Azithromycin Causes a Novel Proarrhythmic Syndrome.

Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, Milne G, Tucker P, George AL, Campbell CM, Pickett RA, Shaffer CM, Chopra N, Yang T, Knollmann BC, Roden DM, Murray KT
Circ Arrhythm Electrophysiol. 2017 10 (4)

PMID: 28408648 · PMCID: PMC5396181 · DOI:10.1161/CIRCEP.115.003560

BACKGROUND - The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.

METHODS AND RESULTS - In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC=110±3 μmol/L) and Na current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for I in cardiomyocytes. Mild block occurred for K currents representing I (CHO cells expressing hERG; IC=219±21 μmol/L) and I (CHO cells expressing KCNQ1+KCNE1; IC=184±12 μmol/L), whereas azithromycin suppressed L-type Ca currents (rabbit ventricular myocytes, IC=66.5±4 μmol/L) and I (HEK cells expressing Kir2.1, IC=44±3 μmol/L).

CONCLUSIONS - Chronic exposure to azithromycin increases cardiac Na current to promote intracellular Na loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.

© 2017 American Heart Association, Inc.

MeSH Terms (28)

Action Potentials Animals Anti-Bacterial Agents Arrhythmias, Cardiac Azithromycin Calcium Channel Blockers Calcium Channels, L-Type CHO Cells Cricetulus Dose-Response Relationship, Drug Electrocardiography, Ambulatory Female Heart Rate HEK293 Cells Humans KCNQ1 Potassium Channel Mice, Inbred C57BL Myocytes, Cardiac NAV1.5 Voltage-Gated Sodium Channel Potassium Channel Blockers Potassium Channels, Inwardly Rectifying Potassium Channels, Voltage-Gated Rabbits Sodium Channel Blockers Telemetry Time Factors Transfection Young Adult

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