Sex Differences and Myocardial Fibrosis in Aortic Stenosis

Study Questions:

In calcific aortic stenosis (AS), myocardial fibrosis has been associated with increased morbidity and mortality. This study examined two surrogate markers of myocardial fibrosis derived from cardiac magnetic resonance (CMR) imaging: late gadolinium enhancement (LGE), a marker of replacement myocardial fibrosis, and extracellular volume (ECV) fraction, a marker of diffuse reactive myocardial fibrosis. What are the determinants of LGE and ECV – in particular, sex – in patients with mild to severe AS?

Methods:

This was a cross-sectional analysis of 249 patients from two prospective studies. Patients had at least mild AS and had undergone both echocardiography and CMR. ECV fraction was calculated from T1-mapping. Univariable and multivariable linear regression and frequency-matched analysis were performed.

Results:

Of the 249 patients, 30% were women; mean age was 66 ± 15 years (vs. 66 ± 12 years in men). Approximately 38% of patients had mild, 28% moderate, and 34% severe AS, based on Vpeak. Women had fewer cardiovascular risk factors (less dyslipidemia, diabetes, and coronary artery disease, p < 0.05 for each) and trends toward less diagnosed hypertension (59% vs. 70%, p = 0.10), and less antagonists of the renin-angiotensin system (36% vs. 48%, p = 0.10). Left ventricular (LV) mass index, the only variable independently associated with all markers of myocardial fibrosis, was smaller in women than in men (p < 0.0001). Despite this, women demonstrated similar LGE and greater ECV fraction across the spectrum of severity of AS and when matched with men by age and cardiovascular risk factors. On multivariable analysis, female sex was independently associated with LGE and ECV.

Conclusions:

While several studies have reported sex-related differences in the LV response to pressure overload, prior reports (primarily in severe AS) have found larger fibrotic burden in men. This study differs in the inclusion of patients with mild and moderate AS and matching of subsets of men and women with similar age, cardiovascular risk profile, and AS severity. The key findings are an independent association of female sex with both LGE and ECV fraction on multivariable analysis and comparable CMR markers of myocardial fibrosis in women, despite significantly smaller LV mass index. The authors note a trend toward less use of antihypertensive medications in women in their cohort, including potentially antifibrotic antagonists of the renin-angiotensin system, but do not discuss this as a potential contributor to their findings.

Perspective:

Noninvasive assessment of myocardial fibrosis by CMR could help determine optimal timing of AVR in asymptomatic patients with severe AS or even milder forms of aortic valve disease. If the findings of this study are borne out in larger studies with longitudinal design, imaging of myocardial fibrosis could be even more important in determining the optimal treatment and timing of intervention in women. The findings of this report, however, differ from those of previous CMR studies, and future studies will be needed to conclusively determine the relationship between sex and myocardial fibrosis in AS.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Hypertension

Keywords: Antihypertensive Agents, Aortic Valve Stenosis, Biological Markers, Coronary Artery Disease, Diabetes Mellitus, Diagnostic Imaging, Dyslipidemias, Echocardiography, Fibrosis, Gadolinium, Heart Defects, Congenital, Heart Valve Diseases, Hypertension, Magnetic Resonance Imaging, Renin-Angiotensin System, Risk Factors, Secondary Prevention, Women


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