To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation.
Randomized controlled animal study.
University research laboratory.
Male domestic pigs.
Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation.
Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05).
Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow.
"If dysfunction is severe and persistent, it may preclude reestablishment of sustained circulation and contribute to the approximately 40% fatality rate reported in victims of out-hospital cardiac arrest before admission to a hospital . Previous work in our laboratory showed that protection of mitochondrial bioenergetic function during cardiac resuscitation resulted in improved post-resuscitation myocardial function . In the present study, erythropoietin elicited similar myocardial effects while concomitantly activating signaling pathways linked to mitochondrial protection. "
[Show abstract][Hide abstract] ABSTRACT: We previously reported beneficial myocardial effects during chest compression after administration of high-dose erythropoietin. We hypothesized that erythropoietin also elicits post-resuscitation myocardial benefits partly linked to protection of mitochondrial bioenergetic function.
Two series of 10 rats each underwent ventricular fibrillation for 10 minutes (series-1) and 8 minutes (series-2) and were randomized to erythropoietin (5,000 U/kg) or 0.9% NaCl before chest compression. Dobutamine was infused post-resuscitation in series-2 harvesting their hearts at 120 minutes.
During chest compression, a statistically insignificant trend showing progressively higher coronary perfusion pressure in the erythropoietin group was observed consistent with previously reported preservation of left ventricular distensibility. Post-resuscitation, in the absence of dobutamine (series-1) erythropoietin failed to improve post-resuscitation myocardial function or survival; in the presence of dobutamine (series-2) all rats survived and those treated with erythropoietin reversed post-resuscitation myocardial dysfunction yielding higher cardiac work index (CWI; 39±3 vs 25±10 mmHg·ml/kg, p<0.01) and higher mean aortic pressure (MAP; 99±4 vs 83±16, p<0.01) at 120 minutes post-resuscitation. Better myocardial function was associated with lesser increases in plasma cytochrome c, attaining levels which inversely correlated with CWI (p=0.026) and MAP (p=0.025). Hearts from erythropoietin-treated rats had higher phosphorylation levels of cytosolic Akt and higher phosphorylation levels of cytosolic and mitochondrial PKCε and maintained cytochrome c oxidase activity.
Erythropoietin activated mitochondrial protective mechanisms that helped maintain bioenergetic function enabling reversal of post-resuscitation myocardial dysfunction in the presence of dobutamine.
American Journal of Translational Research 05/2013; 5(3):316-26. · 3.40 Impact Factor
"We perceived the large divergence of outcomes in our model of LDVF as an excellent opportunity to explore the inter-subject differences in metabolic profile which determine one of the major end-points of cardiac arrest, the electrical failure. While we admit that our model lacks many features of more pre-clinical models of cardiac arrest which permit analysis of survival in terms of post-resuscitation cardiac function and hemodynamics in the whole organism , we believe that the emphasis on the inter-subject differences underlying myocardial response to metabolic stress constitutes a unique strength of our study and is highly relevant in the emerging era of personalized medicine. Indeed, ischemia or metabolic stress may be one of those critical situations where hidden vulnerabilities are revealed or enhanced, ultimately determining the ability of the individual to withstand the challenge. "
[Show abstract][Hide abstract] ABSTRACT: Deterioration of ventricular fibrillation (VF) into asystole or severe bradycardia (electrical failure) heralds a fatal outcome of cardiac arrest. The role of metabolism in the timing of electrical failure remains unknown.
To determine metabolic factors of early electrical failure in an Ex-vivo canine model of cardiac arrest (VF+global ischemia).
Metabolomic screening was performed in left ventricular biopsies collected before and after 0.3, 2, 5, 10 and 20 min of VF and global ischemia. Electrical activity was monitored via plunge needle electrodes and pseudo-ECG. Four out of nine hearts exhibited electrical failure at 10.1±0.9 min (early-asys), while 5/9 hearts maintained VF for at least 19.7 min (late-asys). As compared to late-asys, early-asys hearts had more ADP, less phosphocreatine, and higher levels of lactate at some time points during VF/ischemia (all comparisons p<0.05). Pre-ischemic samples from late-asys hearts contained ∼25 times more inorganic pyrophosphate (PPi) than early-asys hearts. A mechanistic role of PPi in cardioprotection was then tested by monitoring mitochondrial membrane potential (ΔΨ) during 20 min of simulated-demand ischemia using potentiometric probe TMRM in rabbit adult ventricular myocytes incubated with PPi versus control group. Untreated myocytes experienced significant loss of ΔΨ while in the PPi-treated myocytes ΔΨ was relatively maintained throughout 20 min of simulated-demand ischemia as compared to control (p<0.05).
High tissue level of PPi may prevent ΔΨm loss and electrical failure at the early phase of ischemic stress. The link between the two protective effects may involve decreased rates of mitochondrial ATP hydrolysis and lactate accumulation.
PLoS ONE 03/2013; 8(3):e57821. DOI:10.1371/journal.pone.0057821 · 3.23 Impact Factor
"ne phosphate to creatine ratio (pCr/Cr) at ECC 8 minutes. The regression line represents an exponential decay function (R 2 = 0.63, p < 0.001). BL, baseline; VF, ventricular fibrillation; ECC, extracorporeal circulation; PR, postresuscitation; d-w, dry weight. Values are mean ± SEM; *p < 0.05, ‡p < 0.001 vs. NaCl by Student's t-test. (Adapted from Ayoub I et al. Crit Care Med 2007;35:2329–36) (49)."
[Show abstract][Hide abstract] ABSTRACT: Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variable periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as reperfusion injury. At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Studies in animal models of ventricular fibrillation have shown that limiting myocardial cytosolic Na+ overload attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation, which is the main bioenergetic function of mitochondria. This effect is associated with functional myocardial benefits such as preservation of myocardial compliance during chest compression and attenuation of myocardial dysfunction after return of spontaneous circulation. Additional studies in similar animal models of ventricular fibrillation have shown that mitochondrial injury leads to activation of the mitochondrial apoptotic pathway, characterized by the release of cytochrome c to the cytosol, reduction of caspase-9 levels, and activation of caspase-3 coincident with marked reduction in left ventricular function. Cytochrome c also "leaks" into the bloodstream attaining levels that are inversely proportional to survival. These data indicate that mitochondria play a key role during cardiac resuscitation by modulating energy metabolism and signaling apoptotic cascades and that targeting mitochondria could represent a promising strategy for cardiac resuscitation.
Critical care medicine 11/2008; 36(11 Suppl):S440-6. DOI:10.1097/CCM.0b013e31818a89f4 · 6.31 Impact Factor
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