Abstract
Out-of-hospital sudden cardiac arrest is a major public health problem with an overall survival of less than 5%. Upon cardiac arrest, cessation of coronary blood flow rapidly leads to intense myocardial ischemia and activation of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). NHE-1 activation drives Na+ into cardiomyocytes in exchange for H+ with its exchange rate intensified upon reperfusion during the resuscitation effort. Na+ accumulates in the cytosol driving Ca2+ entry through the Na+-Ca2+ exchanger, eventually causing cytosolic and mitochondrial Ca2+ overload and worsening myocardial injury by compromising mitochondrial bioenergetic function. We have reported clinically relevant myocardial effects elicited by NHE-1 inhibitors given during resuscitation in animal models of ventricular fibrillation (VF). These effects include: (a) preservation of left ventricular distensibility enabling hemodynamically more effective chest compressions, (b) return of cardiac activity with greater electrical stability reducing post-resuscitation episodes of VF, (c) less post-resuscitation myocardial dysfunction, and (d) attenuation of adverse myocardial effects of epinephrine; all contributing to improved survival in animal models. Mechanistically, NHE-1 inhibition reduces adverse effects stemming from Na+–driven cytosolic and mitochondrial Ca2+ overload. We believe the preclinical work herein discussed provides a persuasive rationale for examining the potential role of NHE-1 inhibitors for cardiac resuscitation in humans.
Highlights
Out-of-hospital sudden cardiac arrest is a major public health problem worldwide with close to 360,000 cases assessed every year by Emergency Medical Services (EMS) in the United States.In approximately half of these cases, cardiopulmonary resuscitation (CPR) is attempted, and of these only 9% survive the episode and return to their pre-arrest condition with adequate neurological function [1]
The crucial first step in the resuscitation effort is the restoration of cardiac activity, which depends largely on the ability of CPR to generate sufficient coronary blood flow to ameliorate myocardial ischemia and establish the metabolic conditions required for the return of an electrically organized and Molecules 2019, 24, 1765; doi:10.3390/molecules24091765
In a swine model of and closed-chest resuscitation, the use of use of epinephrine resulted in higher resuscitation rates, fewer episodes of ventricular fibrillation (VF) post-resuscitation, and cariporide in a resuscitation protocol that included use of epinephrine resulted in higher resuscitation lesser post-resuscitation myocardial dysfunction [16]
Summary
Out-of-hospital sudden cardiac arrest is a major public health problem worldwide with close to 360,000 cases assessed every year by Emergency Medical Services (EMS) in the United States. The crucial first step in the resuscitation effort is the restoration of cardiac activity, which depends largely on the ability of CPR to generate sufficient coronary blood flow to ameliorate myocardial ischemia and establish the metabolic conditions required for the return of an electrically organized and Molecules 2019, 24, 1765; doi:10.3390/molecules24091765 www.mdpi.com/journal/molecules. The crucial first step in the resuscitation effort is the restoration of cardiac activity, which depends largely on the ability of CPR to generate sufficient coronary blood flow to ameliorate. NHE-1inhibitors inhibitors during cardiac resuscitation discussing mechanisms and physiological effects that during cardiac resuscitation discussing mechanisms and physiological effects thatwe wepropose proposeare are relevant for clinical translation. The cytoplasmic domain includes sites for sites for regulation via phosphorylation-dependent (P) and phosphorylation-independent mechanisms.
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