Elsevier

Journal of Cardiac Failure

Volume 26, Issue 9, September 2020, Pages 781-785
Journal of Cardiac Failure

Brief Report
Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction

https://doi.org/10.1016/j.cardfail.2020.06.008Get rights and content

ABSTRACT

Background

Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown.

Methods and Results

We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QTF) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTFvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QTF interval exposure. Maximum QTF (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QTF from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different.

Conclusions

HFpEF is associated with enhanced response to drug-induced QT interval lengthening.

Section snippets

Methods

Two groups of volunteers ≥18 years of age were enrolled. One group had HFpEF, defined as7 (1) a diagnosis of symptomatic HF, (2) left ventricular ejection fraction of ≥50% documented on echocardiogram within the previous 2 years, and (3) ≥1 of the following echocardiographic findings8: E/E’ > 15; E/A < 0.5; maximum left atrial volume index of >40 mL/m2; and diastolic dysfunction grade 2 or greater. Patients with HFpEF were recruited from HF clinics at Indiana University (IU) Health in

Results

Recruitment was suspended in October 2018 after enrollment of 10 patients per group, due to an inability to enroll the targeted sample size, owing primarily to the stringent HFpEF inclusion criteria and safety-oriented exclusion criteria. Of 2214 patients screened, 2081 met ≥1 exclusion criterion or declined to participate; 43 consented, of whom 23 were subsequently withdrawn due to exclusion criteria (Supplementary Figure S1). Although potential patients were recruited and screened from all

Discussion

This is the first study to investigate whether patients with HFpEF demonstrate enhanced response to drug-induced QT lengthening. Based on higher postibutilide AUECs at 1 and 8 hours in the HFpEF group, indicating greater and more prolonged QT interval exposure, and significantly longer QT intervals during the first 2 hours after ibutilide administration, our findings indicate that patients with HFpEF exhibit a heightened response to drug-induced QT lengthening compared with a matched group of

Conclusions

Patients with HFpEF demonstrate enhanced response to drug-induced QT lengthening. Further study is required to confirm these findings in a larger population and to determine if patients with HFpEF are at increased risk of drug-induced torsade de pointes.

Sources of Funding

Supported by a grant from the Cardiovascular Section of the IU Health-IU School of Medicine Strategic Research Initiative (Center of Excellence in Cardiovascular Research [CECARE] award). This investigation was also supported in part with support from the Indiana Clinical and Translational Sciences Institute funded, in part, by grant number UL1TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. In

Disclosures

Dr Rodgers serves as a consultant, advisory board member, and recipient of research grants for/from Novartis. Dr Rao serves as an advisory board member for Bristol-Myers Squibb, Pfizer, and CryoLife, and on speakers bureaus for Novartis, Boehringer-Ingelheim, Eli Lilly, Bristol-Myers Squibb, and Pfizer. The remaining authors have no relationships with industry.

References (14)

There are more references available in the full text version of this article.

Cited by (2)

Present address: Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Present address: ZS Associates, Princeton, New Jersey.

Present address: AbbVie Inc, North Chicago, Illinois.

View full text