Cardioprotective Effects of the Na
            <sup>+</sup>
            /H
            <sup>+</sup>
            Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

Rupprecht, Hans J.; Dahl, Jürgen vom; Terres, Wolfram; Seyfarth, Karl Melchior; Richardt, Gert; Schultheiß, Heinz Peter; Buerke, Michael; Sheehan, Florence H.; Drexler, Helmut

doi:10.1161/01.cir.101.25.2902

Cited by 193 publications

(132 citation statements)

References 32 publications

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“…Our results are in accordance with studies that reported the improvement of survival of different HF models following treatments with NHE-1 inhibitors (Kusumoto et al 2001;Engelhardt et al 2002;Chahine et al 2005;Baartscheer et al 2005). The experimental evidence implicating NHE-1 as a possible therapeutic target for the treatment of HF and its associated early death has sparked several clinical trials to test the efficacy of NHE-1 inhibitors in HF patients (Rupprecht et al 2000;Theroux et al 2000;Zeymer et al 2001). In one of these trials, the GUARDIAN study, a short-term treatment with cariporide reduced mortality of early post-infarction patients (Theroux et al 2000).…”

Section: Discussionsupporting

confidence: 92%

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Bkaily

Chahine

Al-Khoury

et al. 2015

Can. J. Physiol. Pharmacol.

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Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na + and Ca 2+ overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na + and Ca 2+ overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na + and Ca 2+ overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.

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Section: Discussionsupporting

confidence: 92%

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Bkaily

Chahine

Al-Khoury

et al. 2015

Can. J. Physiol. Pharmacol.

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“…17,18 Sarcolemmal NHE-1 is expressed in human myocardium, 25 and clinical trials have demonstrated myocardial benefits derived from NHE-1 inhibition in subsets of patients undergoing emergent coronary revascularization. 26 Thus, effects similar to those reported here in pigs may also apply to humans and facilitate closed-chest resuscitation from VF. Clinical studies on NHE-1 inhibition during cardiac resuscitation are eagerly awaited.…”

Section: Discussionsupporting

confidence: 70%

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Ayoub

Kolarova

et al. 2003

Circulation

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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.

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“…6) These results suggest that NHE1 is activated in the ischemic and remodeling myocardium, and may play a key role in the development of heart failure after AMI. However, little is known about changes in NHE1 expression in the non-infarcted region after AMI.…”

Section: )mentioning

confidence: 75%

Decreased Expression of Na+/H+ Exchanger Isoform 1 (NHE1) in Non-infarcted Myocardium after Acute Myocardial Infarction.

et al. 2002

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SUMMARYAlthough cardiac NHE1 is activated during myocardial ischemia and reperfusion injury, little is known about changes in expression in non-infarcted myocardium after acute myocardial infarction (AMI). The purpose of this study was to examine left ventricular function and region dependent NHE1 expression after myocardial infarction. Therefore, we produced two AMI models in rats, a small infarction model which was continuously ligated at the branches of the left coronary artery, and an extensive infarction model continuously ligated at the root of the artery. We examined NHE1 mRNA expression using RNase protection assay and protein levels using Western blot analysis in noninfarcted myocardium during the 24 hour period after AMI. The level of NHE1 mRNA and protein expression in the whole heart including the infarcted myocardium did not change after a small infarction. On the other hand, in the case of an extensive infarction, the levels of NHE1 mRNA and protein expression decreased significantly by 21.5% (P<0.05) and by 22.0% (P<0.05), respectively, in non-infarcted myocardium. Left ventricular systolic pressure (LVSP) decreased significantly by 13% and 38% with the branch and root ligation, respectively. However, left ventricular end-diastolic pressure (LVEDP) only increased with the root ligation. These results indicate that NHE1 expression decreased in response to extensive myocardial infarction only in non-infarcted myocardium. The present study may be important in furthering the understanding of NHE1 in myocardial infarction and suggests that decreased expression of NHE1 in non-infarcted myocardium may decrease the extent of cardiac cell injury. (Jpn Heart J 2002; 43: 273-282)

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Cardioprotective Effects of the Na ⁺ /H ⁺ Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

Abstract: Our findings suggest that inhibition of Na(+)/H(+) exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.

Cited by 193 publications

References 32 publications

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Decreased Expression of Na+/H+ Exchanger Isoform 1 (NHE1) in Non-infarcted Myocardium after Acute Myocardial Infarction.

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Cardioprotective Effects of the Na + /H + Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

Abstract: Our findings suggest that inhibition of Na(+)/H(+) exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.

Cited by 193 publications

References 32 publications

Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Decreased Expression of Na+/H+ Exchanger Isoform 1 (NHE1) in Non-infarcted Myocardium after Acute Myocardial Infarction.

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Product

Resources

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Cardioprotective Effects of the Na ⁺ /H ⁺ Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Na⁺–H⁺ exchanger inhibitor prevents early death in hereditary cardiomyopathy