Reduced cardiac output is associated with decreased mitochondrial efficiency in the non-ischemic ventricular wall of the acute myocardial-infarcted dog

Abstract

Cardiogenic shock is the leading cause of death among patients hospitalized with acute myocardial infarction (MI). Understanding the mechanisms for acute pump failure is therefore important. The aim of this study is to examine in an acute MI dog model whether mitochondrial bio-energetic function within non-ischemic wall regions are associated with pump failure. Anterior MI was produced in dogs via ligation of left anterior descending (LAD) coronary artery, that resulted in an infract size of about 30% of the left ventricular wall. Measurements of hemodynamic status, mitochondrial function, free radical production and mitochondrial uncoupling protein 3 (UCP3) expression were determined over 24 h period. Hemodynamic measurements revealed a > 50% reduction in cardiac output at 24 h post infarction when compared to baseline. Biopsy samples were obtained from the posterior non-ischemic wall during acute infarction. ADP/O ratios for isolated mitochondria from non-ischemic myocardium at 6 h and 24 h were decreased when compared to the ADP/O ratios within the same samples with and without palmitic acid (PA). GTP inhibition of (PA)-stimulated state 4 respiration in isolated mitochondria from the non-ischemic wall increased by 7% and 33% at 6 h and 24 h post-infarction respectively when compared to sham and pre-infarction samples. This would suggest that the mitochondria are uncoupled and this is supported by an associated increase in UCP3 expression observed on western blots from these same biopsy samples. Blood samples from the coronary sinus measured by electron paramagnetic resonance (EPR) methods showed an increase in reactive oxygen species (ROS) over baseline at 6 h and 24 h post-infarction. In conclusion, mitochondrial bio-energetic ADP/O ratios as a result of acute infarction are abnormal within the non-ischemic wall. Mitochondria appear to be energetically uncoupled and this is associated with declining pump function. Free radical production may be associated with the induction of uncoupling proteins in the mitochondria.

Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart

“…Acute MI in dog has led to significant upregulation (*1.7-and 3-fold 6 and 24 h post-infarction, respectively) of levels of UCP3 protein, the main cardiac UCP in dog [357], in the non-ischemic wall of the right ventricle (RV) [342]. Mitochondria within the non-ischemic wall have been uncoupled and levels of ROS have significantly been elevated.…”

“…Mitochondria within the non-ischemic wall have been uncoupled and levels of ROS have significantly been elevated. Authors have hypothesized that an increase in ROS induced by acute MI is responsible for the adaptive UCP3 upregulation [342].…”

Stem cell homing and angiomyogenesis in transplanted hearts are enhanced by combined intramyocardial SDF-1α delivery and endogenous cytokine signaling

“…stromal cell-derived factor-1␣; heterotopic heart transplantation; stem cells; cell migration ISCHEMIC HEART DISEASE is the leading cause of heart failure and death (1). Conventional therapeutic options for the treatment of myocardial infarction (MI) are limited to preventing the progression of ventricular remodeling and congestive heart failure (22).…”

Expressional profile of cardiac uncoupling protein-2 following myocardial ischemia reperfusion in losartan- and ramiprilat-treated rats

“…A relationship between cardiac UCP2 expression and cardiac dysfunction has been reported at the chronic stage of heart failure, hypertrophy and diabetes mellitus. [17][18][19] Almsherqi et al 20 demonstrated that mitochondrial UCP3 expression was increased in the posterior non-ischemic wall following anterior myocardial infarction. The authors have suggested that an increase in UCP3 expression would explain the impaired energy metabolism of the non-ischemic area.…”