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Sex Dimorphism in the Myocardial Response to Aortic Stenosis

OBJECTIVES The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. BACKGROUND AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. METHODS This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro – brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. RESULTS In 168 patients (age 70 (cid:1) 10 years, 55% male, indexed aortic valve area 0.40 (cid:1) 0.13 cm 2 /m 2 , mean gradient 47 (cid:1) 4 mm Hg), no sex or age differences in AS severity or functional capacity (6-min walking test) were found. CMR captured sex dimorphism in LV remodeling not apparent by using 2-dimensional echocardiography. Normal geometry (82% female) and concentric remodeling (60% female) dominated in women; concentric hypertrophy (71% male) and eccentric hypertrophy (76% male) dominated in Aortic stenosis (AS) is a disease of both valve and LV. Sex differences may play a role in disease phenotyping. The present study investigated 168 patients with severe symptomatic AS by using echocardiography (echo), cardiac magnetic resonance (CMR), and biomarkers. There were no sex differences in AS severity or functional capacity, but CMR captured a sex dimorphism in the LV remodeling pattern, missed by 2-dimensional echocardiography and more adverse in men with more LV dysfunction (by LVEF, N-terminal pro – brain natriuretic peptide [NT-proBNP], high-sensitivity troponin T [hsTnT]) and myocardial ﬁ brosis (focal and diffuse). Given equal valve severity, LV associations with AS appear more maladaptive in men, with more extreme sex differences than previously reported. Figures 1 and 3 .

I n aortic stenosis (AS), narrowing of the aortic valve is the hallmark of disease progression, but symptom onset and patient outcome are also determined by the left ventricular (LV) response to increasing afterload (1), which remodels in an attempt to maintain normal wall stress. This scenario is highlighted by the limited performance of markers of valve stenosis in predicting symptom onset (2). In contrast, left ventricular ejection fraction (LVEF), left ventricular hypertrophy (LVH), and myocardial fibrosis have all been shown to predict outcomes in AS (3)(4)(5)(6)(7)(8)(9)(10). However, LV remodeling is heterogeneous (11)(12)(13). Four main geometric patterns have been defined: normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. These patterns are based on LV mass, cavity size, and the ratio of these 2 factors (14,15). Functionally, the spectrum of LV responses ranges from hypercontractile to "myopathic" states.
Sex appears to exert an important influence on LV remodeling (11,19,20). Previous research has shown that men are more likely to have higher indexed LV mass, lower LVEF, and increased diastolic myocardial stiffness (21,22), whereas women have more concentric remodeling with higher relative wall thickness and LVEF. To date, however, most studies have relied on echocardiography alone, with only limited combined echocardiography and CMR data available (22).
The goal of the present study was to understand the influence of sex on AS remodeling by using all available modalities to investigate patterns of remodeling at macroscopic and tissue levels. Patients were recruited before pre-operative evaluation, which included a comprehensive assessment with clinical history, resting blood pressure, 6-min walk test (23)  LGE was quantified in grams and as a percentage of the LV using a signal intensity threshold of 3 SDs above the mean remote myocardium. ECV was calcu-
In animal models, sex dimorphism exists in the baseline findings of the heart (difference in size, physiology, gene profiles, and contractile properties), response to pressure or volume overload (more hypertrophy and dilatation, respectively), and cardiomyocyte response to aging and modification of cardiac gene expression (36). Cellular, molecular, and neurohormonal mechanisms for the differential response in men have been proposed, including increased interstitial fibrosis, greater activation of profibrotic and inflammatory pathways, and differential expression of androgen and estrogen receptors (21,(37)(38)(39). Although the interplay of protective effects of estrogens and deleterious effects of androgens may play a key role in the sex dimorphism, the majority of female patients in our study were postmenopausal, and none were receiving hormone replacement therapy. Sex differences in the reninangiotensin system, nitric oxide activity, and norepinephrine release may contribute to differences  Sex and Remodeling in Aortic Stenosis -2 0 1 7 : --study entry sex ratios, if there had been no sex dimorphism, both of these ratios should have been 1.7 to 1. However, the sex dimorphism of cardiac remodeling according to CMR was much more extreme than that according to echocardiography ( Figure 6). There are modality-specific differences in ascertainment that could explain this: cross-sectional echocardiography uses derived wall thickness to cavity width ratios, whereas CMR uses a 3dimensional-derived mass to volume ratio (14,22).
Each technique also has indexed sex-specific reference ranges and cut-points (Online Appendix), which could be inaccurate and magnify differences. These may be differently sensitive to sex-influenced confounders (e.g., a basal septal bulge). Such explanations seem inadequate, however, and the impression

Men maladapted?
Aortic stenosis (AS) is a disease of both valve and LV. Sex differences may play a role in disease phenotyping. The present study investigated 168 patients with severe symptomatic AS by using echocardiography (echo), cardiac magnetic resonance (CMR), and biomarkers. There were no sex differences in AS severity or functional capacity, but CMR captured a sex dimorphism in the LV remodeling pattern, missed by 2-dimensional echocardiography and more adverse in men with more LV dysfunction (by LVEF, N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity troponin T [hsTnT]) and myocardial fibrosis (focal and diffuse). Given equal valve severity, LV associations with AS appear more maladaptive in men, with more extreme sex differences than previously reported. AVAi ¼ indexed aortic valve area; V max ¼ peak velocity; other abbreviations as in Figures 1 and 3. Sex and Remodeling in Aortic Stenosis -2 0 1 7 : --unlikely to have biased our findings. No invasive LV pressure data were obtained; due to stroke risk associated with crossing the aortic valve, this measurement is not routinely performed in our institution.
Imprecision in T1 mapping may have been introduced due to partial-voluming of blood (although this possibility was minimized by using a 10% offset) (Online Appendix) and in those patients with atrial fibrillation (n ¼ 24; 14%). Furthermore, reduced capillary density (lower ECV) or compensatory vasodilatation (higher ECV) may confound ECV measurements, which capture all extracellular space including the intravascular plasma (43,44). Finally, no data were available on the duration of AS.

CMR revealed sex differences in associations between
AS and myocardial remodeling that were not evident from conventional echocardiography. Given equal valve severity, the myocardial response to AS seems more maladaptive in men than previously reported.
These data suggest that more detailed phenotyping of patients with AS is required; the resultant uncovering of a maladaptive ventricular response may be influential in the current debate regarding immediate or deferred intervention for severe AS.