The Role of Metabolic Inflexibility in Heart Failure

Abstract

Heart failure (HF) is a syndrome defined by the inability of the heart to supply adequate nutrients and oxygen to peripheral tissues. One of the most common causes of HF is chronic pressure overload due to hypertension, which leads to hypertrophic remodeling, accompanied by metabolic alterations. These changes are initially compensatory but lead to worse outcomes in the long term, making them targets for therapeutic intervention. When hypertension and diabetes are present simultaneously, a type of HF with preserved ejection fraction (HFpEF) ensues. HFpEF is distinct from HF with reduced ejection fraction (HFrEF) and diabetes in clinical presentation and physiology, necessitating alternative treatments. Understanding metabolic alterations which contribute to the development and progression of HFpEF can aid us greatly in creating these treatments. This study aimed to replicate the cellular metabolic profile in diabetic heart to 1) determine if energy deficiency plays a causative role in HFpEF progression, and 2) test the necessity of glucose oxidation for left ventricular hypertrophy development and progression to HF. Since pyruvate dehydrogenase (PDH) kinase 4 (PDK4) is the predominant PDK found in the heart and PDK4 expression in the heart increases with high circulating fat levels, I employed a genetic approach to modulate its expression in cardiomyocytes specifically. This animal model allows us to control the activity level of PDH by its phosphorylation as seen in diabetic patients while bypassing complications of altering metabolism systemically. Deletion of PDK4 in cardiomyocytes of adult mice prior to a high-fat diet prevented PDH inactivation in response to increased free fatty acids, allowing continued use of glucose for energy production by the TCA cycle. The impact on HFpEF development was unclear as the control group failed to fully develop the phenotype. In a separate experiment, constitutive overexpression of PDK4 gene was used to persistently inhibit PDH before surveying cellular metabolism and its effect on cardiac function at baseline as well as in response to increased cardiac work due to pressure afterload. This revealed that cardiac energetic deficiency did not require hypertrophic growth, and hypertrophic growth was not blunted by lack of glucose oxidation. Taken together, these findings suggest that metabolic inflexibility in cardiomyocytes plays a role in HFrEF development, independently of LVH. Furthermore, the metabolic profile in our animal model resembles what little is known of in HFpEF patients more closely than in diabetic cardiomyopathy, paving the way for future studies