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Heart Rhythm. 2014 Oct;11(10):1827-35. doi: 10.1016/j.hrthm.2014.06.017. Epub 2014 Jun 17.

Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity.

Author information

1
Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
2
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
3
Gilead Sciences, Foster City, California.
4
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.

Abstract

BACKGROUND:

Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias.

OBJECTIVE:

We examined whether selectively targeting late sodium channel current (INa) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide.

METHODS:

Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.4 mg/kg, intravenously [IV]) or flecainide (1 mg/kg, IV, bolus over 2 minutes followed by 1 mg/(kg·h), IV, for 1 hour) administration.

RESULTS:

Left circumflex coronary artery stenosis increased atrial repolarization alternans by 520% (from 9.4 ± 1.2 to 58.3 ± 11.3 μV; P = .029) and T-wave alternans by 1038% (from 30.7 ± 8.2 to 349.3 ± 103.8 μV; P = .049). GS967 prevented ischemia-induced increases in alternans in the left atrium (19.3 ± 5.6 μV vs 58.3 ± 11.3 μV; P = .023) and left ventricle (217.9 ± 95.8 μV vs 349.3 ± 103.8 μV; P < .001) (n = 7). GS967 reduced ischemia-induced increases in depolarization heterogeneity (atrium: from 45% to 28%; ventricle: from 92% to 51%) and repolarization heterogeneity (atrium: 43% to 23%; ventricle: 137% to 91%). GS967 did not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility (left ventricular dP/dt) during ischemia, which was consistent with late INa inhibition. Flecainide (n = 7) amplified ischemia-induced increase in atrial and ventricular repolarization alternans, electrocardiographic heterogeneity, and ventricular fibrillation incidence.

CONCLUSION:

Selective late INa inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles.

KEYWORDS:

Antiarrhythmic drugs; Atrial fibrillation; Atrial ischemia; Depolarization; Heterogeneity; Late I(Na); Repolarization; Ventricular fibrillation; Ventricular ischemia

PMID:
24953379
DOI:
10.1016/j.hrthm.2014.06.017
[Indexed for MEDLINE]

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