A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.
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.
Department of Bioengineering, University of Washington, Seattle 98109, WA, USA.
Jennifer
J
Davis
10244 Normandy Dr., Plymouth 48170, MI, USA.
L Craig
LC
Davis
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati 45247, OH, USA.
Robert N
RN
Correll
Department of Physiology, Temple University, Philadelphia 19122, PA, USA.
Catherine A
CA
Makarewich
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati 45247, OH, USA.
Jennifer A
JA
Schwanekamp
Department of Bioengineering, University of Washington, Seattle 98109, WA, USA.
Farid
F
Moussavi-Harami
Department of Bioengineering, University of Washington, Seattle 98109, WA, USA.
Dan
D
Wang
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati 45247, OH, USA.
Allen J
AJ
York
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford 94305, CA, USA.
Haodi
H
Wu
Department of Physiology, Temple University, Philadelphia 19122, PA, USA.
Steven R
SR
Houser
Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston 02115, MA, USA.
Christine E
CE
Seidman
Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston 02115, MA, USA.
Jonathan G
JG
Seidman
Department of Bioengineering, University of Washington, Seattle 98109, WA, USA.
Michael
M
Regnier
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis 55455, MN, USA.
Joseph M
JM
Metzger
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford 94305, CA, USA.
Joseph C
JC
Wu
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati 45247, OH, USA; Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati 45247, OH, USA. Electronic address: jeff.molkentin@cchmc.org.
Jeffery D
JD
Molkentin
D000818:Animals; D001011:Aorta / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism
D009124:Muscle Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D019703:Calcineurin; D002118:Calcium