PMID- 22143102
OWN - NLM
STAT- MEDLINE
DCOM- 20120404
LR  - 20211021
IS  - 1097-685X (Electronic)
IS  - 0022-5223 (Print)
IS  - 0022-5223 (Linking)
VI  - 143
IP  - 3
DP  - 2012 Mar
TI  - AAV6-betaARKct gene delivery mediated by molecular cardiac surgery with 
      recirculating delivery (MCARD) in sheep results in robust gene expression and 
      increased adrenergic reserve.
PG  - 720-726.e3
LID - 10.1016/j.jtcvs.2011.08.048 [doi]
AB  - OBJECTIVE: Genetic 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 beta-adrenergic receptor kinase 
      (betaARKct) gene transfer on cardiac mechanoenergetics and beta-adrenoreceptor (betaAR) 
      signaling. METHODS: After baseline measurements, sheep underwent MCARD-mediated 
      delivery of 10(14) genome copies of self-complimentary adeno-associated virus 
      (scAAV6)-betaARKct. 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. betaAR 
      density, cyclic adenosine monophosphate levels, and physiologic parameters were 
      evaluated. RESULTS: There 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 betaARKct expression throughout the left ventricle and 
      undetectable expression in extracardiac tissues. Quantitative Western blot data 
      confirmed higher expression of betaARKct 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. CONCLUSIONS: MCARD-mediated 
      betaARKct 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.
CI  - Copyright A(c) 2012 The American Association for Thoracic Surgery. Published by 
      Mosby, Inc. All rights reserved.
FAU - Katz, Michael G
AU  - Katz MG
AD  - Division of Cardiovascular Surgery, Department of Surgery, the University of 
      Pennsylvania School of Medicine, Philadelphia, PA, USA.
FAU - Fargnoli, Anthony S
AU  - Fargnoli AS
FAU - Swain, JaBaris D
AU  - Swain JD
FAU - Tomasulo, Catherine E
AU  - Tomasulo CE
FAU - Ciccarelli, Michele
AU  - Ciccarelli M
FAU - Huang, Z Maggie
AU  - Huang ZM
FAU - Rabinowitz, Joseph E
AU  - Rabinowitz JE
FAU - Bridges, Charles R
AU  - Bridges CR
LA  - eng
GR  - R01 HL083078/HL/NHLBI NIH HHS/United States
GR  - 1-R01-HL083078-01A2/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111203
PL  - United States
TA  - J Thorac Cardiovasc Surg
JT  - The Journal of thoracic and cardiovascular surgery
JID - 0376343
RN  - 0 (Adrenergic beta-Agonists)
RN  - 0 (Receptors, Adrenergic, beta)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.15 (beta-Adrenergic Receptor Kinases)
RN  - L628TT009W (Isoproterenol)
SB  - IM
MH  - Adrenergic beta-Agonists/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - *Cardiac Surgical Procedures
MH  - Cyclic AMP/metabolism
MH  - Dependovirus/*genetics
MH  - Echocardiography, Doppler
MH  - Gene Expression Regulation
MH  - *Gene Transfer Techniques
MH  - *Genetic Vectors
MH  - Heart Ventricles/diagnostic imaging/drug effects/*enzymology
MH  - Hemodynamics
MH  - Isoproterenol/pharmacology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Myocardial Contraction
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptors, Adrenergic, beta/drug effects/genetics/*metabolism
MH  - Sheep
MH  - *Signal Transduction/drug effects/genetics
MH  - Time Factors
MH  - Ventricular Pressure
MH  - beta-Adrenergic Receptor Kinases/*biosynthesis/genetics
PMC - PMC3666102
MID - NIHMS465935
EDAT- 2011/12/07 06:00
MHDA- 2012/04/05 06:00
PMCR- 2013/05/29
CRDT- 2011/12/07 06:00
PHST- 2011/04/15 00:00 [received]
PHST- 2011/07/12 00:00 [revised]
PHST- 2011/08/03 00:00 [accepted]
PHST- 2011/12/07 06:00 [entrez]
PHST- 2011/12/07 06:00 [pubmed]
PHST- 2012/04/05 06:00 [medline]
PHST- 2013/05/29 00:00 [pmc-release]
AID - S0022-5223(11)01057-9 [pii]
AID - 10.1016/j.jtcvs.2011.08.048 [doi]
PST - ppublish
SO  - J Thorac Cardiovasc Surg. 2012 Mar;143(3):720-726.e3. doi: 
      10.1016/j.jtcvs.2011.08.048. Epub 2011 Dec 3.