This study assessed the influence of sex on differences in LV remodeling and outcome in obstructive HCM after ASA in long-term follow-up using CMR imaging. Our current results demonstrated that both men and women had favorable reverse remodeling with significant LV mass regression and EDV increments in the long-term follow-up. Women experienced more clinical events than men after ASA in the follow-up. The overall percentage of the LVM index regression was greater among men. Additionally, male sex, baseline LVM index and change in the LVOT gradient were independently associated with the LV remodeling process, indicating that these factors could be used as indicators for LV mass regression after ASA in patients with HCM. The greater changes in LV reverse remodeling in males might contribute to the better prognosis after ASA compared to females.

Although population-based studies have demonstrated that sex plays an important role in the prevalence, severity and prognosis of HCM, female sex was associated with decreased survival [2,3,4,5]. However, the mechanisms of sex-related differences with respect to prognosis remain unknown. Schulz-Menger et al. found that females with obstructive HCM appeared to experience a significantly larger degree of remodeling, which was mainly determined by relatively increased myocardial mass than male patients [13]. In contrast, Lu et al. demonstrated that women with HCM did not have worse myopathy, but had a smaller LV cavity size and higher indexed maximum wall thickness [5]. Our data suggest that women with HCM had a higher LVM index, smaller LV cavity size and higher LVOT gradient, which might contribute to greater symptoms. In addition, we also found that female patients experienced worse LV remodeling than male patients after ASA, which might account for the poor prognosis for women. Myocardial fibrosis is known to increase in patients with HCM during LV remodeling and negatively influence the clinical course of HCM patients [14]. In this study, we found that female patients had a larger amount of LGE than men, which were both positively related to LV mass.

The mechanisms behind sex differences in HCM are currently not well understood. Sex differences in the hypertrophic response, fibrosis and gene expression suggest that physiological sex differences might play a role [15, 16]. Women are more likely to have concentric remodeling in response to pressure overload and, thus, have smaller LV diastolic chamber volumes, with higher EF [17]. Additionally, a higher degree of fibrosis in female myectomy samples was present than in male myectomy samples [15, 18], which was consistent with our study, indicating that the exacerbated LV remodeling in females might be caused by increased fibrosis, as replacement fibrosis is thought to be a potentiating element of LV remodeling in HCM [19].

Consistent with previous studies [7, 8], our study also found that ASA therapy significantly reduced LV mass and LVOT gradient in both men and women. There was a small increase in LV ejection as a result of a significant increase in LVEDV and a small but significant increase in LVESV at the 16-month follow-up. Previous studies have suggested that female sex is associated with worse survival after septal myectomy [20,21,22]. Furthermore, a recent study demonstrated that female patients with HCM undergoing ASA tended to have a poor prognosis compared with men in the Chinese population [23]. There is currently no clear explanation for why men fare better after ASA. In our study, men had more favorable reverse remodeling after ASA. Multiple regression analysis suggested that the main predictor of reverse remodeling for each category was the baseline level of the LVM index and change in the LVOT gradient, which might contribute to better survival in men. These findings were similar to Sorajja et al.’s result that the severity of the residual LVOT gradient after septal ablation is an important determinant of long-term outcome [24]. As LV remodeling might increase ventricular diastolic stiffening and lead to the compromise of diastolic reserve, which contributes to the greater rate of heart failure in women [5, 25], and LV mass proved more sensitive in predicting the outcome, it is reasonable to speculate that more LV mass regression was associated with greater improvement of diastolic function and, thus, with a better prognosis.

The underlying mechanisms for sex-based differences in the outcome after ASA of sarcomeric HCM are not well understood. However, the age of diagnosis or disease penetrance might be delayed, which might lead to a higher LVOT gradient and worse diastolic function abnormalities in women, thereby contributing to a higher incidence of HF and mortality in women with HCM [26]. Furthermore, women were more likely than men to demonstrate obstructive physiology and abnormalities of diastolic function, including greater pulmonary artery systolic pressure despite similar degrees of hypertrophy, even in HCM patients undergoing myectomy [2, 27]. In addition, this phenomenon might be related to the genetic and endocrine differences between males and females. Sex hormones might modulate the disease phenotype in HCM [28, 29]. Female sex was protective against disease manifestation and progression in a transgenic murine HCM model with myosin heavy-chain mutation [30] and troponin T mutation [31]. In our study, 90.6% of female patients were menopausal women and had worse survival than male patients, suggesting that postmenopausal endocrine changes might impact the clinical course in HCM [2, 32]. Moreover, women were more likely than men to have sarcomere pathogenic variants. Sarcomere variants that cause HCM have been shown to impair diastolic relaxation and lead to a greater burden of heart failure [26]. Other factors, such as societal and cultural factors, might influence the delayed referral and symptom assessment for women [21].

Previous studies have demonstrated that myocardial fibrosis detected by LGE is progressive in some HCM patients and that fibrosis progression is associated with adverse cardiac remodeling [33,34,35]. However, no studies have yet assessed the extent of LGE after ASA in long-term follow-up. Our study demonstrated that the extent of LGE did not significantly increase after ASA. Todiere et al. reported that the increase in LGE extent preferentially occurred in the apical pattern of LV hypertrophy [33]. However, myocardial hypertrophy was mainly involved in the interventricular septum and/or the anterior wall in the patients in our study. Second, Conte et al. and our study showed that the extent of LGE was significantly correlated with LV mass [36]. The favorable LV reverse remodeling might support the mechanistic explanation for the LGE without progression after ASA. Third, genotypic analysis for the screening of sarcomeric mutations was not performed in our study, and a genetic predisposition might condition the rate of progression of fibrosis [33, 35].

There are some limitations in the study. First, the main limitation was the small size of the population. Moreover, due to higher disease penetrance in males, our study did not use a matched-control group design, and the females enrolled in our cohort were older but more symptomatic than the males. However, the baseline risk factors, including hypertension, diabetes and atrial fibrillation, were similar between the sexes. Moreover, in the multivariate analysis, variables, such as age as a dependent factor, were considered and had no effect on the final result. Second, the dropout rate was low for a CMR-based study, and the population was not consecutively recruited for the research, which might have led to the possible existence of selection bias. Third, although we provided LGE by CMR to measure fibrosis, we did not measure extracellular volume fraction (ECV) by T1 mapping. LGE is usually used to measure focal fibrosis, and T1 mapping might be used to quantify ECV as a marker of diffuse fibrosis [37]. Fourth, the precise mechanisms underlying sex-specific differences were not investigated in this study. Whether hormones, such as estrogen and androgen, are involved in the prognostic role of reverse LV remodeling as well as survival outcomes in patients with HCM needs further investigation by new studies.