Volume 16, Issue 8, Pages 1141-1148 (August 2019) Grapefruit juice prolongs the QT interval of healthy volunteers and patients with long QT syndrome  Ehud Chorin, MD, PhD, Aviram Hochstadt, MD, Yoav Granot, MD, Shafik Khoury, MD, Arie Lorin Schwartz, MD, Gilad Margolis, MD, Rami Barashi, MD, Dana Viskin, MD, Eihab Ghantous, MD, Michael Schnapper, MD, Tal Mekori, MD, Dana Fourey, MD, Milton Ernesto Guevara-Valdivia, MD, Manlio F. Marquez, MD, David Zeltzer, MD, Raphael Rosso, MD, Sami Viskin, MD  Heart Rhythm  Volume 16, Issue 8, Pages 1141-1148 (August 2019) DOI: 10.1016/j.hrthm.2019.04.039 Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 1 Design of the thorough QT study. Consented patients were hospitalized twice, 1 week apart, each time for 2 days (period 1 [day 1–2] and period 2 [day 3–4]). Every day started with 3 electrocardiograms (ECGs), recorded 30 minutes apart, defined as baseline ECG of the day. The first day of each hospitalization period (day 1 and day 3) were dedicated to record repeated ECGs (at hourly intervals) without any drug intervention, defined as off-drug ECGs. Patients were randomized to moxifloxacin or grapefruit on day 2. The alternative drug was tested on day 4. The doses used were (1) a single dose of moxifloxacin 400 mg and (2) grapefruit juice (1 L after the baseline ECGs and 2 doses of 0.5 L 4 and 6 hours later. Patients with long QT syndrome underwent baseline and off-drugs ECG recordings on day 1 and then baseline followed by grapefruit on day 2. Heart Rhythm 2019 16, 1141-1148DOI: (10.1016/j.hrthm.2019.04.039) Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 2 QT prolongation after drinking grapefruit juice in a patient with long QT syndrome. Electrocardiogram (ECG) during maximal QT prolongation after the ingestion of grapefruit juice (bottom trace) and off-drug at the same time 1 day previously (top trace). Both traces are from a 61-year-old male patient with long QT syndrome type 1 treated with β-blockers. Note that despite a similar heart rate (46 beats/min vs 48 beats/min), the QT interval is longer after grapefruit administration. This rate-corrected QT (QTc) prolongation >500 ms by grapefruit led to a change in the study protocol: Subsequent patients with long QT syndrome received only 2 doses of grapefruit juice instead of the 3 doses given to healthy controls. Heart Rhythm 2019 16, 1141-1148DOI: (10.1016/j.hrthm.2019.04.039) Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 3 Deviations of the rate-corrected QT (QTc) interval from baseline during different study days with different interventions. All graphs depicted mean with 95% confidence interval. For all panels, delta QTc represents the change in QTc interval from the baseline QTc interval of that particular day, where the baseline QTc interval represents the average QTc interval obtained from 3 electrocardiograms (ECGs) recorded 30 minutes apart before any intervention. The horizontal axis shows the time (in hours) starting after the third baseline ECG. The vertical axis represents changes in the QTc interval (either prolongation or shortening) from baseline (or delta QTc) after a given intervention. Note the different scales in the vertical axis for each panel in this figure. The yellow arrow denotes the timing of administration of oral moxifloxacin after the third baseline electrocardiogram and the pink and red arrows denote repeated administration of grapefruit juice. The symbols denote that the delta QTc from baseline after a given intervention is different from the delta QTc from baseline of the off-drug day at the same time, with the following statistical significance: *P < .05, ‡P < .01, and §P < .001. A: Comparison of delta QTc during the off-drug day before moxifloxacin (in green) and during the off-drug day before grapefruit (in blue). Note that the 2 graphs are similar, never reaching a statistically significant difference. B and C: Delta QTc in healthy volunteers after receiving moxifloxacin (yellow line) or grapefruit (red line) and delta QTc during their respective off-drug study day. D: Delta QTc of patients with long QT syndrome after drinking grapefruit juice (pink line) and during the off-drug day (light green). LQT = long QT. Heart Rhythm 2019 16, 1141-1148DOI: (10.1016/j.hrthm.2019.04.039) Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 4 A: Maximal rate-corrected QT (QTc) prolongation after the different interventions. The colored boxes represent the interquartile range (25th–75th percentiles) for the individual maximal QTc prolongation after each intervention. The thick black line in the box denotes the 50th percentile, and bars represent the range of results excluding outliers. Circles indicate outliers. The symbol *** denotes that the difference between the maximal QTc prolongation after moxifloxacin ingestion and that after grapefruit ingestion in healthy volunteers or after grapefruit ingestion in patients with long QT syndrome is different (P < .001) from the maximal QTc prolongation (with respect to their baseline value) during off-drug study days. B: Percentage of patients reaching a QTc prolongation (with respect to their baseline value) at least once after an intervention. Colored columns represent actual values, and bars represent 95% confidence intervals. Note that in 40% of patients with long QT syndrome, the QTc interval increased by ≥40 ms after drinking grapefruit juice. Heart Rhythm 2019 16, 1141-1148DOI: (10.1016/j.hrthm.2019.04.039) Copyright © 2019 Heart Rhythm Society Terms and Conditions