Coronary microvascular disease: current concepts of pathophysiology, diagnosis and management

Introduction

Angina is chest pain as a result of myocardial ischaemia, and it affects up to 2 million people in the UK. This has historically been viewed as the manifestation of obstructive coronary artery disease (CAD). However, up to 50% of patients with angina, who undergo elective coronary angiography, are found to have nonobstructive coronary artery disease (NOCAD). The term NOCAD encompasses a broad range of pathologies, including coronary microvascular disease (CMD), epicardial coronary artery vasospasm and enhanced cardiac nociception with disparate prognostic outlooks and therapeutic implications. Over half of all patients with NOCAD have CMD, which is associated with a greater risk of major adverse cardiovascular events (MACE). Several studies have demonstrated that women, presenting with angina, are more likely to suffer from NOCAD and CMD. The term CMD was coined in 1988 to describe the abnormality in the microcirculation leading to an inadequate vasodilatory response, or a pathological vasoconstrictive response, to physiological or pharmacological stress. The main parameter used to diagnose CMD is diminished coronary flow reserve (CFR), or impaired ability of the microvasculature to augment its blood flow in response to stress. CFR is defined as the ratio of flow at maximal hyperaemia (usually in response to adenosine) to the flow at rest. In the context of NOCAD, CFR informs about prognosis, the presence of ischaemia and likely response to therapy. The focus of this review article will be on the pathophysiology, diagnosis and contemporary management of CMD.

Coronary microvasculature in health

The coronary vasculature comprises of epicardial arteries (>400 µm), pre-arterioles (100–400 µm), arterioles (<100 µm) and capillaries (<10 µm). The epicardial arteries function as capacitance vessels and respond to shear forces by endothelium-mediated dilatation. Epicardial arteries are visible on coronary angiography but represent only 5–10% of the coronary vasculature. The pre-arterioles, arterioles and capillaries form the coronary microvasculature. The pre-arterioles are characterised by a measurable pressure drop along their length. The arterioles have a high resting tone and are responsible for most of the coronary vascular resistance and dilate in response to changes in myocardial oxygen demand. The capillary bed delivers oxygen and substrates to the myocytes. The coronary circulation matches myocardial oxygen demand with supply via a complex interplay between myogenic tone, metabolic signals and circulating hormones. The endothelium plays an important role in the modulation of vascular tone by synthesising and releasing several vasodilator substances, such as nitric oxide (NO). Increased endothelial wall shear stress and acetylcholine are determinants of coronary blood flow (CBF) in health. Both lead to the biosynthesis of NO, which acts on the neighbouring smooth muscle cells to induce vasodilation via the NO pathway.

Pathophysiology of coronary microvascular disease

Traditionally, the pathophysiology of CMD was thought to be a combination of microvascular architectural changes and endothelial dysfunction. Microvascular architectural changes include microvascular obstruction, with luminal narrowing of the arterioles and capillaries, and capillary rarefaction. Alternatively, or concurrently, endothelial or vascular smooth muscle (VSM) dysfunction may lead to an attenuated vasodilatory response or a pathological vasoconstrictive response to stimuli, leading to a blunted augmentation of, or reduction of, CBF in response to stress. These cellular mechanisms are described in Fig. 1. This can lead to a supply-demand mismatch in CBF, therefore leading to ischaemia and symptoms of angina.

Fig. 1 The endothelial and vascular smooth muscle cellular pathways (adapted from Lanza et al.). Acetylcholine has dual effects on coronary microvasculature. It binds to the muscarinic 3 (M3) receptor on endothelial cells and leads to an influx of intracellular calcium (Ca2+) via the L-type calcium channels. Intracellular Ca2+ binds to the protein calmodulin, and the calcium-calmodulin complex activates the endothelial nitric oxide synthase (eNOS) enzyme, which catalyses the conversion of L-arginine into nitric oxide (NO). NO then diffuses into the neighbouring vascular smooth muscle cell (VSMC) and activates guanylate cyclase (GC) enzyme to catalyse the conversion of guanosine triphosphate (GTP) into cyclic GMP (cGMP). cGMP activates the protein kinase G (PKG), which, via a series of intracellular events, inactivates the calcium channels on the VSMC. This reduces the intracellular influx of Ca2+ into the VSMC, therefore leading to vasodilation. Acetylcholine also binds to the M3 receptor on the surface of VSMCs and, in the presence of endothelial dysfunction, leads to unopposed vasoconstriction. Adenosine (ADE) binds to its receptor (A2a) on the surface of VSMCs; this activates adenylate cyclase (AC) enzyme, which catalyses the conversion of ATP (ATP) to cyclic AMP (cAMP). cAMP activates the protein kinase A (PKA). PKA inactivates the calcium channels and prevents influx of Ca2+, therefore preventing vasoconstriction. Ca2+ enters VSMCs via the L-type calcium channels and binds to the protein calmodulin. The calcium-calmodulin complex activates myosin light chain kinase (MLCK), which phosphorylates myosin light chains (MLCs). MLCs are found on the myosin heads. MLC phosphorylation leads to cross-bridge formation between the myosin heads and the actin filaments, leading to vascular smooth muscle (VSM) contraction. cAMP inhibits MLCK, therefore promoting vasodilation. MLC phosphatase (MLCP) dephosphorylates MLC and promotes unbinding of the myosin-actin filaments, therefore leading to vasodilation. cGMP promotes MLCP activity. Endothelin-1 (ET-1) binds to its receptor (ETA) and activates Rho-kinase, which inhibits MLCP and leads to vasoconstriction. VSM relaxation, and therefore vasodilation, occurs when there is reduced phosphorylation of MLC. This can result from reduced intracellular Ca2+ concentration, inhibition of MLCK by increased intracellular concentration of cAMP and MLCP-activated MLC dephosphorylation.

This has remained the dogma of CMD pathogenesis for the past few decades. However, recent animal models and clinical physiology evaluations suggest that CMD may be a heterogeneous condition comprising distinct endotypes. Rahman et al. have described these endotypes as ‘structural CMD’ and ‘functional CMD’. Both endotypes have an impaired augmentation of CBF in response to intravenous adenosine (CFR < 2.5). However, patients with structural CMD have an elevated minimal microvascular resistance (which translates to reduced maximal CBF), whereas patients with functional CMD have a normal minimal microvascular resistance, but nevertheless have reduced vasodilatory reserve as they have reduced tone at rest.

These endotypes have a similar core phenotype, with both groups demonstrating high prevalence of stress perfusion defects on cardiac magnetic resonance (CMR) imaging and reduced coronary perfusion efficiency, on wave intensity analysis, during physical exercise. However, they differ in their pathogenesis at the microvascular level. Patients with functional CMD were found to have a heightened resting CBF. This is suggestive of a submaximal vasodilatory state at rest, leading to an attenuated vasodilatory capacity in response to physiological stress. The elevated resting CBF in these patients could be an appropriate response to an increased myocardial oxygen demand or it could represent disordered autoregulation of the neuronal nitric oxide synthase (nNOS) pathway, which has been shown to regulate the resting CBF in both health and disease states. On the other hand, patients with structural CMD have a normal resting CBF, similar to patients with preserved CFR, but they have an impaired ability to augment their CBF in response to physiological stress, leading to ischaemia. Patients with structural CMD appear to have more established cardiovascular risk factors, including poorly controlled hypertension, type 2 diabetes mellitus (T2DM) and a higher prevalence of exercise-induced hypertension. It has been hypothesised that the attenuated reduction in afterload with exercise would interrupt the usual synergistic response of the coronary and peripheral circulations and predispose to ischaemia in patients with structural CMD. However, it remains unclear whether patients with structural CMD have an impaired ability to augment their CBF as a result of architectural changes, such as microvascular hypertrophy or fibrosis limiting their ability to vasodilate, or whether it is due to dysregulation of the endothelial NOS (eNOS) pathway, which has been shown to regulate CBF in response to exertion.

The findings of Sezer et al. and Van de Wouw et al. further corroborate those of Rahman et al. Sezer et al. reported a bimodal distribution of impaired CFR in patients with T2DM depending on the duration of diabetes. Diminished CFR was due to elevated resting flow in the early stages of diabetes (<10 years duration) and due to heightened hyperaemic microvascular resistance and a reduction in hyperaemic coronary flow velocity in the latter stages of the disease (>10 years duration). The authors hypothesised that elevated resting flow in the early stages was due to either impaired coronary microvascular autoregulation or an adaptive response to altered myocardial energy metabolism. The authors further hypothesised that the increased resting CBF in the early stages of the disease may have led to structural changes in the coronary microvasculature, such as capillary rarefaction and fibrosis, ultimately leading to the attenuated hyperaemic CBF in the later stages of the disease. Van de Wouw et al. reported that swine that were induced with hypertension, hyperlipidaemia and T2DM were found to have a heightened resting CBF, which led to reduced CFR. The swine demonstrated inefficient myocardial perfusion, requiring higher oxygen consumption for a given level of myocardial work. The abnormalities in myocardial oxygen delivery were accompanied by a reduction in lactate consumption, particularly during exercise, indicating an increased oxygen demand. The authors suggested that the increased oxygen demand was either due to a myocardial substrate shift towards fatty acid oxidation leading to a reduced phosphate:oxygen ratio and increased oxygen consumption, or it was due to mitochondrial uncoupling leading to a reduction in phosphate:oxygen ratio, thereby increasing oxygen consumption at a given level of cardiac work.

These studies have improved our understanding of the pathophysiology of CMD. However, many questions remain unanswered. Is the increased resting CBF in patients with functional CMD due to a dysregulation of the neuronal NOS pathway or is it due to an increased oxygen demand at rest? Is the inability to augment CBF during exertion in patients with structural CMD due to architectural changes or due to dysregulation of the eNOS pathway? Are functional and structural microvascular dysfunction part of a disease continuum of the coronary microvasculature? Further studies are needed to answer these pertinent mechanistic questions.

Although a detailed review of epicardial coronary artery vasospasm, and consequent vasospastic angina (VSA), is beyond the scope of this focussed review, it is worth reviewing some of the features of this condition. Vascular smooth muscle cell (VSMC) contraction is regulated by a complex system of intracellular pathways. The central molecular mechanism leading to VSMC hypercontraction is Rho kinase-mediated enhancement of myosin light chain (MLC) phosphorylation (Fig. 1). Other mechanisms contributing towards coronary vasospasm include endothelial dysfunction, low-grade inflammation and oxidative stress. However, these are unlikely to be the primary drivers of coronary vasospasm, and likely serve as additional pathophysiological risk factors.