Women in the CENTURY trial had higher coronary blood flow (CBF) than men while having a comparable burden of cardiovascular risk factors, similar treatment response and half the coronary events, offering a potential physiological explanation for the delayed clinical manifestation of coronary artery disease (CAD) in women, according to a post hoc analysis published in JACC: Cardiovascular Imaging.

The analysis included 331 women and 697 men aged 40 or older with subclinical, suspected or established CAD from the randomized CENTURY trial, which used PET imaging to quantify CBF and coronary flow capacity. Investigators reanalyzed trial data according to sex, examining risk factors, age, quantitative CBF, coronary flow capacity and clinical outcomes through 14 years of follow-up.

Although women and men were similar in age, BMI, hypertension, diabetes and cumulative summed risk scores, women had less established CAD (23% vs. 46% in men), less coronary artery calcification (62% vs. 88%) and fewer severe PET stress perfusion defects (6% vs. 10%), as well as less diffuse coronary flow capacity (CFC) reduction (29% vs. 47%) and fewer severely reduced CFC maps (7% vs. 17%) (p<0.0001 for all).

Moreover, women compared with men had lower rates of major adverse cardiovascular events (16% vs. 38%; p=0.00001) including death (6% vs. 10%; p=0.015), death or MI (9% vs. 15%; p=0.006) and revascularization (9% vs. 20%; p=0.00001).

They also had significantly higher baseline global CBF at rest (1.00 vs. 0.75 mL/min/g) and during stress (2.38 vs. 1.90 mL/min/g; p=0.0001 for both) compared with men, yielding a women-to-men CBF ratio of 1.33 across age, BMI, risk factors and treatment.

Noting that previous studies have established that women's coronary arteries are approximately 10% smaller than men's, Gould and colleagues estimated that endothelial shear stress (ESS) may be approximately 82% higher in women.

That higher ESS, they suggest, may represent a chronic, diffuse antiatherogenic mechanism that could contribute to delayed clinically manifest CAD in women by up to two decades compared with men, despite a similar burden of traditional cardiovascular risk factors.

"These findings suggest potential, hypothetical new mechanisms for the delayed onset and reduced severity of CAD in women," write the authors. "A sex-specific physiological-fluid dynamic anatomical configuration of the female coronary tree – smaller arteries with higher CBF, generating diffuse antiatherogenic ESS established during childhood – may be a primary mechanism contributing to lifelong reduction in CAD relative to men and to the estrogen paradox."