Azithromycin Causes a Novel Proarrhythmic Syndrome
#MMPMID28408648
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 Jr
; Campbell CM
; Pickett RA
; Shaffer CM
; Chopra N
; Yang T
; Knollmann BC
; Roden DM
; Murray KT
Circ Arrhythm Electrophysiol
2017[Apr]; 10
(4
): ? PMID28408648
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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(50)=110±3 ?mol/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(Na) in cardiomyocytes. Mild block occurred for K(+) currents
representing I(Kr) (CHO cells expressing hERG; IC(50)=219±21 ?mol/L) and I(Ks)
(CHO cells expressing KCNQ1+KCNE1; IC(50)=184±12 ?mol/L), whereas azithromycin
suppressed L-type Ca(++) currents (rabbit ventricular myocytes, IC(50)=66.5±4
?mol/L) and I(K1) (HEK cells expressing Kir2.1, IC(50)=44±3 ?mol/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.
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