Increased expression of Na+−Ca2+ exchanger in the myocardium. Impact on contractility and arrhythmogenesis in heart failure
Increased expression of Na+−Ca2+ exchanger has been reported in the end-stage failing human heart. The functional consequences have been controversially discussed. In isolated muscle strips from end-stage failing human hearts, we have recently demonstrated an inverse correlation of Na+−Ca2+ exchanger expression with the occurrence of diastolic dysfunction. Moreover, it has been hypothesized that different phenotypes of failing human hearts with respect to Na+−Ca2+ exchanger expression may exist. A phenotype with increased expression of the Na+−Ca2+ exchange protein and unchanged protein levels of the sarcoplasmic Ca2+-ATPase was described that demonstrated systolic contractile performance and preserved diastolic function. Therefore, we sought to investigate whether exclusive overexpression of the exchanger molecule would lead to systolic dysfunction. Indeed, healthy adult rabbit myocytes that overexpressed the Na+−Ca2+ exchanger following adenoviral gene transfer demonstrated systolic contractile dysfunction due to a decreased sarcoplasmic reticulum (SR) Ca2+ load. We speculated that this was a result of cellular Ca2+ loss to the extracellular space by increased forward-mode Na+−Ca2+ exchange. These results were in contrast to recent findings by other authors who investigated myocytes from transgenic mice overexpressing Na+−Ca2+ exchanger. In these studies, an increased SR Ca2+ load was found that was suggested to result from an increased reverse-mode Na+−Ca2+ exchange. Differences between the two species might stem from differences in excitation-contraction coupling in particular from differences in intracellular Na+ concentrations.
Furthermore, Na+−Ca2+ exchanger overexpression has been blamed for playing an important role in arrhythmogenesis. We have investigated myocardial Na+−Ca2+ exchanger protein levels from transplant recipients suffering from end-stage cardiac failure. When patients were divided into subgroups according to findings in recent Holter-ECGs, we found that patients with sustained or non-sustained ventricular tachycardia (≥3 consecutive beats) had significantly higher Na+−Ca2+ exchanger protein levels compared to patients without complex ventricular arrhythmias. This finding is in accordance to recent studies in animal models of heart failure. It was suggested that the underlying mechanisms may involve increased forwardmode Na+−Ca2+ exchange following spontaneous SR Ca2+ release due to cytoplasmic Ca2+ overload.
A final paragraph will discuss potential therapeutic implications targeted to Na+−Ca2+ exchange.
Key wordsCa2+ Na+/Ca2+ exchange myocardial contraction sarcoplasmic reticulum heart failure arrhythmia
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