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A mouse model reveals an important role for catecholamine‐induced lipotoxicity in the pathogenesis of stress‐induced cardiomyopathy
Author(s) -
Shao Yangzhen,
Redfors Björn,
Ståhlman Marcus,
Täng Margareta Scharin,
Miljanovic Azra,
Möllmann Helge,
Troidl Christian,
Szardien Sebastian,
Hamm Christian,
Nef Holger,
Borén Jan,
Omerovic Elmir
Publication year - 2013
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfs161
Subject(s) - lipotoxicity , medicine , cardiomyopathy , pathogenesis , endocrinology , heart failure , myocardial stunning , cardiology , stunning , lipid droplet , oxidative stress , cardiac function curve , ischemia , insulin resistance , insulin
Aim Stress‐induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. Methods and results A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC‐like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post‐ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post‐ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post‐ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum‐stressed HL‐1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO‐induced cardiac toxicity and cardiac dysfunction. We also found that ISO‐induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum‐stressed HL‐1 cardiomyocytes. Conclusions The present study demonstrates that lipotoxicity is closely associated with catecholamine‐induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.