A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.

Abstract

The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

• Authors: Jennifer Davis, L Craig Davis, Robert N Correll, Catherine A Makarewich, Jennifer A Schwanekamp, Farid Moussavi-Harami, Dan Wang, Allen J York, Haodi Wu, Steven R Houser, Christine E Seidman, Jonathan G Seidman, Michael Regnier, Joseph M Metzger, Joseph C Wu, Jeffery D Molkentin
• Journal: Cell (Cell) Vol. 165 Issue 5 Pg. 1147-1159 (May 19 2016) ISSN: 1097-4172 [Electronic] United States
• PMID: 27114035 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Muscle Proteins
• Extracellular Signal-Regulated MAP Kinases
• Calcineurin
• Calcium

Topics

• Animals
• Aorta (pathology)
• Calcineurin (metabolism)
• Calcium (metabolism)
• Cardiomyopathy, Dilated (genetics, metabolism, pathology)
• Cardiomyopathy, Hypertrophic, Familial (genetics, metabolism, pathology)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Induced Pluripotent Stem Cells (metabolism, pathology)
• Mice
• Muscle Proteins (genetics, metabolism)
• Mutation
• Myofibrils (metabolism)