TY - JOUR
T1 - Phenotypic variation and targeted therapy of hypertrophic cardiomyopathy using genetic animal models
AU - Gannon, Michael P.
AU - Link, Mark S.
N1 - Publisher Copyright:
© 2019
PY - 2021/1
Y1 - 2021/1
N2 - Hypertrophic cardiomyopathy (HCM) has a variable clinical presentation due to the diversity of causative genetic mutations. Animal models allow in vivo study of genotypic expression through non-invasive imaging, pathologic sampling, and force analysis. This review focuses on the spontaneous and induced mutations in various animal models affecting mainly sarcomere proteins. The sarcomere is comprised of thick (myosin) filaments and related proteins including myosin heavy chain and myosin binding protein-C; thin (actin) filament proteins and their associated regulators including tropomyosin, troponin I, troponin C, and troponin T. The regulatory milieu including transcription factors and cell signaling also play a significant role. Animal models provide a layered approach of understanding beginning with the causative mutation as a foundation. The functional consequences of protein energy utilization and calcium sensitivity in vivo and ex vivo can be studied. Beyond pathophysiologic disruption of sarcomere function, these models demonstrate the clinical sequalae of diastolic dysfunction, heart failure, and arrhythmogenic death. Through this cascade of understanding the mutation followed by their functional significance, targeted therapies have been developed and are briefly discussed.
AB - Hypertrophic cardiomyopathy (HCM) has a variable clinical presentation due to the diversity of causative genetic mutations. Animal models allow in vivo study of genotypic expression through non-invasive imaging, pathologic sampling, and force analysis. This review focuses on the spontaneous and induced mutations in various animal models affecting mainly sarcomere proteins. The sarcomere is comprised of thick (myosin) filaments and related proteins including myosin heavy chain and myosin binding protein-C; thin (actin) filament proteins and their associated regulators including tropomyosin, troponin I, troponin C, and troponin T. The regulatory milieu including transcription factors and cell signaling also play a significant role. Animal models provide a layered approach of understanding beginning with the causative mutation as a foundation. The functional consequences of protein energy utilization and calcium sensitivity in vivo and ex vivo can be studied. Beyond pathophysiologic disruption of sarcomere function, these models demonstrate the clinical sequalae of diastolic dysfunction, heart failure, and arrhythmogenic death. Through this cascade of understanding the mutation followed by their functional significance, targeted therapies have been developed and are briefly discussed.
KW - Animal models of human disease
KW - Cardiomyopathy
KW - Genetics
KW - Hypertrophic cardiomyopathy
KW - Sudden cardiac death
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U2 - 10.1016/j.tcm.2019.11.009
DO - 10.1016/j.tcm.2019.11.009
M3 - Review article
C2 - 31862214
AN - SCOPUS:85077143997
SN - 1050-1738
VL - 31
SP - 20
EP - 31
JO - Trends in Cardiovascular Medicine
JF - Trends in Cardiovascular Medicine
IS - 1
ER -