PMID- 25037619 OWN - NLM STAT- MEDLINE DCOM- 20141106 LR - 20211021 IS - 1097-685X (Electronic) IS - 0022-5223 (Print) IS - 0022-5223 (Linking) VI - 148 IP - 3 DP - 2014 Sep TI - 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. PG - 1065-72, 1073e1-2; discussion1072-3 LID - S0022-5223(14)00732-6 [pii] LID - 10.1016/j.jtcvs.2014.05.070 [doi] AB - OBJECTIVE: Therapeutic safety and efficacy are the basic prerequisites for clinical gene therapy. We investigated the effect of high-dose molecular cardiac surgery with recirculating delivery (MCARD)-mediated adeno-associated virus 9 (AAV9)/sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA2a) gene delivery on clinical parameters, oxidative stress, humoral and cellular immune responses, and cardiac remodeling. METHODS: Ischemic cardiomyopathy was generated in a sheep model. The sheep were assigned to 1 of 2 groups: control (n = 10) and study (MCARD, n = 6). The control group underwent no intervention and the study group received 10(14) genome copies of AAV9/SERCA2a 4 weeks after infarction. RESULTS: Our ischemic model produced reliable infarcts leading to heart failure. The baseline ejection fraction in the MCARD group was 57.6% +/- 1.6% versus 61.2% +/- 1.9% in the control group (P > .05). At 12 weeks after infarction, the MCARD group had superior left ventricular function compared with the control group: stroke volume index, 46.6 +/- 1.8 versus 35.8 +/- 2.5 mL/m(2) (P < .05); ejection fraction, 46.2% +/- 1.9% versus 38.7% +/- 2.5% (P < .05); and left ventricular end-systolic and end-diastolic dimensions, 41.3 +/- 1.7 versus 48.2 +/- 1.4 mm and 51.2 +/- 1.5 versus 57.6 +/- 1.7 mm, respectively (P < .05). The markers of oxidative stress were significantly reduced in the infarct zone in the MCARD group. No positive T-cell-mediated immune response was seen in the MCARD group at any point. Myocyte hypertrophy was also significantly attenuated in the MCARD group compared with the control group. CONCLUSIONS: Cardiac overexpression of the SERCA2a gene by way of MCARD is a safe therapeutic intervention. It significantly improves left ventricular function, decreases markers of oxidative stress, abrogates myocyte hypertrophy, arrests remodeling, and does not induce a T-cell-mediated immune response. CI - Copyright (c) 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved. FAU - Katz, Michael G AU - Katz MG AD - Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. FAU - Fargnoli, Anthony S AU - Fargnoli AS AD - Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. FAU - Williams, Richard D AU - Williams RD AD - Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. FAU - Steuerwald, Nury M AU - Steuerwald NM AD - Molecular Biology Core Facility, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. FAU - Isidro, Alice AU - Isidro A AD - Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. FAU - Ivanina, Anna V AU - Ivanina AV AD - Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC. FAU - Sokolova, Inna M AU - Sokolova IM AD - Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC. FAU - Bridges, Charles R AU - Bridges CR AD - Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas Healthcare System, Charlotte, NC. Electronic address: Charles.Bridges@carolinashealthcare.org. LA - eng GR - R01 HL083078/HL/NHLBI NIH HHS/United States GR - 1-R01HL083078-01A2/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140607 PL - United States TA - J Thorac Cardiovasc Surg JT - The Journal of thoracic and cardiovascular surgery JID - 0376343 RN - 0 (Biomarkers) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) SB - IM MH - Animals MH - Biomarkers/metabolism MH - *Cardiac Surgical Procedures/adverse effects MH - Cardiomegaly/enzymology/genetics/prevention & control MH - Dependovirus/*enzymology/genetics MH - Disease Models, Animal MH - *Gene Transfer Techniques/adverse effects MH - *Genetic Vectors MH - Humans MH - Immunity, Cellular MH - Immunity, Humoral MH - Male MH - Myocardial Infarction/enzymology/genetics/immunology/pathology/physiopathology/*therapy MH - Myocardium/*enzymology/immunology/pathology MH - Oxidative Stress MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/*metabolism MH - Sheep MH - Stroke Volume MH - T-Lymphocytes/immunology MH - Time Factors MH - Ventricular Function, Left MH - Ventricular Remodeling PMC - PMC4170593 MID - NIHMS614534 COIS- No related disclosures or conflicts of interest to report EDAT- 2014/07/20 06:00 MHDA- 2014/11/07 06:00 PMCR- 2015/09/01 CRDT- 2014/07/20 06:00 PHST- 2014/04/25 00:00 [received] PHST- 2014/05/26 00:00 [revised] PHST- 2014/05/27 00:00 [accepted] PHST- 2014/07/20 06:00 [entrez] PHST- 2014/07/20 06:00 [pubmed] PHST- 2014/11/07 06:00 [medline] PHST- 2015/09/01 00:00 [pmc-release] AID - S0022-5223(14)00732-6 [pii] AID - 10.1016/j.jtcvs.2014.05.070 [doi] PST - ppublish SO - J Thorac Cardiovasc Surg. 2014 Sep;148(3):1065-72, 1073e1-2; discussion1072-3. doi: 10.1016/j.jtcvs.2014.05.070. Epub 2014 Jun 7.