Critical role of the coronary microvasculature in heart disease: From pathologic driving force to “innocent” bystander

Abstract

The coronary microvasculature is responsible for providing oxygen and nutrients to myocardial tissue. A healthy microvasculature with an intact and properly functioning endothelium accomplishes this by seemless changes in vascular tone to match supply and demand. Perturbations in the normal physiology of the microvasculature, including endothelial and/or vascular smooth muscle dysfunction, result in impaired function (vasoconstriction, antithrombotic, etc.) and structural (hypertrophic, fibrotic) abnormalities that lead to microvascular ischemia and potential organ damage. While coronary microvascular dysfunction (CMD) is the primary pathologic driving force in ischemia with non-obstructive coronary artery disease (INOCA), angina with no obstructive coronary arteries (ANOCA), and myocardial infarction with non-obstructed coronary arteries (MINOCA), it may be a bystander in many cardiac disorders which later become pathologically associated with signs and/or symptoms of myocardial ischemia. Importantly, regardless of the primary or secondary basis of CMD in the heart, it is associated with important increases in morbidity and mortality. In this review we discuss salient features pertaining to known pathophysiologic mechanisms driving CMD, the spectrum of heart diseases where it places a critical role, invasive and non-invasive diagnostic testing, management strategies, and the gaps in knowledge where future research efforts are needed.

1. Coronary microvasculature

The coronary vasculature, comprised of the epicardial vessels and the coronary microvasculature, is tasked with providing oxygen and nutrients to and removing waste from the myocardium. From proximal to distal, they decrease in size and carry out distinct functions. Epicardial arteries (also known as conduit arteries) are >500 μm in size and their role is to transport blood with minimal resistance. The coronary microvasculature represents all vessels distal to the conductive arteries, including pre-arterioles and arterioles, capillaries, membrane, venules, and pericytes [1]. The coronary microvasculature is the essential determinant of myocardial perfusion, by matching myocardial blood and nutrient supply to cardiac work [2]. Pre-arterioles and arterioles are key regulators of blood flow. Pre-arterioles (~100–500 μm in size) are effective in maintaining a narrow range of pressure at the origin of arterioles despite changes in coronary perfusion. Arterioles (<100 μm in size) function to match blood supply with local oxygen demand via a dilatation response to local metabolites [1]. Capillaries, the most distal and smallest component of the microvasculature (<10 μm), are the primary site of gas and nutrient exchange [3]. Other important components, but less well studied, include pericytes, the membrane, and venules [4].

Acute changes in coronary blood flow mainly occur in response to neurogenic mechanisms as metabolic stimuli are responsible for slower changes and are regulated by microvascular tone through myogenic and flow-mediated responses [5]. Chronic adjustments involve structural remodeling of the coronary microvasculature via changes in the vascular tone regulated by endothelial and metabolic factors along with mechanical forces such as shear stress acting on the endothelium with resulting effects on underlying vascular smooth muscle cells [6]. Perturbations in these mechanisms lead to the pathologic state of coronary microvascular dysfunction.

2. Coronary microvascular dysfunction

Coronary microvasculature dysfunction (CMD) is a result of functional and structural abnormalities of the pre-arterioles, arterioles, and capillaries, culminating in myocardial tissue ischemia, necrosis, and subsequent dysfunction. Clinically, CMD may present as angina-like chest pain with no flow-limiting epicardial coronary artery stenosis on coronary angiography [7]. It is an important clinical entity to recognize since patients with chest pain and no flow-limiting epicardial coronary artery disease may be misdiagnosed as having non-cardiac chest pain. Risk factors for CMD include traditional cardiovascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking. Additional risk factors for CMD include female sex, younger age, and chronic inflammatory conditions such as systemic lupus erythematosus and rheumatoid arthritis [8], [9], [10], [11]. Female sex is a particularly important risk factor; women of peri- or post-menopausal age typically present with greater number and severity of CMD risk factors than men [8]. In fact, nearly half of women who present with chest pain and no obstructive coronary arteries have CMD [12].

Chronic inflammatory states are also associated with CMD. Patients with chronic inflammatory and autoimmune disorders have CMD as assessed by reduced coronary flow reserve (CFR) in the presence of non-obstructive coronary artery disease (CAD) [13], [14], [15]. Elevated high-sensitivity C-reactive protein levels have been documented in subjects with CMD compared to control subjects, suggesting a chronic inflammatory condition [13], [16].

The pathophysiology of CMD encompasses both functional and structural abnormalities including endothelial dysfunction, impaired autoregulation, vasospasm, and microthrombosis. Under normal conditions the coronary endothelium produces vasoactive agents, such as nitric oxide and prostacyclin, to maintain adequate perfusion. An imbalance between vasodilators and vasoconstrictors (favoring vasoconstriction) impairs coronary blood flow [17]. This phenomenon is of paramount importance in the heart because at rest there is a near maximal oxygen extraction such that any increased oxygen demand must be met with proportionally increased coronary blood flow. In CMD, the ability to increase coronary blood flow is attenuated, resulting in myocardial ischemia at times of increased myocardial oxygen demand [18]. Microvascular remodeling consisting of luminal narrowing of the intracardiac arterioles and capillaries, perivascular fibrosis, and destruction of the capillary bed (capillary rarefaction) are pathologic processes that lead to increased arteriolar resistance and decreased tissue perfusion in CMD [3]. Microvascular remodeling resulting in CMD can also occur in patients with flow-limiting epicardial coronary artery disease, providing an explanation as to why anginal symptoms may persist after percutaneous or surgical revascularization of epicardial artery disease [19]. Coronary vasospasm is another significant contributor to CMD in patients with microvascular angina and is associated with endothelial dysfunction. In one study, nearly half of patients with stable angina had normal or near-normal coronary angiograms, but vasoreactivity testing with acetylcholine induced epicardial and/or microvascular coronary spasm in nearly two thirds of them [20]. Lastly, microthrombosis is another pathologic process that is operational in CMD. Elevated serum thrombomodulin (an anti-coagulant) levels have been documented in patients with CMD which is considered a compensatory response that is associated with decreased adverse cardiac events [21], [22].

3. Spectrum of coronary microvascular dysfunction

This pathologic entity is now referred to as symptoms and/or signs of ischemia with non-obstructive coronary artery disease (INOCA) and angina with no obstructive coronary arteries (ANOCA). Furthermore, it is well accepted that it is not a benign condition and rather is associated with significant morbidity and mortality [23]. It is important to note that while INOCA and ANOCA is predominantly diagnosed in women, it also affects men [23], [24]. Data from the Women's Ischemia Syndrome Evaluation (WISE) study suggest that patients with persistent chest pain and no obstructive epicardial coronary artery disease have worse clinical outcomes compared to those without persistent pain including a near 2-fold increase in the risk of myocardial infarction and stroke [25].

Myocardial infarction with non-obstructed coronary arteries (MINOCA) is also common, occurring in 5–10 % of all myocardial infarctions, particularly in younger women with fewer traditional risk factors presenting with non-ST elevation myocardial infarction [26]. The diagnosis of MINOCA is made clinically following coronary angiography that shows no coronary artery stenosis ≥50 % in a potential infarct-related artery [27]. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial the prevalence of MINOCA was ~9 % [28], and one-year non-cardiac death was significantly higher in those with MINOCA compared to those with obstructive disease [28]. While there are some data to suggest that treatment with the standard medications usually prescribed post-myocardial infarction in cases of obstructive disease may be beneficial [29], randomized controlled trial data are lacking. Moreover, due to the heterogenous characteristics of this group it has been suggested that cardiac magnetic resonance (CMR) imaging can more fully delineate MINOCA from other causes of elevated troponin, such as myocarditis, spontaneous coronary artery dissection, coronary embolization [26], and Takotsubo syndrome [30]. This is due to the ability of CMR to identify and quantify myocardial scar. In Takotsubo syndrome, a condition also highly prevalent in women [31], CMD may play a localized role at least in some cases [32], [33].

As previously mentioned, CMD can also be present in patients with flow-limiting lesions in the epicardial coronary arteries. In fact, abnormal microvascular function is thought to precede the development of obstructive epicardial coronary artery disease [34] and may compound the extent of myocardial ischemia [19]. One important consideration is that the presence of CMD in patients with obstructive epicardial coronary artery disease may result in an underestimation of epicardial artery lesion severity when evaluated invasively by fractional flow reserve. In one study, investigators reported that in patients with CMD, the values obtained using fractional flow reserve to identify flow-limiting epicardial artery stenoses were higher than in patients with no evidence of CMD [35]. Not only can this lead to deferred revascularization of an epicardial lesion that is flow-limiting but may also explain why some patients have persistent ischemic symptoms even after “technically” successful revascularization of epicardial artery lesions.

In addition to being a primary driving force in INOCA, ANOCA, and MINOCA, there are many other heart-related conditions where CMD is a bystander, but may play a pathologic role. Systemic hypertension (without angina or signs of ischemia) [36], non-ischemic cardiomyopathy and infiltrative cardiomyopathies [37], diabetic cardiomyopathy [38], hypertrophic cardiomyopathy [39], [40], [41], [42], aortic stenosis [43], [44], and other disorders, such as HIV [45], and chemotherapy-associated cardiomyopathy are associated with CMD [46] (Table 1). Importantly, the bystander presence of CMD in these conditions is associated with worse outcomes. For example, the presence of CMD as measured by decreased CFR in patients with hypertrophic cardiomyopathy is a strong and independent predictor of adverse left ventricular remodeling, left ventricular dysfunction, and adverse clinical outcomes including death [39], [40], [41], [42]. Histologic studies have shown abnormalities of the coronary microvasculature in HCM including smaller lumen and decreased capillary density [47], [48]. CFR is also decreased in aortic stenosis and is related to the severity of the stenotic valve orifice [43]. In this patient population, CMD may promote myocardial fibrosis and left ventricular dysfunction. In one study of patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, CFR improved after the valve was replaced [44]. In hypertensive heart disease, a highly prevalent condition [49], pathologic changes associated with left ventricular hypertrophy include changes in the extracellular matrix, increased size of cardiomyocytes, and derangement of the coronary microvasculature, and can lead to heart failure with a reduced or preserved ejection fraction [50]. Recent data suggest that CMD leading to ischemia and fibrosis plays an important role in the pathophysiology driving heart failure with preserved ejection fraction (HFpEF), a condition associated with significant morbidity and mortality [51], [52]. Decreased coronary blood flow as assessed by coronary reactivity testing is associated with the presence of diastolic dysfunction in patients with HFpEF and a 5-fold increased rate of hospitalization for heart failure exacerbation [51]. Whether CMD-associated ischemia leads to diffuse myocardial fibrosis, diastolic dysfunction and HFpEF is currently being studied in the NIH-funded Women's Ischemia Syndrome Evaluation Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-Heart Failure with Preserved Ejection fraction (WISE preHFrEF) project (ClinicalTrials.gov NCT#03876223).

Table 1.

The spectrum of coronary microvascular dysfunction in heart disease.

CMD as primary driver of pathology

Angina with no obstructive coronary arteries

Ischemia with non-obstructive coronary artery disease

Myocardial infarction with non-obstructed coronary arteries

CMD as “innocent” bystander

Aortic stenosis

Diabetic cardiomyopathy

Hypertensive heart disease

Hypertrophic cardiomyopathy

HIV-associated cardiovascular disease

Chemotherapy-induced cardiomyopathy

Heart failure with preserved ejection fraction

Non-ischemic and infiltrative cardiomyopathy

In the early stages of diabetic cardiomyopathy structural and functional abnormalities of the microvasculature are present that result in impaired myocardial perfusion and subsequent myocardial fibrosis [38]. In these patients, the presence of CMD among diabetics without flow-limiting epicardial stenoses was associated with at least as high and possibly higher rates of cardiac death compared to nondiabetic patients with known obstructive coronary artery disease [53]. Whether CMD is the primary pathologic driver of non-ischemic cardiomyopathy and infiltrative cardiomyopathies (such as Fabry's disease and amyloidosis) or if it is a bystander is unclear [37]. Regardless, the presence of CMD is associated with worse clinical outcomes including heart failure and death and could represent a focus of therapy for patients with these cardiomyopathies [37]. Endothelial dysfunction plays an important role in early cardiac transplant vasculopathy. In one study of heart transplant recipients, investigators reported significant epicardial coronary artery vasoconstriction and increased coronary blood flow in response to acetylcholine one year after transplantation. These patients had normal coronary flow reserve and no angiographic evidence of transplant vasculopathy [54]. Lastly, in people living with HIV, death due to cardiovascular disease has increased and CMD may play an important role [45]. Data suggest that CMD may be more common in HIV patients compared to those without HIV but with similar traditional cardiac risk factors [45]. The coronary microvasculature, therefore, could serve as a novel target for HIV-associated cardiovascular disease [45].

Patients with chronic inflammatory and autoimmune rheumatic disorders such as systemic lupus erythematosus and rheumatoid arthritis, are at increased risk for adverse cardiac events and CMD plays a crucial role in this pathophysiology. A combination of chronic inflammation and oxidative stress results in endothelial dysfunction and capillary rarefaction resulting in microvascular and macrovascular dysfunction [55]. In these patients, reduced CFR is common and is a major cause of chest pain in the absence of epicardial coronary artery disease [56]. CMD has been reported in nearly half of patients with systemic lupus erythematosus with suspected INOCA [57]. In this patient population, microvascular dysfunction is present in multiple organs including the heart, kidneys, lungs, and skin. This underscores an intriguing hypothesis that suggests microvascular dysfunction of the heart is an expression of a systemic illness that worsens with age and is accelerated by vascular risk factors. Blindness, small vessel disease of the brain, pulmonary hypertension, renal failure, and peripheral arterial disease are all conditions where microvascular dysfunction plays a key role [58].

4. Diagnosis

Consensus opinion from the Coronary Vasomotion Disorders International Study Group (COVADIS) suggests that more definitive testing for CMD should be pursued if the patient fulfills the following criteria: (1) presence of symptoms suggestive of myocardial ischemia; (2) objective documentation of myocardial ischemia; (3) absence of obstructive coronary artery disease (defined as <50 % coronary diameter reduction and/or fractional flow reserve >0.80); and (4) confirmation of a reduced coronary blood flow reserve and/or inducible microvascular spasm [59]. Currently diagnostic techniques involve both non-invasive and invasive modalities, each with its own inherent risks and benefits. Non-invasive methods to assess for CMD include transthoracic doppler echocardiography (TTDE) [60], positron emission tomography (PET) [18], CMR [61], and myocardial first-pass computed tomography (CT) [62]. PET is considered the reference standard in non-invasive testing for CMD. It measures myocardial perfusion reserve (MPR) by quantifying myocardial blood flow (MBF) at rest and at maximal hyperemia with an MPR < 2 considered as diagnostic of CMD. TTDE uses a pulsed-wave doppler focused on the mid left anterior descending coronary artery territory to calculate the coronary flow velocity ratio, and a value <2–2.5 suggests impaired microvascular function. This modality, however, is associated with technical pitfalls and requires a steep training curve. CMR measures myocardial perfusion reserve index and provides excellent anatomical visualization of the heart but it not an option in patients with contra-indications and difficult for those with claustrophobia. A major limitation to all these non-invasive tests is that acetylcholine cannot be used to test endothelial function.

Invasive coronary reactivity testing in the cardiac catheterization laboratory offers the benefit of identifying the presence of both abnormal vasodilation and constriction pathways. The ratio between coronary blood flow at maximal pharmacologic stress and at rest (coronary flow reserve) can be measured. Newer catheter-based invasive methods of assessing for CMD have allowed for more direct evaluation of the coronary microvasculature [63]. Despite the availability of an array of invasive and non-invasive diagnostic techniques, a significant number of patients with CMD remain undiagnosed. Circulating biomarkers in CMD to diagnose and follow response to therapy is a promising area of research and may allow point of care testing in a wide patient population from a simple blood draw [64], [65].

5. Management

Medications prescribed for secondary prevention for coronary artery disease and conventional anti-anginal medications have been studied in CMD [66]. In general, these studies are small, short-term pilot studies, with the limitations associated with this type of design. Nonetheless, regimens that include a potent statin in conjunction with maximally tolerated doses of angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers if intolerant) have been associated with amelioration of symptoms and improved microvascular function [67]. In an early study published in 1999, treatment with the beta-blocker, atenolol, resulted in a statistically significant reduction in the number of anginal episodes and was associated with improved quality of life [68]. Vasodilatory beta blockers such as nebivolol likely improve symptoms through activation of the eNOS pathway or preservation of nitric oxide activity [69]. Calcium channel blockers can also contribute to management of CMD via a vasodilatory mechanism [70]. Nitrates have been shown to be most effective in reducing angina when used in combination with either a calcium-channel blocker or a beta-blocker [71]. Treatment with ranolazine was found to improve CFR and decrease angina frequency [72], [73].

It has been proposed that drugs that work against the effects of angiotensin II in the renin-angiotensin-aldosterone system can improve the endothelial dysfunction that drives CMD [74]. One study demonstrated that enalapril therapy reduced exercise-induced ischemia in patients with CMD [75]. In a substudy of WISE, subjects with coronary flow reserve <3.0 following adenosine were randomized to quinapril (80 mg) or placebo for 4 months. Compared to placebo, those randomized to quinapril not only had significantly increased coronary flow reserve on invasive testing, but also had a significant reduction in anginal symptoms [76].

More targeted drugs including endothelin receptor antagonists and rho-kinase inhibitors have also been studied [77]. In another randomized study, simvastatin therapy was shown to significantly improve endothelial function in CMD patients as measured by flow-mediated dilatation of the brachial artery compared to placebo [78]. Moreover, subjects randomized to simvastatin treatment had longer times to ST segment changes on stress testing compared to those randomized to placebo. Novel, non-medication-based therapies including spinal cord stimulation [79], and exercise training [80] have also been studied with positive effects. We refer the reader to the paper published by Bairey Merz and colleagues for a complete review of the current state of CMD treatment [81].

The Women's Ischemia Trial to Reduce Events in Non-Obstructive CAD (WARRIOR, ClinicalTrials.gov NCT#03417388) is a multi-center, prospective study randomizing women with symptoms of ischemia and non-obstructive CAD to usual care or intensive medical therapy including high-intensity statin, aspirin and maximally tolerated angiotensin-converting enzyme inhibitor/or angiotensin receptor blocker [82]. Results of this study will provide important information regarding response to treatment and long-term clinical outcomes to inform future guideline recommendations.

6. Future considerations

While much has been learned about CMD there are still many unanswered questions regarding its pathophysiology. Mechanistic studies are needed to define the extent of structural defects and the functional abnormalities in CMD. Results from these studies will not only help us better understand the pathophysiology driving CMD but may also identify possible targets for novel therapies. Future studies should include men and adolescents to better understand the natural history of this disease process, and other cardiac conditions where CMD is considered an “innocent” bystander but plays a pathologic role and is associated with adverse clinical outcomes. Recently, the concept of multiple organ microvascular dysfunction has been raised [17], [58] and of particular interest CMD and cerebral small vessel disease [83]. Lastly, research focused on identification and validation of biomarkers and genetic polymorphisms may improve our ability to predict risk of developing CMD and to diagnose it sooner.

Funding

Department of DefenseW81XWH-17-2-0030 (Pepine).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.