Myocardial Proteome in Human Heart Failure With Preserved Ejection Fraction.

Summary

Mass spectrometry–based proteomics of human HFpEF myocardium revealed downregulation of mitochondrial transport/organization, oxidative phosphorylation, and protein translation, alongside upregulation of immune/ROS pathways. Two proteomic HFpEF subgroups emerged; the more distinct group was enriched for severe obesity and had lower proteins in fuel metabolism/translation. Modules correlated with LV hypertrophy and RV load implicated proteasome, metabolism, and sarcomere/translation networks.

Key Findings

• Downregulation of mitochondrial transport/organization, oxidative phosphorylation, and protein translation in HFpEF myocardium.
• Upregulation of immune activation, reactive oxygen species, and inflammatory responses.
• Two proteomic HFpEF subgroups; the more distinct group enriched for severe obesity with lower fuel metabolism/translation proteins.
• Gene–protein discordance: higher expression of OXPHOS/metabolism genes but lower corresponding proteins.

Clinical Implications

Supports targeting metabolic reprogramming and translational control in HFpEF, particularly among severely obese patients. Proteomic modules correlated with LV/RV remodeling may yield biomarkers to stratify risk and monitor response.

Limitations

• Control sample size in DIA cohort was limited (n=5), potentially affecting comparisons.
• Observational tissue study cannot establish causality; therapeutic implications require interventional validation.

Future Directions

Test metabolism/translation-targeted interventions in HFpEF, evaluate proteomic biomarkers for patient stratification, and investigate mechanisms underlying gene–protein discordance.