Abstract 2451: Increased Myocardial Sensitivity to IKr Inhibition in Patients With Heart Failure Due to Left Ventricular Systolic Dysfunction
Introduction: Patients with heart failure (HF) are at increased risk of drug-induced torsades de pointes (TdP).
Hypothesis: Myocardial sensitivity to IKr inhibition is enhanced in patients with HF due to left ventricular (LV) systolic dysfunction
Methods: Patients (n=15) with atrial fibrillation or atrial flutter requiring conversion to sinus rhythm; n=6 with NYHA class II–III HF [mean LV ejection fraction (LVEF) 30±9%], and n=9 controls [mean LVEF 54±5%]. Patients with electrolyte abnormalities or receiving other QT-prolonging drugs were excluded. Patients were administered intravenous ibutilide 1mg over 10 minutes. Blood samples and three 12-lead ECGs were obtained prior to and post-infusion and at 5, 15, 30, 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 48 hours post-infusion. Serum ibutilide concentrations were determined and Fridericia-corrected QT (QTF) intervals were measured from leads II, V1, and V5. The majority of (77%) post-infusion QT intervals were obtained in sinus rhythm. Sensitivity to IKr inhibition was expressed as ibutilide concentration at 50% maximum effect on QTF (EC50). Exposure to QTF interval prolongation was assessed by area under the QTF interval-time curves (AUEC).
Results: Ibutilide pharmacokinetics in the two groups were not significantly different. Ibutilide concentration- QTF effect relationships were best described by a sigmoidal Emax model with a hypothetical effect compartment. The predictive power of the model for concentration-effect relationships was best using the maximum QTF measured across the three leads vs the corresponding ibutilide concentration (R2=0.82). AUEC from 0 – 4 hours was larger in the HF group (Table⇓). EC50 was lower in the HF group, indicating that a lower serum ibutilide concentration was required to prolong QTF interval to 50% maximum.
Conclusions: Myocardial sensitivity to IKr inhibition is enhanced in patients with systolic HF, which may contribute to the increased risk of drug-induced TdP.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).