Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.

PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and after adenosine (25 g) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of 10 11 plaqueforming units in each coronary artery) carrying ␤-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n ϭ 9); in another set of animals, PAMGT was performed without coronary vein blockade (n ϭ 5). At 1 wk after gene delivery, the animals were killed. Quantitative ␤-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative ␤-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. ␤-Galactosidase activity increased significantly in the ␤-galactosidase group compared with the saline group: 1.34 Ϯ 0.18 vs. 0.81 Ϯ 0.1 ng (P Յ 0.01) in the left ventricular wall and 0.91 Ϯ 0.1 vs. 0.66 Ϯ 0.07 ng (P Յ 0.05) in the right ventricular wall. PAMGT with selective coronary venous blockade is feasible, reproducible, and safely achieved in a large-animal model.

No abstract

Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.