Abstract
Aim: Increased sodium/calcium exchanger activity (NCX1, an important regulator of cardiomyocyte cystolic calcium) may provoke arrhythmias. Exercise training can decrease NCX1 expression in animals with heart failure improving cytosolic calcium regulation, and could thereby reduce the risk for ventricular fibrillation (VF). Methods: To test this hypothesis, a 2-min coronary occlusion was made during the last minute of exercise in dogs with healed myocardial infarctions; 23 had VF (S, susceptible) and 13 did not (R, resistant). The animals were randomly assigned to either 10-week exercise training (progressively increasing treadmill running; S n = 9; R n = 8) or 10-week sedentary (S n = 14; R n = 5) groups. At the end of the 10-week period, the exercise + ischemia test provoked VF in sedentary but not trained susceptible dogs. On a subsequent day, cardiac tissue was harvested and NCX1 protein expression was determined by Western blot. Results: In the sedentary group, NCX1 expression was significantly (ANOVA, P < 0.05) higher in susceptible compared to resistant dogs. In contrast, NCX1 levels were similar in the exercise trained resistant and susceptible animals. Conclusion: These data suggest that exercise training can restore a more normal NCX1 level in dogs susceptible to VF, improving cystolic calcium regulation and could thereby reduce the risk for sudden death following myocardial infarction.
Highlights
Abnormal myocyte calcium regulation plays a major role in both contractile dysfunction and an increased risk for arrhythmias associated with cardiac disease (Billman, 1991; Bers, 2002; Bers and Weber, 2002)
Elevations in diastolic calcium can provoke oscillations in membrane potential that, if of sufficient magnitude to reach threshold, can trigger extrasystoles (Billman, 1991). These afterdepolarizations have been shown to result primarily from an inward current associated with the activation of the sodium/calcium exchanger (NCX) in the reverse mode
The major findings of the present study are: (1) NCX1 expression is increased in sedentary animals susceptible to ventricular fibrillation (VF) compared to sedentary dogs that were resistant to malignant arrhythmias; and, (2) A 10-week endurance exercise training program significantly reduced NCX1 expression in dogs previous shown to be susceptible to VF but did not alter this protein content in animals that were resistant to life-threatening arrhythmias
Summary
Abnormal myocyte calcium regulation plays a major role in both contractile dysfunction and an increased risk for arrhythmias associated with cardiac disease (Billman, 1991; Bers, 2002; Bers and Weber, 2002). Elevations in diastolic calcium can provoke oscillations in membrane potential (delayed afterdepolarizations) that, if of sufficient magnitude to reach threshold, can trigger extrasystoles (Billman, 1991) These afterdepolarizations have been shown to result primarily from an inward current associated with the activation of the sodium/calcium exchanger (NCX) in the reverse mode (i.e., one Ca2+ out of the cell in exchange with three Na+ into the cell; Blaustein and Lederer, 1999; Philipson and Nicoll, 2000; Satoh et al, 2000; Bers and Weber, 2002; Reuter et al, 2005). An overexpression of NCX would enhance this inward current, in a setting of elevated cytosolic calcium as during myocardial ischemia (Billman, 1991), and thereby could promote arrhythmia formation
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