Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study.

BACKGROUND: African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. METHODS: We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. RESULTS: The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). CONCLUSIONS: SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y.

Efficacy of tuned waveforms based on different membrane time constants on defibrillation thresholds: primary results from the POWER trial.

BACKGROUND: The efficacy of tuned defibrillation waveforms versus the nominal fixed-tilt waveform has been previously studied. However, the optimal membrane time constant for tuning was not known. The POWER (Pulsewidth Optimized Waveform Evaluation tRial) trial was designed to determine the optimal membrane time constant for programming "tuned" biphasic waveforms. METHODS: This acute, multicenter study included 121 implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator patients who were randomized at implant to any two of the three membrane time constant waveforms (2.5, 3.5, and 4.5 ms). Fixed pulse widths were programmed using the measured high voltage shock impedance. The defibrillation threshold (DFT) estimates were obtained using a hybrid protocol starting with an upper limit of vulnerability estimate followed by a step-up/step-down ventricular fibrillation induction process. RESULTS: DFT voltage was significantly lower using 3.5- and 4.5-ms waveforms as compared to the 2.5-ms waveform (P = 0.004 and 0.035, respectively). DFT voltage with both 3.5- and 4.5-ms waveforms was ≤ that obtained with the 2.5-ms waveform in 78.5% of the cases. The mean difference in DFT voltage using the 3.5-ms waveform and the 4.5-ms waveform was not significant (P = 0.4). However, the 3.5-ms waveform gave a lower DFT than the 4.5-ms waveform in 19 patients although the reverse was true in only nine (P = 0.02 not significant for multiple comparisons). CONCLUSIONS: The use of a 3.5- or 4.5-ms time constant-based waveforms had lower DFTs when compared to the 2.5-ms waveform. This study suggests that the first defibrillation attempt at implantation should be with 3.5- or 4.5-ms time constant-based waveforms. The 3.5-ms-based waveform trended toward the best choice.

Temporal stability of defibrillation thresholds with cardiac resynchronization therapy.

BACKGROUND: Defibrillation thresholds (DFTs) are typically stable over time among patients with implantable cardioverter-defibrillators (ICDs). However, the impact of cardiac resynchronization therapy (CRT) on DFTs has not been studied systematically. OBJECTIVE: This study prospectively evaluated the effect of CRT and left ventricular (LV) chamber reverse remodeling on DFTs. METHODS: This prospective, multicenter study evaluated 54 cardiac resynchronization therapy defibrillator (CRT-D) patients. Echocardiography and DFTs were performed both at implantation and at 6 months after implantation. All patients received dual-coil leads and a CRT-D pulse generator. DFTs were measured using a binary search method and tuned biphasic waveforms, where the shock pulse widths were determined by the measured shock impedance. Echocardiograms were analyzed by an independent core laboratory with a responder defined as a decrease of left ventricular end systolic volume >15%. RESULTS: The study cohort was 74% male, with a mean age of 68.7 ± 10.9 years. The baseline ejection fraction was 0.245 ± 0.076, and the mean New York Heart Association class was 2.9 ± 0.4. In CRT responders (n = 32) the mean DFT was 415.6 ± 108.1 V at implantation vs. 415.6 ± 124.7 V at 6 months (P = .9), and in nonresponders (n = 19) the mean DFT was 452.6 ± 102 V at implantation vs. 447.4 ± 112.4 V at 6 months (P = .8). There was no significant change in DFT peak voltage, delivered energy, or shock impedance over time. CONCLUSION: DFTs were unchanged at 6 months in CRT patients with or without LV chamber reverse remodeling.