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Reappraisal of Ischemic Heart Disease

Fundamental Role of Coronary Microvascular Dysfunction in the Pathogenesis of Angina Pectoris

Juan-Carlos Kaski, Filippo Crea, Bernard J. Gersh, and Paolo G. Camici

Abstract

In recent years, it has become apparent that coronary microvascular dysfunction plays a pivotal pathogenic role in angina pectoris. Functional and structural mechanisms can affect the physiological function of the coronary microvasculature and lead to myocardial ischemia in people without coronary atheromatous disease and also in individuals with obstructive coronary artery disease. Abnormal dilatory responses of the coronary microvessels, coronary microvascular spasm, and extravascular compressive forces have been identified as pathogenic mechanisms in both chronic and acute forms of ischemic heart disease. The condition characterized by anginal symptoms and evidence of myocardial ischemia triggered by coronary microvascular dysfunction, in the absence of obstructive coronary disease, is known as microvascular angina. The concept of microvascular angina, however, may extend further to include patients with obstructive coronary artery disease and individuals with angina after coronary revascularization or heart transplantation because coronary microvascular dysfunction contributes to myocardial ischemia in many such patients. Patients with microvascular angina constitute a sizeable proportion of all cases of stable angina undergoing diagnostic coronary angiography and of those with persisting angina after successful coronary revascularization. Coronary microvascular dysfunction is also often responsible for angina in individuals with cardiomyopathy and heart valve disease as well as acute coronary syndrome cases such as Takotsubo syndrome and myocardial infarction with no obstructive coronary artery disease. Patients with stable microvascular angina present typically with effort or rest chest pain and a reduced coronary flow reserve or microvascular spasm. This condition, which affects women and men, can markedly impair quality of life and prognosis and represents a substantial cost burden to healthcare systems and individuals alike. In recent years, progress in the diagnosis of myocardial ischemia and the use of tests to investigate functional and structural causes for a reduced coronary flow reserve and microvascular spasm have allowed the identification of an increased number of cases of microvascular angina in everyday clinical practice. Although some of the available anti-anginal drugs may be helpful, treatment of coronary microvascular dysfunction remains a major challenge. The present article discusses the fundamental role that coronary microvascular dysfunction plays in the pathogenesis of ischemic heart disease, the clinical characteristics of patients presenting with microvascular angina, and possible diagnostic and therapeutic strategies.

The term angina pectoris, proposed >2 centuries ago, is commonly considered to be synonymous with obstructive atherosclerotic epicardial coronary artery disease (CAD). The frequently reported association among angina pectoris (central chest pain), myocardial ischemia, and coronary atherosclerosis has reinforced the concept that anginal pain and myocardial ischemia are almost exclusively caused by obstructive CAD. Diagnostic and therapeutic strategies for angina pectoris in its 2 main forms of presentation, namely, chronic stable angina and acute coronary syndrome (ACS), have been and continue to be based on the obstructive CAD paradigm. Current recommendations in international angina management guidelines are informed by the notion that coronary atheromatous plaques are the main cause for myocardial ischemia. Nonetheless, the latest European Society of Cardiology guidelines acknowledge the pathogenic role of coronary artery spasm and coronary microvascular dysfunction (CMD) in myocardial ischemia, and the “2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guidelines for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease” mention that microvascular disease, with vascular reactivity related to abnormalities in microvascular and endothelial function, contributes to ischemia to a greater extent in women than in men.

Although strategies based on the classical pathophysiological concepts are useful for the management of a substantial proportion of patients with chronic stable angina and the majority of patients with ACS, the paradigm that obstructive CAD is synonymous with myocardial ischemia needs to be revised because it is not universally applicable to individuals presenting with chronic stable angina or to a proportion of patients with ACS. Indeed, functional mechanisms have been documented that can cause myocardial ischemia in the absence of obstructive CAD. Epicardial coronary artery spasm, as initially proposed by Prinzmetal et al and further documented and characterized by Maseri et al, are striking examples. Evidence gathered over the past 30 years has made it clear that functional and structural mechanisms affecting prearterioles, arterioles, and capillaries represent yet another major cause for myocardial ischemia (Figure 1) in the absence of obstructive CAD and can also trigger ischemia in patients with CAD.

Figure 1. The role of coronary microvascular dysfunction in the pathogenesis of ischemic heart disease. Ischemic heart disease can result from several mechanisms, including atheromatous plaques occluding the epicardial coronary arteries, coronary artery spasm, and coronary microvascular dysfunction (CMD). Similar to obstructive epicardial disease, CMD can lead to myocardial ischemia by impairing the ability of the coronary circulation to increase coronary blood flow in response to an increased myocardial oxygen demand. CMD can result from an abnormal vasodilatory ability of the microvasculature, compressive external forces affecting the intramural microvessels, or microvascular spasm. CMD is typically the cause of myocardial ischemia in individuals with angina despite completely normal coronary arteriograms (primary microvascular angina), but it can also trigger myocardial ischemia in several other clinical conditions, including patients with cardiomyopathies and those with obstructive coronary artery disease. VSMC indicates vascular smooth muscle cell.