Effects of Sex on Coronary Microvascular Dysfunction and Cardiac Outcomes

Abstract

Background Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease (CAD). The relative extent to which CMD affects both genders is largely unknown. Methods and Results We investigated 405 men and 813 women referred for evaluation of suspected CAD with no previous history of CAD and no visual evidence of CAD on rest/stress positron emission tomography (PET) myocardial perfusion imaging. Coronary flow reserve (CFR) was quantified and CFR<2.0 used to define the presence of CMD. Major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, late revascularization and hospitalization for heart failure, were assessed in blinded fashion over a median follow-up of 1.3 years (IQR 0.5–2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; P(Fisher exact test)=0.39; P(equivalence)=0.0002). Regardless of gender, CFR was a powerful incremental predictor of MACE (hazard ratio 0.80 [95% CI 0.75–086] per 10% increase in CFR; P<0.0001) and resulted in favorable net reclassification improvement (NRI=0.280 [95% CI 0.049–0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (N=404; 307 female/97 male) without evidence of coronary artery calcification (CAC) on gated CT imaging, CMD was common in both genders, despite normal stress perfusion imaging and zero CAC (44% of men versus 48% of women; P(Fisher exact test)=0.56; P(equivalence)=0.041). Conclusions CMD is highly prevalent among at risk individuals and is associated with adverse outcomes regardless of gender. The high prevalence of CMD in both genders suggests that it may be a useful target for future therapeutic interventions.

Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk?

“…Female sex had a nearly significant association with CMD, with an odds ratio of 1.21 (95% confidence interval, 0.98–1.40) compared with men 33. The high prevalence of endothelial and/or nonendothelial‐dependent CMD26, 31, 33 and their correlation with outcomes26 underscores the role of comprehensive assessment in patients with INOCA. Such functional alterations can be identified at a stage when atherosclerotic lesions are not evident34 and may be useful in designing early effective interventions to prevent the occurrence of subsequent coronary events.…”

“…Studies that additionally characterized function or anatomy such as myocardial ischemia, CFR, plaque characterization, or calcium scoring further demonstrate relatively higher MACE rates related to the presence or degree of such abnormalities (Table 1), in both sexes. CMD was shown to be highly prevalent in stable INOCA patients and a CFR <2 was a powerful incremental predictor of MACE in both women and men 26. In symptomatic subjects from the CONFIRM (coronary CT angiography evaluation for clinical outcomes international multicenter) study there was a 2.5‐fold increase in risk of MI and all‐cause mortality related to a higher CT‐Leaman plaque score 44.…”

“…Previously, the term CSX was used to refer to patients with no obstructive CAD but did not require proof of ischemia23, 24 and also included patients with acute coronary syndromes and no obstructive CAD 22, 23, 25. Advanced evaluation can now identify CMD or macrovascular dysfunction by invasive or noninvasive measurements of CFR in a majority of these patients,12, 26 while coronary atherosclerosis and better characterization of plaques can be assessed by intravascular ultrasound, optical coherence tomography, or computed coronary tomography angiography when not evident or appreciated at invasive coronary angiography 27, 28, 29. Since CSX also includes clinical entities other than ischemia, such as pericardial pain, inappropriate pain perception, and psychiatric syndromes,30 the term INOCA was established to improve the identification and management of patients with ischemia and no obstructive CAD 1.…”

“…Documented MACE rates in stable INOCA patients are summarized in Table 1 4, 10, 15, 26, 35, 36, 37, 38, 39, 40, 41. Additionally, many of these patients have an adverse quality of life, functional status, and exercise capacity with relatively frequent visits to healthcare providers for persistent or recurring disabling symptoms 42.…”

“…The observed elevated MACE rate endorses this as a knowledge gap. Even mild degrees of atherosclerosis or abnormal coronary vasoreactivity are related to increased health risk 4, 26, 83, 84. Furthermore, the majority of MIs result from rupture of nonobstructive plaque, highlighting the importance of optimizing therapy in these patients 85, 86.…”