Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

Imahashi, Kenichi; Kusuoka, Hideo; Hashimoto, Kyoji; Yoshioka, Jun; Yamaguchi, Hitoshi; Nishimura, Tsunehiko

doi:10.1161/01.res.84.12.1401

Cited by 158 publications

(110 citation statements)

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“…An important determinant of sensitivity to ischaemiareperfusion is altered ion homeostasis, especially disturbances in Na þ i handling [11,12]. This study is the first to demonstrate that myocardial Na þ i increased substantially in isolated mouse hearts during ischaemia and increased significantly more in hearts from diabetic db/db hearts than in hearts from control db/+ mice.…”

Section: Discussionmentioning

confidence: 60%

“…At 6 weeks, db/db hearts showed normal recovery of contractile function following ischaemia, whereas at 12 weeks function was markedly reduced [6]. An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na + (Na þ i ) handling [11,12]. As no study has so far investigated this in type 2 diabetes and altered Na + handling may indeed have functional as well as proarrhythmogenic consequences [13], we examined susceptibility to ischaemia-reperfusion in isolated hearts from 12-to 15-week-old db/db mice and from age-matched control db/+ mice, and determined whether and to what extent the amount of Na þ i increase, monitored through 23 Na nuclear magnetic resonance (NMR) spectroscopy during a transient period of ischaemia, could contribute to functional alterations upon reperfusion.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice

et al. 2006

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Aims/hypothesis: An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na + Na þ i À Á handling. As no study has so far investigated this in type 2 diabetes, we examined susceptibility to ischaemia-reperfusion in isolated hearts from diabetic db/db and control db/+ mice and determined whether and to what extent the amount of Naincrease during a transient period of ischaemia could contribute to functional alterations upon reperfusion. Methods: Isovolumic hearts were exposed to 30-min global ischaemia and then reperfused. 23Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor Na þ i and 31 P NMR spectroscopy to monitor intracellular pH (pH i ). Results: A higher duration of ventricular tachycardia and the degeneration of ventricular tachycardia into ventricular fibrillation were observed upon reperfusion in db/db hearts. The recovery of left ventricular developed pressure was reduced. The increase in Na þ i induced by ischaemia was higher in db/db hearts than in control hearts, and the rate of pH i recovery was increased during reperfusion. The inhibition of Na + /H + exchange by cariporide significantly reduced Na þ i gain at the end of ischaemia. This was associated with a lower incidence of ventricular tachycardia in both heart groups, and with an inhibition of the degeneration of ventricular tachycardia into ventricular fibrillation in db/db hearts. Conclusions/ interpretation: These findings strongly support the hypothesis that increased Na þ i plays a causative role in the enhanced sensitivity to ischaemia observed in db/db diabetic hearts.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice

et al. 2006

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“…The pathogenic mechanism underlying reperfusion arrhythmias is largely unknown, but an increase in [Na + ] i during ischemia and/or early reperfusion appears to play a major role (47). Intracellular Na + accumulation can then give rise to [Ca 2+ ] i overload, which in turn increases the propensity for DAD-related arrhythmias by the mechanisms described above.…”

Section: Acute Myocardial Ischemia Ionic Imbalances During Acute Myocmentioning

confidence: 99%

Mechanisms of sudden cardiac death

Rubart

Zipes²

2005

Journal of Clinical Investigation

433

313

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Despite recent advances in preventing sudden cardiac death (SCD) due to cardiac arrhythmia, its incidence in the population at large has remained unacceptably high. Better understanding of the interaction among various functional, structural, and genetic factors underlying the susceptibility to, and initiation of, fatal arrhythmias is a major goal and will provide new tools for the prediction, prevention, and therapy of SCD. Here, we review the role of aberrant intracellular Ca 2+ handling, ionic imbalances associated with acute myocardial ischemia, neurohumoral changes, and genetic predisposition in the pathogenesis of SCD due to cardiac arrhythmia. Therapeutic measures to prevent SCD are also discussed.Sudden cardiac death (SCD) from any cause claims 300,000-400,000 lives a year in the United States. The most common sequence of events leading to SCD appears to be the degeneration of ventricular tachycardia (VT; abnormal acceleration of ventricular rate) into ventricular fibrillation (VF), during which disorganized contractions of the ventricles fail to eject blood effectively, often followed by asystole or pulseless electrical activity. Preexisting coronary artery disease and its consequences (acute myocardial ischemia, scarring from previous myocardial infarction, heart failure) are manifest in 80% of SCD victims. Dilated nonischemic and hypertrophic cardiomyopathies account for the second largest number of SCDs, whereas other cardiac disorders, including congenital heart defects and the known genetically determined ion channel anomalies, account for 5-10% of SCDs (1).While the implantable cardioverter defibrillator (ICD) improves survival in high-risk patients (2), standard antiarrhythmic drug therapy has failed to reduce, and in some instances has increased, the incidence of SCD (3). In fact, the greatest reduction in cardiovascular mortality (including SCD) in patients with clinically manifest heart disease has resulted from the use of beta blockers (4) and non-antiarrhythmic drugs, i.e., those without major direct electrophysiological action in cardiac muscle or the specialized conduction system, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor-blocking agents, lipid-lowering agents, spironolactone, thrombolytic and antithrombotic agents, and perhaps magnesium and omega-3 fatty acids (for review, see ref. 5). These drugs most likely exert their antiarrhythmic potential indirectly by inhibiting or delaying adverse functional and structural remodeling in the diseased heart, i.e., by affecting "upstream events" that contribute to the development of electrophysiological instability.Clinical trials, in general, have failed to define SCD risk markers for specific individuals in the larger general population, where the relative risk of SCD is low but the absolute number of deaths is high. Risk markers include abnormalities in cardiovascular function (left-ventricular ejection fraction), electrocardiographic variables (e.g., late potentials, T-wave alternans, QRS duration, dispersion o...

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“…19 Cytosolic Na ϩ overload becomes a "substrate" for ischemia and reperfusion injury. 20 During closed-chest resuscitation, the coronary blood flow rarely exceeds 20% of normal, failing to reverse ischemia 21 but allowing normoacidic blood to perfuse the coronary circuit. Unremitting ischemia with a large transsarcolemmal proton gradient creates optimal conditions for NHE-1 to remain active throughout chest compression and probably the early minutes after return of spontaneous circulation.…”

Section: Mechanisms Of Protective Actionmentioning

confidence: 99%

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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Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

Cited by 158 publications

References 28 publications

Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice

Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice

Mechanisms of sudden cardiac death

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

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