Microvascular coronary dysfunction in women: pathophysiology, diagnosis, and management

Abstract

Women exhibit a greater symptom burden, more functional disability, and a higher prevalence of no obstructive coronary artery disease compared to men when evaluated for signs and symptoms of myocardial ischemia. Microvascular coronary dysfunction (MCD), defined as limited coronary flow reserve and/or coronary endothelial dysfunction, is the predominant etiologic mechanism of ischemia in women with the triad of persistent chest pain, no obstructive coronary artery disease, and ischemia evidenced by stress testing. Evidence shows that approximately 50% of these patients have physiological evidence of MCD. MCD is associated with a 2.5% annual major adverse event rate that includes death, nonfatal myocardial infarction, nonfatal stroke, and congestive heart failure. Although tests such as adenosine stress cardiac magnetic resonance imaging may be a useful noninvasive method to predict subendocardial ischemia, the gold standard test to diagnose MCD is an invasive coronary reactivity testing. Early identification of MCD by coronary reactivity testing may be beneficial in prognostication and stratifying these patients for optimal medical therapy. Currently, understanding of MCD pathophysiology can be used to guide diagnosis and therapy. Continued research in MCD is needed to further advance our understanding.

Figure 1

Interrelations between chest pain and microvascular dysfunction are important in the pathogenesis of CSX and are likely to determine the patient’s clinical presentation. A given patient with markedly increased pain sensitivity (y axis, arbitrary severity scale 1 to 10) may develop chest pain in response to algogenic cardiac (and probably also non-cardiac) stimuli even in the absence of major coronary microvascular dysfunction or myocardial ischemia. Adenosine and potassium release have been suggested to cause chest pain and ECG changes in CSX patients. Endothelin-1 and the autonomic nervous system modulate pain threshold. Patients with both marked microvascular dysfunction (x axis) and reduced pain threshold will be highly symptomatic and are also likely to have objective evidence of myocardial ischemia. Patients with intermediate degrees of chest pain sensitivity and microvascular dysfunction may have no ischemia or this may be undetectable; the latter depending on the sensitivity of the diagnostic tools employed for investigation and the severity and location of ischemia. Variable interactions between pain threshold and microvascular dysfunction can explain the heterogeneous pathogenesis of CSX. Both pain threshold and microvascular dysfunction have ample gradation spectra regarding severity and are also modulated by factors such as endothelial dysfunction, inflammation, autonomic influences, and psychological mechanisms, among others. Reprinted with permission from Kaski JC. Pathophysiology and Management of Patients With Chest Pain and Normal Coronary Arteriograms (Cardiac Syndrome X). Circulation 2004;109(5):568–572.

Figure 2

Model-Derived Relation Between Capillary Diameter (X-Axis), Myocardial Capillary Density (Z-Axis), and CFR (Y-Axis). Please note that MCD in this diagram stands for Myocardial Capillary Density Reprinted with permission from Kaul S, Jayaweera AR. Myocardial Capillaries and Coronary Flow Reserve. J Am Coll Cardiol 2008;52(17):1399–1401.

Figure 3

Doppler flow wire in coronary artery measures changes in coronary blood flow and peak velocity in response to Acetylcholine (A: Baseline, B: following injection of 10⁻⁴ Ach injection demonstrating constriction of the coronary arteries). Arrow indicates tip of the Doppler flow wire positioned at mid-left anterior descending artery.

Figure 4

Intracoronary Doppler blood flow velocity waveforms before intracoronary adenosine (A), and after intracoronary adenosine infusion (B). CFR is the ratio of average peak velocities before and after adenosine.