of 408 coronary measurements made in 88 coronary vessels during 65 heart catheterizations. In sheep, ABF measured with continuous thermodilution (with saline infusion speeds from 5ml/min to 30ml/min) was accurate when compared with epicardial flow measurements. (Table 1, Fig 1A) Notably, the continuous thermodilution measurement had the tendency to slightly overestimate ABF. (Table 1, Fig 1B) The two methods were equivalent within 15% (Two one-sided test: mean difference: -8.73%; 95% CI: -14.40 to -3.06%, p= 0.016). When comparing test-retest reproducibility between the indices, CFR performed the worst while ACR and MRR performed the best. MRR had a significantly better reproducibility than the IMR. (Table 1, Fig 1C). ABF can accurately be determined by continuous coronary thermodilution. MRR and ACR have a significantly superior reliability and reproducibility compared to IMR and CFR. Unlike ACR, MRR is not vessel or territory-size dependent and is therefore the index of choice for future research and clinical assessment of the microcirculation.

AIMS Assessment of microvascular function in patients with ST-elevation acute myocardial infarction (STEMI) may be useful to determine treatment strategy. The possible role of pressure-bounded coronary flow reserve (pb-CFR) in this setting has not been determined. METHODS AND RESULTS Thermodilution-pressure-wire assessment of the infarct-related artery was performed in 148 STEMI patients before stenting and/or at completion of primary percutaneous coronary intervention (PPCI). The extent of the myocardial injury was assessed with cardiovascular magnetic resonance imaging at 48-hours and 6-months after STEMI. Post-PPCI pb-CFR was impaired (<2) and normal (>2) in 69.9% and 9.0% of the cases respectively. In the remaining 21.1% of the patients, pb-CFR was "indeterminate". In this cohort, pb-CFR correlated poorly with thermodilution-derived coronary flow reserve (k=0.03, p=0.39). The index of microcirculatory resistance (IMR) was significantly different across the pb-CFR subgroups. Similarly, significant differences were observed in microvascular obstruction (MVO), myocardium area-at-risk and 48-hours infarct-size (IS). A trend towards lower 6-month IS was observed in patients with high (>2) post-PPCI pb-CFR. Nevertheless, pb-CFR was inferior to IMR in predicting MVO and the extent of IS. CONCLUSIONS Pb-CFR can identify microvascular dysfunction in patients after STEMI and provided superior diagnostic performance compared to thermodilution-derived CFR in predicting MVO. However, IMR was superior to both pb-CFR and thermodilution-derived CFR and consequently, IMR was the most accurate in predicting all of the studied CMR endpoints of myocardial injury after PPCI.

The impact of aortic stiffness in the development of coronary microvascular dysfunction in chronic coronary syndrome (CCS) remains unknown. Invasive aortic pressure curves, routinely recorded during coronary angiography, provide an opportunity to assess aortic stiffness through pulse wave analysis and relate to measures of coronary microvascular dysfunction. To investigate the relationship between invasive aortic pulse wave features – such as pulse pressure, augmentation index, and reflection time – and (i) thermodilution-derived indices of coronary flow and (ii) major adverse cardiovascular events (MACE) in patients with CCS. CCS-patients were prospectively included the day before coronary angiography. Coronary flow was assessed in the LAD using the thermodilution technique during coronary angiography at rest and during adenosine infusion. Index of microcirculatory resistance (IMR), baseline resistance index (BRI), hyperemic flow velocity (HFV), resting flow velocity (RFV), and microvascular resistance reserve (MRR) were recorded. Aortic pressure waveforms recorded during coronary angiography were analysed using a dedicated software. Pulse pressure, augmentation index, and reflection time (time interval from waveform onset to the reflected wave) were determined. Follow-up was conducted through the population registry, telephone calls and review of medical records. Pulse wave metrics were analysed in relation to indices of microvascular function with linear regression. Skewed variables were log-transformed. Cox regression analyses were used for pulse wave metrics in relation to MACE, defined as death, myocardial infarction or hospitalization due to heart failure. Three-hundred and eighty-six patients, with median age 68 years (IQR 59-74), including 95 (25%) women, were included in the analysis. Median follow-up was 5.4 years (IQR 3.2–6.6), during which 52 patients experienced a MACE. Pulse pressure was associated with RFV and inversely associated with BRI, and MRR but not with IMR or HFV (Figure 1). Augmentation index was associated with HFV (β = 10 [95% CI 1.6–19]) and RFV (β = 11 [95% CI 1.3 – 20.0]). Reflection time was inversely associated with HFV (β = -0.014 [95% CI -0.026 – -0.003]) and RFV (β = -0.018 [95% CI -0.030 – -0.005]). Pulse pressure was associated with MACE (HR 1.03 [95% CI 1.01 – 1.04]; Figure 2) before but not after adjustment for age and gender (HR 1.01 [95% CI 1-1.03). Augmentation index and reflection time were not associated with MACE (Figure 2). Pulse pressure derived from invasive aortic pulse wave is associated with higher coronary microcirculatory resting flow velocity, lower microcirculatory coronary resting resistance and lower non-endothelial dependent vasodilatory capacity in the LAD. Furthermore, in patients with CCS, invasive central pulse pressure is associated with MACE in crude analysis but not after adjustments for age and gender.  

Background: Synchronous computation of coronary angiography-derived fractional flow reserve (CAG-FFR) and coronary angiography-derived index of microcirculatory resistance (CAG-IMR) is a novel coronary angiography-based method for on-site assessment of suspected myocardial ischemia in patients with coronary artery disease (CAD). Methods: This trial is a prospective, multicenter, controlled study designed to assess the diagnostic performance of CAG-FFR and CAG-IMR in patients with suspected myocardial ischemia using wire-based FFR and IMR as reference standards. The functional parameters were calculated using a reduced order computational fluid dynamics solver that incorporates thrombolysis in myocardial infarction (TIMI) frame count and aortic pressure recorded by a disposable invasive pressure sensor. Results: CAG-FFR was computed in 325 patients, demonstrating a patient-level diagnostic accuracy of 95.4%, sensitivity of 95.9%, and specificity of 95.1%. The area under the receiver operating characteristic curve (AUC) of CAG-FFR was 0.977. Patient-specific aortic pressure adoption significantly improved the accuracy of CAG-FFR in the “gray zone” compared to fixed-pressure models. In addition, CAG-IMR was successfully computed in 180 patients, showing a patient-level diagnostic accuracy of 95.5%, sensitivity of 96.4%, and specificity of 95.2%. The AUC of CAG-IMR in diagnosing abnormal coronary microcirculatory dysfunction was 0.973. Conclusions: Synchronous computation of CAG-FFR and CAG-IMR demonstrated higher feasibility and excellent diagnostic accuracy compared to wire-based FFR and IMR, highlighting its clinical potential for CAD evaluation.

Background Measurement of the contrast-flow quantitative flow ratio (cQFR) is a novel method for rapid computational estimation of fractional flow reserve (FFR). Discordance between FFR and cQFR has not been completely characterised. Methods We performed a post-hoc analysis of 504 vessels with angiographically intermediate stenosis in 504 patients who underwent measurement of FFR, coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and Duke jeopardy score. Results In total, 396 (78.6%) and 108 (21.4%) lesions showed concordant and discordant FFR and cQFR functional classifications, respectively. Among lesions with a reduced FFR (FFR+), those with a preserved cQFR (cQFR−) showed significantly lower IMR, shorter mean transit time (Tmn), shorter lesion length (all, p<0.01) and similar CFR and Duke jeopardy scores compared with lesions showing a reduced cQFR (cQFR+). Furthermore, lesions with FFR+ and cQFR− had significantly lower IMR and shorter Tmn compared with lesions showing a preserved FFR (FFR−) and cQFR+. Of note, in cQFR+ lesions, higher IMR lesions were associated with decreased diagnostic accuracy (high-IMR; 63.0% and low-IMR; 75.8%, p<0.01). In contrast, in cQFR− lesions, lower IMR lesions was associated with decreased diagnostic accuracy (high-IMR group; 96.8% and low-IMR group; 80.0%, p<0.01). Notably, in total, 31 territories (6.2%; ‘jump out’ group) had an FFR above the upper limit of the grey zone (>0.80) and a cQFR below the lower limit (≤0.75). In contrast, five territories (1.0%; ‘jump in’ group) exhibited opposite results (FFR of ≤0.75 and cQFR of >0.80). The ‘jump out’ territories showed significantly higher IMR values than ‘jump in’ territories (p<0.01). Conclusions FFR− with cQFR+ is associated with increased microvascular resistance, and FFR+ with cQFR− showed preservation of microvascular function with high coronary flow. Microvascular function affected diagnostic performance of cQFR in relation to functional stenosis significance.

BACKGROUND Patients with coronary microvascular dysfunction (CMD) are at increased risk of major adverse cardiovascular events. The index of microcirculatory resistance (IMR) is more specific than coronary flow reserve (CFR) for CMD diagnosis, but the microvascular resistance reserve (MRR) shows potential due to its hemodynamic adjustments. Our study evaluated the diagnostic utility of IMR, MRR, and their combination in CMD diagnosis for patients experiencing angina and non-obstructive coronary arteries (ANOCA). METHODS This observational study analyzed data from the Coronary Microvascular Disease Registry (CMDR) of ANOCA patients at two tertiary care centers from 2021 to 2024. Demographics, lab results, and microvascular testing outcomes using bolus thermodilution were evaluated. Participants were grouped by MRR and IMR levels to evaluate CMD prevalence. RESULTS Between December 3, 2021, and July 31, 2024, 279 patients with ANOCA underwent invasive microvascular function assessment. Most were female (67.4 %), with an average age of 61.6 ± 11.0 years. CMD prevalence varied by group: 100 % in low MRR/high IMR, 92.3 % in high MRR/high IMR, 13.9 % in low MRR/low IMR, and 2.8 % in high MRR/low IMR (P < 0.001). IMR showed high diagnostic accuracy (81.6 % sensitivity, 99.5 % specificity), while MRR had 79 % sensitivity and 69.5 % specificity. Combining high IMR and low MRR improved specificity to 100 % but reduced sensitivity (65.8 %). ROC analysis showed AUCs of 0.80 (MRR), 0.97 (IMR), and 0.98 (IMR + MRR). CONCLUSIONS The combination of IMR and MRR enhanced diagnostic specificity for CMD in patients with ANOCA, highlighting their complementary value. Future studies should focus on larger cohorts to validate these findings.

AIMS We aimed to investigate the impact of concordance or discordance of fractional flow reserve (FFR) and coronary flow reserve (CFR) on coronary flow profiles and microvascular resistance after percutaneous coronary intervention (PCI), and the prognostic impact of the periprocedural physiological indices. METHODS AND RESULTS A total of 249 de novo physiologically significant coronary lesions from 231 patients who underwent FFR, CFR, and index of microcirculatory resistance (IMR) examinations before and after PCI were included. Baseline characteristics and physiological indices were compared between the concordant (FFR ≤0.80 and CFR <2.0, n=114) and discordant (FFR ≤0.80 and CFR ≥2.0, n=135) groups. Follow-up data were collected to determine predictors of cardiac events. Shortening of the mean transit time, CFR improvement, and decrease in the hyperaemic IMR were all significantly greater in the concordant territories. Cox proportional hazards analysis showed that a lower pre-PCI CFR was an independent predictor of adverse events at a median follow-up of 26.5 months, whereas neither the pre- nor post-PCI FFR was predictive of events. Event-free survival was significantly worse in patients with a lower pre-PCI CFR. CONCLUSIONS FFR/CFR concordantly abnormal territories provide a favourable benefit as assessed by coronary physiological indices after elective PCI. The pre-PCI CFR may predict adverse cardiac events.

BACKGROUND Coronary microvascular dysfunction (CMVD) is associated with adverse cardiovascular outcome. We aimed to determine the prevalence of CMVD and factors related to index of microcirculatory resistance (IMR) in consecutive patients with chronic coronary syndrome (CCS) undergoing elective coronary angiography. METHODS AND RESULTS Non-interventional physicians enrolled 274 patients with CCS before angiography, to minimize selection bias by PCI-operators. Fractional flow reserve (FFR) and IMR were measured in the LAD. Subjects with extensively diseased LAD, no measures due to technical reasons or violation of protocol were excluded from the analysis (n = 54). The proportion of patients with IMR corrected for collateral flow (IMRcorr) >25 units was 25% (95% confidence interval [CI] 19%-31%) in all 220 patients. In subjects with FFR ≤0.80 in the LAD the proportion of IMRcorr > 25 units was 21% (95% CI 13%-30%) as compared to subjects with FFR >0.80, 29% (95% CI 21%-36%), p = .268. Haemoglobin (p < .005; r2 = 0.084), FFR in the LAD (p = .001; r2 = 0.049), creatinine clearance (p = .001; r2 = 0.049; inversely), and NT-pro-BNP (p = .038; r2 = 0.021) were independently associated with IMRcorr in multivariate linear regression analysis. CONCLUSIONS We report that IMRcorr is associated with renal dysfunction, NT-proBNP, FFR in the LAD and, for the first time, blood haemoglobin. One in four of patients referred for coronary angiography due to CCS have CMVD defined as IMRcorr > 25 in the LAD.

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Abnormal coronary circulation is linked to poor patient outcomes. The predictive values of comprehensive physiological assessments in patients with non-obstructive coronary artery disease (NOCAD) have not been fully investigated. The study aimed to evaluate the predictive value of a comprehensive approach that combines fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) in patients with NOCAD. FFR, CFR, and IMR were measured in the left anterior descending artery of 226 patients with NOCAD. The primary endpoint was defined as adverse cardiovascular events including cardiovascular death, heart failure, coronary revascularization, cerebral infarction, and peripheral vascular events. Optimal cutoffs predicting the endpoint were 0.89 for FFR, 2.3 for CFR and 18.0U for IMR. Among the patients, 53 were negative for all indices, 80 positive for one, and 93 positive for two or three. During a median follow-up period of two years, 29 adverse events occurred, with the distribution as follows: 1 (1.9%) in patients with all negative indices, 5 (6.2%) in those with one positive index, and 23 (24.7%) in those with two or three positive indices. Kaplan-Meier curve analysis demonstrated significantly worse event-free survival in patients with an increasing number of positive indices (χ2=18.5, P<0.001). The presence of two or three positive indices was an independent predictor of the endpoint (hazard ratio 7.280, p<0.001). Combining FFR, CFR, and IMR is an effective method for predicting cardiovascular events in patients with NOCAD.

BACKGROUND The relation between the resting full cycle ratio (RFR) and fractional flow reserve (FFR) is not fully understood. This study aims to investigate the influence of coronary microvascular dysfunction, assessed by the index of microvascular resistance (IMR), on RFR compared to FFR in patients undergoing functional assessment for coronary stenosis. MATERIALS AND METHODS Two-hundred patients with borderline stenosis underwent functional assessment of RFR, FFR, coronary flow reserve (CFR) and IMR. Retriever operator curve analysis was performed to assess the diagnostic value of RFR in patients with (IMR ≥ 24) and (IMR < 24). RESULTS Median RFR did not differ significantly in patients with IMR ≥ 24 compared to patients with IMR < 24: 0.89 (interquartile range (IQR) 0.84, 0.95) vs. 0.90 (IQR 0.84, 0.92), p = 0.29). FFR was significantly higher in patients with IMR ≥ 24 compared to patients with IMR < 24: median FFR 0.85 (IQR (0.76, 0.92)) vs. 0.82 (IQR 0.73, 0.86), p = 0.009, and median CFR was significantly lower 1.80 (IQR 1.40, 2.55) vs. 2.70 (IQR 1.80, 3.95), p < 0.001. The diagnostic value of RFR was high (Area under the curve (AUC) 0.89 95 % Confidence Interval: [0.85, 0.93]) and AUC did not differ between patients with IMR ≥ 24 compared to patients with IMR < 24: 0.89 vs. 0.90, p = 0.89. An overall optimal cut off of 0.88 was identified. The cut off did not differ significantly between patients with IMR ≥ 24 compared to patients with IMR < 24: 0.88 vs. 0.90, p = 0.397. CONCLUSION In patients with coronary borderline stenosis, the coronary microvascular function did not influence on the cut off values or AUC of RFR compared to FFR.

Aims Coronary microvascular dysfunction (CMD) is a heterogeneous condition defined by reduced coronary flow reserve (CFR). The new index ‘microvascular resistance reserve’ (MRR) has been developed, but its role is unclear. We investigate the relationships between functional indices in ANOCA (angina and non-obstructive coronary arteries) patients and evaluate the hemodynamic features of different CMD subtypes. Methods We enrolled consecutive ANOCA patients assessed by using the bolus thermodilution technique. CFR, index of microcirculatory resistance (IMR) and MRR were estimated and correlated with each other. Patients were divided into two groups based on CMD presence (CFR < 2.5). Subsequently, high-hyperaemic-resistance (HHR) and low-hyperaemic-resistance (LHR) CMD subtypes were defined according to IMR values (cut-off 25). Microvascular flow and resistance were estimated both at rest and during hyperaemia with Tmnrest/IMRrest and Tmnhyp/IMR, respectively. All functional indices were compared between groups. Results In total, 108 patients were enrolled: 66 patients in the normal group (CFR ≥ 2.5), 20 in the HHR-CMD group (CFR < 2.5 and IMR ≥ 25) and 22 in the LHR-CMD group (CFR < 2.5 and IMR < 25). MRR strongly correlated (r = 0.968, P < 0.01) with CFR, showing a good discriminatory power (area under the curve = 0.97) and accuracy (85%) for detecting CMD. LHR-CMD patients showed reduced microvascular resistance (IMRrest 34.3 ± 15.1, P < 0.01) and increased resting flow (Tmnrest 0.37 ± 0.17, P < 0.01), while HHR-CMD patients had impaired hyperaemic flow (Tmnhyp 0.45 ± 0.24 P < 0.01). MRR was reduced in CMD patients (P < 0.01), with no differences between CMD subtypes (P = 0.66). Conclusions In ANOCA patients, MRR and CFR are strongly correlated and could be considered as functionally interchangeable tools. IMR is crucial for differentiating CMD endotypes.

Renal Functional Reserve (RFR) stands as a subject of significant scientific discussion,holding promise as a diagnostic tool for early detection of subclinical renal disorders. Literature establishes a link between chronic kidney disease & cardiovascular disease (CVD). This study aims to assess RFR in patients with coronary microvascular dysfunction (CMD), while maintaining preserved renal function (eGFR≥60ml/min/1.73m2 by CKD-EPI criteria)&proteinuria<400mg/24hr. The investigation seeks to provide insights into the nuanced relationship between renal function&CMD, offering potential early indicators of CVD. This is a single-center, prospective study enrolling patients with CMD. In the absence of significant coronary artery disease, functional coronary circulation assessment was performed. Coronary flow reserve (CFR) & index of microvascular resistance (IMR) were measured invasively with bolus thermodilution technique. In all participants, RFR was estimated by endogenous creatinine clearance after oral protein load (cooked meal, 1.2gr/kg). Normal RFR was defined as≥30 ml/min/1.73m2. Also, patients with CMD were offered 24-hour Ambulatory Blood Pressure Monitoring (ABPM). A total of 25 participants have been enrolled so far in study: 11 without CMD - control group [7 female, 64%, mean age: 52.9±8.8 years) & 14 with CMD – CMD group (11 female, 79%, mean age: 53.5±10,3 years). CMD patients were classified into 2 groups, structural & functional endotype (CFR<2.5 & IMR≥25 were considered abnormal). The RFR value for CMD & control group is 7.4±6.3 vs 36.3±5.8 ml/min/1.73m2 respectively (p<0.05). This difference between groups remained statistically significant after controlling for confounding factors. It was found that RFR value for functional & structural CMD endotype was 3.8±2.6 & 9.6±7,2 ml/min/1.73m2 respectively (p=0.06). Furthermore, no statistical significance was found between RFR and IMR, CFR indices. According to data from ABPM, there were no significant differences in ambulatory blood pressure (both systolic and diastolic) between the two endotypes of CMD, as well as no relationship with RFR was observed. However, the proportion of non-dipping BP pattern was significantly higher in functional CMD endotype (p<0.05). It was not found correlation between RFR & non-dipping phenotype. Impaired RFR is evident across all individuals experiencing microvascular angina. Furthermore, those with functional CMD exhibit a diminished RFR when compared with their counterparts with structural CMD. RFR does not exhibit a correlation with blood pressure levels or the absence of a nocturnal dipping pattern. In light of the hypothesis asserting that appraising renal functional reserve serves as an early diagnostic measure for subclinical renal disorders, promptly recognizing individuals with distinct phenotypes could facilitate tailoring therapeutic interventions on an individual basis.Functional Coronary AngiogramCMD group baseline characteristics

Coronary microvascular dysfunction (CMD) is a heterogeneous condition defined by a reduced coronary flow reserve (CFR) and low/high values of index of microvascular resistance (IMR). A new index, the microvascular resistance reserve (MRR) has been developed, but its clinical significance is unclear. We aimed to investigate the relationships between functional indices in ANOCA (Angina and No Obstructive Coronary Arteries) patients and to assess the hemodynamic and clinical characteristics of different CMD subtypes. We prospectively enrolled consecutive ANOCA patients who underwent a comprehensive functional assessment of microvascular domain by thermodilution technique. CFR, IMR and MRR were estimated and correlated each other. Patients were divided in two groups according to the presence of CMD (defined by a CFR<2.5). Subsequently High Hyperaemic Resistance (HHR) and Low Hyperaemic Resistance (LHR) CMD subtypes were defined according to low or high IMR values respectively (cut-off 25). Microvascular flow and resistance were estimated both at rest and during hyperaemia with Tmnrest /IMRrest and Tmnhyp/IMR respectively. All functional indices were compared between groups. one hundred and eight patients were available for the analysis. 66 patients in the Normal Group (CFR≥2.5), 20 patients in HHR CMD (CFR<2.5 and IMR≥25), 22 patients in LHR CMD (CFR<2.5 and IMR<25). MRR showed a strong correlation (r 0.966, p <0.01) with CFR, while a mild and negatively correlation was found between CFR and IMR (r -0.242, p=0.01) and MMR and IMR (r -0.261, p<0.01). MRR showed a good discriminatory power (AUC 0.97, 95% CI 0.94 – 0.99) and accuracy (85%) in detecting CMD when compared to CFR. LHR CMD patients showed reduced microvascular resistance (IMRrest 34.3±15.1 vs 90.1±54.5 Normal Group vs 75.8±28.9 HHR CMD, p<0.01) and increased flow at rest (Tmnrest 0.37±0.17 vs 0.96±0.62 Normal Group vs 0.81±0.43 HR CMD, p<0.01), while HHR CMD patients had impaired flow during hyperemia (Tmnhyp 0.45±0.24 vs 0.26±0.18 Normal Group vs 0.21±0.07 LR CMD p<0.01). MRR was reduced in CMD patients (Normal 4.70±1.78 vs CMD 2.20±0.59, p<0.01), with no differences between CMD subtypes (HHR 2.17±0.47 vs LHR CMD 2.24±0.70, p=0.66). In INOCA patients, MRR and CFR are strongly correlated and could be considered as functionally interchangeable tools. LHR CMD subtype is characterized by a pathological low resistance and high flow at rest while HHR CMD presented an impaired flow during hyperaemia.

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Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.

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Heart failure with preserved ejection fraction (HF

Coronary microvascular dysfunction (CMD) refers to structural and functional abnormalities of the coronary microcirculation, which may be diagnosed using invasive coronary physiology. CMD is responsible for impaired diastolic cardiac function. It has recently been suggested that left atrial strain (LASr) represents a highly sensitive tool for detecting cardiac diastolic function abnormalities. Accordingly, the aim of this study was to investigate the relationship between CMD and LASr. Consecutively enrolled patients with non-obstructed coronary arteries (NOCA) underwent CMD and LASr evaluation by invasive thermodilution and noninvasive echocardiography, respectively. Forty-two (42) patients were included, out of which 26 presented with CMD. There were no significant differences between CMD-positive and negative patients in terms of clinical and echocardiographic characteristics. LASr was significantly reduced in patients with CMD (24.6% ± 6.1 vs. 30.3 ± 7.8%, p = 0.01). A moderate correlation was observed between coronary flow reserve and LAsr (r = 0.47, p = 0.002). A multivariate logistic regression analysis demonstrated that CMD was independently associated with LASr (OR = 0.88, 95%CI 0.78-0.99.135, p = 0.04). A LASr cut-off of 25.5% enabled an optimal classification of patients with or without CMD. Patients with NOCA and CMD had a significantly reduced LASr compared with patients without CMD, suggesting the early impairment of diastolic function in these patients.

Takotsubo syndrome (TTS) has been a recognized clinical entity for 31 years, since its first description in 1990. TTS is now routinely diagnosed in patients who present with acute chest pain, electrocardiographic changes, troponin elevation, unobstructed coronary arteries, and a typical pattern of circumferential left ventricular wall motion abnormalities that usually involve the apical and midventricular myocardium. Increasing understanding of this intriguing syndrome stems from wider recognition, possible increasing frequency, and a rising number of publications focused on the pathophysiology in clinical and laboratory studies. A comprehensive understanding of TTS pathophysiology and evidence-based treatments are lacking, and specific and effective treatments are urgently required. This paper reviews the pathophysiology of this fascinating syndrome; what is known from both clinical and preclinical studies, including review of the evidence for microvascular dysfunction, myocardial beta-adrenergic signaling, inflammation, and electrophysiology; and where focused research needs to fill gaps in understanding TTS.

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Coronary microvascular dysfunction (CMD) can result from structural and functional abnormalities at the intramural and small coronary vessel level affecting coronary blood flow autoregulation and consequently leading to impaired coronary flow reserve. CMD often co-exists with epicardial coronary artery disease but is also commonly seen in patients with various forms of heart disease, including dilated, hypertrophic, and infiltrative cardiomyopathies. CMD can go unnoticed without any symptoms, or manifest as angina, and/or dyspnea, and contribute to the development of heart failure, and even sudden death especially when co-existing with myocardial fibrosis. However, whether CMD in non-ischemic cardiomyopathy is a cause or an effect of the underlying cardiomyopathic process, or whether it can be potentially modifiable with specific therapies, remains incompletely understood.

Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

Coronary microvascular inflammation is hypothesized to play a fundamental role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). No study has directly evaluated both endothelium-dependent and independent coronary microvascular function in HFpEF. Consecutive patients with HFpEF undergoing invasive coronary physiologic testing and echocardiography were examined. Endothelial function was quantified by the increase in coronary blood flow in response to intracoronary infusion of acetylcholine (10 Coronary microvascular dysfunction is common in patients with HFpEF and is caused equally by endothelium-dependent and independent mechanisms, but the presence of microvascular dysfunction cannot be identified from clinical markers and co-morbidities alone. Patients with HFpEF and endothelium-independent microvascular dysfunction display worse diastolic dysfunction and outcomes.

Coronary microvascular dysfunction (CMD), which mimics symptoms of obstructive coronary artery disease, has significant prognostic implications. While epicardial adipose tissue normally has a protective role, increased epicardial adipose tissue is associated with inflammation and may contribute to CMD. However, a direct correlation remains unclear. We aimed to investigate this association. The CMDR (Coronary Microvascular Disease Registry) is a prospective, 2-center registry that is enrolling patients with angina and nonobstructive coronary artery disease who underwent invasive hemodynamic assessment of the coronary microvasculature. Patients with chest computed tomography within 1 year of CMD evaluation were included. We measured epicardial fat volume (EFV) and calculated the EFV index. Logistic regression analysis was used to investigate the association between EFV and EFV index to CMD. Our study included 130 CMDR patients with associated chest CT; 35 were diagnosed with CMD. The CMD-negative patients were younger than the CMD-positive patients (58.52±11.97 versus 63.37±9.56 years; Our results suggest a strong association between EFV index (a significant risk factor) and the presence of CMD. Future studies involving larger cohorts are needed to confirm the association of epicardial adipose tissue with CMD and investigate therapeutic targets to prevent CMD. URL: https://www.clinicaltrials.gov; unique identifier: NCT05960474.

Coronary microvascular dysfunction (CMD) is well-characterized in the context of coronary artery disease, but its relationship to obstructive hypertrophic cardiomyopathy (oHCM) is poorly understood. In addition, the impact of percutaneous transluminal septal myocardial ablation (PTSMA) on CMD has not been fully evaluated. Between October 2023 and May 2024, PTSMA was performed on 10 patients with oHCM. A pressure guidewire in the left anterior descending artery (LAD) was used to invasively assess CMD before and after the procedure. Measurements were recorded for resting full-cycle ratio (RFR), fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). The 10 patients had a median age of 66 [57-75] years, with a resting left ventricular pressure gradient of 44 [17-84] mmHg, measured via catheterization. Prior to PTSMA, the RFR measured in the LAD was 0.93 [0.91-0.96], and the FFR was 0.95 [0.92-0.95], which were both within normal limits. However, the CFR was reduced to 1.8 [1.6-2.1], and the IMR was elevated to 31 [25-39], which indicated CMD. Post-procedure, the left ventricular pressure gradient decreased to 5 [2-8] mmHg, CFR improved to 2.5 [2.2-3.6], and IMR decreased to 22 [17-26], indicating improvement in CMD. In patients with oHCM, myocardial hypertrophy contributes to left ventricular outflow tract obstruction and CMD. This study demonstrated that PTSMA as a septal reduction therapy improved the left ventricular pressure gradient and CMD.

No abstract

Microvascular dysfunction is defined as reduced coronary flow reserve in the absence of an epicardial stenosis. This study determined its prevalence and relation to regional myocardial function in chronic total coronary occlusions (TCO). After recanalization and stenting of a TCO (duration, >4 weeks) in 42 patients, coronary flow velocity reserve (CFVR) was measured by intracoronary Doppler. In a subset of 27 patients, intracoronary pressure was recorded to obtain the fractional flow reserve (FFR). In 21 patients, the CFVR was reassessed after 24 hours. CFVR was <2.0 in 55% of all patients. In the subgroup with simultaneous pressure recordings, 52% of patients showed a CFVR<2.0 and a FFR>/=0.75, indicating microvascular dysfunction. Both reduced CFVR and reduced FFR occurred in only 2 patients (7.7%). CFVR and FFR were not correlated (r=0.03). A low CFVR was associated with a higher baseline average peak velocity (35.6+/-16.6 versus 22.4+/-11.5 cm/s; P=0.006). Doppler parameters did not change within 24 hours. Regional dysfunction had no influence on CFVR. Patients with diabetes and/or hypertension had a lower CFVR than those without this comorbidity (1.86+/-0.69 versus 2.36+/-0.45; P<0.05). Microvascular dysfunction was observed in 55% of TCOs, independent of the impairment of regional myocardial function. Dysfunction was observed more often in patients with diabetes and hypertension. Neither CFVR or FFR alone is appropriate for assessing angioplasty results in patients with a TCO; CFVR should be combined with FFR to differentiate microvascular dysfunction from residual coronary stenosis or diffuse disease.

Objective The index of microvascular resistance (IMR) is an invasive method for quantifying the coronary microvasculature independent of the presence and degree of epicardial stenosis during cardiac catheterization, whereas the Selvester QRS score, which is related to myocardial damage, is a relatively simple and non-invasive measurement procedure. We investigated the relationship between the QRS score and coronary microvascular dysfunction (CMD) assessed via IMR. Methods Data from 74 patients who underwent invasive coronary physiological measurements were retrospectively reviewed. Using a coronary wire, we measured IMR by the hyperemic mean transit time and distal coronary pressure. We also determined a simplified QRS score following the Selvester QRS score criteria by 12-lead electrocardiography. After determining the best cutoff value for the QRS score to predict IMR ≥25, which was defined as CMD by the Coronary Vasomotion Disorders International Study Group, patients were categorized into the QRS score ≥3 (n=16) and the QRS score 0-2 (n=58) groups. Results IMR in the QRS score ≥3 group was significantly higher in comparison to the QRS score 0-2 group (31; IQR: 19-57 vs. 20; IQR: 14-29, p<0.01). The percentage of patients with IMR ≥25 in the QRS score ≥3 group was significantly higher than that in the QRS score 0-2 group (69% vs. 34%, p=0.01). Conclusion A higher QRS score was associated with CMD, as estimated by IMR. The Selvester QRS score is noninvasive parameter that is potentially useful for predicting CMD.

The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD). Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product. Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p < 0.0001), and CFR (1.19 ± 0.38 vs. 2.23 ± 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function. Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.

Pressure-based fractional flow reserve (FFR) and flow-based coronary flow reserve (CFR) assess the functional status of coronary artery disease (CAD) during cardiac catheterization. Complex hemodynamics may not be adequately explained by either pressure or flow alone. Consequently, pressure-drop coefficient (CDP, the ratio between pressure-drop across a stenosis and distal dynamic pressure) that combines both pressure and flow measurements has been developed to distinguish between epicardial stenosis (ES) and microvascular disease (MVD). A global multicenter ILIAS registry was used to analyze CDP in relation to FFR/CFR among 961 subjects for 1342 intracoronary pressure and flow measurements. The correlation between FFR and CFR with CDP was analyzed. The receiver operating characteristic (ROC) curve was used to determine the CDP cut-off value, corresponding to FFR = 0.80 and 0.75 and CFR = 2.0. Both linear (r = 0.68) and logarithmic (r = 0.75) correlation of CDP with combined FFR and CFR improved (p < 0.001) in relation to either FFR or CFR individually. The CDP cut-off values to predict the four possible disease combinations based on FFR(0.8) and CFR(2.0) are: 1) 0 to 15.78 (absence of both diseases); 2) 15.78 to 27.25 (absence of ES and presence of MVD); 3) 27.25 to 73.77 (presence of ES and absence of MVD); and 4) CDP ≥ 73.77 (presence of both diseases). Similar CDP cut-off ranges were obtained for FFR = 0.75 and CFR = 2.0. The established diagnostic cut-off values of CDP can differentiate between the concomitant ES and MVD, improving the functional assessment of CAD. Fractional flow reserve and coronary flow reserve assess the functional status of coronary artery disease (CAD) during cardiac catheterization, but the complex hemodynamics may not be adequately explained by either parameter alone. Pressure-drop coefficient (CDP) is a novel composite parameter that combines both pressure and flow measurements to delineate between epicardial stenosis (ES) and microvascular disease (MVD). ILIAS registry was used to analyze the diagnostic performance of CDP relative to FFR/CFR. The receiver operating characteristic curve was used to determine the CDP cut-off values, that delineate the various combinations of ES and MVD; hence, improving the functional assessment of CAD.

An elevation in cardiac troponin-I (cTnI) after elective percutaneous coronary intervention (PCI) is because of cardiac necrosis and has prognostic implications. Primary microvascular dysfunction, evident before PCI, and paucity of coronary collaterals at baseline may influence cTnI. We selected 22 patients awaiting elective PCI for a single-vessel, type-A coronary stenosis, with normal left ventricular function and a normal preprocedure cTnI. Intracoronary pressure and Doppler flow were measured during coronary balloon occlusion to derive microvascular resistance: Rp=[Pd(occl)-Pv]/APVoccl and collateral resistance: Rcoll=[Pa-Pd(occl)]/APVoccl, at each stage of PCI, where Pa is mean aortic pressure, Pv is central venous pressure, Pd(occl) is mean distal pressure, Rp is coronary microvascular resistance, Rcoll is coronary collateral resistance, and APVoccl is average peak velocity during coronary balloon occlusion. The resistance indices were compared with postprocedural cTnI levels measured at 24 h. There was a relationship between baseline Rp before PCI and elevated plasma cTnI levels at 24 h. Mean (SEM) Rp (mmHg/cm/s) increased for each cTnI tertile: T1 (mean cTnI 0.04 ng/ml): 1.3 (0.3), T2 (mean cTnI 0.13 ng/ml): 3.1 (0.4), and T3 (mean cTnI 2.5 ng/ml): 4.6 (0.7) (P=0.002). Baseline Rcoll (mmHg/cm/s) was similarly related to cTnI result and mean values showed an increasing trend: T1: 11.1 (1.9), T2: 14.5 (2.3), and T3: 19.5 (3.4) (P=0.12). Serial coronary balloon occlusions did not significantly alter Rp (P=0.82) or recruit coronary collaterals (P=0.69). Primary coronary microvascular dysfunction and poor collaterals at baseline are associated with post-PCI necrosis.

Endothelial dysfunction is one of the hallmarks of vascular abnormalities in metabolic diseases and has been repeatedly demonstrated in coronary and peripheral circulation in mice fed high-fat diet (HFD), particularly after long-term HFD. However, the temporal relationship between development of coronary microvascular endothelial dysfunction and deterioration in diastolic and systolic cardiac function after short-term feeding with HFD has not yet been studied. This study aimed to correlate the changes in coronary microvascular endothelial function and global cardiac performance indices in vivo after short-term feeding with HFD in mice. Short-term feeding with a HFD (60% fat + 1% cholesterol) resulted in severely impaired coronary microvascular function, as evidenced by the diminished effect of nitric oxide synthase inhibition (by L-NAME) assessed using T

Impaired hyperemic myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM), despite normal epicardial coronary arteries, results in microvascular dysfunction. The aim of the present study was to determine the relative contribution of extravascular compressive forces to microvascular dysfunction in HCM. Eighteen patients with symptomatic HCM and normal coronary arteries and 10 age-matched healthy volunteers were studied with PET to quantify resting and hyperemic MBF at a subendocardial and subepicardial level. In HCM patients, MRI was performed to determine left ventricular (LV) mass index (LVMI) and volumes, echocardiography to assess diastolic perfusion time, heart catheterization to measure LV outflow tract gradient (LVOTG) and LV pressures, and serum NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) as a biochemical marker of LV wall stress. Hyperemic MBF was blunted in HCM vs. controls (2.26 +/- 0.97 vs. 2.93 +/- 0.64 ml min(-1) g(-1), P < 0.05). In contrast to controls (1.38 +/- 0.15 to 1.25 +/- 0.19, P = not significant), the endocardial-to-epicardial MBF ratio decreased significantly in HCM during hyperemia (1.20 +/- 0.11 to 0.88 +/- 0.18, P < 0.01). This pattern was similar for hypertrophied septum and lateral wall. Hyperemic MBF was inversely correlated with LVOTG, NT-proBNP, left atrial volume index, and LVMI (all P < 0.01). Multivariate regression analysis, however, revealed that only LVMI and NT-proBNP were independently related to hyperemic MBF, with greater impact at the subendocardial myocardial layer. Hyperemic MBF is more severely impaired at the subendocardial level in HCM patients. The level of impairment is related to markers of increased hemodynamic LV loading conditions and LV mass. These observations suggest that, in addition to reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to microvascular dysfunction in HCM patients.

Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by co-morbidities and a systemic proinflammatory state, resulting in coronary microvascular dysfunction (CMD), as well as myocardial fibrosis. The purpose of this study is to examine the relation between myocardial perfusion reserve (MPR) and diffuse myocardial fibrosis in patients with HFpEF using cardiovascular magnetic resonance. A single center study was performed in 19 patients with clinical HFpEF and 15 healthy control subjects who underwent quantitative first-pass perfusion imaging to calculate global MPR. T1 mapping was used to assess fibrosis and to calculate extracellular volume. Spiral cine displacement encoded stimulated echo was used to calculate myocardial strain. Comprehensive 2D echocardiograms with speckle tracking, cardiopulmonary exercise testing, and brain natriuretic peptide levels were also obtained. In patients with HFpEF, mean left ventricular EF was 61% ± 9% and left ventricular mass index 45 ± 12 g/m

Patients with myocardial ischemia without obstructive coronary artery disease often have coronary microvascular dysfunction (CMD) and associated increased risk of cardiovascular (CV) events and anginal hospitalizations. Epicardial adipose tissue (EAT) covers much of the myocardium and coronary arteries and when dysfunctional, secretes proinflammatory cytokines and is associated with CV events. While oxidative stress and systemic inflammation are associated with CMD, the relationship between EAT and CMD in women is not well known. Women diagnosed with CMD (n = 21) who underwent coronary computed tomography with coronary artery calcium (CAC) scoring were compared to a reference group (RG) of women referred for CAC screening for preventive risk assessment (n = 181). EAT attenuation (Hounsfield units (HU)) was measured adjacent to the proximal right coronary artery, along with subcutaneous adipose tissue (SCAT). Two-sample t-tests with unequal variances were utilized. Mean age of the CMD group was 56 ± 8 years and body mass index (BMI) was 31.6 ± 6.8 kg/m Women with CMD have decreased EAT attenuation compared to RG women. EAT-mediated inflammation and changes in vascular tone may be a mechanistic contributor to abnormal microvascular reactivity. Clinical trials testing therapeutic strategies to decrease EAT may be warranted in the management of CMD.

Patients with angina symptoms and/or signs of ischemia but no obstructive coronary artery disease (INOCA) pose a diagnostic and therapeutic challenge. The purpose of this study was to test whether an interventional diagnostic procedure (IDP) linked to stratified medicine improves health status in patients with INOCA. The authors conducted a randomized, controlled, blinded clinical trial of stratified medical therapy versus standard care in patients with angina. Patients with angina undergoing invasive coronary angiography (standard care) were recruited. Patients without obstructive CAD were immediately randomized 1:1 to the intervention group (stratified medical therapy) or the control group (standard care, IDP sham procedure). The IDP consisted of guidewire-based assessment of coronary flow reserve, index of microcirculatory resistance, fractional flow reserve, followed by vasoreactivity testing with acetylcholine. The primary endpoint was the mean difference in angina severity at 6 months (assessed by the Seattle Angina Questionnaire summary score). A total of 391 patients were enrolled between November 25, 2016, and November 12, 2017. Coronary angiography revealed obstructive disease in 206 (53.7%). One hundred fifty-one (39%) patients without angiographically obstructive CAD were randomized (n = 76 intervention group; n = 75 blinded control group). The intervention resulted in a mean improvement of 11.7 U in the Seattle Angina Questionnaire summary score at 6 months (95% confidence interval [CI]: 5.0 to 18.4; p = 0.001). In addition, the intervention led to improvements in the mean quality-of-life score (EQ-5D index 0.10 U; 95% CI: 0.01 to 0.18; p = 0.024) and visual analogue score (14.5 U; 95% CI: 7.8 to 21.3; p < 0.001). There were no differences in major adverse cardiac events at the 6-month follow-up (2.6% controls vs. 2.6% intervention; p = 1.00). Coronary angiography often fails to identify patients with vasospastic and/or microvascular angina. Stratified medical therapy, including an IDP with linked medical therapy, is routinely feasible and improves angina in patients with no obstructive CAD. (CORonary MICrovascular Angina [CorMicA]; NCT03193294).

Recent analyses have found that coronary microvascular dysfunction (CMD) portends a poor prognosis in patients with and without obstructive epicardial coronary artery disease (CAD). Chest pain in the absence of epicardial CAD is a common entity. Angina caused by CMD, microvascular angina (MVA), is often indistinguishable from that caused by obstructive epicardial CAD. The recent emergence of noninvasive techniques that can identify CMD, such as stress positron-emission tomography (PET) and cardiovascular magnetic resonance (CMR) myocardial perfusion imaging, allow improved identification of MVA. Using these tools, higher risk patients with MVA can be differentiated from those at lower risk in the heterogeneous population historically labeled as cardiac syndrome X. Likewise, MVA can be diagnosed in those with obstructive epicardial CAD who have persistent angina despite successful revascularization. There is little evidence to support current treatment strategies for MVA and current literature has not clearly defined CMD or whether therapy improves prognosis.

Microvascular angina (MVA) is defined as angina pectoris caused by abnormalities of small coronary arteries. In its most typical presentation, MVA is characterized by angina attacks mainly caused by effort, evidence of myocardial ischemia on non-invasive stress tests, but normal coronary arteries at angiography. Patients with stable MVA have excellent long-term prognoses, but often present with persistent and/or worsening of angina symptoms. Treatment of MVA is initially based on standard anti-ischemic drugs (beta-blockers, calcium antagonists, and nitrates), but control of symptoms is often insufficient. In these cases, several additional drugs, with different potential anti-ischemic effects, have been proposed, including ranolazine, ivabradine, angiotensin-converting enzyme (ACE) inhibitors, xanthine derivatives, nicorandil, statins, alpha-blockers and, in perimenopausal women, estrogens. In patients with 'refractory MVA', some further alternative therapies (e.g., spinal cord stimulation, pain-inhibiting substances such as imipramine, rehabilitation programs) have shown favorable results.

There are gender differences in the presentation, diagnosis, and treatment of chest pain. When compared to men, women may have more atypical presentations of chest pain. In addition, current diagnostic tools are often not definitive regarding cardiac etiology for chest pain in women. The current diagnostic model of chest pain focuses on significant obstructions within the large coronary arteries as the cause for angina. Microvascular angina (MVA) represents an under-recognized pathophysiologic mechanism that may explain the apparent disparities and elucidate an etiology for the common finding in women of chest pain, ischemia on stress testing, and no obstructive coronary artery disease (CAD) on angiography in the presence of abnormal coronary reactivity testing. Endothelial dysfunction, estrogen deficiency, and abnormal nociception play a role in the pathophysiology of MVA. Treatments are targeted toward these underlying mechanisms. Recognizing the role gender and other pathophysiologic models of chest pain can play in the work-up and treatment of angina may identify a treatable cardiac condition, that would otherwise be discounted as non-cardiac in origin.

We sometimes encounter patients with microvascular angina (MVA), a disease characterized by anginal pain without abnormal coronary arteriographic findings or coronary spasm. More than 40 years have passed since MVA was first confirmed. The terms 'syndrome X', 'cardiac syndrome X' and 'microvascular dysfunction' have also been used to describe conditions similar to MVA, but all with slightly different definitions. The cause of MVA seems almost certain to be organic and functional abnormalities of the small arteries of the heart. Patients with MVA are likely to suffer from endothelial dysfunction and other microvascular abnormalities of both the coronary and peripheral arteries. The major treatment of MVA has been medication, most often calcium channel blockers. The prognosis of MVA is generally excellent, although symptoms remain in many studies. Some MVA patients with accompanying hypertensive heart disease have gone on to develop progressive left ventricular dysfunction, with poor prognosis. The different definitions applied to the terms used to describe this condition, what we refer to here as MVA, can confound issues involved in diagnosis, prognosis and proper treatment. Therefore, it is extremely important to distinguish primary MVA without underlying heart disease from secondary MVA to explore the disease mechanism and examine the clinical characteristics. It is more than 40 years since Likoff first confirmed this disease; therefore, all researchers know that strict diagnostic criteria for MVA should be immediately established.

No abstract

Many patients with chest pain who are relieved to learn that they have no obstructive stenoses at diagnostic angiography are misclassified as having noncardiac chest pain. Only recently have we developed the conceptual framework and diagnostic tools to understand that ischemic heart disease is not exclusively caused by obstructive coronary artery disease, but often has its origin in the microcirculation. This article will focus on the diagnosis and treatment of microvascular angina as a cause of myocardial ischemia in patients with abnormal but 'normal appearing' coronary arteries.

In women presenting for evaluation of suspected ischemic symptoms, a diagnosis of normal coronary arteries is 5 times more common than it is in men. These women are often labelled as having cardiac syndrome X, and a subset of them have microvascular angina caused by microvascular coronary dysfunction (MCD). MCD is not benign and is associated with an annual 2.5% cardiac event rate. Noninvasive testing for MCD remains insensitive, although newer imaging modalities, such as adenosine cardiac magnetic resonance imaging, appear promising. The gold standard for diagnosis of MCD is coronary reactivity testing, an invasive technique that is not available in many countries. With regard to treatment, large-scale trials are lacking. Although research is ongoing, the current platform of therapy consists of antiangina, antiplatelet, and endothelium-modifying agents (primarily angiotensin-converting enzyme inhibitors and statins).

Angina without coronary artery disease (CAD) has substantial morbidity and is present in 10% to 30% of patients undergoing angiography. Coronary microvascular dysfunction (CMD) is present in 50% to 65% of these patients. The optimal treatment of this cohort is undefined. We performed a systematic review to evaluate treatment strategies for objectively-defined CMD in the absence of CAD. We included studies assessing therapy in human subjects with angina and coronary flow reserve or myocardial perfusion reserve <2.5 by positron emission tomography, cardiac magnetic resonance imaging, dilution methods, or intracoronary Doppler in the absence of coronary artery stenosis ≥50% or structural heart disease. Only 8 papers met the strict inclusion criteria. The papers were heterogeneous, using different treatments, endpoints, and definitions of CMD. The small sample sizes severely limit the power of these studies, with an average of 11 patients per analysis. Studies evaluating sildenafil, quinapril, estrogen, and transcutaneous electrical nerve stimulation application demonstrated benefits in their respective endpoints. No benefit was found with L-arginine, doxazosin, pravastatin, and diltiazem. Our systematic review highlights that there is little data to support therapies for CMD. We assess the data meeting rigorous inclusion criteria and review the related but excluded published data. We additionally describe the next steps needed to address this research gap, including a standardized definition of CMD, routine assessment of CMD in studies of chest pain without obstructive CAD, and specific therapy assessment in the population with confirmed CMD.

No abstract

Angina with no angiographic stenosis, commonly called "microvascular angina," encompasses a wide continuum of coronary pathophysiology in conflicting published reports. Comprehensive quantitative myocardial perfusion offers new insights beyond overly simplistic coronary flow reserve. Integrating regional absolute stress flow, relative stress flow, coronary flow reserve, and qualitative subendocardial perfusion gradient on tomograms of relative images, provides correct diagnosis, quantitative physiological classification, and potential treatment. Angina without angiographic stenosis is associated with abnormal quantitative perfusion with rare, but instructive, exceptions. However, microvascular dysfunction without angina is common, particularly associated with risk factors. Reduced subendocardial/epicardial relative activity is common with diffuse coronary artery disease without focal stenosis with or without angina depending on the severity of reduced subendocardial perfusion. Precision quantitative myocardial perfusion in 5,900 cases objectively classifies angina with no angiographic stenosis into 4 categories: subendocardial ischemia due to diffuse coronary artery disease (most common), overlooked stenosis, diffuse microvascular dysfunction due to risk factors or specific microvasculopathies, and nonischemic cardiac pain mechanisms (rare), or some mix of these prototypes, of which 95% associate with risk factors, or subclinical or clinically manifest coronary atherosclerosis needing vigorous risk factor treatment.

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.

Sex differences in cardiovascular diseases can be classified as those which are specific to one sex and those that differ in incidence, prevalence, etiology, symptomatology, response to treatment, morbidity, and mortality in one sex compared to the other. All sex differences in cardiovascular conditions have their basis in the combined expression of genetic and hormonal differences between women and men. This chapter addresses how understanding basic mechanisms of hormone responses, imaging diagnostics, and integration of genomics and proteomics has advanced diagnosis and improved outcomes for cardiovascular conditions, apart from those related to pregnancy that are more prevalent in women. These conditions include obstructive coronary artery disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, diseases of the cardiac muscle including heart failure and takotsubo cardiomyopathy, and conditions related to neurovascular dysregulation including hot flashes and night sweats associated with menopause and effects of exogenous hormones on vascular function. Improvement in technologies allowing for noninvasive assessment of neuronally mediated vascular reactivity will further improve our understanding of the basic etiology of the neurovascular disorders. Consideration of sex, hormonal status, and pregnancy history in diagnosis and treatment protocols will improve prevention and outcomes of cardiovascular disease in women as they age.

Infarction (MINOCA) and ischaemia (INOCA) with non-obstructive coronary disease are recent non-conventional presentations of coronary syndromes that are increasingly recognised in the clinical arena, particularly with the availability of new cardiovascular imaging techniques. Both are related to heart failure (HF). MINOCA is not associated with benign outcomes, and HF is among the most prevalent events. Regarding INOCA, microvascular dysfunction has also been found to associate with HF, particularly with preserved ejection fraction (HFpEF). Regardless of the several aetiologies underlying HF in MINOCA, it is likely related to LV dysfunction, where secondary prevention is not yet clearly established. Regarding INOCA, coronary microvascular ischaemia has been associated to endothelial dysfunction leading ultimately to diastolic dysfunction and HFpEF. MINOCA and INOCA are clearly related to HF. In both, there is a lack of studies on the identification of the risk factors for HF, diagnostic workup and, importantly, the appropriate primary and secondary prevention strategies.

The Cardiovascular Disease in Women Committee of the American College of Cardiology, in conjunction with interested parties (from the National Heart, Lung, and Blood Institute, American Heart Association, and European Society of Cardiology), convened a working group to develop a consensus on the syndrome of myocardial ischemia with no obstructive coronary arteries. In general, these patients have elevated risk for a cardiovascular event (including acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures) compared with reference subjects and appear to be at higher risk for development of heart failure with preserved ejection fraction. A subgroup of these patients also has coronary microvascular dysfunction and evidence of inflammation. This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area. Working group members critically reviewed available literature and current practices for risk assessment and state-of-the-science techniques in multiple areas, with a focus on next steps needed to develop evidence-based therapies. This report presents highlights of this working group review and a summary of suggested research directions to advance this field in the next decade.

No abstract

Patients with epicardial coronary vasospastic angina (VSA) may be likely to have coronary microvascular dysfunction, although mixed results have been reported. The aim of this study was to evaluate coronary microvascular function in detail using novel invasive physiologic indices, such as resistive reserve ratio (RRR) and microvascular resistance reserve (MRR). A total of 45 patients undergoing intracoronary acetylcholine (ACh) provocation test and invasive coronary circulatory evaluation using a thermodilution method were prospectively included. VSA was diagnosed as angiographic vasospasm accompanied by chest pain and/or ischemic electrocardiographic changes by intracoronary injection of ACh. Coronary circulation was assessed with physiologic indices including fractional flow reserve, resting and hyperemic mean transit time (Tmn), coronary flow reserve (CFR), basal resistance index, index of microcirculatory resistance (IMR), RRR, and MRR. Of 45 patients, 23 (51.1%) were diagnosed as having VSA. Patients with positive ACh test had longer resting Tmn (slower coronary flow velocity), higher basal resistance index, and greater RRR and MRR than those without, while fractional flow reserve, CFR, and IMR did not differ significantly between the two groups. In conclusion, although conventional measures such as CFR and IMR failed to show significant differences, RRR and MRR, novel invasive coronary physiologic indices, provided counterintuitive insights that coronary microvascular dilation function was better preserved in patients with VSA than those without.

Increased microvascular resistance may impair hyperemic coronary flow by limiting the maximal and constant vasodilation, resulting in increased fractional flow reserve (FFR) due to the underestimation of the translesional pressure gradient. We examined whether microvascular resistance affects FFR after successful percutaneous coronary intervention (PCI). We measured FFR and the index of microcirculatory resistance (IMR) in 104 coronary arteries of 98 patients after successful elective stenting. FFR values were compared according to the quartiles of the IMR values. Coronary flow was assessed using the hyperemic mean transit time (Tmn ). The IMR values for the interquartile ranges of 8.5-11.3, 13.9-16.3, 20.9-24.5, and 34.2-61.6 were 10.2, 15.1, 22.8, and 38.2, respectively. Both FFR and Tmn values differed significantly across the IMR quartiles (P < 0.001). The angiographic and intravascular ultrasound findings and post-PCI cardiac troponin levels showed no significant difference across the IMR quartiles. Multivariate logistic regression analysis revealed that the left anterior descending artery lesion location (odds ratio [OR] 0.17, 95% confidence interval [CI] 0.06-0.49, P = 0.001), IMR (OR 1.05, 95% CI 1.01-1.09, P = 0.012), and minimal cross-sectional lumen area (OR 1.49, 95% CI 1.03-2.17, P = 0.036) were independent predictors of increased FFR. Increased microvascular resistance may reduce coronary flow and increase FFR after successful elective PCI.

Functional impairment of coronary microcirculation is thought to be a major pathway in the development of primary cardiac involvement in SSc; however, the underlying mechanism is not fully understood. We aimed to investigate the mechanisms of coronary flow reserve (CFR) reduction in patients with SSc. Seventeen SSc patients and 17 gender- and age-matched controls were enrolled. Coronary angiography and determination of coronary flow parameters including index of myocardial resistance (IMR) using intracoronary pressure wire at basal conditions and during vasodilator-induced maximal hyperaemia were performed. Transit times of repeated intracoronary saline injection were measured to evaluate the role of cold exposure. SSc patients with decreased CFR had accelerated basal coronary flow velocity (P < 0.05), and their IMR in hyperaemia (IMR(hyp)) did not differ from either SSc patients with normal CFR or from the controls (P = 0.292 and P =  0.308). The coronary flow velocity of SSc patients correlated with the IMR at baseline (IMR(bas)) (r  = 0.56, P  = 0.019). Injection of room temperature saline did not provoke changes in coronary transit times. The lack of decrease in the maximal vasodilatation response indicates that there is no irreversible functional damage at the level of the coronary arterioles. In patients with reduced CFR, the decreased basal IMR and higher velocity reflect compensatory vasodilatory mechanisms probably triggered by ischaemic signals deriving from abnormal myocardial microcirculation.

The purpose of this study is to summarize cumulative evidence suggesting that the combination of fractional flow reserve (FFR), coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) might provide a more comprehensive invasive assessment of ischaemic heart disease (IHD). Myocardial flow impairment in IHD results from both obstructive and nonobstructive causes. However, its diagnosis is primarily stenosis-centred. Although FFR provides valuable information on obstructive disease, its theoretical framework largely neglects the importance of nonobstructive concomitant involvement. Substantial evidence suggests, however, that nonobstructive IHD has important prognostic implications, and CFR and IMR are readily available tools for its concomitant diagnosis. Furthermore, CFR and IMR have independently been shown to improve IHD risk stratification. Further studies should address whether this more comprehensive IHD diagnosis, derived from the combination of FFR, CFR and IMR, may improve prognostic risk stratification and guide therapeutic strategies aiming for both obstructive and nonobstructive IHD involvement. FFR, CFR and IMR have independently been shown to improve IHD risk stratification. Their combined use is feasible and appealing, and might lead to a more comprehensive invasive assessment of IHD.

The expression "slow coronary flow phenomenon" (SCFP) indicates a slow progression of the contrast seen at the coronary angiography in the absence of epicardial stenosis and/or of other conditions associated with decreased coronary flow velocity. While microvascular abnormalities are suspected to underlie the mechanism of SCFP, they have never been directly demonstrated. Fifteen anginal patients with a positive stress test and no evidence of epicardial lesions (obstructive coronary artery disease, coronary ectasia, or coronary spasm) were enrolled. In eight patients, the diagnosis of SCFP was made (TIMI frame count>average +2SD). All subjects underwent measurement of the coronary flow reserve (CFR) and the index of microvascular resistance (IMR) using an intracoronary thermodilution method (RADI medical systems). There was no difference between groups in age, cardiovascular risk factors, blood pressure and heart rate, coronary artery diameter and fractional flow reserve (an index of the presence of epicardial stenosis). At rest, microvascular resistances (mean transit timexdistal pressure) were significantly higher in the SCFP group (SCFP: 104+/-31 versus 53+/-27, P<0.01). Showing normal responsiveness to vasodilators, this difference was abolished after induction of hyperemia (SCFP group: 34+/-22; control: 22+/-15, P=ns); coronary flow reserve was normal in the subjects with the SCFP (3.6+/-1.6). We provide the first human in vivo evidence that resting microvascular resistances are increased in patients with the SCFP. At the same time, showing an intact capacity to vasodilate, microvascular resistances were normal during hyperemia, and coronary flow reserve was not impaired in SCFP patients.

Recently, a novel method to estimate wedge pressure (P

Fractional flow reserve (FFR) can guide percutaneous coronary intervention (PCI) in multivessel disease (MVD). However, the effect of target vessel (TV) stenting on subsequent FFR measurements in remote non-TVs (NTVs) is unknown. We investigated the effect of TV stenting on NTV FFR in patients with MVD. Patients with MVD (>50% stenosis, ≥2 vessels >2.5 mm diameter; n = 51) undergoing elective PCI were studied. NTV distal pressure, aortic pressure, and saline-bolus thermodilution transit time (Tmn) were measured at baseline and during maximal hyperemia to derive FFR, index of myocardial resistance (IMR), and coronary flow reserve (CFR). PCI was then performed to the TV and the measurements repeated. Collaterals were assessed by modified Rentrop score before and after TV stenting. Mean FFR increased in the NTV after stenting the TV (0.79 ± 0.02 vs. 0.81 ± 0.02; P < 0.01), particularly in patients with normal baseline IMR (0.77 ± 0.02 vs. 0.80 ± 0.02; P = 0.001; n = 41). In this group, PCI to the TV increased remote microvascular resistance (NTV IMR increased from 12.5 ± 0.7 to 16.3 ± 1.4; P = 0.007; and CFR decreased from 3.0 ± 0.2 to 2.4 ± 0.2; P = 0.008). This change was independent of angiographic loss of coronary collaterals from the NTV. Elective TV PCI increases NTV FFR due to an increase in remote coronary microvascular resistance in patients with normal microvascular function. The effect of stent deployment on subsequent FFR measurements in other arteries should be considered.

Although the widespread adoption of timely invasive reperfusion strategies over the last two decades has significantly improved the prognosis of patients with ST-segment elevation myocardial infarction (STEMI), up to half of patients after angiographically successful primary percutaneous coronary intervention (PCI) still have signs of inadequate reperfusion at the level of coronary microcirculation. This phenomenon, termed coronary microvascular dysfunction (CMD), has been associated with impaired prognosis. The aim of the present review is to describe the collected evidence on the occurrence of CMD following primary PCI, means of assessment and its association with the infarct size and clinical outcomes. Therefore, the practical role of invasive assessment of CMD in the catheterization laboratory, at the end of primary PCI, is emphasized, with an overview of available technologies including thermodilution- and Doppler-based methods, as well as recently developing functional coronary angiography. In this regard, we review the conceptual background and the prognostic value of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), hyperemic microvascular resistance (HMR), pressure at zero flow (PzF) and angiography-derived IMR. Finally, the so-far investigated therapeutic strategies targeting coronary microcirculation after STEMI are revisited.

Coronary microvascular dysfunction (CMD), characterized by impaired regulation of blood flow in the coronary microcirculation, plays a key role in the pathogenesis of ischemic heart disease and is increasingly recognized as a contributor to adverse cardiovascular outcomes. Despite its clinical importance, CMD remains underdiagnosed due to the reliance on invasive procedures such as pressure wire-based measurements of the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR), which are costly, time-consuming, and carry procedural risks. To date, no study has sought to quantify CMD indices using data-driven approaches while leveraging the rich information contained in coronary angiograms. To address these limitations, this study proposes a novel data-driven framework for inference of CMD indices based on coronary angiography. A physiologically validated multi-physics model was used to generate synthetic datasets for data-driven model training, consisting of CMD indices and computational angiograms with corresponding contrast intensity profiles (CIPs). Two neural network architectures were developed: a single-input-channel encoder-MLP model for IMR prediction and a dual-input-channel encoder-MLP model for CFR prediction, both incorporating epistemic uncertainty estimation to quantify prediction confidence. Results demonstrate that the data-driven models achieve high predictive accuracy when evaluated against physics-based synthetic datasets, and that the uncertainty estimates are positively correlated with prediction errors. Furthermore, the utility of CIPs as informative surrogates for coronary physiology is demonstrated, underscoring the potential of the proposed framework to enable accurate, real-time, image-based CMD assessment using routine angiography without the need for more invasive approaches.

Coronary Microvascular Dysfunction (CMD) is characterized by impaired vasodilation and can lead to insufficient blood flow to the myocardium during stress or exertion, affecting millions of people globally. Despite their diagnostic value, invasive, wire-based diagnosis techniques of CMD, such as index of microcirculatory resistance (IMR) and coronary flow reserve (CFR), are underutilized due to their complexity and inconsistency. Coronary angiography, one of the most commonly used imaging modalities, offers valuable flow information that assists in diagnosing CMD. However, this information is not fully understood or utilized in current clinical practice. In this study, a 3D-0D coupled multi-physics computational fluid dynamics (CFD) model was developed and calibrated to simulate and study the process of contrast injection and washout during clinical angiography. A contrast intensity profile (CIP) was introduced to describe the dynamics of coronary angiography data. Additionally, sensitivity studies were conducted to evaluate the influence of various coronary lumped parameter model (LPM) parameters on the shapes of CIPs. The results demonstrate that the multi-physics model can be effectively calibrated to produce physiologically meaningful hemodynamic results. Sensitivity studies reveal that resistance has a greater impact on the rising and falling slopes of CIP than capacitance, with higher resistance amplifying this effect. The model and results are presented here. These results are potentially transformative, as they provide a tool for interpreting angiographic data and ultimately extracting information concerning coronary microcirculation.

The relationship between measures of stenosis and microvascular resistance is of importance due to medical decisions being based on these values. This research investigates the impact of varying microvascular resistance on fractional flow reserve (FFR) and hyperaemic stenosis resistance (hSR). Microvascular resistance is classified using hyperaemic microvascular resistance (hMR). Additionally, hMR using the upstream pressure value (hMRPa) has also been calculated and is compared to hMR measured conventionally. Tests were conducted at three different degrees of stenosis (quantified by percent area) in a coronary flow circuit with varying downstream resistance to simulate the microvasculature. Pressure and flow values are recorded across the stenosed section, allowing for calculation of the diagnostic indexes. Results indicate that for a constant degree of stenosis, FFR would increase with increasing microvascular resistance while hSR would remain almost constant. hMRPa was found to approach hMR as the stenosis severity decreased, and the pressure gradient decreased. In the results shown here, with sufficiently high downstream resistance, an 84% stenosis could produce an FFR value over 0.8. This result suggests that there is the potential for misdiagnosis of the severity of stenosis when combined with elevated microvascular resistance. Consequently, decisions on the clinical significance of a stenosis, classified by FFR, need to consider the effect of the microvascular resistance.

More than 10 million coronary angiograms are performed globally each year, providing a gold standard for detecting obstructive coronary artery disease. Yet, no obstructive lesions are identified in 70% of patients evaluated for ischemic heart disease. Up to half of these patients have undiagnosed, life-limiting coronary microvascular dysfunction (CMD), which remains under-detected due to the limited availability of invasive tools required to measure coronary flow reserve (CFR). Here, we introduce PUNCH, a non-invasive, uncertainty-aware framework for estimating CFR directly from standard coronary angiography. PUNCH integrates physics-informed neural networks with variational inference to infer coronary blood flow from first-principles models of contrast transport, without requiring ground-truth flow measurements or population-level training. The pipeline runs in approximately three minutes per patient on a single GPU. Validated on synthetic angiograms with controlled noise and imaging artifacts, as well as on clinical bolus thermodilution data from 20 patients, PUNCH demonstrates accurate and uncertainty-calibrated CFR estimation. This approach establishes a new paradigm for CMD diagnosis and illustrates how physics-informed inference can substantially expand the diagnostic utility of available clinical imaging.

Super-resolution ultrasound (SRUS) visualises microvasculature beyond the ultrasound diffraction limit (wavelength($λ$)/2) by localising and tracking spatially isolated microbubble contrast agents. SRUS phantoms typically consist of simple tube structures, where diameter channels below 100 $μ$m are not available. Furthermore, these phantoms are generally fragile and unstable, have limited ground truth validation, and their simple structure limits the evaluation of SRUS algorithms. To aid SRUS development, robust and durable phantoms with known and physiologically relevant microvasculature are needed for repeatable SRUS testing. This work proposes a method to fabricate durable microvascular phantoms that allow optical gauging for SRUS validation. The methodology used a microvasculature negative print embedded in a Polydimethylsiloxane to fabricate a microvascular phantom. Branching microvascular phantoms with variable microvascular density were demonstrated with optically validated vessel diameters down to $\sim$ 60 $μ$m ($λ$/5.8; $λ$ =$\sim$ 350 $μ$m). SRUS imaging was performed and validated with optical measurements. The average SRUS error was 15.61 $μ$m ($λ$/22) with a standard deviation error of 11.44 $μ$m. The average error decreased to 7.93 $μ$m ($λ$/44) once the number of localised microbubbles surpassed 1000 per estimated diameter. In addition, the less than 10$\%$ variance of acoustic and optical properties and the mechanical toughness of the phantoms measured a year after fabrication demonstrated their long-term durability. This work presents a method to fabricate durable and optically validated complex microvascular phantoms which can be used to quantify SRUS performance and facilitate its further development.

In this paper, we are concerned with the simulation of blood flow in microvascular networks and the surrounding tissue. To reduce the computational complexity of this issue, the network structures are modeled by a one-dimensional graph, whose location in space is determined by the centerlines of the three-dimensional vessels. The surrounding tissue is considered as a homogeneous porous medium. Darcy's equation is used to simulate flow in the extra-vascular space, where the mass exchange with the blood vessels is accounted for by means of line source terms. However, this model reduction approach still causes high computational costs, in particular, when larger parts of an organ have to be simulated. This observation motivates the consideration of a further model reduction step. Thereby, we homogenize the fine scale structures of the microvascular networks resulting in a new hybrid approach modeling the fine scale structures as a heterogeneous porous medium and the flow in the larger vessels by one-dimensional flow equations. Both modeling approaches are compared with respect to mass fluxes and averaged pressures. The simulations have been performed on a microvascular network that has been extracted from the cortex of a rat brain.

Endothelial cells release various vasorelaxing molecules, such as nitric oxide and prostacyclin, along with defined factors that induce hyperpolarization of vascular smooth muscle cells through the opening of calcium-sensitive potassium channels. Potassium channel-dependent vasorelaxation is prevalent in microvessels and can partially compensate for deficiencies in other vasodilatory mechanisms. Enhancing this backup vasorelaxant mechanism may aid the treatment of microvascular disorders, such as cerebral small vessel disease and preeclampsia, a pregnancy-specific hypertensive syndrome, which is characterized by systemic endothelial dysfunction. The development of pharmacological potassium channel openers has encountered significant challenges, including issues of specificity, safety concerns, and off-target effects. This study critically evaluates the advantages and drawbacks of integrating hyperpolarization into a holistic vasorelaxant strategy for managing ischemic disease through single or combination drug therapies.

The significant rates of post-operative arterial thrombus formation following the sutured anastomosis (surgical connection) of vessels in microvascular reconstruction has kindled the development of engineered solutions such as the UNILINK coupler. These devices reduce thrombosis rates, which recent numerical studies suggest to be due to decreases in shear strain rate across the anastomosis site when compared to sutured vessels. In this work we develop and analytically solve the first mathematical model for the problem of microvascular anastomosis, leading to the discovery that the rates of thrombosis using these surgical coupling devices could be further reduced by decreasing the gradient of the wall deformation at the join.

Within animals, oxygen exchange occurs within networks containing potentially billions of microvessels that are distributed throughout the animal's body. Innovative imaging methods now allow for mapping of the architecture and blood flows within real microvascular networks. However, these data streams have so far yielded little new understanding of the physical principles that underlie the organization of microvascular networks, which could allow healthy networks to be quantitatively compared with networks that have been damaged, e.g. due to diabetes. A natural mathematical starting point for understanding network organization is to construct networks that are optimized accordingly to specified functions. Here we present a method for deriving transport networks that optimize general functions involving the fluxes and conductances within the network. In our method Kirchoff's laws are imposed via Lagrange multipliers, creating a large, but sparse system of auxiliary equations. By treating network conductances as adiabatic variables, we derive a gradient descent method in which conductances are iteratively adjusted, and auxiliary variables are solved for by two inversions of O(N^2) sized sparse matrices. In particular our algorithm allows us to validate the hypothesis that microvascular networks are organized to uniformly partition the flow of red blood cells through vessels. The theoretical framework can also be used to consider more general sets of objective functions and constraints within transport networks, including incorporating the non-Newtonian rheology of blood (i.e. the Fahraeus-Lindqvist effect). More generally by forming linear combinations of objective functions, we can explore tradeoffs between different optimization functions, giving more insight into the diversity of biological transport networks seen in nature.

Microvascular imaging has advanced significantly with ultrafast data acquisition and improved clutter filtering, enhancing the sensitivity of power Doppler imaging to small vessels. However, the image quality remains limited by spatial resolution and elevated background noise, both of which impede visualization and accurate quantification. To address these limitations, this study proposes a high-resolution cross-correlation Power Doppler (HR-XPD) method that integrates spatial radiality weighting with Doppler signal coherence analysis, thereby enhancing spatial resolution while suppressing artifacts and background noise. Quantitative evaluations in simulation and in vivo experiments on healthy human liver, transplanted human kidney, and pig kidney demonstrated that HR-XPD significantly improves microvascular resolvability and contrast compared to conventional PD. In vivo results showed up to a 2 to 3-fold enhancement in spatial resolution and an increase in contrast by up to 20 dB. High-resolution vascular details were clearly depicted within a short acquisition time of only 0.3 s-1.2 s without the use of contrast agents. These findings indicate that HR-XPD provides an effective, contrast-free, and high-resolution microvascular imaging approach with broad applicability in both preclinical and clinical research.

In this work, we introduce an algorithmic approach to generate microvascular networks starting from larger vessels that can be reconstructed without noticeable segmentation errors. Contrary to larger vessels, the reconstruction of fine-scale components of microvascular networks shows significant segmentation errors, and an accurate mapping is time and cost intense. Thus there is a need for fast and reliable reconstruction algorithms yielding surrogate networks having similar stochastic properties as the original ones. The microvascular networks are constructed in a marching way by adding vessels to the outlets of the vascular tree from the previous step. To optimise the structure of the vascular trees, we use Murray's law to determine the radii of the vessels and bifurcation angles. In each step, we compute the local gradient of the partial pressure of oxygen and adapt the orientation of the new vessels to this gradient. At the same time, we use the partial pressure of oxygen to check whether the considered tissue block is supplied sufficiently with oxygen. Computing the partial pressure of oxygen, we use a 3D-1D coupled model for blood flow and oxygen transport. To decrease the complexity of a fully coupled 3D model, we reduce the blood vessel network to a 1D graph structure and use a bi-directional coupling with the tissue which is described by a 3D homogeneous porous medium. The resulting surrogate networks are analysed with respect to morphological and physiological aspects.

Blood coagulation is governed by tightly regulated reaction networks that unfold within a flowing, heterogeneous microvascular environment. Reduced kinetic models of the intrinsic and extrinsic pathways have seen limited in vitro validation, and their behavior within spatially resolved flow fields remains largely unexplored. Here, we embed two established reduced networks into a recently proposed mesoscale particle-based framework that resolves fluid momentum transport alongside multispecies advection-diffusion-reaction dynamics. We investigate the initiation phase of coagulation by simulating thrombin formation in microvascular geometries and in vitro assays, and we assess the framework's ability to reproduce thrombin generation curves (TGCs) under physiologically relevant conditions. We further examine how variations in fibrinogen levels - an important determinant of clot structure and a biomarker for inflammation and thrombosis - affect thrombin and fibrin formation. Overall, this study provides a unified computational approach for analysing how biochemical kinetics interact with transport processes, offering insights relevant to thrombosis modeling and blood diagnostics.

The simulation of microcirculatory blood flow in realistic vascular architectures poses significant challenges due to the multiscale nature of the problem and the topological complexity of capillary networks. In this work, we propose a novel deep learning-based reduced-order modeling strategy, leveraging Graph Neural Networks (GNNs) trained on synthetic microvascular graphs to approximate hemodynamic quantities on anatomically realistic domains. Our method combines algorithms for synthetic vascular generation with a physics-informed training procedure that integrates graph topological information and local flow dynamics. To ensure the physical reliability of the learned surrogates, we incorporate a physics-informed loss functional derived from the governing equations, allowing enforcement of mass conservation and rheological constraints. The resulting GNN architecture demonstrates robust generalization capabilities across diverse network configurations. The GNN formulation is validated on benchmark problems with linear and nonlinear rheology, showing accurate pressure and velocity field reconstruction with substantial computational gains over full-order solvers. The methodology showcases significant generalization capabilities with respect to vascular complexity, as highlighted by tests on data from the mouse cerebral cortex. This work establishes a new class of graph-based surrogate models for microvascular flow, grounded in physical laws and equipped with inductive biases that mirror mass conservation and rheological models, opening new directions for real-time inference in vascular modeling and biomedical applications.

High-sensitivity clutter filtering is a fundamental step in ultrasound microvascular imaging. Singular value decomposition (SVD) and robust principal component analysis (rPCA) are the main clutter filtering strategies. However, both strategies are limited in feature modeling and tissue-blood flow separation for high-quality microvascular imaging. Recently, deep learning-based clutter filtering has shown potential in more thoroughly separating tissue and blood flow signals. However, the existing supervised filters face the challenges of interpretability and lack of in-vitro and in-vivo ground truths. While the interpretability issue can be addressed by algorithm deep unfolding, the training ground truth remains unsolved. To this end, this paper proposes an unsupervised unfolded rPCA (U2-rPCA) method that preserves mathematical interpretability and is insusceptible to learning labels. Specifically, U2-rPCA is unfolded from an iteratively reweighted least squares (IRLS) rPCA baseline with intrinsic low-rank and sparse regularization. A sparse-enhancement unit is added to the network to strengthen its capability to capture the sparse micro-flow signals. U2-rPCA is like an adaptive filter that is trained with part of the image sequence and then used for the following frames. Experimental validations on a in-silico dataset and public in-vivo datasets demonstrated the outperformance of U2-rPCA when compared with the SVD-based method, the rPCA baseline, and another deep learning-based filter. Particularly, the proposed method improved the contrastto-noise ratio (CNR) of the power Doppler image by 2 dB to 10 dB when compared with other methods. Furthermore, the effectiveness of the building modules of U2-rPCA was validated through ablation studies.

We analyse mathematical models in order to understand how microstructural features of vascular networks may affect blood-flow dynamics, and to identify particular characteristics that promote the onset of self-sustained oscillations. By focusing on a simple three-node motif, we predict that network "redundancy", in the form of a redundant vessel connecting two main flow-branches, together with differences in haemodynamic resistance in the branches, can promote the emergence of oscillatory dynamics. We use existing mathematical descriptions for blood rheology and haematocrit splitting at vessel branch-points to construct our flow model; we combine numerical simulations and stability analysis to study the dynamics of the three-node network and its relation to the system's multiple steady-state solutions. While, for the case of equal inlet-pressure conditions, a "trivial" equilibrium solution with no flow in the redundant vessel always exists, we find that it is not stable when other, stable, steady-state attractors exist. In turn, these "nontrivial" steady-state solutions may undergo a Hopf bifurcation into an oscillatory state. We use the branch diameter ratio, together with the inlet haematocrit rate, to construct a two-parameter stability diagram that delineates regimes in which such oscillatory dynamics exist. We show that flow oscillations in this network geometry are only possible when the branch diameters are sufficiently different to allow for a sufficiently large flow in the redundant vessel, which acts as the driving force of the oscillations. These microstructural properties, which were found to promote oscillatory dynamics, could be used to explore sources of flow instability in biological microvascular networks.

In computational modelling of coronary haemodynamics, imposing patient-specific flow conditions is paramount, yet often impractical due to resource and time constraints, limiting the ability to perform a large number of simulations particularly for diseased cases. We aimed to compare coronary haemodynamics quantified using a simplified flow-split strategy with varying exponents against the clinically verified but computationally intensive multiscale simulations under both resting and hyperaemic conditions in arteries with varying degrees of stenosis. Six patient-specific left coronary artery trees were segmented and reconstructed, including three with severe (>70%) and three with mild (<50%) focal stenoses. Simulations were performed for the entire coronary tree to account for the flow-limiting effects from epicardial artery stenoses. Both a 0D-3D coupled multiscale model and a flow-split approach with four different exponents (2.0, 2.27, 2.33, and 3.0) were used. The resulting prominent haemodynamic metrics were statistically compared between the two methods. Flow-split and multiscale simulations did not significantly differ under resting conditions regardless of the stenosis severity. However, under hyperaemic conditions, the flow-split method significantly overestimated the time-averaged wall shear stress by up to 16.8 Pa (p=0.031) and underestimate the fractional flow reserve by 0.327 (p=0.043), with larger discrepancies observed in severe stenoses than in mild ones. Varying the exponent from 2.0 to 3.0 within the flow-split methods did not significantly affect the haemodynamic results (p>0.141). Flow-split strategies with exponents between 2.0 and 3.0 are appropriate for modelling stenosed coronaries under resting conditions. Multiscale simulations are recommended for accurate modelling of hyperaemic conditions, especially in severely stenosed arteries.

Background. Different mechanisms have been proposed to relate atrial fibrillation (AF) and coronary flow impairment, even in absence of relevant coronary artery disease (CAD). However, the underlying hemodynamics remains unclear. Aim of the present work is to computationally explore whether and to what extent ventricular rate during AF affects the coronary perfusion. Methods. AF is simulated at different ventricular rates (50, 70, 90, 110, 130 bpm) through a 0D-1D multiscale validated model, which combines the left heart-arterial tree together with the coronary circulation. Artificially-built RR stochastic extraction mimics the \emph{in vivo} beating features. All the hemodynamic parameters computed are based on the left anterior descending (LAD) artery and account for the waveform, amplitude and perfusion of the coronary blood flow. Results. Alterations of the coronary hemodynamics are found to be associated either to the heart rate increase, which strongly modifies waveform and amplitude of the LAD flow rate, and to the beat-to-beat variability. The latter is overall amplified in the coronary circulation as HR grows, even though the input RR variability is kept constant at all HRs. Conclusions. Higher ventricular rate during AF exerts an overall coronary blood flow impairment and imbalance of the myocardial oxygen supply-demand ratio. The combined increase of heart rate and higher AF-induced hemodynamic variability lead to a coronary perfusion impairment exceeding 90-110 bpm in AF. Moreover, it is found that coronary perfusion pressure (CPP) is no longer a good measure of the myocardial perfusion for HR higher than 90 bpm.