Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography is Associated with Severely Impaired Coronary Flow Reserve, not Obstructive Disease
Background—Cardiovascular disease (CVD) fatality rates are higher for women as compared with men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large and small vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events.
Methods—Consecutive patients (N=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography (PET) and with left ventricular ejection fraction >40% were followed (median 3.0 years) for a composite endpoint of major adverse cardiovascular events including cardiovascular death and hospitalization for nonfatal myocardial infarction (MI) or heart failure. Extent and severity of angiographic CAD were estimated using the CAD prognostic index, and CFR quantified using PET.
Results—Although women relative to men had lower pretest clinical scores, rates of prior MI and burden of angiographic CAD (p<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings and early revascularization (adjusted HR 2.05, 95%CI 1.05-4.02, p=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed higher frequency of nonobstructive CAD while men showed higher frequency of severely obstructive CAD (p=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (p<0.0001, p for interaction=0.04).
Conclusions—Women referred for coronary angiography had significantly lower burden of obstructive CAD relative to men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.
- Received April 30, 2016.
- Revision received October 14, 2016.
- Accepted October 26, 2016.