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Sleep fragmentation induces heart failure in a hypertrophic cardiomyopathy mouse model by altering redox metabolism
Karthikeyan Bose1, Radhika Agrawal2, Thiagarajan Sairam2
1The Knight Cardiovascular Institute and Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
Insights
Sleep fragmentation (SF) worsens cardiac hypertrophy into heart failure (HF) by damaging mitochondria and disrupting metabolism. Regularizing sleep may improve outcomes for patients with hypertrophic cardiomyopathy and sleep disorders.
Area of Science:
- Cardiovascular Biology
- Sleep Medicine
- Mitochondrial Research
Background:
- Sleep fragmentation (SF) disrupts circadian rhythms and impacts cardiovascular health.
- The role of SF in the progression from cardiac hypertrophy to heart failure (HF) remains unestablished.
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition associated with increased risk of heart failure.
Purpose of the Study:
- To investigate the impact of SF on the progression of HCM to HF.
- To elucidate the molecular mechanisms underlying SF-induced cardiac dysfunction in HCM.
Main Methods:
- Generated a transgenic mouse model with a patient-specific MYBPC3 variant causing HCM.
- Exposed HCM mice to SF and compared cardiac pathophysiology with non-SF controls.
- Analyzed mitochondrial function, sarcomere structure, apoptosis, and redox metabolic pathways.
Main Results:
- SF significantly exacerbated cardiac pathology in HCM mice.
- SF induced mitochondrial damage, sarcomere disarray, and apoptosis in the HCM heart.
- These SF-driven changes promoted the transition from hypertrophy to a heart failure phenotype, primarily via redox metabolic pathways.
Conclusions:
- Sleep fragmentation is a novel risk factor for the transition from cardiac hypertrophy to heart failure.
- SF exacerbates HCM by targeting mitochondrial and redox metabolic pathways.
- Clinical interventions focusing on regularizing sleep patterns may benefit HCM patients with sleep disorders and a worse prognosis.
Abstract:
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.
