Diseases of the Coronary Microcirculation: Diagnosis and Treatment

Background: Coronary microvascular dysfunction (CMD) comprises a variety of pathogenic mechanisms that impair the microcirculation of the heart. Clinical studies have shown that 30–50% of patients suffering from myocardial ischemia without significant coronary artery stenosis have CMD. The disease is associated with elevated mortality and poor quality of life. Whenever a patient presents with symptoms of angina pectoris and no underlying disease is detected by the usual methods, CMD should be considered a possible cause.

Methods: This review is based on publications retrieved by a selective search in PubMed and on current international guidelines and recommendations of specialty societies.

Results: The diagnosis of CMD is based on objective evidence of a microvascular origin of symptoms. The guidelines contain a class IIa recommendation for invasive coronary flow reserve and microvascular resistance measurements. Noninvasive tests such as positron emission tomography and cardiac magnetic resonance imaging are less accurate and are given a class IIb recommendation. No high-quality therapeutic trials are available to date, and the treatment of CMD is thus based on that of chronic coronary syndrome. Lifestyle modification is performed to reduce risk factors. Patients with an abnormal coronary flow reserve or elevated microvascular resistance can be treated with an ACE inhibitor or angiotensin receptor blocker. Beta-blockers and calcium channel antagonists can relieve angina pectoris. Statins lower the LDL level and have positive pleiotropic effects. First-line treatment can be supplemented with further medications.

Conclusion: Approximately 25% of patients with CMD have symptoms that do not respond to intensive treatment with the currently available modalities. New treatments, including interventional therapies, are being studied. Their long-term benefit remains to be assessed and compared to that of the existing methods.

Even today, physicians are still puzzled by patients presenting with myocardial ischemia in the absence of hemodynamically significant coronary artery stenosis. The majority of these patients are incorrectly diagnosed with noncardiac chest pain and discharged from specialist care (1). In a registry study, Patel et al. (2) found that in 59% of patients with suspected coronary artery disease (CAD), coronary angiography showed normal coronary arteries or nonobstructive CAD. Despite marked symptoms, many of these patients are not diagnosed satisfactorily and consequently do not receive adequate treatment (3). The fact that an unremarkable angiography does not in any way rule out vascular dysfunction is often overlooked (4). In addition, patients with epicardial vascular disease may also have a disorder of small intramyocardial vessels with associated functional phenomena. Coronary microvascular dysfunction (CMD) is defined as a mismatch between cardiac oxygen demand and supply due to a dysfunction of microvessels (diameter <500 µm) (5, 6). Together with microvascular spasm, CMD is part of a condition known as ischemia with non-obstructive coronary arteries (INOCA; or MINOCA: myocardial infarction with non-obstructive coronary arteries) (7). Over the past few years, it has gained in importance and comprises various pathogenic mechanisms that result in impaired microcirculatory function. The differential diagnosis in patients with angina pectoris with no underlying disease should thus always include CMD (clinical prevalence 30–50% [1]). Diseases of the coronary microcirculation are associated with elevated mortality and poor quality of life. A meta-analysis (8) to investigate the association between CMD and future events revealed an almost fourfold increase in mortality and a fivefold increase in the risk of serious cardiovascular events compared to patients without CMD (odds ratio [OR] 3.93; 95% confidence interval: [2.91; 5.30]; p<0.001; OR 5.16 [2.81; 9.47]; p<0.001). Given its high prevalence and the potentially fatal complications associated with CMD (death from cardiovascular disease, [N]STEMI), it is vital to identify these patients with targeted diagnostic investigations so that repeated, invasive testing that does no lead to a definite diagnosis can be avoided and symptomatic treatment can be initiated.

Methods

This review is based on pertinent publications retrieved from a selective literature search in the PubMed database and on current international guidelines and recommendations of specialty societies (Box).

Box

Literature search

Pathogenesis

The coronary artery system basically consists of three compartments. The proximal compartment comprises the large epicardial coronary arteries visualized in coronary angiography; this is where obstructive atherosclerosis and thus the underlying structural mechanisms, such as the formation of stenosing plaques, manifest (9). Pre-arterioles, with a diameter of 100 μm to 500 μm, form the intermediate compartment and create significant resistance to blood flow, for example due to perivascular fibrosis and inflammatory processes (Figure 1 “Structural mechanisms [microvascular]”). The distal compartment is composed of arterioles with a diameter less than 100 μm (11); here, the main structural and functional mechanisms are similar to those in the intermediate compartment. The microcirculation is composed of the pre-arterioles, arterioles and capillaries.

Figure 1

Epicardial and microvascular mechanisms of ischemia, adapted from (10)

A key functional mechanism is based on the phenomenon of increased vascular resistance under resting conditions, with or without impairment of vasodilatation (elevated vascular resistance associated with hyperemia) (10). Increased vasoconstriction of the microvessels, referred to as microvascular spasm, is abnormal (10). Especially in patients with risk factors for CAD or with underlying cardiomyopathy, CMD can also be the result of structural changes (Figure 1).

Clinical manifestation

Angina pectoris caused by coronary microvascular dysfunction is referred to as microvascular angina (MVA) (10). Microvascular angina can occur in patients without history of obstructive CAD or left-ventricular hypertrophy (10) and should be distinguished from MVA related to concomitant disease. Patients with MVA typically report retrosternal thoracic discomfort or pressing or stinging chest pain and show signs of ischemia in noninvasive studies (1, 12). Symptoms can occur both during exercise and at rest; in addition, many of the patients with MVA frequently suffer from angina equivalents, such as dyspnea.

In summary, recurrent, exertional chest pain after invasive exclusion of obstructive CAD should raise suspicion of the possible presence of MVA.

Diagnosis

The diagnosis of MVA should be based on objective evidence supporting the microvascular origin of the symptoms (13) (Table 1). While the current German National Disease Management Guidelines for Chronic Coronary Heart Disease do not provide any recommendations for the treatment of patients with microvascular dysfunction, the current Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes of the European Society of Cardiology (12) state that accurate assessment of microvascular function is a critical prerequisite for setting a specific treatment strategy. Two principal mechanisms underlying CMD should be tested separately.

Table 1

Diagnostic parameters for suspected microvascular angina, adapted from Ong et al. (1) and Kunadian et al. (7)

Impaired microcirculatory conductance can be diagnosed by measuring the coronary flow reserve (CFR) or the microvascular resistance. The coronary reserve is defined as the ratio between the maximum coronary blood flow under conditions of hyperemia and the resting blood flow. Thus, a reduction in coronary reserve can be the result of both inadequate vasodilation (reduced flow under conditions of hyperemia) and increased coronary flow already under resting conditions. However, the measurement is prone to errors, for example in patients with myocardial hypertrophy, coronary artery fistulas or high blood pressure, in whom resting blood flow is generally increased. While coronary flow reserve can be determined both invasively with cardiac catheterization and non-invasively, microvascular resistance can only be measured invasively.

The assessment of microvascular endothelial function is a requirement for the diagnosis of arteriolar dysregulation. Which test is ultimately chosen depends on availability, expertise of the examiner and suspected pathomechanism (Table 2).

Table 2

Diagnostic methods for the assessment of CMD, based on the current guidelines on chronic coronary syndrome (12)

Noninvasive diagnostic techniques

When noninvasive tests are used to establish the diagnosis of CMD (Table 2), it is necessary to first rule out the presence of hemodynamically significant coronary stenosis (10). The measurement methods used to describe microvascular function are based on the quantification of coronary blood flow (5). Transthoracic Doppler echocardiography determines the maximum diastolic blood flow in the epicardial arteries at rest and during exercise after administration of adenosine or dipyridamole. Coronary flow velocity reserve (CFVR) is the ratio derived from these measurements; in patients with normal coronary arteries, CFVR is a surrogate parameter for microvascular function (14). A sensitivity of 89% and specificity of 90% has been reported for the detection of a change in CFVR, along with marked examiner dependence (15). Positron emission tomography is the gold standard for the non-invasive measurement of myocardial blood flow; standardized methods for the diagnosis and documentation of microvascular dysfunction that are based on this technique are described in the consensus paper of the JACC Cardiovascular Imaging Expert Panel (16). This imaging technique allows to quantify microvascular function based on the measurement of myocardial blood flow (5). Here, the coronary flow reserve is determined by measuring myocardial blood flow at rest and during maximum hyperemia (14). This is typically induced by continuous intravenous administration of adenosine that directly triggers coronary vasodilation via various adenosine receptors. It has been shown that there is an inverse relationship between CFR and the occurrence of cardiovascular events (hazard ratio 0.80 [0.75; 0.86] per 10% increase in coronary flow reserve [17]). Cardiac magnetic resonance imaging is also gaining in importance. Coronary flow reserve and myocardial blood flow can be derived by quantifying resting and stress perfusion, analogous to PET (14). Semi-quantitative methods determine the myocardial perfusion reserve index (MPRI) (sensitivity 73%, specificity 74% with an MPRI<1.84 [18]), which is a surrogate parameter for the coronary flow reserve (14).

Invasive diagnostic techniques

CMD can be accurately diagnosed during one cardiac catheterization procedure (Figure). A detailed description of these methods is provided in a Consensus Paper of the British Heart Foundation/National Institute for Health Research (6). Impaired microcirculatory conductance can be diagnosed by measuring the coronary flow reserve or the microvascular resistance (12). To determine the microvascular resistance, the microvascular resistance index and the coronary flow reserve are calculated by combining the intracoronary pressure with data from a thermodilution procedure. To this end, a coronary pressure wire is inserted through which all measurements are taken. Both coronary flow reserve and vascular resistance are usually determined while vasodilators, such as adenosine, papaverine or regadenoson, are intravenously administered (12). The patient in the Figure was diagnosed with microvascular angina using this approach (ICD-10 I20.9).

Figure

Cardiological findings with suspected microvascular dysfunction

If the described endothelium-independent vasodilation is found to be unimpaired, endothelium-dependent microvascular function should be assessed (3). The guidelines (12) issue a class IIb recommendation for selective intracoronary administration of acetylcholine, which allows conclusions to be drawn about arteriolar dysregulation. This approach involves the intracoronary administration of escalating doses of acetylcholine (2 µg, 20 µg und 100 µg); as a result, patients may experience angina pectoris and bradycardic arrhythmias.

In coronary arteries with intact endothelium, exposure to acetylcholine results in the dilation of epicardial and microvascular blood vessels (3). ECG changes typical of ischemia along with reproduced angina pectoris in the absence of epicardial spasm (defined as a reduction in vascular diameter of more than 90%) is suggestive of microvascular coronary spasm (3, 12, 19). The authors of this review (TG and TM) use a standardized protocol to diagnose coronary spasm.

Management

Due to the lack of robust data, it is challenging to determine the best therapeutic strategy (3). Thus, in everyday clinical practice, treatment is often empirical (10, 20), based on small studies only some of which ultimately demonstrated pathophysiological links with microvascular angina. Given the lack of specific recommendations on microvascular angina, the levels of evidence stated below refer to the management of chronic coronary syndrome (12). Thus, in all patients with symptomatic CMD, the treatment of stable angina pectoris should include individual modifications of lifestyle factors to minimize existing risk factors (evidence level C), to alleviate symptoms and to improve the quality of life (12).

Drug treatment should target the main mechanism responsible for microvascular dysfunction (12) (Figure 2). For cardiovascular risk reduction, the use of ACE inhibitors or angiotensin receptor blockers (ARBs) should be considered in patients with abnormal coronary flow reserve or increased microvascular resistance and an unremarkable acetylcholine provocation test (evidence level A in patients with additional arterial hypertension, otherwise level B); ACE inhibitors improve CFR in patients with microvascular dysfunction (21). Statins (evidence level A) reduce LDL levels and thus cardiovascular risk; their use is further supported by their pleiotropic effects, such as the reduction in atherosclerosis-related inflammatory reactions or improvements in endothelial function. For example, a single-blind study showed that the time to onset of symptoms (585 ± 165s versus 507 ± 110s) and ST segment depression (419 ± 162s versus 256 ± 102s) during an exercise ECG was prolonged (in patients treated with pravastatin) (22). The first-line therapy of angina pectoris should include beta-blockers (evidence level A) (12, 23). If this does not achieve adequate symptom control, beta-blockers can be combined with calcium channel blockers; the latter can also be administered alone in patients intolerant to beta-blockers (evidence level A). In 1985, Cannon et al. showed that the use of calcium channel blockers in patients with chronic coronary syndrome without stenosing CAD reduced the frequency of angina (21 ± 21 versus 35 ± 27 episodes) and the required dose of nitroglycerine (23 ± 27 versus 41 ± 50 tablets) (Table 3) (24). The effectiveness of short-acting nitrates (evidence level B) varies widely and has to be frequently reassessed; long-acting nitrates are often ineffective (7). Furthermore, blood vessels with a diameter of less than 100 µm are always resistant to nitrates; consequently, nitrates should play no role in the treatment of MVA (25). First-line treatment can be supplemented with further medications. Ranolazine (evidence level B) leads to an improvement in ventricular compliance and this, in turn, is thought to have an impact on microvascular function. In this respect, there is conflicting evidence from clinical trials (7, 26, 27, 28, 29). However, Rambarat et al. (30) demonstrated that stratification by baseline CFR can be useful. When treated with ranolazine, patients with low CFR showed an improvement in angina pectoris, measured using the Seattle Angina Questionnaire (SAQ, range 0 [daily angina] to 100 points [never angina] Δ 9.14 ± 17.55 versus Δ −0.29 ± 14.24; [1.14; 17.72], equivalent to a clinically significant reduction in angina). Ivabradin can alleviate angina pectoris, although it has no direct effect on microvascular function. The improvement in symptoms may be due to a reduction in heart rate (10). However, the effectiveness in patients with MVA has not yet been adequately evaluated (7, 28, 31). Implantation of a coronary sinus reducer during cardiac catheterization is a novel treatment strategy. The reducer has been approved for the treatment of patients with CAD and refractory angina pectoris and is currently evaluated also in patients with MVA in clinical trials (for example, the COSIMA trial).

Figure 2

Therapeutic strategies for microvascular dysfunction

Table 3

Selected studies on the drug treatment of chronic coronary syndrome

In patients with microvascular spasm, calcium channel blockers are the first-line antianginal drugs of choice, in addition to control of cardiovascular risk factors and optimization of lifestyle factors (4, 12). The guidelines (12) recommend treatment of microvascular spasm in the same way as epicardial spasm and thus also the use of long-acting nitrates.

Clinical implications and perspectives

The most recent guidelines (12) addressed CMD for the first time and made recommendations for treatment (32). In about 25% of patients, the symptoms do not respond to the selected treatment, despite presumably optimal therapy (33). While enhanced external counter pulsation (EECP) and spinal cord stimulation (SCS) can alleviate angina pectoris and increase exercise capacity, they should only be considered in patients with symptoms refractory to the first-line and second-line drug treatments mentioned above (7, 34). The latter invasive method has so far been used in patients with severe obstructive CAD and refractory angina pectoris. Ekre et al. (35) found that the improvement in angina pectoris with SCS was comparable to that of bypass surgery (self-reported symptoms in the Nottingham Health Profile reduced at six months from 24 ± 3 to 15 ± 2 points). Of particular note is the new emphasis on invasive hemodynamic diagnosis. In the CorMicA trial, Ford et al. (4) showed that invasive coronary function testing in combination with a stratified medical therapy significantly improved the health status of patients with angina pectoris without obstructive CAD. Their data showed that the study intervention resulted in an improvement of angina symptoms at six months (improvement of SAQ-measured quality of life by 10.48 points; [2.18; 18.79]). The WARRIOR trial (NCT03417388) is investigating the effects of an intensified treatment with statins, ACE inhibitors and aspirin compared to standard of care in patients with symptoms or signs of ischemia without obstructive CAD (7, 34). The randomized COSIMA trial (NCT04606459) takes a novel interventional treatment approach. Patients with symptomatic MVA receive either a drug treatment in conformity with existing guidelines or a sinus reducer. In a randomized cross-over study (MACCHUS), we showed that the “reduction” of the coronary sinus with a Swan-Ganz balloon, which simulates a sinus reducer, triggers a decrease in coronary microvascular resistance in patients with microvascular angina (Ullrich et al., in press, JAMA Cardiology). The hypothesis that this phenomenon leads to an improvement in quality of life and alleviation of angina symptoms has been confirmed preliminarily in three small cohort studies (36, 37, 38).

In the future, CMD should be recognized as a clinically important entity in routine practice. Awareness of the disease must be continuously raised among medical professionals in order to ensure that affected patients are identified and treated in a timely manner (7).

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 4 February 2023, revised version accepted on 24 August 2023.

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Dr. med. Helen Ullrich-Daub

Universitätsmedizin Mainz, Zentrum für Kardiologie, Kardiologie 1

Deutsches Zentrum für Herz-Kreislauf-Forschung

Standort RheinMain

Langenbeckstraße 1

55131 Mainz

Germany

Cite this as:
Ullrich-Daub H, Daub S, Olschewski M, Münzel T, Gori T: Diseases of the coronary microcirculation: diagnosis and treatment. Dtsch Arztebl Int 2023; 120: 739–46. DOI: 10.3238/arztebl.m2023.0205

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