The Role of Oxidative Stress in Heart Failure: Mechanisms and Therapeutic Targets

Heart failure is characterised by increased production of reactive oxygen species (ROS), which contribute to apoptotic signalling. Changes in excitation-contraction coupling in heart failure promote increased calcium extrusion and decreased calcium uptake by myocardial mitochondria. Mitochondrial calcium is required to increase the Krebs cycle flux to generate sufficient nicotinamide adenine dinucleotide (NADH) to match the increased energy demand seen in heart failure. Reduced NADH availability can decrease levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), leading to a loss of NADPH-mediated antioxidant capacity and thereby increasing ROS emission and oxidative damage. Accordingly, a group of therapies that increase mitochondrial calcium, such as sodium glucose-linked transporter 2 inhibitors and ranolazine, have been investigated as potential treatments in heart failure. Proposed mechanisms include reducing calcium extrusion from mitochondria via the Na⁺/Ca²⁺/Li⁺ exchanger. A second group of emerging therapies targets oxidative stress by directly scavenging ROS (MitoQ and SS-31) and has also been studied for use in heart failure. Contemporary research developments propose an alternative approach to targeting oxidative stress by enhancing endogenous antioxidant capacity through the administration of nicotinamide adenine dinucleotide (NAD) precursors, thereby increasing intracellular NAD availability.