Dataset Information

Azithromycin Causes a Novel Proarrhythmic Syndrome.

ABSTRACT: 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 (IC50=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 INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr (CHO cells expressing hERG; IC50=219±21 ?mol/L) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12 ?mol/L), whereas azithromycin suppressed L-type Ca++ currents (rabbit ventricular myocytes, IC50=66.5±4 ?mol/L) and IK1 (HEK cells expressing Kir2.1, IC50=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.

SUBMITTER: Yang Z

PROVIDER: S-EPMC5396181 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Azithromycin Causes a Novel Proarrhythmic Syndrome.

Yang Zhenjiang Z Prinsen Joseph K JK Bersell Kevin R KR Shen Wangzhen W Yermalitskaya Liudmila L Sidorova Tatiana T Luis Paula B PB Hall Lynn L Zhang Wei W Du Liping L Milne Ginger G Tucker Patrick P George Alfred L AL Campbell Courtney M CM Pickett Robert A RA Shaffer Christian M CM Chopra Nagesh N Yang Tao T Knollmann Bjorn C BC Roden Dan M DM Murray Katherine T KT

Circulation. Arrhythmia and electrophysiology 20170401 4

<h4>Background</h4>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, ...[more]

PMID: 28408648

Similar Datasets

Project description:BackgroundLosses of slaughter-weight pigs due to transport stress are both welfare and economic concerns to pork producers. Historically, the HAL-1843 mutation in ryanodine receptor 1 was considered responsible for most of the losses; however, DNA testing has effectively eliminated this mutation from commercial herds. We identified two sibling barrows in the USMARC swine herd that died from apparent symptoms of a stress syndrome after transport at 12 weeks of age. The symptoms included open-mouth breathing, skin discoloration, vocalization and loss of mobility.ResultsWe repeated the original mating along with sire-daughter matings to produce additional offspring. At 8 weeks of age, heart rate and electrocardiographs (ECG) were monitored during isoflurane anesthesia challenge (3% for 3 min). Four males from the original sire-dam mating and two males from a sire-daughter mating died after one minute of anesthesia. Animals from additional litters were identified as having a stress response, sometimes resulting in death, during regular processing and weighing. Affected animals had elevated plasma creatine phosphokinase (CPK) levels before and immediately after isoflurane challenge and cardiac arrhythmias. A pedigree containing 250 pigs, including 49 affected animals, was genotyped with the Illumina PorcineSNP60 Beadchip and only one chromosomal region, SSCX at 25.1-27.7 Mb over the dystrophin gene (DMD), was significantly associated with the syndrome. An arginine to tryptophan (R1958W) polymorphism in exon 41 of DMD was the most significant marker associated with stress susceptibility. Immunoblots of affected heart and skeletal muscle showed a dramatic reduction of dystrophin protein and histopathology of affected hearts indicated muscle fiber degeneration.ConclusionsA novel stress syndrome was characterized in pigs and the causative genetic factor most likely resides within DMD that results in less dystrophin protein and cardiac abnormalities that can lead to death under stressful conditions. The identification of predictive markers will allow us to determine the prevalence of this disease in commercial swine populations. This defect also provides a unique biomedical model for human cardiomyopathy associated with muscular dystrophy that may be superior to those available because of the similarities in anatomy and physiology and allow advances in gene therapies for human disease.

Dataset Information

Azithromycin Causes a Novel Proarrhythmic Syndrome.

Publications

Azithromycin Causes a Novel Proarrhythmic Syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets