The role of cardiac lipotoxicity in the pathogenesis of diabetic cardiomyopathy

Abstract

Cardiomyopathy, the presence of cardiac dysfunction independent of ischemic heart disease and/or hypertension, is becoming a more prominent condition in our diabetic patient population. Unfortunately, we do not yet understand the mechanism(s) responsible for causing diabetic cardiomyopathy. With the recent explosion in the obesity and Type 2 diabetes epidemic, our understanding of dyslipidemia and the adverse effects of lipid surplus on cellular and organ function has grown considerably. Numerous studies now illustrate that excess lipid accumulation may exert direct toxic effects on cellular function, a term coined ‘lipotoxicity’. As obesity and Type 2 diabetes are significant risk factors for cardiovascular disease, cardiac lipotoxicity may represent a significant component mediating the diabetic cardiomyopathy phenotype. Therefore, a more complete understanding of how cardiac lipotoxicity is regulated and how different lipid metabolites cause cellular dysfunction may lead to the discovery of novel targets to treat cardiomyopathy in our diabetic patient population.

Keywords::

• cardiac lipotoxicity
• ceramide
• diabetes
• diabetic cardiomyopathy
• diacylglycerol
• fatty acid oxidation
• fatty acid uptake
• obesity
• triacyglycerol

Financial & competing interests disclosure

JR Ussher is a Venture-Sinai fellow of the Lunenfeld-Tanenbaum Research Institute and a fellow of the Alberta Innovates Health Solutions. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

Diabetes and cardiovascular disease

• Diabetes significantly increases one's risk for cardiovascular disease, which is the number one cause of death in this patient population.

Diabetic cardiomyopathy

• Diabetic cardiomyopathy is a form of cardiovascular disease independent of coronary artery disease and/or hypertension, of which there are currently no approved therapies.

Pathophysiology of diabetic cardiomyopathy

• Cardiac insulin signaling/insulin resistance: While insulin signaling in the coronary vasculature may be impaired in diabetes, the hyperinsulinemia associated with Type 2 diabetes may result in enhanced myocardial Akt signaling, contributing to excessive growth of the myocardium and subsequent cardiac hypertrophy. Insulin-induced inhibition of fork head box-containing protein O may also be defective in the diabetic heart.

• Endoplasmic reticulum stress: Rodent models of both Type 1 and Type 2 diabetes are frequently associated with endoplasmic reticulum stress in the heart.

• Mitochondrial dysfunction: Impaired mitochondrial function in the diabetic heart is associated with increased oxidative stress and impaired energy production.

• All three of these components of diabetic cardiomyopathy are also associated with changes in myocardial lipid metabolism.

Cardiac lipotoxicity

• The accumulation of lipid in the myocardium may induce contractile dysfunction, a term referred to as ‘cardiac lipotoxicity’, and this may contribute to the cardiomyopathy in our diabetic patient population.

  • – Excessive triacylglycerol content in the heart is associated with left ventricular dysfunction.

  • – Ceramide accumulation in the heart may induce cardiac myocyte apoptosis and impair myocardial glucose utilization.

  • – Increases in myocardial diacylglycerol content have been shown to impair insulin-stimulated glucose metabolism in the heart through activation of protein kinase C isoforms.

• An improved understanding of the regulation of lipid metabolism and how lipids accumulate in the heart may result in novel targets to treat diabetic cardiomyopathy.

Targeting cardiac lipotoxicity to treat diabetic cardiomyopathy

• Fatty acid oxidation

  • – Ongoing debate continues regarding whether increasing or reducing fatty acid oxidation rates can alleviate the progression of diabetic cardiomyopathy.

  • – Increasing fatty acid oxidation rates has been proposed to reduce myocardial triacylglycerol, diacylglycerol and ceramide content, which should reduce cardiac lipotoxicity.

  • – By contrast, reducing fatty acid oxidation rates may improve myocardial carbohydrate metabolism and ensuing contractile efficiency.

• Fatty acid uptake

  • – Limiting excessive myocardial fatty acid uptake has been shown to protect against diabetic cardiomyopathy.

  • – This is associated with a reduction in both myocardial lipid accumulation and fatty acid oxidation rates, which may make it a better target than manipulating fatty acid oxidation rates directly.

Notes