Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism
ABSTRACT 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.
- SourceAvailable from: Raúl Gazmuri
[Show abstract] [Hide abstract]
- "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. "
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 01/2013; 5(3):316-26. · 3.23 Impact Factor
[Show abstract] [Hide abstract]
- "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)."
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 · 6.15 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: In an indoor mm-wave propagation environment, although the channel is time-invariant for a long time, the requirement of very high data rate makes the system design a hard mission and the severe MAI caused by asynchronous users in the uplink makes it worse. Although the MC-CDMA system for WPAN applications, on a 62.5 GHz carrier frequency, performs well for the single user scenario, it is very sensitive to MAI. We consider the adoption of joint detection (JD) to improve the BER performance. However, traditional JD, realized in the time domain, is too complicated to implement. Therefore, we proposed a simplified JD in the frequency domain, based on the specific characteristics of the MC-CDMA system matrix. Computer simulation results show that the JD MMSE-BLE scheme outperforms all the other data detection methods, especially for heavy system load with very low spreading factor and is realizable due to much less complexity compared with that of JD in the time domain.Vehicular Technology Conference, 2004. VTC 2004-Spring. 2004 IEEE 59th; 06/2004