Mechanisms underlying the impaired contractility of diabetic cardiomyopathy

Abstract

Cardiac dysfunction is a well-known consequence of diabetes, with sustained hyperglycaemia leading to the development of a cardiomyopathy that is independent of cardiovascular disease or hypertension. Animal models of diabetes are commonly used to study the pathophysiology of diabetic cardiomyopathy, with the hope that increased knowledge will lead ultimately to better therapeutic strategies being developed. At physiological temperature, left ventricular trabeculae isolated from the streptozotocin rat model of type 1 diabetes showed decreased stress and prolonged relaxation, but with no evidence that decreased contractility was a result of altered myocardial Ca²⁺ handling. Although sarcoplasmic reticulum (SR) Ca²⁺ reuptake appeared slower in diabetic trabeculae, it was offset by an increase in action-potential duration, thereby maintaining SR Ca²⁺ content and favouring increased contraction force. Frequency analysis of t-tubule distribution by confocal imaging of ventricular tissue labeled with wheat germ agglutinin or ryanodine receptor antibodies showed a reduced T-power for diabetic tissue, but the differences were minor in comparison to other models of heart failure. The contractile dysfunction appeared to be the result of disrupted F-actin in conjunction with the increased type I collagen, with decreased myofilament Ca²⁺ sensitivity contributing to the slowed relaxation.

Keywords: Diabetic cardiomyopathy; Heart failure; Contractility; T-tubules; Excitation-contraction coupling; Calcium homeostasis

Core tip: Diabetic patients develop a cardiomyopathy that is independent of vascular disease, and is thought to develop as a direct result of the prolonged hyperglycaemia. Animal models of diabetes can help us understand the cellular mechanisms that lead ultimately to contractile dysfunction of diabetic cardiomyopathy. The streptozotocin rat model of type 1 diabetes has slowed Ca²⁺ transients and twitch force kinetics, with reduced myofilament Ca²⁺ sensitivity. Myocytes are decreased in volume in diabetic hearts, with reduced and disrupted F-actin, and type 1 collagen is increased. Together, these changes all contribute to the reduced contractility of diabetic cardiomyopathy.