Heart failure and loss of metabolic control

Abstract

Heart failure is a leading cause of morbidity and mortality worldwide, currently affecting 5 million Americans. A syndrome defined on clinical terms, heart failure is the end result of events occurring in multiple heart diseases, including hypertension, myocardial infarction, genetic mutations and diabetes, and metabolic dysregulation, is a hallmark feature. Mounting evidence from clinical and preclinical studies suggests strongly that fatty acid uptake and oxidation are adversely affected, especially in end-stage heart failure. Moreover, metabolic flexibility, the heart's ability to move freely among diverse energy substrates, is impaired in heart failure. Indeed, impairment of the heart's ability to adapt to its metabolic milieu and associated metabolic derangement are important contributing factors in the heart failure pathogenesis. Elucidation of molecular mechanisms governing metabolic control in heart failure will provide critical insights into disease initiation and progression, raising the prospect of advances with clinical relevance.

Figure 1. Glucose and fatty acid metabolic pathways in the cardiomyocyte

Glucose is transported into the cardiomyocyte by glucose transporters (GLUT). Following phosphorylation by hexokinase (HK), glucose-6-phosphate (G6P) is fed into the glycogen synthetic pathway, glycolysis, or the pentose phosphate pathway (PPP). Phosphofructokinase 1 (PFK 1) is the first commitment enzyme of glycolysis. The glycolytic product pyruvate is transported into mitochondria or converted to lactate by lactate dehydrogenase (LDH). Pyruvate dehydrogenase (PDH) is a pivotal enzyme to catabolize pyruvate to acetyl CoA, which ultimately enters the citrate acid cycle. PDH enzymatic activity is inhibited by PDK4-dependent phosphorylation and stimulated by dephosphorylation via PDH phosphatase. Free fatty acids (FFAs) are transported into cardiomyocytes by diffusion or via a fatty acid translocase, such as CD36. Once inside the cell, FFAs are esterified to fatty acyl CoA by fatty acyl CoA synthase (FACS). The carnitine shuttle, composed of CPT-I, CPT-II, and CAT, is responsible for the transport of FFA from the cytosol to mitochondria for beta-oxidation, which generates acetyl CoA for the citric acid cycle. Glucose and FFA metabolic pathways are subject to complex reciprocal regulation. Citrate can be transported to the cytosol, where it undergoes lysis to acetyl CoA. Cytosolic acetyl CoA is converted to malonyl CoA by acetyl CoA carboxylase (ACC). Malonyl CoA is a potent inhibitor of CPT-1 and FFA metabolism.

Figure 2. Heart failure progression and metabolic derangements

The healthy heart is a metabolic omnivore, capable of utilizing virtually any available nutrient. Progression of heart failure correlates with progressive metabolic derangements, which include insulin resistance, elevations in intracellular FFA levels, and mitochondrial dysfunction. Moreover, hyperactivation of the neurohumonal system leads to alterations in substrate availability in heart. In the early stages of heart failure, FFA uptake and oxidation remain either unchanged or moderately increased, while glucose oxidation is increased. When faced with persistent stress, advanced-stage heart failure emerges, and oxidation of both glucose and FFA are severely diminished. AMI, acute myocardial infarction.