Abstract P278: Coronary Microvascular Dysfunction Is Associated With Augumented Autophagy-lysosomal Signaling In Mice With Hypercholesterolemic Diet

Accumulating evidence indicates coronary microvascular dysfunction (CMD) contributes to myocardial ischemia with or without epicardial coronary atherosclerosis. However, it remains unknown which molecular pathway is associated with compromised coronary microvascular function preceding the development of myocardial ischemic injury. Recent studies suggest that autophagy-lysosomal signaling pathway is involved in the regulation of endothelial homeostasis under various metabolic stresses such as hypercholesterolemia. In this study, the early effects of hypercholesterolemia on the function and integrity of coronary microcirculation were studied in mice and the expressions of various molecular markers of autophagy-lysosome pathway were also determined in the coronary circulation. Mice were fed a hypercholesterolemic paigen diet (PD) for 8 weeks and coronary microvascular function was determined by measuring coronary flow reserve (CFR) under baseline and hyperemic conditions. The effects of PD on cardiac function or remodeling were also assessed by echocardiograph or immunohistochemistry studies. In PD-fed hypercholesterolemic mice, hyperemia-induced increase in CFR was significantly abrogated compared to that in normal chow diet-fed (ND) control mice (PD: 1.583±0.4193 vs. ND: 3.087±0.586) (n=7-8). The diet-induced hypercholesterolemia did not lead to cardiac dysfunction (EF%, PD: 59.870±7.549 vs ND: 64.040±9.088) or hypertrophic remodeling (LV mass (mg), PD: 92.240±14.410 vs ND: 96.030±25.07). PD increased mild cardiac inflammation and fibrosis but did not resulted in rarefaction in the myocardium. In small coronary arterial wall, PD induced endothelial inflammasome activation and inflammation, which was accompanied by upregulation of autophagy and lysosome signaling pathway. In conclusion, hypercholesterolemic diet induces CMD without alterations in cardiac function or remodeling. These alterations in coronary microvascular function represent the early effects of diet-induced hypercholesterolemia, which may be ameliorated with activation of autophagy and lysosome signaling pathways.

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Coronary microvascular function in athletes with abnormal exercise test results

Netherlands Heart Journal ◽

10.1007/s12471-019-01336-6 ◽

2019 ◽

Vol 27 (12) ◽

pp. 621-628

Author(s):

D. A. J. P. van de Sande ◽

P. C. Barneveld ◽

J. Hoogsteen ◽

P. A. Doevendans ◽

H. M. C. Kemps

Keyword(s):

Coronary Flow Reserve ◽

Myocardial Ischaemia ◽

Coronary Flow ◽

A Priori ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Endothelin 1 ◽

Flow Reserve ◽

Coronary Microvascular Function

Abstract Aims In asymptomatic athletes, abnormal exercise test (ET) results have a poor positive predictive value. It is unknown whether abnormal ET results in the absence of obstructive coronary artery disease (CAD) are related to coronary microvascular dysfunction. It is also unknown whether they should be considered false-positive ET results or a consequence of physiological adaptation to sport. In our study, we evaluated whether athletes with abnormal ET results and documented myocardial ischaemia in the absence of obstructive CAD have an attenuated microvascular function and whether coronary microvascular dysfunction is related to endothelial dysfunction. Methods and results Nine athletes with concordant abnormal ET and myocardial perfusion scintigraphy (MPS) results without obstructive CAD were compared with age- and gender-matched individuals with a low-to-intermediate a priori risk of CAD. Coronary flow reserve was assessed by Rubidium-82 positron emission tomography (PET) imaging. Endothelin‑1 concentrations were measured to evaluate endothelial function. Coronary flow reserve was significantly lower in athletes (3.3 ± 0.8 versus 4.2 ± 0.6, p = 0.014 respectively). Endothelin‑1 levels were significantly higher in athletes (1.3 ± 0.2 pg/ml versus 1.0 ± 0.2 pg/ml, p = 0.012 respectively). There was no correlation between endothelin‑1 concentrations and mean global coronary flow reserve (r = 0.12). Conclusion Athletes with abnormal ET and MPS outcomes indicative for myocardial ischaemia and no obstructive CAD have a lower coronary flow reserve compared with non-athletes with low-to-intermediate a priori risk of CAD, suggesting an attenuated coronary microvascular function. Higher endothelin‑1 concentrations in athletes suggest that endothelial-dependent dysfunction is an important determinant of the attenuated microvascular function.

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Imaging of microvascular disease

The ESC Textbook of Cardiovascular Imaging ◽

10.1093/med/9780198849353.003.0033 ◽

2021 ◽

pp. 481-494

Author(s):

Paolo G. Camici ◽

Ornella Rimoldi

Keyword(s):

Myocardial Ischaemia ◽

Imaging Techniques ◽

Microvascular Disease ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Maximal Increase ◽

Asymptomatic Subjects ◽

Coronary Microvascular Function

Beside obstructive disease of the epicardial coronary arteries dysfunction of the coronary microvasculature has emerged in the past 20 years as an additional mechanism of myocardial ischaemia. The coronary microvasculature cannot be directly visualized in vivo, therefore, both invasive and non-invasive techniques, have been developed to assess parameters that depend directly on coronary microvascular function. Studies at the microcirculatory level entail the use of vasodilators to obtain near-maximal vasodilation. The ratio of the maximal increase of blood flow above its resting value the coronary flow reserve (CFR) allows to gain an insight into the integrated circulatory function. The diagnostic accuracy of imaging techniques can be exploited to detect impairments of myocardial perfusion in asymptomatic subjects with cardiovascular risk factors. The assessment of the coronary microvascular function has provided novel details on the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia bearing also important prognostic implications.

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Standard exercise stress testing attenuates peripheral microvascular function in patients with suspected coronary microvascular dysfunction

BMC Sports Science Medicine and Rehabilitation ◽

10.1186/s13102-021-00246-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Massimo Nardone ◽

Steven Miner ◽

Mary McCarthy ◽

Heather Edgell

Keyword(s):

Stress Testing ◽

Acute Exercise ◽

Reactive Hyperemia ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Exercise Stress ◽

Exercise Stress Testing ◽

Coronary Microvascular Dysfunction ◽

Vascular Assessment ◽

Flow Reserve

Abstract Background The effect of exercise on the microvasculature of patients with suspected coronary microvascular dysfunction (CMD), assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT; EndoPAT), is unknown. The present study aimed to determine if standard clinical exercise stress testing (GXT) affected peripheral microvascular function, as determined by the reactive hyperemia index (RHI and LnRHI), in patients with suspected CMD. Methods In a cross-sectional study, patients (n = 76) were grouped based on whether the GXT was performed; 1) prior to (exercisers; n = 30), or 2) after the vascular assessment (non-exercisers; n = 46). Patients with an adenosine index of microvascular resistance > 25, adenosine coronary flow reserve (CFR) < 2.0, and/or acetylcholine CFR < 1.5 were considered to have CMD (n = 42). RHI and LnRHI quantified finger pulse amplitude hyperemia following 5 min of forearm ischemia. Results LnRHI was lower in patients with CMD compared to patients without CMD, while LnRHI was also lower in exercisers compared to non-exercisers (LnRHI: CMD Non-Exercisers: 0.63 ± 0.25; CMD Exercisers: 0.54 ± 0.19; No CMD Non-Exercisers: 0.85 ± 0.23; No CMD Exercisers: 0.63 ± 0.26; Condition and Exercise Main Effects: Both P < 0.01). In patients who did not exercise prior to the vascular assessment, the receiver operating characteristic curve (ROC) for LnRHI to predict CMD was 0.76 (95% CI: 0.62–0.91; P < 0.01). However, in patients who performed exercise prior to the vascular assessment, the ROC for LnRHI to predict CMD was 0.60 (95% CI: 0.40–0.81; P = 0.34). Conclusions CMD is associated with impaired peripheral microvascular function and preceding acute exercise is associated with further reductions of LnRHI. Further, acute exercise abolished the capacity for RH-PAT to predict the presence of CMD in patients with chest pain and non-obstructive coronary arteries. RH-PAT measurements in patients with suspected CMD should not be conducted after exercise has been performed.

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Abstract 9946: Impact of Sex Differences on Invasive Measures of Coronary Microvascular Dysfunction in Patients With Angina in the Absence of Obstructive Coronary Artery Disease

Circulation ◽

10.1161/circ.130.suppl_2.9946 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuhei Kobayashi ◽

Yasuhiro Honda ◽

William F Fearon ◽

Shigemitsu Tanaka ◽

Peter J Fitzgerald ◽

...

Keyword(s):

Coronary Artery Disease ◽

Sex Differences ◽

Coronary Artery ◽

Coronary Flow ◽

Obstructive Coronary Artery Disease ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve ◽

Artery Disease

Background: Coronary microvascular dysfunction is associated with worse long-term outcomes, especially in women. Coronary flow reserve (CFR) is typically used to interrogate microvascular function; however its variability limits reliability. Alternatively, the index of microcirculatory resistance (IMR) is a direct measure of the microvasculature, but has been less thoroughly studied. We investigated sex differences in CFR and IMR in patients with angina in the absence of obstructive coronary artery disease (CAD). Methods: We prospectively enrolled 117 women and 40 men with angina in the absence of obstructive CAD. We performed CFR, IMR, fractional flow reserve (FFR), and quantitative coronary angiography (QCA) in the left anterior descending artery. Coronary flow was assessed with a thermodilution method by obtaining mean transit time (Tmn: an inverse correlate to absolute flow) at rest and hyperemia. IMR was measured as distal coronary pressure at hyperemia x hyperemic Tmn. Results: All patients had minimal or no atherosclerosis by QCA (%diameter stenosis: 23.2±12.3%), and epicardial disease was milder in women (FFR: 0.88±0.04 vs. 0.87±0.04, p=0.04). IMR was similar between the sexes (20.7±9.8 vs. 19.1±8.0, p=0.45), but CFR was lower in women (3.8±1.6 vs. 4.8±1.9, p=0.004). This was primarily due to a shorter resting Tmn in women (p=0.005), while hyperemic Tmn was identical (p=0.79) (Figure). The shorter resting Tmn in women, reflecting increased resting coronary flow, accounted for the lower CFR. In multivariate analysis, female sex was an independent predictor of lower CFR and shorter resting Tmn, but not a predictor of IMR or hyperemic Tmn. Conclusions: Despite women and men having similar microvascular function by IMR, CFR is lower in women. This discrepancy appears to be due to differences in resting coronary flow between the sexes. The impact of sex differences should be considered in interpretation of physiologic indices using resting coronary flow.

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MRI-based in vivo detection of coronary microvascular dysfunction before alterations in cardiac function induced by short-term high-fat diet in mice

Scientific Reports ◽

10.1038/s41598-021-98401-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Grzegorz Kwiatkowski ◽

Anna Bar ◽

Agnieszka Jasztal ◽

Stefan Chłopicki

Keyword(s):

Endothelial Dysfunction ◽

Cardiac Function ◽

High Fat Diet ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

High Fat ◽

Short Term ◽

Systemic Insulin Resistance ◽

Coronary Microvascular Function

AbstractEndothelial 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 T1 mapping via in vivo MRI. Deterioration of coronary microvascular function was detected as early as after 7 days of HFD and further declined after 8 weeks on a HFD. HFD-induced coronary microvascular dysfunction was not associated with impaired myocardial capillary density and was present before systemic insulin resistance assessed by a glucose tolerance test. Basal coronary flow and coronary reserve, as assessed using the A2A adenosine receptor agonist regadenoson, were also not altered in HFD-fed mice. Histological analysis did not reveal cardiomyocyte hypertrophy or fibrosis. Increased lipid accumulation in cardiomyocytes was detected as early as after 7 days of HFD and remained at a similar level at 8 weeks on a HFD. Multiparametric cardiac MRI revealed a reduction in systolic heart function, including decreased ejection rate, increased end-systolic volume and decreased myocardial strain in diastole with impaired ejection fraction, but not until 4 weeks of HFD. Short-term feeding with HFD resulted in early endothelial dysfunction in coronary microcirculation that preceded alteration in cardiac function and systemic insulin resistance.

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Abstract 14277: Serum Nt-prob-type Natriuretic Peptide is Associated With Coronary Microvascular Dysfunction in Patients With Angina and Non-obstructive Coronary Artery Disease

Circulation ◽

10.1161/circ.142.suppl_3.14277 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ali Ahmad ◽

Jaskanwal D Sara ◽

Michel T Corban ◽

Takumi Toya ◽

Ilke Ozcan ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Natriuretic Peptide ◽

Obstructive Coronary Artery Disease ◽

Inverse Correlation ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Flow Reserve ◽

Artery Disease ◽

And Gender

Title: Serum NT-proB-type Natriuretic Peptide is associated with Coronary Microvascular Dysfunction in Patients with Angina and Non-obstructive Coronary Artery Disease Authors: Ali Ahmad, MD, Jaskanwal D. Sara, MBChB, Michel T. Corban, MD, Takumi Toya, MD, Ilke Özcan, MD, Lilach O. Lerman, MD PhD, Amir Lerman, MD Introduction: Coronary microvascular dysfunction (CMD) is prevalent in patients with heart failure with preserved ejection fraction. Subclinical ischemia and myocardial fibrosis in CMD might raise filling pressure, a hallmark of HFpEF, which induces secretion of NT-proB-type natriuretic peptide (NTpro-BNP). We sought to explore the relationship between CMD and NT-proBNP. Methods: We studied 698 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<40% angiographic stenosis) who underwent invasive CMD evaluation and had NT-proBNP checked within 6 weeks. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2.5 in response to intracoronary adenosine injection. Results: Overall mean age was 52.8±12.2 years, and women represented 69% of the patients. Log NT-proBNP showed a modest inverse correlation with CFR (Pearson’s R = -0.22, P<0.0001; Figure 1 ), which remained significant after adjusting for age and gender (Standardized ß coefficient = -0.14; P = 0.001). Patients with CMD had higher levels of NT-proBNP than those without (82 [44-190] vs. 62 (33-130], P <0.0001; Figure 2) . Conclusion: Declining coronary microvascular function is correlated with higher NT-proBNP levels. Patients with CMD had higher levels of NT-proBNP, a marker of elevated LV pressure, contributing to the possible role of CMD in early HFpEF pathophysiology. Keywords: Coronary microvascular dysfunction, NT-proBNP

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Coronary Microcirculation in Heart Failure with Preserved Systolic Function

Current Pharmaceutical Design ◽

10.2174/1381612824666180711124131 ◽

2018 ◽

Vol 24 (25) ◽

pp. 2960-2966

Author(s):

Zorana Vasiljevic ◽

Gordana Krljanac ◽

Marija Zdravkovic ◽

Ratko Lasica ◽

Danijela Trifunovic ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Microvascular Dysfunction ◽

Left Ventricular ◽

Coronary Microcirculation ◽

Left Ventricular Ejection ◽

Coronary Microvascular Dysfunction ◽

Fractional Flow ◽

Flow Reserve

Background: The Heart Failure with Preserved Ejection Fraction (HFpEF) is defined as the preserved left ventricular ejection fraction (LVEF) with the signs of heart failure, elevated natriuretic peptides, and either the evidence of the structural heart disease or diastolic dysfunction. The importance of this form of heart failure was increased after studies where the mortality rates and readmission to the hospital were founded similar as in patients with HF and reduced EF (HFrEF). Coronary microvascular ischemia, cardiomyocyte injury and stiffness could be important factors in the pathophysiology of HFpEF. Methods: The goal of this work is to analyse the relationship of HFpEF and coronary microcirculation in previous studies. Results: The useful diagnostic marker of coronary microcirculation in HFpEF may be the parameters measured by transthoracic echocardiography (TTE), the coronary flow reserve (CFR), as well as fractional flow reserve (FFR) and quantitative myocardial contrast echocardiography (MCE). Cardiac magnetic resonance (CMR) imaging represents the diagnostic gold standard in HFpEF. Coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD) is poorly understood and may be more prevalent amongst women than men. Troponin level may be important in risk stratification of HEpEF patients. Conclusion: There are no precise answers with respect to the pathophysiological mechanism, nor are there any precise practical clinical assessment of and diagnostic method for coronary microvascular dysfunction and diastolic dysfunction. In accordance with that, there is no well-established treatment for HFpEF.

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Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF

European Heart Journal ◽

10.1093/eurheartj/ehy531 ◽

2018 ◽

Vol 39 (37) ◽

pp. 3439-3450 ◽

Cited By ~ 108

Author(s):

Sanjiv J Shah ◽

Carolyn S P Lam ◽

Sara Svedlund ◽

Antti Saraste ◽

Camilla Hage ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Endothelial Dysfunction ◽

Ejection Fraction ◽

Microvascular Dysfunction ◽

Left Ventricular ◽

Coronary Microvascular Dysfunction ◽

Preserved Ejection Fraction ◽

Transthoracic Doppler Echocardiography ◽

Flow Reserve

Abstract Aims To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69–81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). Conclusions PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

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