The Late Sodium Current Conditions Myocardial Repolarization And Relaxation Of The Aged Heart

Diastolic dysfunction and delayed ventricular repolarization are observed in the elderly, but whether these defects are intimately associated in the progressive manifestation of the aging myopathy remains to be determined. Interestingly, aging in experimental animals is coupled with increased late Na current (INaL) in cardiomyocytes, raising the possibility that INaL conditions the modality of electrical recovery and relaxation of the aged heart. Thus, male wild-type (WT) and genetically engineered mice with phosphomimetic (gain-of-function, GoF) or ablated (loss-of-function, LoF) mutations of the sodium channel Nav1.5 at Ser571, a phosphorylation site mediating INaL enhancement, were studied. With respect to WT mice at ~5 months of age (m), animals at ~18 m had 20% prolongation of the QT interval of the electrocardiogram and declined diastolic left ventricular filling, consisting of a 23% increase in isovolumic relaxation time (IVRT). These defects were reversed by INaL inhibition with GS967. Prolonged repolarization and impaired LV filling occurred prematurely in GoF mice (QT, +20%; IVRT, +8%, at ~5 m vs. WT), whereas age-related alterations were largely attenuated in LoF animals. At ~24 months, QT interval was not different in WT (66±4 ms) and GoF (70±5 ms) mice but was shorter in LoF (64±5 ms) animals, with respect to GoF. Similarly, IVRT was comparable in WT (22±2 ms) and GoF (22±2 ms) mice, but shorter in LoF (18±3 ms). In field stimulated cells, with respect to WT myocytes at ~5 m, WT cells at ~24 m had prolonged time to peak (+26%) and time to 50% relaxation (+44%). Delayed cell contraction/relaxation was apparent in GoF myocytes at ~5 m (+12% and +27%, with respect to WT), and further deteriorated with age. In contrast, LoF myocytes at ~5 m had contractile kinetics comparable to adult WT cells, and modest alterations occurred in cells at ~24 m. Importantly, inhibition of INaL was effective in correcting kinetics of cell mechanics in old WT mice and adult and old GoF animals but had no effect in LoF myocytes and WT cells at ~5 months. Collectively, these results document that the late Na+ current modulates the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction in the elderly.