Energy Metabolism in the Failing Right Ventricle: Limitations of Oxygen Delivery and the Creatine Kinase System

Figure 1. Capillary density is decreased and capillary supply area in the right ventricle (RV) is increased by MCT treatment. (A) Exemplar images showing intense fluorescent labelling of capillaries (magenta arrows) and less intense labelling of sarcolemma (white arrows) with FITC-conjugated lectin. (B) Capillary locations were digitized (green circles), and the area of tissue supplied by each capillary was calculated by Voronoi tessellation (black lines). (C) Capillary density was reduced in MCT and less so in MCT+BB compared to CON. (D) There were no differences between groups in the ratio of capillaries to muscle fibers. (E) The capillary supply area was greater in MCT and MCT+BB than CON, but was reduced in MCT+BB compared to MCT. n = 6 hearts per group. * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 2. Computer modelling predicts RV hypoxia in pulmonary arterial hypertension (PAH) is ameliorated by beta-1 blocker (BB) treatment. (A) Example heat maps showing areas of high PO2 surrounding capillary locations (white circles) and hypoxic regions distal to the capillaries. (B) Mean tissue PO2 was reduced in MCT and MCT+BB compared to CON. (C) The hypoxic area was greater in MCT than CON, but was reduced in MCT+BB compared to MCT. ** p < 0.01, *** p < 0.001. n = 6 rats per group.

Figure 3. Coupling of mitochondrial respiration to the creatine kinase (CK) system is decreased in MCT. (A–C) The increase in O2 consumption of permeabilized RV myocytes upon sequential titration of ADP was measured in the absence (solid line) or presence (dashed line) of Cr. (D) The relative difference in KmADP with Cr compared to without Cr was greater in CON than MCT, but not greater than in MCT+BB. * p < 0.05. n = 8 CON, 5 MCT, 3 MCT + BB independent replicates.

Figure 4. Cartoon representation of proposed changes in structure and function of RV myocytes in PAH. In CON cells (left), the densely packed capillary network delivers O2 evenly throughout the myocardium, maintaining a high PO2 (red regions). Mitochondria utilize O2 for oxidative phosphorylation, generating ATP. Mitochondrial-bound CK (CK-mt) use ATP to generate PCr, which diffuses to cytosolic sites of high ATP turnover, such as myofilaments, where cytosolic CK converts it back to ATP. This maintains a high ATP:ADP ratio in the myofilaments, allowing them to work properly, and a low ATP:ADP ratio in mitochondria, promoting ATP synthesis. In MCT cells (right), RV myocyte hypertrophy increases the diffusion distance of O2 from the capillaries, resulting in hypoxic cores developing within muscle fibres (blue regions). These areas are unable to meet metabolic needs entirely aerobically, so they become reliant on glycolysis. Energy transport to hypoxic cores is further impaired by reduced expression of CK isoforms, resulting in accumulation of ADP in myofilaments and reduced mitochondrial respiration. Cartoon was created using Servier Medical Art by Servier, which is licensed under a Creative…