Abstract 20068: Enhanced Pyruvate Dehydrogenase Activity Improves Myocardial Hemodynamics and Return to Spontaneous Circulation in a Murine Model of Cardiac Arrest
Rationale: Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of pyruvate dehydrogenase kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown. We hypothesized that post-CA hypothermia is associated with the inhibition of PDK activity resulting in increased PDH activity. We further hypothesized that an inhibitor of PDK activity, dichloroacetate (DCA) would improve post-CA outcomes.
Methods and Results: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 12-minute KCl-induced CA followed by cardiopulmonary resuscitation. CA increased myocardial lactate (87% increase, p<0.01), decreased PDH activity (24% reduction, p<0.01) and increased PDK expression (18% increase, p<0.01) compared to Sham controls. In contrast, post-CA hypothermia (30°C) reduced myocardial lactate (25% reduction, p<0.01), and PDK expression (18% reduction, p<0.05) while increasing PDH activity (30% increase, p<0.01). These metabolic changes were associated with improved post-CA myocardial function (ejection fraction: 27.2±2.0% vs. 50.9±3.1%, p<0.001; aorta systolic pressure: 72.3±3.0 vs. 132.7±7.3 mmHg, p<0.001) and increased 72-hour survival (28% vs. 75%, p<0.001). To determine if enhancing PDH activity could improve post-CA outcomes in normothermic mice, we pretreated mice with the PDK inhibitor DCA (0.2 mg/g body weight), 30 min prior to CA. DCA improved the time to return of spontaneous circulation (128±4 vs.113±3 seconds, p<0.01) and enhanced post-CA myocardial hemodynamics (aortic systolic pressure: 96±4 vs. 123±3 mmHg, p<0.001). DCA was also associated with a trend in improved 72-hour survival (24% vs. 50%, p=0.06).
Conclusions: Enhanced PDH activity is associated with improvements in post-CA resuscitation outcomes and may be a promising target for post-CA therapeutic investigation.
Author Disclosures: L. Piao: None. Y. Fang: None. W. Sharp: None.
- © 2016 by American Heart Association, Inc.