Identifying the Therapeutic Window for Treatment of Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) affects 1:200 of the population, and is associated with altered metabolic activity and hypercontractile function. We have previously demonstrated that the cardiac L-type Ca2+ channel (LTCC) can regulate mitochondrial function due to an association via the cytoskeletal network. We have also shown that human HCM causing mutations in cardiac troponin I or β-myosin heavy chain lead to a faster LTCC inactivation rate, and impaired functional communication between LTCC and mitochondria in mouse models of human disease (cTnI-G203S and αMHC403/+ respectively). This results in a “hypermetabolic” mitochondrial state, which precedes development of HCM. Application of a peptide derived against the LTCC alpha-interacting domain (AID-TAT) slows LTCC inactivation rate and decreases metabolic function in wt cardiomyocytes. We examined the efficacy of in vivo exposure of cTnI-G203S and αMHC403/+ mice to AID-TAT (10 μM 3x/wk, 5wk) on mitochondrial function by assessing alterations in mitochondrial membrane potential (Ψm, JC-1 fluorescence) and mitochondrial metabolic activity (MMA, flavoprotein autofluorescence). Treatment of pre-cardiomyopathic cTnI-G203S mice normalised Ψm (AID-TAT: 20.1 ± 2.2% increase, n = 18 vs AID(S)-TAT: 30.3 ± 1.8% increase, n = 18; p < 0.05), and MMA (AID-TAT: 17.8 ± 2.1% increase, n = 29 vs AID(S)-TAT: 42.3 ± 5.0% increase, n = 26; p < 0.05). AID-TAT also prevented hypertrophy as evidenced by changes on echocardiography. Treatment of post-cardiomyopathic αMHC403/+ mice normalised Ψm (AID-TAT: 20.6 ± 3.4% increase, n = 6 vs AID(S)-TAT: 30.3 ± 1.7% increase, n = 24; p < 0.05), but not MMA (AID-TAT: 29.2 ± 2.8% increase, n = 14 vs AID(S)-TAT: 40.8 ± 6.6% increase, n = 13; p = NS). Treatment did not appear to reverse hypertrophy. We conclude that early-intervention AID-TAT treatment may be more effective in restoring mitochondrial function and preventing development of HCM.