TY - JOUR
T1 - Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy
T2 - Obesity-Related Cardiac Defects as a Major Disease Modifier
AU - Nollet, Edgar E
AU - Westenbrink, B Daan
AU - de Boer, Rudolf A
AU - Kuster, Diederik W D
AU - van der Velden, Jolanda
PY - 2020/11/17
Y1 - 2020/11/17
N2 - Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype-phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity-induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity-related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation-induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.
AB - Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype-phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity-induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity-related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation-induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.
U2 - 10.1161/JAHA.120.018641
DO - 10.1161/JAHA.120.018641
M3 - Article
C2 - 33174505
VL - 9
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 22
M1 - e018641
ER -