The purpose of this study was to investigate the correlation between serum SERCA2a levels at admission and the occurrence of adverse events after discharge in patients with heart failure. From the study, we can find that in female patients, the risk ratio of developing adverse events increases with the increase of SERCA2A levels. However, the results of previous animal or clinical studies suggest that upregulation of myocardial tissue SERCA2a expression by gene transduction is effective in improving cardiac function and reducing the occurrence of adverse cardiovascular events [9,10]. This differs from our observed results, which may be due to the difference in SERCA2a expression in myocardial tissue versus serum in heart failure patients, and serum levels of SERCA2a may be associated with increased release of SERCA2a from myocardial tissue injury, reflecting increased myocardial tissue injury and thus contributing to the occurrence of prognostic adverse events. As shown in Table I: the mean values of LVEF and E/A were higher in the group of patients with low serum SERCA2a heart failure than in the group with high serum SERCA2a levels, but none of them were statistically different, which we speculate is related to the small sample size of this study. Patients requiring mechanical circulatory support before heart transplantation have been found to have lower serum SERCA2a levels than clinically stable patients [11], and low serum SERCA2a levels have also been associated with a higher incidence of rejection after heart transplantation [6, 7]. This differs from our study suggesting that it is the female population of heart failure patients with high serum levels of SERCA2a that is more likely to cause the occurrence of prognostic adverse events, probably because the previous study population was mainly patients with advanced heart failure, whereas the population included in our present study was admitted with acute heart failure attack or acute exacerbation of chronic heart failure, with NYHA classification of I and II in 46.4% (33 ). Secondly, the results we observed were presented in the female population, and the results of previous studies were discussed in terms of the total study population, lacking gender subgroups; therefore, are there gender differences causing the observed results to differ? This needs to be confirmed by more clinical studies in the future.
Also, in this study we found that higher serum SERCA2a levels at admission in the female group were associated with an increased risk ratio of adverse events after discharge, and the trend analysis further confirmed this correlation (p=0.02); while no such correlation was observed in male patients. We speculate that there is a gender difference between serum SERCA2a levels and the occurrence of adverse events after hospital discharge. The current study suggests that there are some gender differences in heart failure in terms of epidemiology, pathophysiology, treatment response, prognosis and biomarkers [12, 13]. For example, among the traditional risk factors for heart failure, obesity, diabetes mellitus and mental/psychological stress are of greater risk for women than men. Diabetes and obesity can drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation [20] and are associated with a predilection for HFpEF in women. Among the etiologies of heart failure, coronary macrovascular disease and myocardial infarction predominate in men [13-16], while coronary microvascular dysfunction, hypertension and immune inflammatory mechanisms predominate in women [13, 17, 18]. This is consistent with a predilection for HErEF in male patients and HFpEF in female patients [19]. Similarly, in the general population, natriuretic peptide levels are higher in women than in men, which may be related to the fact that testosterone decreases cardiac natriuretic peptide levels [21] and estrogen can increase cardiac natriuretic peptide levels by directly increasing cardiac natriuretic peptide gene expression and release [22, 23]. In contrast, in the population of heart failure patients, women have lower natriuretic peptide levels than men, and this difference may be related to the difference in the prevalence of HF in men and women with reduced ejection fraction (HFrEF) versus preserved ejection fraction (HFpEF) [12]. In addition, echocardiographic studies have shown that women with HFpEF are more likely to have concentric LV remodeling, more severe diastolic dysfunction, including more severe LV diastolic injury, and higher LV filling pressures compared with men [24].
The current gender disparity in heart failure clinics is due to the fact that too few women are recruited to heart failure clinical trials (20-25% of cohorts) and therefore treatment guidelines are primarily based on data from men [13]. There is a large knowledge gap regarding gender-specific mechanisms, optimal drug doses for women, and gender-specific criteria for device therapy. Gender differences, and in particular the lack of awareness of these differences, may lead to a gender bias in heart failure salvage and may result in a poor prognosis for women. In this study, serum SERCA2a levels may have been associated with the occurrence of post-discharge adverse events in female heart failure patients, whereas no such correlation was observed in the male population. The indication of gender differences in the correlation of serum SERCA2a levels on the occurrence of adverse events after hospital discharge in heart failure patients provides an additional perspective for researchers to understand the gender differences in the development of heart failure related to prognosis, and the underlying pathophysiological mechanisms need to be elucidated by further studies.