ArticleJournal of the American Heart Association2012
Biological Heart Rate Reduction Through Genetic Suppression of Gα(s) Protein in the Sinoatrial Node.
Article in Journal of the American Heart Association, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Gene Therapy Approaches to Biological Pacemakers.Journal of cardiovascular development and disease · 2018Review
- Cardiac gene therapy with adeno-associated virus-based vectors.Current opinion in cardiology · 2017Article
- Article
- Improving lipoprotein profiles by liver-directed gene transfer of low density lipoprotein receptor gene in hypercholesterolaemia mice.Journal of genetics · 2016Article
- Gene therapy to restore electrophysiological function in heart failure.Expert opinion on biological therapy · 2015Review
- Atrial fibrillation complicated by heart failure induces distinct remodeling of calcium cycling proteins.PloS one · 2015Article
- The Use of Gene Therapy for Ablation of Atrial Fibrillation.Arrhythmia & electrophysiology review · 2014Article
- The in vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G proteins.American journal of physiology. Regulatory, integrative and comparative physiology · 2013Article
- Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K(+) channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells.British journal of pharmacology · 2013Article
- Genetic silencing of pacemaker cells: local intervention with global implications.Journal of the American Heart Association · 2012Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundElevated heart rate represents an independent risk factor for cardiovascular outcome in patients with heart disease. In the sinoatrial node, rate increase is mediated by β(1) adrenoceptor mediated activation of the Gα(s) pathway. We hypothesized that genetic inactivation of the stimulatory Gα(s) protein in the sinoatrial node would provide sinus rate control and would prevent inappropriate heart rate acceleration during β-adrenergic activation. METHODS AND
resultsDomestic pigs (n=10) were evenly assigned to receive either Ad-small interfering RNA (siRNA)-Gα(s) gene therapy to inactivate Gα(s) or adenovirus encoding for green fluorescent protein (Ad-GFP) as control. Adenoviruses were applied through virus injection into the sinoatrial node followed by epicardial electroporation, and heart rates were evaluated for 7 days. Genetic inhibition of Gα(s) protein significantly reduced mean heart rates on day 7 by 16.5% compared with control animals (110±8.8 vs 131±9.4 beats per minute; P<0.01). On β-adrenergic stimulation with isoproterenol, we observed a tendency toward diminished rate response in the Ad-siRNA-Gα(s) group (Ad-siRNA-Gα(s), +79.3%; Ad-GFP, +61.7%; n=3 animals per group; P= 0.294). Adverse effects of gene transfer on left ventricular ejection fraction (LVEF) were not detected following treatment (LVEF(Ad-siRNA-Gαs), 66%; LVEF(Ad-GFP), 60%).
conclusionsIn this preclinical proof-of-concept study targeted Ad-siRNA-Gα(s) gene therapy reduced heart rates during normal sinus rhythm compared with Ad-GFP treatment and prevented inappropriate rate increase after β-adrenergic stimulation. Gene therapy may provide an additional therapeutic option for heart rate reduction in cardiac disease. (J Am Heart Assoc. 2012;1:jah3-e000372 doi: 10.1161/JAHA.111.000372).
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