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J Am Coll Cardiol, 2007; 50:253-260, doi:10.1016/j.jacc.2007.03.047 (Published online 28 June 2007).
© 2007 by the American College of Cardiology Foundation
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Percutaneous Cardiac Recirculation-Mediated Gene Transfer of an Inhibitory Phospholamban Peptide Reverses Advanced Heart Failure in Large Animals

David M. Kaye, MD, PhD*,1,2,*, Arthur Preovolos, BS*,1,3, Tanneale Marshall, BS*, Melissa Byrne, PhD*,1,3, Masahiko Hoshijima, PhD{dagger}, Roger Hajjar, MD{ddagger}, Justin A. Mariani, MD*, Salvatore Pepe, PhD*, Kenneth R. Chien, MD, PhD{ddagger} and John M. Power, PhD*,1,2

* Baker Heart Research Institute, Melbourne, Australia
{dagger} Institute of Molecular Medicine, University of California–San Diego, La Jolla, California
{ddagger} Massachusetts General Hospital, Cardiovascular Research Center, Harvard Medical School, and the Harvard Stem Cell Institute, Boston, Massachusetts.


Figure 1
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  		Figure 1 Percutaneous Approach to Recirculating Cardiac Gene Delivery

(A) Diagram demonstrates the position of catheters placed within the heart. (B) Circuit diagram for recirculating gene delivery to the myocardium. V = viral vector.

 

Figure 2
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  		Figure 2 Perfusate Distribution Pattern Following Cardiac Recirculation

Pattern of distribution of indocyanine green through the myocardium during recirculation, as determined by near-infrared spectroscopy (left panels = anterior view; right panels = cross section). Images show a clear demarcation between perfused and nonperfused regions, the latter corresponding with the nonperfused right coronary artery distribution.

 

Figure 3
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  		Figure 3 Myocardial Pattern of Gene Expression Following Recirculating Delivery

(A) Hematoxylin and eosin-stained section of nonfailing myocardium 2 weeks after cardiac adenovirus ß-galactosidase (AdLacZ) recirculation, without evidence of inflammation or ischemic damage. (B and C) Immunohistochemical sections of nonfailing myocardium stained for ß-galactosidase 2 weeks after direct intracoronary (B) and recirculating (C) delivery of AdLacZ.

 

Figure 4
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  		Figure 4 Delivery Mode Determines the Extent of Extracardiac Transgene Expression

Immunohistochemical sections of lung stained for ß-galactosidase 2 weeks after direct intracoronary (A) and recirculating (B) delivery of adenovirus ß-galactosidase (AdLacZ). Immunohistochemical sections of liver stained for ß-galactosidase after direct intracoronary (C) and recirculating (D) delivery of AdLacZ.

 

Figure 5
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  		Figure 5 Hemodynamic Effect of S16E Gene Delivery on the Failing Heart

Echocardiographic and hemodynamic effects of AdS16EPLN (n = 9) gene transfer to the failing ovine heart compared with AdLacZ (lacZ) (n = 6) treated animals. (A) Left ventricular (LV) ejection fraction; (B) LV end-diastolic area;(C) LV end-diastolic pressure (EDP); (D) Peak positive dP/dt. Solid bars = before gene delivery; open bars = 2 weeks after gene delivery. AdLacZ = adenovirus ß-galactosidase; AdS16EPLN = adenovirus serine-to-glutamate "pseudo-phosphorylated" phospholamban mutant.

 

Figure 6
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  		Figure 6 Effect of S16E Gene Delivery on Phospholamban Expression

(A) Western blots showing expression of total and phospho-phospholamban (pPLN) in nonfailing and failing myocardium (after AdLacZ and AdS16EPLN). (B) Bar graphs demonstrating the pPLN:total phospholamban (tPLN) ratio in control nonfailing (n = 4) and heart failure (HF) AdLacZ (n = 4) and AdS16E (n = 5) treated animals. *p = 0.05 versus control; {wedge}p < 0.05 versus HF-AdLacZ. Abbreviations as in Figure 5.

 

Figure 7
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  		Figure 7 Effect of S16E Gene Delivery on SERCA Activity

Sarcoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) (SERCA) activity in control nonfailing (n = 3) and heart failure (HF) AdLacZ (n = 4) and AdS16E (n = 4) treated animals. Abbreviations as in Figure 5.

 




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