Metabolic modulation and cellular therapy of cardiac dysfunction and failure

•  Introduction •  Metabolic modulation ‐  Metabolism in the normal heart ‐  Substrate uptake and oxidation ‐  Oxidative phosphorylation ‐  ATP transport and utilization‐  Metabolism in heart failure ‐  Changes in substrate utilization ‐  Effects on oxidative phosphorylation ‐  Changes in ATP transport and utilization•  Medications that influence metabolism in heart failure ( Table 2) •  Cell therapy ‐  Skeletal muscle myoblasts ‐  Human embryonic stem cells ‐  Bone marrow derived adult stem cells ‐  Haematopoietic stem cells ‐  Mesenchymal stem cells (MSC) ‐  Endothelial progenitor cells (EPCs)‐  Cardiac stem cells•  Mechanisms of stem cell mediated myocardial regeneration •  Clinical applications of stem cells2 Potential metabolic modulators in heart failure(1) Long‐chain 3‐ketoacyl coenzyme A thiolase inhibitor Trimetazidine(2) CPT I inhibitors Perhexiline  Etomoxir  Oxfenicin(3) PPAR‐γ activators Rosiglitazone  PioglitazoneAbstract At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β‐blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.