Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Abstract

Background-Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. Methods and Results-Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0Ϯ0.2 to 1.5Ϯ0.3 cm with NaCl, PϽ0.001 versus 0.9Ϯ0.1 to 1.1Ϯ0.3 cm with cariporide, PϭNS), maintained the coronary perfusion pressure above resuscitability thresholds (10Ϯ8 versus 19Ϯ3 mm Hg before attempting defibrillation, PϽ0.05), and increased resuscitability (2 of 8 versus 8 of 8, PϽ0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD 60 at 2 minutes after resuscitation; 75Ϯ29 versus 226Ϯ16 ms, PϽ0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. Conclusions-NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

Role of NHE1 in the Cellular Dysfunction of Acute Metabolic Acidosis

“…Its effect on myocardial carbon dioxide concentration is not clear. Be that as it may, elegant studies of cardiac arrest induced by ventricular fibrillation revealed improvement in cardiac function during fibrillation [25] and significant attenuation of postresuscitation ventricular arrhythmias including prevention of recurrent episodes of ventricular fibrillation with cariporide and other NHE1 inhibitors in both pig and rat models (table 1) [26,27,28,29,30,31,32]. …”

Protecting Mitochondrial Bioenergetic Function During Resuscitation from Cardiac Arrest

“…41,42 A functionally similar phenomenon known as ischemic contracture was reported in the early seventies during open heart surgery when operations were conducted under normothermic conditions in fibrillating hearts 43,44 and more recently after prolonged intervals of untreated VF. 45 However, ischemic contracture is associated with profound reductions in myocardial ATP and often leads to a “stony heart” heralding irreversible ischemic injury.…”

“…Experimentally, these repolarization abnormalities are short-lived (5 to 10 minutes) and coincide with the interval of increased propensity for ventricular arrhythmias and recurrent VF. 42 These repolarization abnormalities and reperfusion arrhythmias can be markedly attenuated by NHE-1 inhibition. 42 …”

“…42 These repolarization abnormalities and reperfusion arrhythmias can be markedly attenuated by NHE-1 inhibition. 42 …”

“…45 However, ischemic contracture is associated with profound reductions in myocardial ATP and often leads to a “stony heart” heralding irreversible ischemic injury. 46 Reductions in left ventricular distensibility observed during cardiac resuscitation is a different phenomenon: (1) it occurs much earlier than the “stony heart” starting coincident with reperfusion during the resuscitation effort, 41,42 (2) it is associated with less ATP depletion, 40 (3) it has been attributed to myocardial energy deficit compounded by cytosolic and mitochondrial Ca 2+ overload precluding complete relaxation of individual cardiomyocytes, (4) it evolves into diastolic dysfunction upon return of spontaneous circulation, 47 (5) it is largely reversible, 48 and (6) it is amenable to therapeutic intervention (Figure 4). …”