Proteomic signatures predict depressed cooperativity and increased calcium sensitivity in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) affects over half of all heart failure patients. We recently reported several deficits in the tension-calcium relationship from isolated skinned cardiomyocytes from HFpEF patients, including depressed cooperativity, increased calcium sensitivity, and depressed maximum tension. Here, we sought to identify whether proteomic signatures associate with these deficits. We obtained total proteomic profiles, consisting of 2250 proteins, from right ventricular endomyocardial biopsies in 43 patients. Machine learning based cluster analysis revealed two clusters of proteomic profiles, Group 1 (n=31) and Group 2 (n=12). Compared to Group 1, patients in Group 2 had depressed E/A ratio (p=0.048) and smaller left ventricles (p=0.02) on echocardiography, right ventricular dysfunction (p=0.08) on right heart catheterization, and worsened HF symptoms based on New York Heart Association functional class (p=0.054). Analysis of tension-calcium relationships revealed that myocytes from Group 2 had a higher Hill coefficient (p=0.0001), indicative of better cooperativity, and increased calcium sensitivity (p=0.001), but no differences in maximum tension. We next identified which proteins correlated with Hill coefficient and calcium sensitivity using univariate regression. We found that 330 proteins negatively correlated with Hill coefficient, while 298 proteins positivity correlated with calcium sensitivity, corresponding more to Group 2. Gene ontology pathway analysis revealed these proteins (either set) were enriched for metabolic processes, including fatty acid metabolism, mitochondrial respiration, and cellular biosynthetic processes. This poses an intriguing linkage between downregulation of mitochondrial metabolic processes and enhanced cooperativity and calcium sensitivity. The latter is reported in HF with reduced EF, but the former seems unique to HFpEF. Metabolite perturbations may affect sarcomere post-translational modification, driving shifts in cooperativity and calcium sensitivity. Further studies are ongoing to identify the cause of these myofilament calcium-tension changes and implications.