ArticleThe Journal of thoracic and cardiovascular surgery2012
AAV6-βARKct gene delivery mediated by molecular cardiac surgery with recirculating delivery (MCARD) in sheep results in robust gene expression and increased adrenergic reserve.
Article in The Journal of thoracic and cardiovascular surgery, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- Adeno-associated viral (AAV) vector-mediated therapeutics for diabetic cardiomyopathy - current and future perspectives.Clinical science (London, England : 1979) · 2021Review
- Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure.ESC heart failure · 2020Article
- G protein-coupled receptor kinases as therapeutic targets in the heart.Nature reviews. Cardiology · 2019Review
- Analysis of recombinant adeno-associated viral vector shedding in sheep following intracoronary delivery.Gene therapy · 2019Article
- Current Landscape of Heart Failure Gene Therapy.Journal of the American Heart Association · 2019Review
- Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.Scientific reports · 2019Article
- GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion.Cell death discovery · 2018Article
- Systemic and Persistent Muscle Gene Expression in Rhesus Monkeys with a Liver De-Targeted Adeno-Associated Virus Vector.Human gene therapy · 2017Article
- Mitigation of myocardial fibrosis by molecular cardiac surgery-mediated gene overexpression.The Journal of thoracic and cardiovascular surgery · 2016Article
- AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure.European journal of heart failure · 2015Article
- Safety and efficacy of high-dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca(2+) adenosine triphosphatase delivered by molecular cardiac surgery with recirculating delivery in ovine ischemic cardiomyopathy.The Journal of thoracic and cardiovascular surgery · 2014Article
- The potential of adeno-associated viral vectors for gene delivery to muscle tissue.Expert opinion on drug delivery · 2014Review
- Heart failure gene therapy: the path to clinical practice.Circulation research · 2013Review
- Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure.The Annals of thoracic surgery · 2013Article
- MCARD-mediated gene transfer of GRK2 inhibitor in ovine model of acute myocardial infarction.Journal of cardiovascular translational research · 2013Article
- Gene therapy for heart failure: where do we stand?Current cardiology reports · 2013Review
- Potential of gene therapy as a treatment for heart failure.The Journal of clinical investigation · 2013Article
- AAV-mediated gene therapy for heart failure: enhancing contractility and calcium handling.F1000prime reports · 2013Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
objectiveGenetic modulation of heart function is a novel therapeutic strategy. We investigated the effect of molecular cardiac surgery with recirculating delivery (MCARD)-mediated carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) gene transfer on cardiac mechanoenergetics and β-adrenoreceptor (βAR) signaling.
methodsAfter baseline measurements, sheep underwent MCARD-mediated delivery of 10(14) genome copies of self-complimentary adeno-associated virus (scAAV6)-βARKct. Four and 8 weeks after MCARD, mechanoenergetic studies using magnetic resonance imaging were performed. Tissues were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. βAR density, cyclic adenosine monophosphate levels, and physiologic parameters were evaluated.
resultsThere was a significant increase in dP/dt(max) at 4 weeks: 1384 ± 76 versus 1772 ± 182 mm Hg/s; and the increase persisted at 8 weeks in response to isoproterenol (P < .05). Similarly, the magnitude of dP/dt(min) increased at both 4 weeks and 8 weeks with isoproterenol stimulation (P < .05). At 8 weeks, potential energy was conserved, whereas in controls there was a decrease in potential energy (P < .05) in response to isoproterenol. RT-qPCR confirmed robustness of βARKct expression throughout the left ventricle and undetectable expression in extracardiac tissues. Quantitative Western blot data confirmed higher expression of βARKct in the left ventricle: 0.46 ± 0.05 versus 0.00 in lung and liver (P < .05). Survival was 100% and laboratory parameters of major organ function were within normal limits.
conclusionsMCARD-mediated βARKct delivery is safe, results in robust cardiac-specific gene expression, enhances cardiac contractility and lusitropy, increases adrenergic reserve, and improves energy utilization efficiency in a preclinical large animal model.
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Registered trials
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