A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

BACKGROUND: Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive. METHODS: A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques. RESULTS: The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics. CONCLUSIONS: These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

Role of Ideal Cardiovascular Health Metrics in Reducing Risk of Incident Arrhythmias.

AIMS: Cardiovascular health (CVH) has been proved to reduce cardiovascular disease burden and mortality, but data are lacking regarding cardiac arrhythmias. The aim of this study was to assess the association between CVH metrics and atrial fibrillation/flutter (AF), ventricular arrhythmias and bradyarrhythmias. METHODS AND RESULTS: This study analyzed data from the ARIC (Atherosclerosis Risk in Communities) cohort, with participants recruited from four different communities across the United States. CVH metrics were scored at baseline (1987 to 1989) following the AHA's recommendations and categorized as poor, intermediate, or ideal. Arrhythmia episodes were diagnosed by ICD-9 code. Adjusted associations were estimated using Cox models and event rates and population attributable fractions were calculated by CVH metrics category. The study population consisted of 13078 participants, with 2548 AF, 1363 ventricular arrhythmias, and 706 bradyarrhythmias occurred. The adjusted hazard ratios (HRs) for ideal (vs. poor) CVH metrics were 0.59 (95% confidence interval [CI]: 0.50 to 0.69) for AF, 0.38 (95% CI: 0.28 to 0.51) for ventricular arrhythmias, and 0.70 (95% CI: 0.51 to 0.97) for bradyarrhythmia. The risk of incident arrhythmias decreased steadily as the CVH metrics improved from 0 to 14 scores. The adjusted population attributable fractions were calculated to be 29.9% for AF, 54.4% for ventricular arrhythmias, and 21.9% for bradyarrhythmia, respectively. The association between CVH metrics and incident arrhythmias was also seen in people who remained free of coronary heart disease over the follow-up. CONCLUSION: Achieving ideal CVH metrics recommendations by AHA in midlife was associated with a lower risk of incident arrhythmias later in life.

(1) Intermediate and ideal levels of cardiovascular health metrics are associated with a markedly reduced risk of developing incident arrhythmias, including atrial fibrillation/flutter, ventricular arrhythmias and bradyarrhythmia, independent of coronary heart disease. (2) A majority of incident arrhythmias could be prevented if the risk profile of the entire population were optimized. (3) These findings emphasize the significance of public health policies that improve cardiovascular health to reduce the social and economic burden of arrhythmias.