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Sex-specific cardiovascular protein levels and their link with clinical outcome in heart failure
Marie de Bakker1, Mylène Loncq de Jong1, Teun Petersen1,2
1Department of Cardiology, Erasmus MC Cardiovascular Institute, University Medical Center Rotterdam, Room Na-316, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
Insights
Cardiovascular protein levels differ between sexes in heart failure with reduced ejection fraction (HFrEF) patients, but their predictive value for adverse outcomes remains consistent over time for both women and men.
Area of Science:
- Cardiovascular Medicine
- Proteomics
- Biomarker Discovery
Background:
- Heart failure with reduced ejection fraction (HFrEF) affects millions globally, with distinct pathophysiological mechanisms potentially influenced by sex.
- Understanding sex-specific differences in circulating protein profiles is crucial for improving prognostication and treatment strategies in HFrEF.
- Current prognostic models for HFrEF may not fully capture sex-based variations in protein biomarkers.
Purpose of the Study:
- To investigate sex-specific differences in baseline cardiovascular protein profiles in HFrEF patients.
- To determine if the prognostic value of serially measured proteins differs between women and men with HFrEF.
- To enhance the understanding of HFrEF pathophysiology and optimize the use of circulating proteins for prognostication.
Main Methods:
- Longitudinal study of 250 stable HFrEF patients with trimonthly blood sampling over a median of 26 months.
- Analysis of baseline and serial protein levels using the Olink Cardiovascular III panel.
- Application of linear regression for sex-based differences in baseline levels and joint models for longitudinal prognostic associations.
Main Results:
- Significant sex differences were observed in baseline levels of several cardiovascular proteins, with some higher in women (e.g., fatty acid-binding protein 4) and others in men (e.g., matrix metalloproteinase-3).
- No significant differences were found between sexes in the longitudinal associations of proteins with the primary endpoint (cardiovascular death, heart transplantation, LVAD, or HF hospitalization).
- Peptidoglycan recognition protein 1 showed a suggestive interaction with sex, being more strongly associated with adverse outcomes in women.
Conclusions:
- While baseline cardiovascular protein profiles exhibit sex-specific differences in HFrEF, their temporal associations with adverse outcomes do not appear to differ significantly between women and men.
- These findings suggest that established protein biomarkers may have similar prognostic utility across sexes in HFrEF, despite baseline level variations.
- Further research is warranted to explore the clinical implications of sex-specific protein differences and their role in HFrEF pathophysiology.
Aims:
This study aims to provide insight into sex-specific cardiovascular protein profiles and their associations with adverse outcomes, which may contribute to a better understanding of heart failure (HF) pathophysiology and the optimal use of circulating proteins for prognostication in women and men.
Methods And Results:
In 250 stable patients with HF with reduced ejection fraction (HFrEF), we performed trimonthly blood sampling (median follow-up: 26 [17-30] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or one sample closest to censoring and applied the Olink Cardiovascular III panel. We used linear regression to study sex-based differences in baseline levels and joint models to study differences in the prognostic value of serially measured proteins. In 66 women and 184 men (mean age of 66 and 67 years, respectively), 21% and 28% reached the PEP, respectively. Mean baseline levels of fatty acid-binding protein 4, secretoglobin family 3A member 2, paraoxonase 3, and trefoil factor 3 were higher in women (Pinteraction : 0.001, 0.007, 0.018, and 0.049, respectively), while matrix metalloproteinase-3, interleukin 1 receptor-like 1, and myoglobin were higher in men (Pinteraction : <0.001, 0.001, and 0.049, respectively), independent of clinical characteristics. No significant differences between sexes were observed in the longitudinal associations of proteins with the PEP. Only peptidoglycan recognition protein 1 showed a suggestive interaction with sex for the primary outcome (Pinteraction = 0.028), without multiple testing correction, and was more strongly associated with adverse outcome in women {hazard ratio [HR] 3.03 [95% confidence interval (CI), 1.42 to 6.68], P = 0.008} compared with men [HR 1.18 (95% CI, 0.84 to 1.66), P = 0.347].
Conclusions:
Although multiple cardiovascular-related proteins show sex differences at baseline, temporal associations with the adverse outcome do not differ between women and men with HFrEF.
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