Preclinical efficacy and safety of KCNH2-G628S gene therapy for post-operative atrial fibrillation
Autor: | Barur R. Rajeshkumar, Julie A. Hutt, Zhao Liu, Yoshihiro Azuma, J. Kevin Donahue, Kai-Lai Duan |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
Pulmonary and Respiratory Medicine
ERG1 Potassium Channel medicine.medical_specialty Swine medicine.medical_treatment 030204 cardiovascular system & hematology Article 03 medical and health sciences 0302 clinical medicine Internal medicine Atrial Fibrillation medicine Animals Humans Sinus rhythm Heart Atria 030212 general & internal medicine Myocardial infarction Postoperative Period Cardiac Surgical Procedures Saline Stroke medicine.diagnostic_test business.industry Atrial fibrillation Genetic Therapy medicine.disease Cardiac surgery Anesthesia Cardiology Surgery Cardiology and Cardiovascular Medicine business Complication Electrocardiography |
Popis: | Background Postoperative atrial fibrillation (POAF) is the most common complication occurring after cardiac surgery. Multiple studies have shown significantly increased risks of stroke, myocardial infarction, and death associated with POAF. Current prophylaxis strategies are inadequate to eliminate this problem. We examined the preclinical efficacy and safety of KCNH2-G628S gene transfer to prevent POAF. Methods Domestic pigs received AdKCNH2-G628S by epicardial atrial gene painting and atrial pacemaker implantation for continuous-burst pacing to induce atrial fibrillation. In an initial dose-ranging evaluation, 3 pigs received 5 × 10 10 to 5 × 10 11 virus particles. In the formal study, 16 pigs were randomized to 3 groups: 5 × 10 11 virus particles of AdKCNH2-G628S with 20% Pluronic P407 in saline, 20% Pluronic P407 in saline with no virus, and saline alone. Animals were followed with daily efficacy and safety evaluations through the period of peak adenovirus-mediated transgene expression. After 14 days, pacing was discontinued, and the animals were followed in sinus rhythm for an additional 14 days to assess any longer-term toxicity. Results In the primary efficacy analysis, the G628S animals exhibited a significant increase in the average time in sinus rhythm compared with the Pluronic control group (59 ± 7% vs 14 ± 6%; P = .009). There was no significant difference between the Pluronic and saline controls (14 ± 6% vs 32 ± 12%; P = .16). Safety assessment showed improved left ventricular function in the G628S animals; otherwise there were no significant differences among the groups in any safety measure. Conclusions These data indicate that KCNH2-G628S gene therapy can successfully and safely reduce the risk of AF. |
Databáze: | OpenAIRE |
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