Cardiac Dysfunction and Metabolism: Unravelling the Molecular Cross-Talk

Abstract

The interactions between cardiac metabolism and function at the molecular level are complex, but can be understood in terms of several broad concepts. First, function and metabolism are linked by acute mechanisms involving coupling of ATP demand to ATP synthesis, AMPK activation and various covalent and allosteric modifications of key enzymes, and by transcriptional mechanisms. Second, altered metabolic fluxes are not primary causes of cardiac injury; injury is caused by the cytoplasmic accumulation of toxic metabolic intermediates. These intermediates accumulate when there is a mismatch between the supply and utilization of metabolic fuels, and this can be produced either by excessive supply or reduced metabolic flux of a fuel. Third, changes in metabolism can be adaptive (as occurs in physiological hypertrophy), maladaptive in parallel with cardiac dysfunction (as occurs in pathological hypertrophy), or maladaptive as an antecedent and cause of cardiac dysfunction (as occurs in pathological hypertrophy). Finally, from an evolutionary perspective, disease results when the metabolic and functional phenotype is inappropriate for the environment; this can result from a phenotypically inappropriate response (e.g. pathological hypertrophy), or from a constraint that prevents the heart from adapting appropriately (e.g. reduced metabolic reserve). This book chapter reviews the latest evidence that is emerging about the operation of interactions between metabolism and function at the metabolic level in terms of these key concepts.