Multicenter HFpEF study identifies sex disparity linked with two discrete cardiac proteomic signatures.
Publication Year:
2025
PubMed ID:
41446146
Funding Grants:
Public Summary:
Heart failure with preserved ejection fraction (HFpEF) is a massive public health issue that is now more common than the traditional form of heart failure (HFrEF). While doctors have long noted that women and men experience HFpEF differently—especially as they age or deal with metabolic issues like diabetes—a new study analyzing actual heart tissue samples discovered that these differences aren't strictly based on a person's biological sex. Instead, by looking at the heart's proteins, researchers found that HFpEF actually splits into two entirely distinct molecular blueprints, or "clusters." One cluster shows major changes in the heart's physical pumping structure, while the other shows breakdown in how heart cells communicate with their surrounding supportive tissue. By uncovering these two specific protein profiles rather than viewing HFpEF as a single disease, scientists now have a precise map to design targeted, personalized drugs for patients based on their specific molecular type.
Scientific Abstract:
Heart failure with preserved ejection fraction (HFpEF) is epidemic, with an incidence exceeding that of heart failure with reduced ejection fraction (HFrEF). Sex differences in HFpEF phenotype have been observed, particularly linked to aging and metabolic comorbidities in women. Here, we report a multi-centre proteomic analysis of HFpEF and HFrEF cardiac samples. Using tissues and clinical data derived from multiple institutional biobanks, in-depth characterization of the proteome of ventricular samples was undertaken. Relative to HFrEF, the HFpEF cohort exhibited minimal proteome composition overlap and pronounced heterogeneity. A key finding of this investigation is that sex per se did not confer a distinctive proteomic HFpEF signature. Rather, two HFpEF proteomic profiles were identified, differing significantly in sex ratios. The identification of two Clusters revealed that HFpEF has two predominant proteomic signatures at the molecular level, marked by differences in the extent and nature of structural and contractile machinery and by local cellular and ECM communications. Upstream regulator analysis identified various molecular leads to be pursued in defining these two HFpEF profiles. Our findings offer specific opportunities for new exploration of therapeutic options to target the spectrum of HFpEF proteomic diversity and identify potential drug targeting prospects.