Diastolic heart failure, i.e., heart failure with preserved ejection fraction (HFpEF) constitutes more than half of heart failure cases and lacks effective treatment. The conserved C-terminal end segment of cardiac troponin I (cTnI) functions in regulating cardiac muscle relaxation. Our previous studies found that isolated cTnI C-terminal end 27 amino acids peptide (cTnI-C27) preserves an intrinsic 3D structure same as that in intact cTnI and retains binding affinity for tropomyosin with a myofilament Ca 2+ -desensitization effect when added to skinned cardiac muscle sections (PMID: 31505197; 33814345). To establish the functionality of cTnI-C27 peptide for clinical applications as a therapeutic reagent to correct myocardial diastolic dysfunction and treat HFpEF, we further developed in vivo delivery and cardiac muscle-specific expression of cTnI-C27 peptide to test the therapeutic effect on HFpEF mice. A recombinant adeno-associated virus (AAV9) vector was constructed using an enhanced cardiac troponin T gene promoter to express a cDNA encoding human cTnI-C27 peptide. The recombinant AAV was i.v. injected into wild-type (WT) and transgenic mice expressing a hypertrophic cardiomyopathy (HCM) alpha-tropomyosin mutant (Tm-E180G). PCR confirmed the delivery of cTnI-C27 AAV into the mouse cardiac muscle. Echocardiography studies detected significant effects of the cardiac muscle-specific expression of HcTnI-C27 peptide on cardiac function in vivo from 2.5 to 14 days post-AAV injection, showing increased left ventricular diastolic volume and an effective correction of the supercontractivity/HFpEF phenotype of Tm-E180G hearts. Ex vivo working heart studies 14 days post-AAV treatment confirmed the improved myocardial diastolic function in WT and Tm-E180G hearts, supporting the therapeutic efficacy of cTnI-C27 peptide on correcting diastolic dysfunction of cardiac muscle for use in the treatment of HFpEF in HCM.
Feng et al. (2026) studied this question.