Enhanced Sensitivity to Drug‐Induced QT Interval Lengthening in Patients With Heart Failure Due to Left Ventricular Systolic Dysfunction

Abstract

Patients with heart failure (HF) are at increased risk for drug-induced torsades de pointes (TdP) due to unknown mechanisms. Our objective was to determine if sensitivity to drug-induced QT interval lengthening is enhanced in patients with HF. In this multicenter, prospective study, 15 patients with atrial fibrillation or flutter requiring conversion to sinus rhythm were enrolled: 6 patients with New York Heart Association class II to III HF (mean ejection fraction [EF], 30% ± 9%), and 9 controls (mean EF, 53% ± 6%). Patients received ibutilide 1 mg intravenously. Blood samples and 12-lead electrocardiograms were obtained prior to and during 48 hours postinfusion. Serum ibutilide concentrations at 50% maximum effect on Fridericia-corrected QT (QTF) intervals (EC50) were determined, and areas under the effect (QTF interval vs time) curves (AUECs) were calculated. Ibutilide concentration–QTF relationships were best described by a sigmoidal Emax model with a hypothetical effect compartment. Median [interquartile range] AUEC from 0 to 4 hours was larger in the HF group than in controls (1.86 [1.86-1.93] vs 1.82 [1.81-1.84] s·h; P = .04). Median EC50 was lower in the HF group (0.48 [0.46-0.49] vs 1.85 [1.10-3.23] μg/L; P = .008). Sensitivity to drug-induced QT interval lengthening is enhanced in patients with systolic HF, which may contribute to the increased risk of drug-induced TdP.

Acquired long QT syndrome in chronic kidney disease patients

“…The dysfunction of these ion channels may also explain why people with HF are more susceptible to drug-induced LQTS than normal individuals. For example, the incidence of TdP caused by ibutilide was between 5.9% and 11.4% in patients with left ventricular dysfunction and between 1.7% and 4.1% in normal individuals [61].…”

Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts

“…Ventricular arrhythmia is a major cause of death in patients with heart failure (HF). 1 Multiple randomized clinical trials [2][3][4] conducted in patients with HF documented increased ventricular arrhythmia or mortality in patients randomized to the drug treatment arm. These results suggested that HF predisposes patients to drug-induced arrhythmias.…”

Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium

“…A recent study confirmed that there is enhanced sensitivity to drug-induced QT interval lengthening in patients with HF due to left ventricular systolic dysfunction. 5 The mechanisms by which HF increases the risk of drug-induced arrhythmia and reduces drug safety remain poorly understood. Previous studies showed that HF is associated with down-regulation of multiple K + currents ( I to , I Ks , I Kr , I K1 and I KATP ) 6,7 but upregulation of apamin-sensitive K + current ( I KAS ) conducted through the small conductance Ca 2+ activated K + (SK) channels.…”