Using the largest hospitalization-based database representative of the US population, we found that there were significant differences in clinical outcomes between males and females who were hospitalized for HF. Among the female group, we observed significantly lower levels of in-hospital mortality, lower requirement for mechanical ventilation, mechanical circulatory support, and vasopressor use. However, prolonged length of stay and disposition other than home were higher among females. Our study showed that sex has a substantial influence on clinical outcomes after HF hospitalizations. Our findings could have significant implications in the management of HF which differs between males and females.
Similar to our findings, a study by Sun et al. showed that age-standardized mortality after HF was significantly lower among females, and upon accounting for other risk factors, female sex was associated with notable reduction in mortality10. Similarly, in another study by Taylor et al., females had a 14% age-adjusted lower risk of mortality (HR, 0.86, 95% CI: 0.84–0.88), compared to males11. Likewise, Goyal et al. found that many hospital outcomes were significantly better among females including in-hospital mortality which was 7% lower among females, compared to males12. In addition to lower mortality rate, we also found that females required lower rates of mechanical ventilation, mechanical circulatory support, and vasopressor use. Several factors could be responsible for these findings. For example, females have lower risk for developing myocardial fibrosis compared to males13. Males tend to have increased fibrosis in response to stress such as pressure overload14,15. This could be due to estrogen, which is implicated to directly lower collagen formation in cardiac fibroblasts among females while increasing it among males. In addition, there are also differences in mitochondrial functions and energy metabolism between the sexes. For example, in HF, female hearts exhibit a less significant decrease in the expression of genes associated with lipid and energy metabolism compared to male hearts16,17. This results in better retention of mitochondrial integrity and functionality among females after HF thereby also contributing to improved calcium handling and better management of reactive oxygen species (ROS) and thus lower sensitivity to HF. Females have greater levels of estrogen which has shown to have some protective effects on mitochondria which is accomplished through greater levels of expression of proteins that participates in TCA cycle and mitochondrial oxidative processes18,19. Estrogen accomplishes these processes through directly stimulating the genes that are encoded in the mitochondrial DNA. These protective mechanisms are active not only in the earlier stages of pressure overload that precedes HF but also during the ischemia-reperfusion phase that occurs after the HF20,21. In addition, females also constitutionally exhibit a higher resilience to cardiomyocyte loss after myocardial infarction compared to males22. Females have enhanced recovery following percutaneous coronary intervention, reduced apoptosis, and necrosis, as well as decreased occurrences of expansion of infarcts or delayed healing following cardiac ischemia23. In spite of these compelling evidences that highlight the importance of female sex for better outcomes in HF, studies have also shown that there were no differences in clinical outcomes between the sexes. For example, a survival analysis that used data from the North American registry and included 22 million HF hospitalizations found that there were no gender-specific differences in HF-associated mortality across majority of the states within the US24. Similarly, results from TOPCAT (Aldosterone Antagonist Therapy for Adults With HF and Preserved Systolic Function) trial which included 3,445 patients with HF showed that all-cause mortality and cardiovascular mortality did not differ significantly between the sexes25. Given these equivocal evidence it is imperative that other factors such as sexual dimorphism in treatment response and differences in metabolism that could either increase or decrease the effect of these associations should be explored to better understand the subtleties in these relationships.
Sex dimorphism has an important role in several diseases, including cardiovascular disorders26,27,28,29. Sex-based differences play a huge impact on the biomarker profiling that are associated with clinical outcomes in cardiovascular disorders30. For example, biomarkers pertaining to a specific cardiovascular diseases such as natriuretic peptides and cardiac troponins involved in myocardial injury, C-reactive protein in inflammation, leptin and adiponectin in adipose tissue metabolism, and galectin-3 and soluble ST2 in fibrosis are expressed differentially between the sexes and may have different circulating baseline levels, thereby modifying the disease outcomes. Genetic factors, epigenetic changes, age-dependent hormonal imbalances, and immunological variations between both sexes could also influence the development of sex dimorphism observed in cardiovascular disorders7,8,29. Future studies should explore the genomic aspects of sexual dimorphism in HF outcomes.
Surprisingly, our study also observed that prolonged length of stay, and disposition other than home were significantly higher in female, compared to males. Although we could not identify the specific reasons for these findings in our analysis, they could be due to better survival rates among females, compared to males. Hence, we conducted a sensitivity analysis where we compared prolonged length of stay between males and females after excluding the patients who died during hospitalization. However, in the sensitivity analysis, we found that prolonged length of stay did not differ between the sexes. Inherent pathophysiological differences in HF, as well as differences in convalescence and recovery rates could be the reasons for these differences.
Limitations
There are some limitations for this study. First, the NIS is an administrative database and uses ICD-10-CM codes for identifying primary and secondary diagnosis. These are obtained from discharge data. Hence, there could be error during coding which could have led to misclassification bias leading to minor errors in national estimates. Second, each NIS sampling unit originates from a hospitalization and does not contain distinct patient identities. Hence, readmissions cannot be distinguished from index admissions. Approximately 24% of Medicare patients with HF are readmitted within 30 days after admission, even after adjusting for risk. Among these readmissions, nearly 20–30% are due to recurring HF exacerbations. Thus, research utilizing the NIS cannot differentiate between a distinct HF hospitalization and a HF readmission. Third, sex as reported in the database and could not be ascertained as the sex at birth or self-reported sex. Fourth, our findings are constrained by an absence of long-term follow-up and are applicable only for a short inpatient period. Due to the cross-sectional nature of the study design, causality cannot be determined. Fifth, the NIS does not have echocardiographic data, guideline-directed adjunctive medical or device therapy or other adjunct treatment, or lab values. Sixth, NIS does not have information on hormonal and chromosome related factors. Availability of such data could have improved our understanding of the differences in outcomes between male and female HF hospitalizations.
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