Details

Autor(en) / Beteiligte

• Mosqueira, Diogo
• Smith, James G.W.
• Bhagwan, Jamie R.
• Denning, Chris

Titel

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

Ist Teil von

• Trends in molecular medicine, 2019-09, Vol.25 (9), p.775-790

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings. In this article we compare recent progress in unveiling multiple HCM mechanisms in different models, highlighting similarities and discrepancies. We explore how insight is facilitating the design of new HCM therapeutics, including those that regulate metabolism, contraction and heart rhythm, providing a future perspective for treatment of HCM. HCM is a prevalent and complex disease governed by multiple molecular mechanisms, and there is currently no efficient cure. New treatment strategies are under development, and several drugs are reaching the final stages of clinical trials, with partial efficacy.HCM disease models vary in complexity. Furthermore, they are limited by sample availability, demanding logistics, preparation artefacts, oversimplicity, and species-differences relative to the human cardiovascular physiology, often producing conflicting results.Application of genome-editing technology to hPSCs enables unlimited isogenic sets of heart cells in which the primary mutation is the only change, allowing elucidation of disease phenotypes and genetic causation.Uncovering new disease mechanisms and targets will pave the way to more efficient HCM therapeutics.