Pathophysiology of Coronary Microvascular Dysfunction

Abstract

Ischemic heart disease (IHD) is commonly recognized as the consequence of coronary atherosclerosis and obstructive coronary artery disease (CAD). However, a significant number of patients may present angina or myocardial infarction even in the absence of any significant coronary artery stenosis and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. The term “coronary microvascular dysfunction” (CMD) encompasses several pathogenic mechanisms resulting in functional and/or structural changes in the coronary microcirculation and determining angina and myocardial ischemia in patients with angina without obstructive CAD (“primary” microvascular angina), as well as in several other conditions, including obstructive CAD, cardiomyopathies, Takotsubo syndrome and heart failure, especially the phenotype with preserved ejection fraction. The pathogenesis of CMD is complex and involves the combination of functional and structural alterations leading to impaired coronary blood flow and resulting in myocardial ischemia. In the absence of therapies specifically targeting CMD, attention has been focused on the role of modifiable risk factors. Here, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD, with a particular focus on the role of cardiovascular risk factors and comorbidities. Moreover, we discuss the specific pathogenic mechanisms of CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.

Ischemic heart disease (IHD) is still a leading cause of disability and death worldwide, presenting as acute (ACS) and chronic coronary syndromes.¹ Coronary atherosclerosis is a major cause of IHD and, in the past years, most efforts have been made mainly towards the identification and treatment of obstructive coronary artery disease (CAD) (defined as any coronary artery stenosis >50%), with IHD and obstructive CAD often used as synonymous or interchangeable terms.¹

However, a significant number of patients presenting with angina or myocardial ischemia do not have obstructive CAD.² Emerging evidence suggests that mechanisms other than coronary atherosclerosis may determine angina and myocardial ischemia in these patients and, in particular, that impairment of the coronary microcirculation may be involved, with its role being increasingly recognized in recent years.²

The term “coronary microvascular dysfunction” (CMD) encompasses several pathogenic mechanisms resulting in functional and/or structural changes in the coronary microcirculation and determining myocardial ischemia in patients with angina without obstructive CAD (the so-called “primary” microvascular angina [MVA]) as well as in several other conditions, including obstructive CAD, cardiomyopathies, Takotsubo syndrome (TTS) and heart failure (HF), especially the phenotype with preserved ejection fraction (HFpEF).^2,3 Furthermore, recent evidence demonstrated that correct identification of CMD and consequent targeted therapy is associated with improvements in angina relief and quality of life.⁴

The purpose of this review is to provide updated evidence in the current understanding of the pathophysiological mechanisms of CMD, focusing on the relevance of cardiovascular risk factors and comorbid conditions as well as its mechanistic and prognostic role across the spectrum of cardiovascular diseases.

Physiology of Coronary Arterial Circulation

Coronary arterial circulation can be depicted as 2 uninterrupted compartments with decreasing size and distinct functions.

The proximal compartment is formed by the epicardial coronary vessels, conductance arteries with a cross-sectional diameter >500 µm, visible on coronary angiography and the site of obstructive atherosclerosis. The epicardial vessels normally contribute <10% to coronary vascular resistance and become of hemodynamic significance only when >70% of the arterial lumen is obstructed.⁵

The distal compartment consists of the coronary microcirculation, including all vessels with a cross-sectional diameter <500 µm such as the pre-arteriolar vessels (500–100 µm diameter), intramural arterioles (diameter <100 µm) and capillaries.⁵ The coronary microcirculation is formed by resistive arteries and is responsible for >70% of the coronary resistance under physiological circumstances, playing a critical role in the physiological regulation of myocardial blood flow supply in response to changes in metabolic demands of the myocardium. Indeed, at rest myocardial oxygen extraction is already near-maximal and myocardial oxygen delivery is almost completely dependent on coronary blood flow (CBF).⁶ In healthy individuals, any increase in myocardial metabolic demand is met by progressive vasodilation of coronary arterioles and modulation of vascular resistance, with an increase of CBF up to 5-fold.⁵

CMD

CMD refers to the spectrum of alterations occurring at the level of the coronary microcirculation leading to an impaired CBF and ultimately resulting in myocardial ischemia.⁷ In particular, CMD is characterized by an inability to increase CBF in relation to myocardial metabolic demand and/or by coronary microvascular spasm, resulting in a supply-demand mismatch that may remain subclinical or determine symptomatic myocardial ischemia.⁸

The mechanisms underlying CMD are complex, involving the combination of functional and structural alterations in the coronary microcirculation that, taken together, can reduce the CBF reserve and produce regional ischemia in the absence of any epicardial stenosis (Figure 1).⁵

Figure 1.

Functional, structural and molecular alterations in the coronary microcirculation determining coronary microvascular dysfunction. EDHF, endothelium-derived hyperpolarizing factors; eNOS, endothelial NO synthetase; ET-1, endothelin-1; NO, nitric oxide; ROS, reactive oxygen species; VSMCs, vascular smooth muscle cells.

Functional Alterations

The main functional alterations responsible for CMD are related to the presence of impaired vasodilation and/or increased constriction of the coronary microcirculation (microvascular spasm).

Impaired vasodilation may be due to endothelium-dependent and/or endothelium-independent mechanisms.^7–9 Endothelial cells regulate vasomotor activity by synthesizing and releasing vasoactive factors such as the vasodilator prostaglandins (e.g., prostacyclin), nitric oxide (NO) and endothelium-derived hyperpolarizing factor(s) (EDHFs), as well as vasoconstrictor mediators such as endothelin-1 (ET-1).⁵ Interestingly, endothelium-derived NO mainly mediates vasodilatation of the epicardial coronary arteries, while EDHFs are the predominant mediator of endothelium-dependent vasodilatation of coronary microvessels.¹⁰ Endothelium-independent mechanisms are less understood and likely involve impaired relaxation of vascular smooth muscle cells (VSMCs) as well as an increased release of vasoconstrictor agonists (i.e., ET-1), an enhanced susceptibility of VSMCs to normal vasoconstrictor stimuli and an abnormal autonomic activity.^7–9

Coronary spasm refers to the spectrum of vasomotor abnormalities both in the epicardial coronary vessels and the coronary microcirculation that limits the blood flow supply to the myocardium and produces myocardial ischemia.^11–13

Finally, the presence of autonomic dysfunction, characterized by an imbalance between the sympathetic and parasympathetic systems, is implicated in the pathogenesis of CMD, especially in clinical situations in which normal non-neural vasodilator mechanisms are impaired (e.g., dyslipidemia and type 2 diabetes mellitus [T2DM]) and following myocardial infarction (MI) and/or percutaneous coronary intervention (PCI) procedures.¹⁴

Structural Alterations

The main structural abnormalities associated with CMD are hypertrophic inward remodeling of coronary resistance arteries with luminal narrowing of the intramural arterioles and capillaries, perivascular fibrosis, reduced microvascular density and capillary rarefaction.⁵ These alterations are particularly frequent in the context of left ventricular hypertrophy, such as in hypertrophic cardiomyopathy (HCM) and hypertensive heart disease, where the adverse remodeling of arterioles extends to the whole left ventricle and results in medial wall thickening (due to smooth muscle hypertrophy and increased collagen deposition) and varying degrees of intimal thickening, altering the coronary physiology and therefore impairing CBF.^7–9

Underlying Molecular Mechanisms

The presence of oxidative stress due to enhanced production of reactive oxygen species (ROS) and the consequent inflammatory response plays a central role in determining CMD.¹⁵ In particular, the activation of nicotinamide adenine dinucleotide phosphate oxidases (Nox) is the major system accounting for the ROS production triggering p66^Shc phosphorylation and translocation within the mitochondria. p66^Shc is a pro-apoptotic protein that further enhances ROS generation by altering the mitochondrial bio-energetic properties and stimulating the activity of Nox, thus generating a vicious cycle of ROS augmentation.¹⁶

Moreover, intracellular accumulation of ROS promotes the transformation of NO in peroxynitrite radicals and uncouples the endothelial NO synthetase (eNOS), switching its activity from a NO- to a ROS-producing enzyme and impairing NO-mediated vasodilation.¹⁷

Another pathway strongly implicated in CMD is the RhoA/Rho-kinase activation that leads to ROS production, enhanced ET-1 vasoconstriction activity and inflammation through the induction of proinflammatory molecules both in VSMCs and endothelial cells. Furthermore, it is also implicated in the modulation of calcium sensitivity, and rho-kinase-induced myosin light chain diphosphorylation with resultant VSMC hypercontraction is a major mechanism in the pathogenesis of coronary artery spasm, as demonstrated by the efficacy of intracoronary administration of the rho-kinase inhibitor fasudil.¹⁸

Finally, epigenetic modifications, such as those commonly detected in aging, may be implicated in increasing ROS production, reducing the expression of antioxidant enzymes and promoting proinflammatory cytokine production through activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), thus fostering inflammation-mediated endothelial cell activation, upregulation of adhesion molecules, platelet and leucocyte adhesion and loss of endothelial barrier functions.¹⁶

Cardiovascular Risk Factors and CMD

The same risk factors implicated in the occurrence of obstructive CAD (e.g., T2DM, obesity, hypertension, dyslipidemia) may contribute to the development of CMD (Figure 2). Of importance, the control of modifiable risk factors plays a critical role in the management of patients with CMD, considering the absence of specific therapies targeting CMD.⁶

Figure 2.

Role of cardiovascular risk factors in determining coronary microvascular dysfunction. CBF, coronary blood flow; ET-1, endothelin-1; NO, nitric oxide; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus.

Diabetes and Prediabetic Status

T2DM is highly prevalent in patients with CMD, and the extensive metabolic alterations associated (including oxidative stress, chronic inflammation, hyperglycemia, hyperinsulinemia, insulin resistance [IR]) are responsible for direct myocardial injury, endothelial dysfunction and microvascular dysfunction in multiple organs such as the heart, retina, kidneys and skin.^6,19

Hyperglycemia may suppress endothelium-dependent vasodilation and establish permanent vascular damage through many intracellular pathways.²⁰ In particular, polyol production alters the NADH/NAD⁺ ratio balance, leading to production of ROS, oxidative stress and the activation of diacylglycerol-protein kinase C with eventual cardiomyocyte death, mitochondrial damage, collagen deposition and alteration of endothelial response to vasodilatory stimuli.²¹ Protein nonenzymatic glycation and formation of advanced glycation endproducts (AGEs), induced by chronic hyperglycemia, can alter enzyme activity, decrease ligand binding, modify protein half-life and alter immunogenicity.²² The main deleterious effects related to AGE production and deposition are mediated through the interaction with their receptors (RAGE), which are implicated in NF-κB pathway activation, and subsequent overproduction of inflammatory cytokines, ET-1, tissue factor and ROS.²³

Moreover, microvascular damage is not only related to AGE deposition, vascular inflammation and reduced NO production, but also a direct effect of T2DM itself, which depletes endothelial cells and reduces capillary surface area.¹⁹

Furthermore, IR can lead to pathway-specific impairment in phosphatidylinositol 3-kinases-dependent signaling, causing an imbalance between the production of NO and secretion of ET-1.²⁴ Moreover, by affecting noncardiac tissues (i.e., skeletal muscle, adipose tissue and liver), IR causes an increase in proinflammatory mediators and the release of free fatty acids, fostering myocardial lipotoxicity and affecting coronary microvascular endothelial cells through disruption of eNOS signaling.²⁵

Finally, IR and hyperglycemia are also relevant to the platelet dysfunction in the T2DM population, promoting the release of preformed/newly-synthetized proteins from platelet granules and further enhancing the local inflammatory process.²⁶

Hypertension

Hypertension causes functional and structural alterations in the microcirculation that aggravate CMD.⁶ Indeed, the microvascular hallmarks of hypertension (inward remodeling of resistance arteries and microvascular rarefaction) significantly affect microvascular resistance and therefore play an important role in reducing CBF.²⁷ The injurious effects of hypertension are remarkably enhanced by the presence of other comorbidities (T2DM in particular).²⁸

Dyslipidemia

Patients with dyslipidemia exhibit reduced coronary flow reserve (CFR) from the early stages of atherosclerosis and before any angiographic evidence of coronary stenosis.²⁹ Indeed, plasma levels of total cholesterol and low-density lipoprotein (LDL)-cholesterol inversely correlate with the measurement of the index of microcirculatory resistance (IMR), independently of the severity of coronary atherosclerosis or the number of diseased vessels.⁶

Impaired endothelium-dependent vasodilation in the arterioles is particularly relevant in hypercholesterolemic patients with CMD, in part because of increased generation of ROS. In fact, the detrimental role of oxidized-LDL in epicardial vessels is present also in microvessels, where endothelium-dependent dilation of arterioles is impaired by the reduction in the expression and function of eNOS and a low NO bioavailability.³⁰

Furthermore, mechanisms such as inflammation and innate/adaptive immune cell responses are involved in the pathogenesis of dyslipidemia-induced CMD.³¹

Obesity and Metabolic Syndrome

The presence of metabolic dysregulation linked to obesity and metabolic syndrome can lead to endothelial dysfunction with attenuation of endothelium-dependent vasodilation resulting from reduced NO bioavailability and increased vasoconstrictor responses to ET-1, prostaglandin H2, and thromboxane A2.⁹

In addition, patients with metabolic syndrome also show exaggerated α-adrenergic coronary vasoconstriction due to increased sympathetic activity as well as hyperactivity of the renin-angiotensin-aldosterone system and the consequent angiotensin II-mediated coronary vasoconstriction.³²

Moreover, adipocytes and the perivascular adipose tissue-derived adipokines (leptin, resistin, interleukin-6, and tumor necrosis factor-α) play a central role inducing a proinflammatory state and therefore promoting oxidative stress in the endothelium and impairing endothelial function and NO bioavailability, either directly or through increased ET-1 production.⁹ Finally, adipocyte-derived free fatty acids and leptin also contribute to determining an increased adrenergic tone.³²

Female Sex

The presence of CMD is particularly frequent in women, especially in the postmenopausal state.³³ Moreover, despite a lower prevalence of obstructive CAD than men,⁶ women show similar prevalence of MI with ST-segment elevation.³⁴ In fact, experimental data suggest complex estrogen-related sex-specific differences in the regulation of NO-mediated microvascular vasomotor function in females and males and, moreover, the presence of cardiovascular risk factors (e.g., smoking and T2DM) has a different effect on mortality depending on age and sex.³⁴

Pathophysiology of CMD Across the Spectrum of Different Cardiovascular Diseases

CMD is prevalent across different cardiovascular diseases, having a pathophysiological and prognostic role in specific populations. Of importance, several invasive and noninvasive imaging techniques have been validated to assess microvascular function and integrity in clinical practice (Table 1), thus allowing the assessment of CMD in each of the following conditions (Table 2).⁵

Table 1. Noninvasive and Invasive Diagnostic Techniques to Investigate Coronary Microvascular Dysfunction

Modality	Technique	Agent	Parameter	Diagnostic threshold	Pro	Cons
Noninvasive diagnostic techniques
1) TTDE	Pulsed-wave Doppler on the proximal LAD artery	Adenosine Dipyridamole	CFRV	CFRV <2	• Readily available and inexpensive • No radiation exposure • No adverse events	• Limited to LAD region • Operator-dependent • Technical pitfalls (poor acoustic window in obese, lung diseases) • Obstructive CAD needs to be excluded • Assessment of vasodilatory microvascular function only
2) PET	Dynamic first-pass vasodilator stress and then rest perfusion imaging	Adenosine, 15O-H2O, 13N-ammonia, 82Rb	MPR MBF	MPR <2	• Gold standard for noninvasive assessment of microvascular function • Global evaluation of all coronary territories at the same time	• Limited availability and high cost • Radiation exposure • Limited spatial resolution • Time-consuming • Obstructive CAD needs to be excluded
3) CMR	Dynamic first-pass vasodilator stress and then rest perfusion imaging	Adenosine, regadenoson, gadolinium-based contrast agents	MPR MBF CMR-derived MPR index	MPR index <2	• No radiation exposure • All coronary territories evaluated at the same time • Image quality is widely independent of individual characteristics (e.g.,: obesity) • Identification of underlying structural heart disease and CMD	• Limited availability and high cost • Time-consuming • Limited ability for absolute quantification of MBF • Obstructive CAD needs to be excluded • Contraindicated in patients with severe renal disease, claustrophobia, arrhythmias and implanted devices
4) CT scan	Dynamic first-pass vasodilator stress and then rest perfusion imaging	Adenosine, regadenoson, iodine-based contrast agents	MPR	MPR <2	• Combined assessment of epicardial and microvascular disease with one tool • Evaluation of all coronary territories • CTA-derived FFR (FFRCT)	• Radiation exposure • Risk of contrast-induced nephropathy • Overestimation of MBF (due to the vasodilatory effect of iodinated contrast) • Limited ability for absolute quantification of MBF • Still needs to be validated in CMD
Invasive diagnostic techniques
1) Coronary angiography	Dynamic passage of angiographic contrast	Iodine-contrast agent	TIMI flow TFC	TIMI-2 TFC >25 frames	• Simply and readily available • No additional costs or radiation	• Semiquantitative assessment • Does not provide information regarding the mechanism of CMD (impaired dilation vs. microvascular spasm)
2) Intracoronary temperature-pressure wire	Estimate of CBF using bolus (calculating the mean transit time) or continuous thermodilution techniques (no need for pharmacological agents to induce hyperemia)	Adenosine Papaverine Saline solution	CFR IMR	CFR <2–2.5 IMR >25U	• Combined assessment of impaired vasodilation and microvascular hyperconstrictive response • IMR is specific for microcirculation and is not affected by resting hemodynamics	• CFR does not distinguish between microvascular and epicardial disease • Cutoff values for IMR still debated
3) Intracoronary Doppler flow-pressure wire	Direct measurement of coronary peak flow velocity	Adenosine	CFR HMR	CFR <2.5 HMR >1.7 mmHg/cm per s	• HMR is independent of resting coronary flow • Better reproducibility and correlation with PET than IMR	• Technical complexity • Cutoff values for HMR still debated
4) Intracoronary provocative testing	Intracoronary infusion of vasoactive agents	Acetylcholine Ergonovine	–	–	• Easy to assess • Simple and safe • No need for additional equipment	• Additional contrast and radiation • Does not provide direct evidence of microvascular spasm

*MPR is preferred to CFR when is not calculated invasively. CAD, coronary artery disease; CFR, coronary flow reserve; CFRV, coronary flow reserve velocity; CMD, coronary microvascular dysfunction; CMR, cardiac magnetic resonance; CT, computed tomography; FFR, fractional flow reserve; HMR, hyperemic microvascular resistance; IMR, index of microvascular resistance; LAD, left anterior descending artery; MBF, myocardial blood flow; MPR myocardial perfusion reserve; PET, positron emission tomography; TIMI, Thrombolysis in Myocardial Infarction; TFC, TIMI frame count; TTDE, transthoracic Doppler echocardiography.

Table 2. Classification of Coronary Microvascular Dysfunction CMD According to Different Clinical Scenarios

Group	Clinical presentation	Syndrome	Main pathogenic mechanisms
CMD in patients without obstructive CAD, myocardial disease and valvular heart disease	Angina or angina equivalent	INOCA MINOCA Takotsubo syndrome Angina post-PCI/CABG	Endothelial cell and VSMC dysfunction, vascular remodeling resulting in impaired vasodilation or microvascular spasm, thromboembolism (MINOCA)
CMD in patients with obstructive CAD	Angina or angina equivalent	Atherosclerotic chronic coronary syndrome or ACS	Endothelial cell and VSMC dysfunction, vascular remodeling resulting in impaired vasodilation (>chronic coronary syndrome), microvascular obstruction (>ACS)
CMD in patients with myocardial diseases and valvular heart diseases	Dyspnea, exercise intolerance and/or angina	HFpEF Diabetic cardiomyopathy Aortic stenosis Infiltrative cardiomyopathy Hypertrophic cardiomyopathy Dilated cardiomyopathy	Microvascular rarefaction, extramural compression, vascular remodeling, VSMC dysfunction
Iatrogenic CMD	Often asymptomatic	Post elective PCI Post elective CABG Cardiac allograft vasculopathy	Luminal obstruction, autonomic dysfunction, proinflammatory systemic response

ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; HFpEF, heart failure with preserved ejection fraction; INOCA, ischemia with nonobstructive coronary arteries; MINOCA; myocardial infarction with nonobstructive coronary arteries; PCI, percutaneous coronary intervention; VSMC, vascular smooth muscle cell.

CMD in Patients With Nonobstructive CAD

The term “ischemia with nonobstructive coronary artery” (INOCA) identifies a significant proportion of patients with symptoms and signs of ischemia without obstructive CAD, resulting in the clinical picture of primary MVA, in which CMD is an important cause of symptoms.³ MVA represents up to 40% of patients presenting with signs and symptoms of myocardial ischemia with normal or near-normal (<50% diameter stenosis) coronary arteries on coronary angiography,^2,8 and the Coronary Vasomotion Disorders International Study (COVADIS) Group established standardized criteria for its identification² (Table 3).

Table 3. Diagnostic Criteria for Microvascular Angina According to Coronary Vasomotion Disorders International Study (COVADIS) Group

1. Symptoms of myocardial ischemia	2. Absence of obstructive CAD† assessed by	3. Objective evidence of myocardial ischemia	4. Evidence of impaired coronary microvascular function
• Effort and/or rest angina	• Coronary computed tomography angiography	• Ischemic ECG changes during an episode of chest pain	• Impaired CFR (<2.5)
• Angina equivalent (i.e., shortness of breath)	• Invasive coronary angiography	• Stress-induced chest pain and/or ischemic ECG changes*	• Coronary microvascular spasm, defined as reproduction of symptoms, ischemic ECG shifts but no epicardial spasm during acetylcholine testing • Abnormal IMR (>25) • “Coronary slow flow” phenomenon (TIMI frame count >25)

Definitive microvascular angina (MVA) is only diagnosed if all 4 criteria are present. Suspected MVA is diagnosed if symptoms of ischemia (1) are present with no obstructive CAD (2), but only objective evidence of myocardial ischemia (3) or evidence of impaired coronary microvascular function (4) is present. ^†Obstructive CAD is defined as >50% diameter reduction or FFR <0.80 *In the presence or absence of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality. ECG, electrocardiogram. Other abbreviations as in Table 1.

The major risk factors for INOCA are dyslipidemia, obesity, metabolic syndrome and T2DM. Indeed, as mentioned before, the presence of metabolic dysregulation leads to endothelial dysfunction, increased sympathetic activity and promotes a proinflammatory state.^9,32

CMD may be also involved in the pathogenesis of ACS. Nonobstructive ACS is a heterogeneous clinical condition with multiple potential causes, involving both epicardial and microvascular causes as well as cardiac nonischemic etiologies.⁹ Among these patients, MI with nonobstructed coronary arteries (MINOCA) (<50% diameter stenosis in any major epicardial vessel) refers to those presenting with an ischemic mechanism responsible for myocyte injury and troponin elevation.⁵ MINOCA is more common in women and in patients presenting with non-ST-elevation MI; coronary microvascular spasm seems to be responsible for up to 16% of cases. Indeed, while impaired vasodilation is the most common identifiable mechanism for symptoms in patients with effort angina, microvascular spasm is usually associated with angina at rest, and sometimes with an acute presentation as MINOCA.^35,36 Another microvascular cause of MINOCA is the obliteration of the coronary microcirculation by thromboembolism (from the left heart, paradoxical embolism due to right-to-left shunt or hereditary thrombophilic disorders).³⁵ Finally, the presence of CMD is particularly relevant also in the pathogenesis of TTS. Indeed, a sympathetic overreactivity following a stressful event may trigger a local myocardial spillover of catecholamines resulting in acute microvascular coronary vasoconstriction and myocardial stunning.^37,38

CMD in Patients With Obstructive CAD

In patients with obstructive CAD, CMD may coexist and determine myocardial ischemia in regions supplied by arteries without stenosis, as well as synergistically contribute to the reduced CFR, and determine myocardial ischemia in regions with epicardial flow limitation.⁷ In fact, preserved coronary arteriolar vasodilator capacity in conjunction with the development of collateral flow may serve to prevent the occurrence of stress-induced myocardial ischemia.³⁹

Moreover, the reduction in post-stenotic perfusion pressure may be able to trigger functional and structural alterations of the microvasculature distal to the stenosis.⁴⁰ Functional alterations may consist of an exaggerated ET-1-induced vasoconstriction together with impaired vasodilator function.⁴¹ Structural alterations might include inward remodeling of coronary resistance arteries enhanced by ET-1, and arteriolar and capillary rarefaction distal to the coronary stenosis.⁶ In particular, microvascular rarefaction appears precociously and persists even after efficacious percutaneous or surgical revascularization.⁴² This phenomenon may partly explain the recently published data of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial on the limited prognostic efficacy of revascularization in patients with inducible moderate-to-severe ischemia and ≥50% stenosis in a major epicardial vessel, underscoring the importance of properly studying the microvascular compartment and to consider mechanisms independent of the epicardial arteries in ischemia symptoms.⁴³

Of interest, recurrent or persistent angina has been shown to occur in up to one-third of patients treated with effective PCI, in particular when T2DM is a known comorbidity.⁴³ The exact contribution to myocardial ischemia and angina of CMD in obstructive CAD is difficult to demonstrate, because of the presence of flow-limiting stenosis, but the clinical relevance of CMD may become evident after the removal of the epicardial obstruction by PCI.⁴⁴

In patients with STEMI, the occurrence of coronary microvascular obstruction (CMVO) represents an acute form of CMD. In this setting, primary PCI (pPCI) is the reperfusion strategy of choice.⁴⁵ However, despite restoring the patency of epicardial coronary vessels, pPCI may fail to achieve optimal reperfusion of myocardial tissue because of the structural and functional impairment of coronary microcirculation occurring in up to 60% of patients.⁴⁵ Of importance, the occurrence of CMVO represents an important predictor for future adverse events, with higher incidence of left ventricular remodeling, HF, and death.⁴⁵ The pathogenesis of CMVO is complex and mechanisms involved are multiple and interacting, including distal atherothrombotic embolization, ischemia–reperfusion injury with endothelial cell death together with cardiomyocyte death, myocardial edema leading to microvascular compression ab-extrinseco, and individual susceptibility associated with pre-existing CMD.^5,45

CMD in Patients With Myocardial Diseases and Valvular Heart Diseases

CMD in HFpEF HFpEF is an umbrella term encompassing a clinically heterogeneous syndrome characterized by classic symptoms and signs of HF despite a normal or near-normal EF.⁴⁶ Comorbidities, such as hypertension, metabolic syndrome and T2DM, are independent risk factors for HFpEF, supporting a comorbidity-driven systemic and cardiac structural and functional derangement.⁴⁷ The presence of underlying CMD due to increased oxidative stress and microvascular inflammation is likely involved in its pathogenesis. Indeed, experimental studies showed that limited endothelial-dependent NO bioavailability promotes proliferation of fibroblasts and myofibroblasts and affects energy-dependent cardiomyocyte relaxation through the hypophosphorylation of the cytoskeletal protein titin.³ Moreover, the inflamed microvascular endothelium allows the migration of monocytes and the release of transforming growth factor (TGF)-β that promotes the differentiation of fibroblasts into myofibroblasts, and collagen production and cross-linking.⁴⁸ However, it is still a matter of debate whether CMD leads to diastolic dysfunction and ultimately HFpEF or the typical alterations associated with HFpEF secondarily lead to CMD. Previous studies suggested that women with CMD often have left ventricular diastolic dysfunction and are at increased risk of developing HFpEF,³ and, recently, Taqueti et al showed that the presence of both CMD and diastolic dysfunction was associated with a markedly increased (>5-fold) risk of HFpEF hospitalization.⁴⁹

CMD in Aortic Stenosis Up to 40% of patients with aortic stenosis experience angina that occurs frequently in the absence of obstructive CAD. Moreover, these patients have reduced CBF, impaired CFR and reduced exercise capacity.⁵⁰

A complex array of abnormalities in myocardial remodeling, coronary microvascular function and pressure gradients are responsible for the distortion of coronary flow and symptoms including: (1) reduced diastolic time of coronary filling (because of prolonged systole); (2) increased diastolic filling pressure (compressing the endocardium and leading to a selective hypoperfusion of the subendocardium); (3) delayed peak systolic forward flow and reduced velocity time integral; (4) disrupted backward expansion wave; (5) capillary rarefaction, arteriolar remodeling and perivascular fibrosis; (6) reversal of normal endocardial-epicardial blood flow ratio at rest, resulting in subendocardial ischemia; (7) low coronary perfusion pressure due to Venturi effect when compared with intracavitary pressure; and (8) increased intramyocardial systolic pressure and delay in myocardial relaxation at the end of systole (which further reduces the time of coronary filling and perfusion).⁵⁰ Of interest, percutaneous and surgical aortic valve replacement are associated with the restoration of myocardial perfusion and contractility and improved microcirculatory function by reducing left ventricular wall stress.⁵¹

CMD in Infiltrative Heart Disease In Anderson-Fabry disease, CMD accounts for the presence of angina in the absence of obstructive CAD and is due to the presence of myocyte hypertrophy, replacement fibrosis, hypertrophy and proliferation of VSMCs and endothelial cells, narrowing intramural arteries, with consequent increase in coronary vascular resistance and myocardial oxygen demand.⁵²

Cardiac amyloidosis is characterized by the extracellular deposition of insoluble fibrils composed of misfolded proteins. The pathogenetic mechanisms of CMD include structural changes of the intramyocardial arteries (infiltration and thickening of the vascular wall with vessel lumen obstruction), functional abnormalities related to the imbalance of autonomic regulation and endothelial dysfunction, and extravascular factors (perivascular and interstitial amyloid deposits), resulting in increased left mass and extramural compression, decreased left ventricular compliance and increased diastolic filling pressure.⁵³

Finally, up to 25% of patients with sarcoidosis have myocardial involvement, although only 5% of patients show clinical manifestations of cardiac disease. Even if only a few patients have obstructive CAD, angina is a frequent symptom in sarcoidosis and the presence of reduced CFR has been demonstrated in such patients, but the underlying mechanisms are still unclear.⁵⁴

CMD in HCM The HCM phenotype is characterized by cardiomyocyte hypertrophy that involves a complex interplay of myocyte disarray, interstitial fibrosis with thickened fibers encasing myocytes, mitral valve and subvalvular abnormalities, and coronary microvascular remodeling. All these structural abnormalities are relevant for the pathogenesis of CMD, and several studies have demonstrated that CFR is more blunted in the subendocardium and the more hypertrophied areas, but is also impaired in the nonhypertrophied ones, in line with the evidence of widespread remodeling of intramural arterioles at autopsy.⁵

CMD and Coronavirus Disease 19 (COVID-19)

Even though the main clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involve the respiratory tract, a significant proportion of patients with COVID-19 manifest troponin release early in the course of the disease, thus reflecting the occurrence of myocardial injury.⁵⁵ Of note, the occurrence of CMD is probably one of the mechanisms responsible for the development of myocardial injury in these patients.

Indeed, CMD may be the consequence of an exaggerated systemic inflammatory response due to host immune system dysregulation consequent to viral infection, thus leading to an exaggerated cytokine release, the inflammasome activation, and finally a proinflammatory milieu that contributes to CMD and diffuse intravascular coagulation.⁵⁵ Moreover, the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE-2), is widely expressed in several organs, including the heart pericytes and endothelial cells. Therefore, SARS-CoV-2 can exert a direct action on microvessels, resulting in capillary endothelial cell dysfunction and microvascular impairment.⁵⁶

Finally, the occurrence of CMD can also contribute to the onset of TTS during the SARS-CoV-2 infection.^38,56

Iatrogenic CMD

In patients undergoing PCI, CMD may occur and limit the clinical benefit due to distal embolization of plaque material during the stenting procedure or to functional alterations occurring in a pre-existent CMD. Moreover, the drug eluted by the stents after PCI has been shown to trigger vasoconstrictor disorders, probably enhancing a pre-existing endothelial dysfunction, with negative effects on both endothelial cell and VSMC function of the active stent drugs released downstream.⁵³ In addition, ischemia due to balloon inflations and stretching of the artery may elicit a sympathetic increase of α-adrenergic constrictor tone in the microcirculation.⁴³

CMD may occur also after coronary artery bypass grafting and it may be due to multiple factors such as cardioplegia, extracorporeal circulation, periprocedural ischemia and inflammatory response.⁵⁷

Finally, CMD is also common in heart transplant recipients with cardiac allograft vasculopathy (CAV) and, importantly, CMD has been shown to be independently associated with the onset of epicardial CAV and with a higher risk of death, regardless of CAV onset.⁵⁸

Conclusions

CMD represents a combination of structural and functional abnormalities affecting the coronary microcirculation. CMD may manifest across a broad spectrum of cardiovascular diseases with different underlying mechanisms. However, the still limited knowledge of the mechanisms of CMD precludes specific therapeutic interventions. Thus, further research is warranted in order to develop personalized forms of treatment.

Funding / Conflicts of Interest

None.

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