Coronary "Microvascular Dysfunction": Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics

Abstract

Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

Keywords: coronary microvessels; glycocalyx; mast cells; platelet aggregation; stable angina pectoris; vascular ageing; vasodilator autacoids.

Figure 1

Evaluations of structural determinants of coronary flow reserve in (A) a canine model and (B) patients undergoing coronary bypass surgery, with data related to single large coronary artery stenoses. Note disparities between stenosis–flow reserve relationship in (A) versus (B). Reproduced, with permission from Gould KL, JACC Cardiovascular Imaging, 2009 [2].

Figure 2

Schematic representation of large and small coronary vasculature, with corresponding investigations to examine the functional status of each region. Invasive physiological assessments tools can be specific for macrocirculation (FFR and nonhyperemic indices—iFR, RFR, DFR) and microcirculation (IMR and hMR) or can assess coronary circulation as a whole (CFR). CFR = coronary flow reserve, DFR: diastolic hyperaemic free ratio, FFR = fractional flow reserve, hMR = hyperaemic microvascular resistance, iFR: instantaneous wave-free ratio, IMR: index of microvascular resistance, RFR: resting full-cycle ration.

Figure 3

Determinants of turnover of components of the endothelial glycocalyx under resting and inflammatory conditions. Note continuous interactions with circulating blood cells even under resting conditions and chemical bases for glycocalyx “shedding” under inflammatory conditions. Modified, with permission, from Hu et al., Frontiers in Cell and Developmental Biology, 2021 [47].

Figure 4

Plasma concentrations of the glycocalyx component syndecan-1 in normal (“control” subjects compared with concentrations in patients with known coronary artery spasm during acute and chronic phases). Reproduced with permission from Imam-H et al., Br. J. Pharmacol., 2021 [51].

Figure 5

Biochemical “cascades” controlling integrity of nitric oxide (NO) and prostacyclin (PGI₂) signalling individually and in combination in respect to homeostasis within endothelium and platelets. Note associations of signalling defects (★) with a variety of cardiovascular disease states. Reproduced with permission, from Chirkov-YY et al., Int. J. Mol. Sci., 2022 [61].

Figure 6

Schematic representation of modulators and mediators of effects of mast cell activation: the potential impact of mast cell degranulation on glycocalyx damage and resultant microvascular inflammation, increased microvascular permeability, impaired microvascular autocidal function, and platelet activation/aggregation.