A Mitochondrial Basis for Heart Failure Progression

Fig. 1. Pressure–volume loop and pressure–volume area. The PV loop begins at beginning of diasystole (A) and fills through diastole to point B. From B to C is the beginning of systole (isovolumic contraction) where pressure rises but the aortic valve is closed and volume does not change. At point C, left ventricular pressure exceeds aortic diastolic pressure and the aortic valve opens, leading to ejection and a fall in left ventricular volume down to point D, where the aortic valve closes. From D to A, left ventricular rapidly falls and the cycle begins again. The pressure–volume loop and the triangular dark shaded area to the left form the pressure–volume area (PVA). The smaller, grey loop to the right represents an example of the PV loop in heart failure

Fig. 2. Diagrammatic illustration of the linkage between ATP supply and demand via phosphate shuttles and with regulation by calcium. Changes in concentrations of ATP, ADP and phosphate (Pi) will shift the equilibrium of the creatine kinase reaction, increasing ADP near mitochondria and stimulating oxidative phosphorylation and the Krebs cycle. Increases in intracellular calcium stimulate both contraction and mitochondrial ATP production, harmonising the two processes

Fig. 3. Signalling pathways linking calcium, reactive oxygen species (ROS), calcium-calmodulin-dependent kinase (CaMKII) and their downstream effects. Intracellular calcium enters the cell via L-type calcium channels (LTCC), enters the mitochondrion via mitochondrial calcium uniporter (MCU) to stimulate the citric acid cycle, activates CaMKII and is taken up into the sarcoplasmic reticulum via the sarcoplasm-endoplasmic reticulum ATPase (SERCA). CaMKII is activated by intracellular calcium, reactive oxygen species (ROS) production and beta-adrenoreceptors. It increases intracellular calcium levels by inhibiting SERCA and activating ryanodine receptor (RyR), as well as causing hypertrophic gene expression by activating histone deacetylases (HDACs). The sodium-calcium exchanger (NCLX) exchanges sodium and calcium across the mitochondrial membrane

Fig. 4. Pathways in reactive oxygen species (ROS) production. Electrons ‘leaking’ across the electron transport chain produce superoxide (O2−), which is converted to hydrogen peroxide (H2O2) by superoxide dysmutase (SOD), both of which are reactive oxygen species. Hydrogen peroxide may be converted to water by using NADPH as an electron donor. NADPH is formed from NADH via nicotinamide nucleotide transhydrogenase (NNT), so a reduction in NADH availability due to increased ATP demand will reduce antioxidant capacity within the cell

Fig. 5. Overall schematic linking increased mechanical work to damaging processes causing heart failure progression. Blue boxes indicate adaptive processes and red boxes maladaptive processes