Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence

Abstract

The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism, increased oxidative stress and activation of pro-inflammatory pathways associated with diabetes mellitus, which can induce cardiac remodelling and dysfunction. In this Review, Tan and colleagues discuss the pathogenesis of diabetic cardiomyopathy and describe signalling pathways that might be potential therapeutic targets. Diabetic cardiomyopathy is characterized by adverse structural remodelling (including cardiac hypertrophy and fibrosis), early-onset diastolic dysfunction and late-onset systolic dysfunction. At present, treatment regimens for diabetes-associated cardiovascular disease rely on conventional therapies that focus on optimizing glycaemic control, lowering lipid levels and reducing oxidative stress. Pathophysiological factors that contribute to diabetic cardiomyopathy include metabolic disturbances, insulin resistance, formation and crosslinking of advanced glycation end products, mitochondrial damage, oxidative stress, inflammation and cell death. Several new potential treatment strategies that target myocardial fibrosis, inflammation, oxidative stress and insulin resistance have shown promising results in preclinical studies but require validation in randomized clinical trials.