Gender Gap, Inflammation and Acute Coronary Disease: Are Women Resistant to Atheroma Growth? Observations at Autopsy

From The Journal of Invasive Cardiology
Richard J. Frink, MD

Abstract
Background: Gender differences that exist in patients with acute coronary disease (ACD) are unexplained. We sought to determine if these differences could be related to differences in the pathologic substrate found in the coronary arteries at the time of death.

Methods: The hearts of 83 patients (64 men and 19 women) who died of ACD were obtained fresh and uncut at the autopsy table. The coronary arteries were injected with a colored barium gelatin mass. After formalin fixation, the epicardial arteries were dissected intact, decalcified and cut at 2-3 mm intervals, with all segments mounted for histologic study. The severity of luminal stenosis and the frequency of adventitial inflammation, intimal calcification and atheromas were determined microscopically for each segment. Plaque burden was determined histologically by assessing the severity of luminal stenosis for each coronary segment. The number of plaque ruptures (PRs), with and without luminal thrombosis, were tabulated for each heart in the study. These results were compared with 22 control patients who died of noncoronary disease.

Results: There are gender similarities as well as significant differences in the pathologic substrate of patients who die of ACD. Active, inflammatory atherosclerosis and associated ACDs develop earlier in life in men than in women, and are associated with death at an earlier age, producing a "gender gap." There were no significant gender differences in the frequency of PRs. The women were significantly older than the men and had more extensive active disease, but had the same overall plaque burden as men, suggesting women may be resistant to plaque growth, particularly atheroma growth.
Conclusions: Gender gap appears to be related to factors peculiar to women who resist atheroma growth, delaying PR and the onset of ACD.

Introduction
The gender differences that exist in patients with acute coronary disease (ACD) remain largely unexplained and may reflect anatomic, biologic or pathophysiologic differences.[1,2]
Women who develop ACD are often older than men, typically die at an older age and have a worse prognosis following acute myocardial infarction (AMI), or after interventions such as coronary bypass graft surgery (CABG) or percutaneous coronary intervention (PCI).[2-6]
These differences, often referred to as "gender gap", are consistently present in all countries and cultures where coronary artery disease exists.[1]

The low frequency of ACD in premenopausal women suggests they are "protected" or resistant in some way to developing atherosclerosis and subsequent ACD,[1,2,7-9] but the mechanism of such resistance is unknown.
The protective factor(s) appear to be powerful and are not found to operate through lipid-related mechanisms.[9] Additionally, levels of known common risk factors do not explain gender gap.[1,9] Even women with heterozygous familial hyperlipidemia appear to be protected.[10]
A sudden increase in ACD does not occur at the time of menopause,[1] as might be expected if this resistance were related to female hormones.
In fact, the administration of female hormones to the postmenopausal woman is associated with increased risk of ACD.[11]
The presence or absence of female hormones does not explain gender gap.[1,9,12]