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Gender-specific differences in proteomics in patients with heart failure and reduced ejection fraction

The reduced ejection fraction (HfrEF) is one of the most severe manifestations of cardiovascular disease. The results of previous studies have shown a lower risk of hospitalization for heart failure (HF) and mortality in women with HFrEF than in men. In this study, the authors from the Netherlands investigated gender-specific differences in proteomics in patients with heart failure and the predictive value of repeatedly measured circulating proteins in patients with heart failure and HfrEF. 

HF significantly impacts many tissues and organs throughout the body. The circulating protein levels in patients with HF reflect their production in non-cardiac tissues due to the failing heart or other underlying comorbidities.

About the study

This prospective cohort study included 382 patients with stable HfrEF. According to European Society of Cardiology guidelines, the patients  were older than 18 years and were diagnosed with chronic HF more than three months before inclusion. Follow-up visits were scheduled every three months. The blood samples were collected at baseline and each follow-up visit.

The clinical committee determined the study endpoints. The primary endpoint comprised the composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and hospitalization for the management of acute or worsened HF. Only the first endpoint was used for analysis in patients with multiple endpoints. The authors selected all baseline samples and two samples closest to the primary endpoint.


In total, 104 (27.2%) women and 278 (72.8%) men were included, with similar mean ages (62 ± 13 versus 64 ± 13, respectively). Women had a significantly lower body mass index and were more frequently current smokers than men.

The ischemic etiology of HF was more frequent in men. Women had a lower prevalence of myocardial infarction, percutaneous coronary intervention, and atrial fibrillation, and lower median baseline level of high-sensitivity troponin T. There were no clinically relevant differences between genders in mean left ventricular ejection fraction, B-type natriuretic peptide or C-reactive protein.

1,070 samples were available during a median follow-up of 25 months. The researchers used aptamer-based proteomic assay to assess 1105 circulating proteins previously associated with cardiovascular (patho)physiology.

There were significant differences in baseline levels of circulating proteins between genders. After correction for multiple testing, 55 proteins showed statistically significant differences based on gender. Women had higher levels of 34 proteins, including, heart-type fatty acid binding protein, adiponectin, osteoprotegerin, and galectin-3. Men had higher levels of 21 proteins, including prostate-specific antigen, interleukin 1 receptor-like 1, myoglobin, and transforming growth factor β1.

According to the authors, five biological processes that dominated the female circulating protein profile were associated with extracellular matrix organization, positive regulation of insulin-like growth factor receptor signaling pathway, and dendrite regeneration. Five processes that dominated the male circulating protein profile were related to the positive regulation of apoptotic processes, cell death, and musculoskeletal movements.

During a median follow-up of 25 months, 23 women and 91 men reached the primary endpoint. Although baseline cardiovascular protein levels differed between women and men, the predictive value of repeatedly measured circulating proteins did not appear to differ.

Endothelin-1 was more strongly associated with the primary endpoint in men than women. Endothelin-1 is considered to be a predictor of adverse clinical outcomes in HF and plays a key role in numerous aspects of cardiac physiology and pathology, such as hypertension, cardiac contractility, and cardiac remodeling. The primary endpoint was positively associated with somatostatin in men, and inversely associated in women. Somatostatin, also known as growth hormone inhibiting hormone, has strong regulatory effects throughout the body, such as suppression of insulin-like growth factor I, growth hormone, and insulin.


This study has shown that the baseline levels of cardiovascular proteins differed between women and men. The predictive value of repeatedly measured circulating proteins did not differ between genders, except for endothelin-1 and somatostatin.

The researchers speculated that observed differences may be caused by the role of sex hormones or sex hormone receptors, the presence of extracellular matrix organization, and/or sex-specific differences in cardiovascular epigenetics. However, the exact mechanisms are not completely understood.

Understanding the gender-specific profiles of cardiovascular proteins and their associations with the risk of adverse outcomes may help to improve the understanding of the pathophysiological processes.

This article was published in Biology of Sex Differences.

Journal Reference

de Bakker M et al. Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure. Biol Sex Differ; 2023: 14, 29.

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