Peter J Schwartz1,2, Massimiliano Gnecchi3,4, Federica Dagradi1, Silvia Castelletti1, Gianfranco Parati5,6, Carla Spazzolini1, Luca Sala2, Lia Crotti1,2,5,6. 1. Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Via Pier Lombardo 22, Milan, Italy. 2. Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, Via Zucchi 18, Cusano Milanino Italy. 3. Coronary Care Unit, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, IRCCS Policlinico San Matteo Foundation, Viale Golgi 19, Pavia, Italy. 4. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi 19, Pavia, Italy. 5. Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Piazzale Brescia 20, Milan, Italy. 6. Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza, Italy.
Abstract
AIMS: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients. METHODS AND RESULTS: After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. In both patients, the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. On treatment, both patients developed diarrhoea, Pt1 more than Pt2. CONCLUSION: This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2patients, we tested whether the commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients. METHODS AND RESULTS: After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. In both patients, the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. On treatment, both patients developed diarrhoea, Pt1 more than Pt2. CONCLUSION: This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature. Published on behalf of the European Society of Cardiology. All rights reserved.
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