Sleep fragmentation induces heart failure in a hypertrophic cardiomyopathy mouse model by altering redox metabolism
Karthikeyan Bose,
Radhika Agrawal,
Thiagarajan Sairam,
Jessenya Mil,
Matthew P. Butler,
Perundurai S. Dhandapany
Affiliations
Karthikeyan Bose
The Knight Cardiovascular Institute and Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA
Radhika Agrawal
Cardiovascular Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (DBT-inStem), Bangalore, India
Thiagarajan Sairam
Cardiovascular Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (DBT-inStem), Bangalore, India
Jessenya Mil
The Knight Cardiovascular Institute and Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA
Matthew P. Butler
Oregon Institute of Occupational Health Sciences, and Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA
Perundurai S. Dhandapany
The Knight Cardiovascular Institute and Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA; Cardiovascular Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine, Bangalore (DBT-inStem), Bangalore, India; Corresponding author
Summary: Sleep fragmentation (SF) disrupts normal biological rhythms and has major impacts on cardiovascular health; however, it has never been shown to be a risk factor involved in the transition from cardiac hypertrophy to heart failure (HF). We now demonstrate devastating effects of SF on hypertrophic cardiomyopathy (HCM). We generated a transgenic mouse model harboring a patient-specific myosin binding protein C3 (MYBPC3) variant displaying HCM, and measured the progression of pathophysiology in the presence and absence of SF. SF induces mitochondrial damage, sarcomere disarray, and apoptosis in HCM mice; these changes result in a transition of hypertrophy to an HF phenotype by chiefly targeting redox metabolic pathways. Our findings for the first time show that SF is a risk factor for HF transition and have important implications in clinical settings where HCM patients with sleep disorders have worse prognosis, and strategic intervention with regularized sleep patterns might help such patients.
