TY - JOUR
T1 - Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure
AU - Fargnoli, Anthony S.
AU - Katz, Michael G.
AU - Yarnall, Charles
AU - Isidro, Alice
AU - Petrov, Michael
AU - Steuerwald, Nury
AU - Ghosh, Sriparna
AU - Richardville, Kyle C.
AU - Hillesheim, Richard
AU - Williams, Richard D.
AU - Kohlbrenner, Erik
AU - Stedman, Hansell H.
AU - Hajjar, Roger J.
AU - Bridges, Charles R.
N1 - Funding Information:
This study was supported by National Institutes of Health grant 1-R01 HL083078-01A2 (C.R.B.). We acknowledge the NHLBI Gene Therapy Resource Program. The authors thank Catherine Tomasulo, Louella Pritchette, and Marina Sumaroka for technical assistance; James J. Pilla and Ted Plappert for MRI and echocardiography; Jane Ingram, Natalia Zinchenko, and Amber Smith for histology; Einar Heiberg for MRI software; and the veterinarians and veterinary technicians of the University of Pennsylvania.
PY - 2013/8
Y1 - 2013/8
N2 - Background: The sarcoplasmic reticulum calcium ATPase (SERCA2a) is an important molecular regulator of contractile dysfunction in heart failure. Gene transfer of SERCA2a mediated by molecular cardiac surgery with recirculating delivery (MCARD) is a novel and clinically translatable strategy. Methods: Ischemic heart failure was induced by ligation of OM1 and OM2 in 14 sheep. Seven sheep underwent MCARD-mediated AAV1-SERCA2a delivery 4 weeks after myocardial infarction, and seven sheep served as untreated controls. Magnetic resonance imaging - based mechanoenergetic studies were performed at baseline, 3 weeks, and 12 weeks after infarction. Myocyte apoptosis was quantified by Tdt-mediated nick-end labeling assay. Myocyte cross-sectional area and caspase-8 and caspase-9 activity was measured with imaging software, specific fluorogenic peptides, and immunohistochemistry. Results: MCARD-mediated AAV1-SERCA2a gene delivery resulted in robust cardiac-specific SERCA2a expression and stable improvements in global and regional contractility. There were significantly higher stroke volume index, left ventricular fractional thickening, and ejection fraction at 12 weeks in the MCARD group than in the control group (30 ± 3 vs 21 ± 2 mL/m2; 12% ± 5% vs 3% ± 3%; and 43 ± 4 vs 32 ± 4, respectively, all p < 0.05). Apoptotic myocytes were observed more frequently in the control group than in the MCARD-SERCA2a group (0.57.2 ± 0.16 AU vs 0.32.4 ± 0.08 AU, p < 0.05). MCARD-SERCA2a also resulted in decreased caspase-8 and caspase-9 expression and decreased myocyte area in the border zone of transgenic sheep compared with control sheep (14.6% ± 1.2% vs 2.9% ± 0.7%; 18.2% ± 1.9% vs 8.6% ± 1.4%; and 102.1 ± 3.8 μm2 vs 88.1 ± 3.6 μm2, all p < 0.05). Conclusions: MCARD-mediated SERCA2a delivery results in robust cardiac specific gene expression, improved contractility, and a decrease in both myocyte apoptosis and myocyte hypertrophy.
AB - Background: The sarcoplasmic reticulum calcium ATPase (SERCA2a) is an important molecular regulator of contractile dysfunction in heart failure. Gene transfer of SERCA2a mediated by molecular cardiac surgery with recirculating delivery (MCARD) is a novel and clinically translatable strategy. Methods: Ischemic heart failure was induced by ligation of OM1 and OM2 in 14 sheep. Seven sheep underwent MCARD-mediated AAV1-SERCA2a delivery 4 weeks after myocardial infarction, and seven sheep served as untreated controls. Magnetic resonance imaging - based mechanoenergetic studies were performed at baseline, 3 weeks, and 12 weeks after infarction. Myocyte apoptosis was quantified by Tdt-mediated nick-end labeling assay. Myocyte cross-sectional area and caspase-8 and caspase-9 activity was measured with imaging software, specific fluorogenic peptides, and immunohistochemistry. Results: MCARD-mediated AAV1-SERCA2a gene delivery resulted in robust cardiac-specific SERCA2a expression and stable improvements in global and regional contractility. There were significantly higher stroke volume index, left ventricular fractional thickening, and ejection fraction at 12 weeks in the MCARD group than in the control group (30 ± 3 vs 21 ± 2 mL/m2; 12% ± 5% vs 3% ± 3%; and 43 ± 4 vs 32 ± 4, respectively, all p < 0.05). Apoptotic myocytes were observed more frequently in the control group than in the MCARD-SERCA2a group (0.57.2 ± 0.16 AU vs 0.32.4 ± 0.08 AU, p < 0.05). MCARD-SERCA2a also resulted in decreased caspase-8 and caspase-9 expression and decreased myocyte area in the border zone of transgenic sheep compared with control sheep (14.6% ± 1.2% vs 2.9% ± 0.7%; 18.2% ± 1.9% vs 8.6% ± 1.4%; and 102.1 ± 3.8 μm2 vs 88.1 ± 3.6 μm2, all p < 0.05). Conclusions: MCARD-mediated SERCA2a delivery results in robust cardiac specific gene expression, improved contractility, and a decrease in both myocyte apoptosis and myocyte hypertrophy.
UR - http://www.scopus.com/inward/record.url?scp=84881159632&partnerID=8YFLogxK
U2 - 10.1016/j.athoracsur.2013.04.021
DO - 10.1016/j.athoracsur.2013.04.021
M3 - Article
C2 - 23773730
AN - SCOPUS:84881159632
SN - 0003-4975
VL - 96
SP - 586
EP - 595
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 2
ER -