Pyruvate Protection of Myocardium and Brain Following Cardiopulmonary Arrest and Resuscitation




Sharma, Arti B.


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Sharma, Arti Bashu, Pyruvate Protection of Myocardium and Brain Following Cardiopulmonary Arrest and Resuscitation. Doctor of Philosophy (Molecular Physiology), December 2006; 167 pp; 29 figures; bibliography, 206 titles. Approximately 350,000 people experience cardiac arrest in the United States each year, and merely 4-33% of the victims survive to hospital discharge. Cardiac and neurological injuries following resuscitation are the main factors responsible for mortality. Neurodeficit and cognitive dysfunction following recovery from cardiac arrest may persist for us to two years and greatly compromise quality of life in survivors. Loss of effective circulating blood volume during cardiac arrest results in ischemia, energy depletion, ionic imbalance, calcium overload, acidosis and oxidant mediated cytotoxicity. The burst of reactive oxygen species upon reperfusion imposes an oxidant burden resulting in modification of cellular components such as membrane phospholipids and proteins, and the initiation of inflammatory and cell death cascades. This injury is most pronounced in organs with high metabolic demands such as the heart and brain. Therapies aimed at reducing metabolic impairments such as energy depletion and oxidative stress may mitigate post-resuscitation complications, improve survival and enhance quality of life. Pyruvate, a natural metabolite of the glycolytic pathway, has been shown to enhance post-ischemic energy and antioxidant reserves, and effects improvements in calcium homeostasis and metabolic acidosis. The main purpose of this investigation was to evaluate pyruvate as a corrective metabolic intervention during cardiopulmonary resuscitation and examine its cardio- and neuroprotective effects following recovery from cardiopulmonary arrest. To address these objectives as a canine model of 5 min cardiopulmonary arrest, open chest cardiac compressions (OCCC) and resuscitation was developed. In the first study intravenous sodium pyruvate or control NaCl was administered during the first 30 min of resuscitation and its effects on cardiac function and metabolites examined through the first 3 h following return of spontaneous circulation. Cardiac arrest resulted in a severe collapse of myocardial phosphocreatine phosphorylation potential and antioxidant redox state. Pyruvate treatment substantially enhanced recovery of energy and antioxidant reserves during early reperfusion. Pyruvate also enhanced contractile performance and carotid blood flow at 15-25 min return of spontaneous circulation (ROSC), and better maintained cardiac function at 3 h ROSC. Thus a latent effect of temporary metabolic correction by intravenous pyruvate therapy during early resuscitation was manifest as improved cardiac function, 3 h after the acute insult. Oxidative stress during resuscitation can modify membrane lipids and proteins. Inactivation of myocardial enzymes may exacerbate ischemic derangements of myocardial metabolism. To study the impact of cardiac arrest on left ventricular enzymes, beagles were subjected to cardiac arrest and myocardial enzyme activities were measured in snap-frozen left ventricle. Severe depletion of glutathione (GSH) antioxidant redox state occurred during cardiac arrest, which recovered partially following cardiac massage and then completely during early ROSC. Concomitant with oxidant stress, activities of phosphofructokinase, citrate synthase, aconitase, malate dehydrogenase, creatine kinase, glucose 6-phosphate dehydrogenase and glutathione reductase fell sharply during arrest, and recovered gradually after resuscitation and ROSC, in parallel with GSH redox state. We then tested whether oxidative stress is responsible for the loss of enzyme activity during cardiac arrest. Metabolic (pyruvate) or pharmacological (N-acetylcysteine) antioxidants were infused iv for 30 min immediately before cardiac arrest. Antioxidant pretreatments augmented phosphofructokinase, aconitase and malate dehydrogenase activities before arrest, and enhanced these activities, as well as citrate synthase and glucose 6-phosphate dehydrogenase, during arrest. Cardiac arrest thus reversibly inactivates several important myocardial metabolic enzymes, while protection of these enzymes by antioxidants implicates oxidative stress as a principal mechanism of enzyme inactivation. The third part of this investigation was directed towards addressing the question whether metabolic correction with pyruvate therapy during ROSC, would extend protection and enhance neurological recovery over an extended period of 3 days following cardiac arrest-resuscitation. Neurological evaluation in the days following recovery from cardiac arrest revealed considerable impairment of function. Activation of matrix metalloproteinases and increased myeloperoxidase activity were also detected in frozen brain tissue. Loss of viable neuronal structure and cell death as indicted by histological evidence and TUNEL were detected 3 days following arrest. Treatment with pyruvate for the first hour of reperfusion prevented neurological deficit on days 1 and 2 of recovery, partially mitigated the inflammatory response and prevented neuronal loss. By preventing early metabolic disturbances during resuscitation and immediate reperfusion, intravenous pyruvate therapy protected the heart and brain from dysfunction and injury. The following figure summarizes these major findings. [see dissertation] Figure: Pyruvate mediated metabolic protection following cardiopulmonary arrest-resuscitation.