Metformin ameliorates cardiac conduction delay by regulating microRNA-1 in mice.

Cardiac conduction delay may occur as a common complication of several cardiac diseases. A few therapies and drugs have a good effect on cardiac conduction delay. Metformin (Met) has a protective effect on the heart. This study's aim was to investigate whether Met could ameliorate cardiac conduction delay and its potential mechanism. Cardiac-specific microRNA-1 (miR-1) transgenic (TG) and myocardial infarction (MI) mouse models were used. Mice were administered with Met in an intragastric manner. We found that the expression of miR-1 was significantly up-regulated in H2O2 treated cardiomyocytes as well as in TG and MI mice. The protein levels of inwardly rectifying potassium channel 2.1 (Kir2.1) and Connexin43 (CX43) were down-regulated both in cardiomyocytes treated with H2O2 as well as cardiac tissues of TG and MI mice, as compared to their controls. Furthermore, the PR and QT intervals were prolonged, action potential duration (APD) was delayed, and conduction velocity (CV) was reduced, with upregulation of miR-1 in the hearts. In the meanwhile, intercalated disc injuries were found in the hearts of MI mice. Interestingly, Met can noticeably inhibit miR-1 upregulation and attenuate the changes mentioned above. Taken together, this suggested that Met could play an important role in improving cardiac conduction delay through inhibition of miR-1 expression. Our study proposes that Met is a potential candidate for the treatment of cardiac conduction delay and provides a new idea of treating arrhythmia with a drug.

Awareness of, and Compliance with, Domperidone Revised Labeling After a Risk-Minimization Activity in Europe.

BACKGROUND AND OBJECTIVE: Risk-minimization measures (RMM), including label revisions were implemented in Europe for domperidone because of evidence of increased incidence of cardiac arrhythmia and sudden cardiac death. In accordance with the guideline on good pharmacovigilance practices, the European Medicines Agency Pharmacovigilance Risk Assessment Committee requested to conduct two studies to evaluate the effectiveness of these risk minimization measures. METHODS: In Belgium, France, Germany, Spain, and the UK, surveys were conducted to assess physicians' knowledge on the updated domperidone labeling information, and a drug-utilization study (DUS) was conducted using healthcare databases to assess domperidone prescribing patterns before and after the RMM. Four DUS sensitivity analyses (scenarios) evaluated uncertainty regarding domperidone treatment duration and indication. RESULTS: Among 1805 physicians participating in the survey, most were aware of the approved indication (nausea and vomiting, 80%), treatment duration (≤ 7 days, 70%), and maximum adult daily dose (10 mg three times daily, 84%). Only 33% selected the on-label indication from a list of indications for which they would prescribe domperidone. Awareness was low for medications contraindicated for concomitant use (26%) and contraindicated conditions (4%). In the DUS, under the optimistic scenario, a large improvement in labeling compliance from pre- to post-implementation period was observed in France (27% vs. 69%), while Belgium, Germany, Spain, and the UK showed small improvements (< 10%). In the other scenarios, there was little to no improvement in compliance with the revised labeling from the pre- to post-implementation periods in most countries. CONCLUSIONS: The survey findings documented that most physicians in all five countries were aware of the main aspects of the revised labeling. Results of the DUS were inconclusive regarding the effect of the RMM and compliance with the revised labeling for all countries except France.