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Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular
Rodolfo Bonatti1, Ana Flavia Garcia Silva1, Julio Americo Pereira Batatinha1
1Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Insights
Selective late sodium channel current (INa) inhibition with GS967 effectively reduced cardiac electrical instability during ischemia. Unlike flecainide, GS967 prevented arrhythmias and protected both atria and ventricles.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Pharmacology
Background:
- Ischemic heart disease poses a dual risk for atrial and ventricular arrhythmias.
- Understanding the mechanisms underlying cardiac electrical instability during ischemia is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the efficacy of selectively targeting the late sodium channel current (INa) using GS-458967 (GS967) in reducing cardiac electrical instability.
- To compare the effects of GS967 with a clinically relevant dose of flecainide.
Main Methods:
- Anesthetized pigs underwent monitoring of repolarization and electrocardiographic heterogeneity.
- Left circumflex coronary artery stenosis was induced to simulate ischemic conditions.
- GS967 or flecainide was administered intravenously, and their effects on cardiac electrical parameters were assessed.
Main Results:
- Ischemia significantly increased atrial and ventricular repolarization alternans and electrocardiographic heterogeneity.
- GS967 prevented these ischemia-induced increases, stabilizing atrial and ventricular electrical activity.
- Flecainide, however, exacerbated ischemia-induced abnormalities and increased ventricular fibrillation incidence.
Conclusions:
- Selective late INa inhibition with GS967 demonstrates potent protective effects against ischemia-induced electrical abnormalities.
- GS967 effectively mitigates both depolarization and repolarization disturbances in the atria and ventricles.
- These findings suggest GS967 as a promising therapeutic agent for managing arrhythmias associated with ischemic heart disease.
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.
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