Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction

Introduction

Up to half of patients with angina and non-obstructive coronary artery disease (NOCAD) have evidence of coronary microvascular disease (CMD). Coronary microvascular disease is defined as an abnormality in the microcirculation leading to an inadequate vasodilatory response, or a pathological vasoconstrictive response, to physiological or pharmacological stress. Coronary microvascular disease can be due to endothelial and/or vascular smooth muscle (VSM) (endothelium-independent) dysfunction. Contemporary invasive tests used to diagnose CMD are based on assessing the ability of the microvasculature to augment blood flow in response to a vasodilator stimulus, i.e. the flow reserve. Endothelium-independent CMD is defined as a coronary flow reserve (CFR) of <2.5 in response to adenosine, whereas endothelium-dependent CMD is defined as acetylcholine flow reserve of <1.5 in response to acetylcholine. In the context of NOCAD, diminished CFR and/or acetylcholine flow reserve is associated with inducible ischaemia, impaired quality of life, and increased risk of adverse cardiovascular outcomes. There is emerging evidence linking coronary microvascular dysfunction to heart failure with preserved ejection fraction (HFpEF), with up to 75% of patients with HFpEF suffering from impaired CFR despite the absence of obstructive coronary artery disease. Heart failure with preserved ejection fraction is a heterogeneous syndrome characterized by exercise intolerance. The contemporary cognizance is that HFpEF, like NOCAD, is an umbrella term comprising distinct endotypes, each with disparate underlying pathophysiology, therapeutic targets, and prognosis. Coronary microvascular disease-related HFpEF (CMD–HFpEF) represents one distinct endotype (Figure 1). In this review article, we will discuss the mechanistic role played by CMD in the pathogenesis of CMD–HFpEF, including abnormalities in cardiac–coronary coupling, which underlie the intimate relationship between myocardial perfusion and diastolic function.

Figure 1

This figure illustrates that heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes, each with disparate underlying pathophysiology, therapeutic options, and outcomes. Patients can be characterized clinically according to factors such as pathophysiology (A), or they can be characterized using artificial intelligence-derived clusters that groups patients according to their clinical characteristics and clinical outcomes (B). Note: (B) is illustrative and not based on real data. CMD, coronary microvascular disease; HFpEF, heart failure with preserved ejection fraction.

Cardiac–coronary coupling

Myocardial perfusion is dependent on CFR and the dynamic interaction between myocardium and microvasculature. As a result of the phasic compression and decompression of intramyocardial vessels, coronary flow is intimately linked to myocardial relaxation and contraction; this process is called cardiac–coronary coupling, which can be readily characterized by coronary wave intensity analysis. Wave intensity analysis defines the nature (accelerating or decelerating flow) and origin (aortic, designated as forward, or microcirculatory, designated as backward) of energy fluxes that govern coronary blood flow (CBF). The backward expansion wave (BEW) is the main driver of flow in the healthy heart and it is secondary to decompression of the microvasculature in early diastole. Therefore, it is directly related to the degree of ventricular relaxation (lusitropy). The other major accelerating wave is the forward compression wave, which corresponds to the rise in aortic pressure after the aortic valve opens in early systole. The major decelerating wave is the backward compression wave (BCW), which arises during isovolumetric contraction. The relative balance of these wave energies is encapsulated in perfusion efficiency, which is the proportion of accelerating energy in relation to total energy flux; perfusion efficiency increases with exercise and pharmacologically induced microvascular dilation in health. In contrast, perfusion efficiency decreases with both exercise and pharmacologically induced microvascular dilation in CMD, primarily driven by attenuation of the accelerating BEW and accentuation of the decelerating BCW during exercise. Attenuation of the BEW during exercise can result from impaired lusitropy and a diastolic dysfunction phenotype that manifests during higher workloads, with resultant subendocardial ischaemia. Alternatively, subendocardial ischaemia during exercise may precipitate ischaemia-induced diastolic dysfunction, with diminished lusitropy subsequently impairing coronary perfusion further and resulting in an ischaemic cascade. As coronary flow is intimately linked with myocardial relaxation (and contraction), it can be challenging to ascertain causality between ischaemia and diastolic dysfunction.

Impaired ventricular relaxation has an adverse impact on coronary flow. In a coronary Doppler study of patients with unobstructed coronary arteries and either normal left ventricular (LV) function or a cardiomyopathic process, early diastolic coronary flow at rest and CFR were attenuated in those with abnormal LV relaxation. Diastolic coronary flow was further reduced with an increase in heart rate in patients with impaired LV relaxation at rest.

These concepts underpin the intimate relationship between coronary flow and ventricular relaxation state (Figure 2). Alteration of this relationship lies at the forefront of the CMD–HFpEF pathophysiology. This will be discussed in more detail later in the review article.

Figure 2

The left panel represents a normal control: the backward expansion wave becomes augmented on exertion, indicating enhanced lusitropy and myocardial perfusion. The right panel represents a patient with coronary microvascular disease: The backward compression wave indicates deceleration of flow and is augmented during exertion in these patients, whereas the backward expansion wave is attenuated. Note that diastole is defined electrically and all haemodynamic traces are gated to the R wave. The traces of aortic pressure, coronary pressure, and flow velocity are ensemble-averaged waveforms in a single calibrated wave. The wave intensity values (W/m2/s2) are for illustration purposes only and do not represent real data. The transthoracic echocardiogram-derived Doppler traces demonstrate normal left ventricular diastolic function in a control patient and impaired left ventricular diastolic function in a patient with coronary microvascular disease. BCW, backward compression wave; BEW, backward expansion wave; FCW, forward compression wave; FEW, forward expansion wave; LV, left ventricular; TTE, transthoracic echocardiogram.

Pathophysiology of coronary microvascular disease

Traditionally, CMD has been attributed to a combination of microvascular architectural changes (such as microvascular obstruction and rarefaction), endothelial dysfunction, and/or VSM dysfunction. Endothelial or VSM (endothelium-independent) dysfunction may lead to an attenuated vasodilatory or a pathological vasoconstrictive response to stimuli, leading to a blunted augmentation of, or reduction of, CBF in response to stress. This can cause a supply–demand mismatch, leading to myocardial ischaemia. The cellular mechanisms regulating microvascular tone are summarized in Figure 3. However, recent animal models and clinical physiology evaluations suggest that coronary microvascular dysfunction may be a heterogeneous condition comprising distinct entities that form part of a disease spectrum. Based on physiology assessment in the catheter laboratory, we have described the presence of two distinct CMD endotypes, termed ‘structural CMD’ and ‘functional CMD’. Both endotypes display impaired augmentation of CBF in response to intravenous adenosine (CFR < 2.5). However, whilst patients with structural CMD have an elevated minimal microvascular resistance (MR) (which translates to reduced maximal CBF), patients with functional CMD have a normal minimal MR but an attenuated vasodilatory reserve as they have reduced tone at rest. The endotypes have a similar core phenotype, with both groups demonstrating high prevalence of inducible ischaemia and inefficient cardiac–coronary coupling during physical exercise, but their pathogenesis differs at the microvascular level. Vascular tone is mediated by nitric oxide (NO), which is synthesized by NO synthase (NOS). Patients with functional CMD have heightened resting CBF and NOS activity, reflecting a near-maximal vasodilatory state at rest (reduced resting microvascular tone), leading to an attenuated vasodilatory capacity in response to physiological stress. Endothelial NOS (eNOS) is thought to maintain hyperaemic CBF in response to hypoxia and shear stress, whilst neuronal NOS (nNOS) is thought to maintain CBF at rest (at least in the healthy heart). The elevated resting CBF in patients with functional CMD could be due to up-regulation of nNOS either as an appropriate response to an increased myocardial oxygen demand at rest or due to disordered autoregulation. Conversely, patients with structural CMD have normal resting CBF but an impaired ability to augment CBF in response to physiological stress and diminished peripheral endothelium-dependent dilatation, precipitating exercise-induced hypertension. The attenuated reduction in afterload with exercise interrupts the usual synergistic response of the coronary and peripheral circulations and predisposes 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 irreversible architectural changes, such as microvascular hypertrophy and fibrosis, limiting their ability to vasodilate, or whether this reflects a reversible disequilibrium of the pathways that mediate vasomotor tone, such as eNOS dysfunction.

Figure 3

Acetylcholine has dual effects on coronary microvasculature. It binds to the muscarinic 3 receptor on endothelial cells and leads to an influx of intracellular calcium via the L-type calcium channels. Intracellular calcium binds to the protein calmodulin, and the calcium–calmodulin complex activates the endothelial nitric oxide synthase enzyme, which catalyzes the conversion of L-Arginine into nitric oxide. Nitric oxide then diffuses into the neighbouring vascular smooth muscle cell and activates soluble Guanylate Cyclase enzyme to catalyze the conversion of Guanosine Triphosphate into cyclic Guanosine Monophosphate. Cyclic Guanosine Monophosphate activates the protein kinase G, which, via a series of intracellular events, inactivates the calcium channels on the vascular smooth muscle cell. This reduces the intracellular influx of calcium into the vascular smooth muscle cell, therefore leading to vasodilation. Acetylcholine also binds to the muscarinic 3 receptor on the surface of vascular smooth muscle cells and, in the presence of endothelial dysfunction, leads to unopposed vasoconstriction. Calcium enters vascular smooth muscle cells via the L-type calcium channels and binds to the protein calmodulin. The calcium–calmodulin complex activates myosin light chain kinase, which phosphorylates myosin light chains. Myosin light chains are found on the myosin heads and myosin light chain phosphorylation leads to cross-bridge formation between the myosin heads and the actin filaments, leading to vascular smooth muscle contraction. Myosin light chain phosphatase dephosphorylates myosin light chain and promotes unbinding of the myosin-actin filaments, therefore leading to vasodilation. Cyclic Guanosine Monophosphate promotes myosin light chain phosphatase activity. The myosin head detaches from the actin binding site after adenosine triphosphate attaches to the myosin head. This adenosine triphosphate is then hydrolyzed to adenosine diphosphate and inorganic phosphate by the myosin head; this adenosine diphosphate and inorganic phosphate is then released by the myosin head after the power stroke. At this point, the myosin head is ready for the next adenosine triphosphate to allow detachment from the myosin head. ACh, acetylcholine; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca2+, calcium; cGMP, cyclic Guanosine Monophosphate; eNOS, endothelial nitric oxide synthase; GTP, Guanosine Triphosphate; M3, muscarinic 3; MLCs, myosin light chains; MLCK, myosin light chain kinase; MLCP, Myosin light chain phosphatase; NO, nitric oxide; Pi, inorganic phosphate; PKG, protein kinase G; sGC, soluble Guanylate Cyclase; VSMC, vascular smooth muscle cell.

Similar pathobiological endotypes have been described by other groups. A bimodal distribution of impaired CFR has been reported in patients with type 2 diabetes mellitus (T2DM) depending on the duration of diabetes. In the early stages of diabetes (<10-year duration), CFR was diminished due to elevated resting CBF whereas in the latter stages of the disease (>10-year duration), this was mainly due to a reduction in maximal CBF (secondary to heightened hyperaemic MR). The elevated resting flow in the early stages of T2DM may represent impaired coronary microvascular autoregulation or an appropriate adaptive response to altered myocardial energy metabolism. Furthermore, it is conceivable that the increased resting CBF in the early stages of T2DM may lead to shear stress-induced architectural changes in the coronary microvasculature, contributing to heightened MR during hyperaemia, leading to an attenuated maximal CBF in the later stages of the disease. Animal studies have corroborated the findings of elevated resting CBF being associated with coronary microvascular dysfunction and myocardial ischaemia. In a swine model, animals with CMD were found to have heightened resting CBF, with a correspondingly high basal myocardial oxygen consumption (MVO2). The former meant that, despite maintaining their hyperaemic CBF, there was reduced CFR. As elevated MVO2 could not be matched by augmenting blood flow (i.e. myocardial oxygen delivery), there was a reduction in lactate consumption indicating anaerobic metabolism, and therefore, ischaemia. The authors of this study suggested that the basal oxygen demand was elevated either due to a myocardial substrate shift towards fatty acid oxidation leading to a reduced phosphate:oxygen ratio and an increased oxygen consumption for adenosine triphosphate (ATP) production or that it was due to mitochondrial uncoupling leading to a reduction in the phosphate:oxygen ratio, thereby increasing oxygen consumption at any given level of cardiac work. Interestingly, in a cohort of 74 women with angina, unobstructed coronary arteries and impaired CFR, low basal CBF (measured indirectly as basal average peak velocity) was associated with higher LV end-diastolic pressure and impaired diastolic strain. There was no difference in cardiovascular risk factors or LV structure between women with low and high basal CBF. The authors concluded that low basal CBF is associated with worse myocardial performance and may eventually lead to heart failure. This cohort of patients demonstrated similar physiological properties as patients with structural CMD. These mechanistic and clinical studies suggest that coronary microvascular dysfunction may lie on a spectrum, with normal function at one end and CMD–HFpEF at the other.

Finally, whilst the NO pathway is central to the development of CMD, dysfunction of the endothelin-1 (ET-1) pathway has also been implicated. Endothelin-1 is a highly potent coronary arteriolar vasoconstrictor; this effect is mediated by activation of the G-protein coupled endothelin A receptors on VSM cells. A specific genetic allele, which is associated with higher serum ET-1 levels, impaired myocardial perfusion on cardiac magnetic resonance imaging and reduced exercise tolerance has been identified in patients with angina and CMD. This supports the role of ET-1 dysregulation in the pathogenesis of CMD, as well as the possibility of precision medicine using genetics to target the ET-1 pathway in patients with CMD.