Targets for therapy in sarcomeric cardiomyopathies

Abstract

To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics.

Keywords: Dilated cardiomyopathy; Energetics and microvasculature; Gene therapy; Hypertrophic cardiomyopathy; Ion channels.

Figure 1

Several myofilament proteins may be target of treatment to reverse primary functional changes of the sarcomeres. CB, cross-bridge; TnC, troponin C; TnI, troponin I; TnT, troponin T; LC, light chain; C protein, myosin-binding protein C. Modified from Ferrantini et al.

Figure 2

Treatment of sarcomeric cardiomyopathies may be directed at non-sarcomeric targets such as ion channels, β-adrenergic receptors, and Ca²⁺/CaMKII. In addition, metabolic therapy, such as perhexiline, may be targeted at the mitochondria to improve the energetic status of the heart. Modified from Coppini et al.