Myocardial Energetic Alterations in Post Myocardial Infarction Left Ventricular Remodeling, Hibernating Myocardium and Pacing Induced Congestive Heart Failure and Amelioration with Stem Cell Transplantation

摘要

Post infarction left ventricular (LV) remodeling is associated with decreased Phosphocreatine/Adenosine triphosphate (PCr/ATP) ratio and these abnormalities are worsened during increased cardiac workload. However, chronic hibernating myocardium is able to preserve a normal energetic state as reflected by a normal PCr/ATP ratio up to 6 months despite a reduction in perfusion reserve and regional function. Furthermore, the decrease in PCr/ATP ratio with increased workload in hibernating myocardium is similar to normal myocardium. This is probably related to an intrinsic down-regulation in the mitochondrial function which minimizes oxidative stress and leads to a balanced supply and demand at baseline and increased work load. Congestive heart failure (CHF) is associated with intrinsic alterations in mitochondrial oxidative phosphorylation and significant decrease in PCr/ATP ratio which are independent of ischemia. ATP sensitive potassium (KATP) channel blockade in the failing heart is associated with a significant decrease in the PCr/ATP ratio and ATP production rate via Creatine Kinase which is associated with a decrease in myocardial blood flow and tissue hypoxia. Thus, in failing hearts the balance between myocardial ATP demands (or oxygen demands) and delivery are critically dependent on functioning KATP channels. Bone marrow derived multiprogenitor cell (MPC) transplantation in a porcine model of post infarct LV remodeling resulted in long term improvement in ventricular function and myocardial bioenergetics despite minimal engraftment of stem cells. Vascular density in the border zone was increased after cell transplantation. In vitro, the stem cells significantly inhibited Tumor Necrosis Factor alpha induced mitochondrial membrane potential change and cytochrome C release from myocytes. Cell transplantation also resulted in long term differential expression of genes which included a downregulation of mitochondrial oxidative enzymes and upregulation of Myocyte Enhancer Factor 2a (MEF2a) and ZFP91. Thus, the beneficial effects of stem cell transplantation are most likely related to the "trophic effects" of cells on the host myocardium, which include promotion of angiogenesis, maintenance of mitochondrial integrity, and inhibition of apoptosis of ischemia threatened and overstretched myocytes in the border zone myocardium along with differential expression of genes relating to metabolism and apoptosis.