Invasive Assessment of Coronary Microvascular Function

The critical role of the coronary microvascular compartment and its invasive functional assessment has become apparent in light of the significant proportion of patients presenting signs and symptoms of myocardial ischemia, despite the absence of epicardial disease, or after the adequate treatment of it. However, coronary microvascular dysfunction (CMD) represents a diagnostic challenge because of the small dimensions of the coronary microvasculature, which prevents direct angiographic visualization. Several diagnostic tools are now available for the invasive assessment of the coronary microvascular function, which, in association with the physiological indices used to investigate the epicardial department, may provide a comprehensive evaluation of the coronary circulation as a whole. Recent evidence suggests that the physiology-guided management of CMD, although apparently costly and time-consuming, may offer a net clinical benefit in terms of symptom improvement among patients with angina and ischemic heart disease. However, despite the results of several observational studies, the prognostic effect of the physiology-driven management of CMD within this population is currently a matter of debate, and therefore represents an unmet clinical need that urgently deserves further investigation.

Effects of Shexiang Baoxin Pill for Coronary Microvascular Function: A Systematic Review and Meta-Analysis

Background: The coronary microvascular dysfunction has attracted more and more attention in recent years, but there is still a lack of effective treatment. Shexiang Baoxin Pill is one of the commonly used drugs for the treatment of coronary artery disease in China. More recently, some studies found that it has the effect of improving coronary microvascular function.Objective: To evaluate the effects of Shexiang Baoxin Pill for coronary microvascular function.Methods: Databases including MEDLINE, Web of Science, CNKI, Wanfang, The Cochrane Library, EMbase, VIP and CBM were searched from inception to June 2021 to screen out relevant clinical studies. The 2019 version 2 of the Cochrane risk of bias tool (RoB2) were used to assess the methodological quality of the included studies. RevMan 5.3 software was used for meta-analysis.Results: Eleven studies meeting the criteria were included, with a total of 1,075 patients. The results of meta-analysis showed that compared with conventional treatment alone, combination of Shexiang Baoxin Pill and conventional treatment can further increase the coronary flow reserve (CFR) [mean difference (MD) = 0.43, 95%CI (0.28, 0.58), p < 0.000 01], decrease the index of microvascular resistance (IMR) [MD = −4.23, 95%CI (−5.49, −2.97), p < 0.000 01], increase serum nitric oxide (NO) [MD = 11.96, 95%CI (2.74, 21.18), p = 0.001] and decrease serum hypersensitive C-reactive protein (hs-CRP) [MD = −2.49, 95%CI (−3.08, −1.90), p < 0.000 01], but did not increase the time of duration on the exercise testing (TET) [MD = 3.64, 95%CI (−1.17, 8.45), p = 0.14]. In terms of safety, a total of 10 patients developed adverse reactions in the intervention group and 17 patients developed adverse reactions in the control group.Conclusion: Current evidence suggests that Shexiang Baoxin Pill may be effective in the improvement of coronary microvascular function when used in combination with conventional treatment. However, due to the low quality of the included studies, lack of placebo control and high heterogeneity among different studies, we should take a cautious attitude towards this conclusion. Moreover, the safety of Shexiang Baoxin Pill remains uncertain, more high-quality clinical studies are needed to verify the efficacy and safety of this drug in the future.Systematic Review Registration: [website], identifier [registration number: CRD42021265113].

Relationship of Laser-Doppler-Flow and coronary perfusion and a concise update on the importance of coronary microcirculation in donor heart machine perfusion

BACKGROUND: Machine perfusion (MP) is a novel method for donor heart preservation. The coronary microvascular function is important for the transplantation outcome. However, current research on MP in heart transplantation focuses mainly on contractile function. OBJECTIVE: We aim to present the application of Laser-Doppler-Flowmetry to investigate coronary microvascular function during MP. Furthermore, we will discuss the importance of microcirculation monitoring for perfusion-associated studies in HTx research. METHODS: Porcine hearts were cardioplegically arrested and harvested (Control group, N = 4). In an ischemia group (N = 5), we induced global ischemia of the animal by the termination of mechanical ventilation before harvesting. All hearts were mounted on an MP system for blood perfusion. After 90 minutes, we evaluated the effect of coronary perfusion pressures from 20 to 100 mmHg while coronary laser-doppler-flow (LDF) was measured. RESULTS: Ischemic hearts showed a significantly decreased relative LDF compared to control hearts (1.07±0.06 vs. 1.47±0.15; p = 0.034). In the control group, the coronary flow was significantly lower at 100 mmHg of perfusion pressure than in the ischemia group (895±66 ml vs. 1112±32 ml; p = 0.016). CONCLUSIONS: Laser-Doppler-Flowmetry is able to reveal coronary microvascular dysfunction during machine perfusion of hearts and is therefore of substantial interest for perfusion-associated research in heart transplantation.

Effect of SGLT2 inhibition on coronary microvascular function in patients with type 2 diabetes

Background Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor reduces risk of cardiovascular death and heart failure but the underlying mechanisms remain poorly understood. It has been suggested that a shift in fuel source in the myocardium from glucose and free fatty acids to the more energy efficient ketogenesis reduces oxidative stress involved in coronary microvascular damage, leading to improved coronary microvascular function. Purpose To test the hypothesis that treatment with the SGLT2 inhibitor empagliflozin improves non-endothelial dependent coronary microvascular function. Methods We included 26 patients with type 2 diabetes in a double blinded, placebo-controlled cross-over study. Participants were treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was change in coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Secondary endpoints were change in echocardiographic parameters of cardiac systolic function and 184 cardiovascular protein biomarkers. Results Nineteen patients completed both study periods according to protocol. There was a significant weight loss and reduction in Hba1c after empagliflozin treatment (table). We found no improvement in CFVR and parameters of cardiac systolic function. We observed a general tendency of reduction in level of cardiovascular biomarkers after empagliflozin treatment (figure) with significant difference between empagliflozin and placebo for 27 proteins, including IL18, ST2, YKL40, ACE2 and leptin. Conclusions Despite a significant weight loss and reduction in Hba1c after empagliflozin treatment, we found no effect on non-endothelial dependent coronary microvascular function in patients with type 2 diabetes mellitus. Improvement in multiple biomarkers may indicate underlying mechanisms but need confirmation in larger studies. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Council for Independent Research Table 1. Change in outcome parameters Figure 1. Change in biomarker levels

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

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 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.

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.