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(Circulation. 2004;110:330-336.)
© 2004 American Heart Association, Inc.

Original Articles

Intracoronary Adenovirus Encoding Adenylyl Cyclase VI Increases Left Ventricular Function in Heart Failure

N. Chin Lai, PhD; David M. Roth, PhD, MD; Mei Hua Gao, PhD; Tong Tang, PhD; Nancy Dalton, MS; Yin Yin Lai, BSc; Matthew Spellman; Paul Clopton, MS; H. Kirk Hammond, MD

From the Departments of Medicine (N.C.L., M.H.G., T.T., N.D., Y.Y.L., M.S., H.K.H.) and Anesthesiology (D.M.R.), University of California, San Diego, and the VA San Diego Healthcare System (N.C.L., D.M.R., M.S., P.C., H.K.H.), San Diego, Calif.

Correspondence to H. Kirk Hammond, MD, Professor of Medicine, UCSD, VA San Diego Healthcare System (111-A), 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail khammond{at}ucsd.edu

Received April 14, 2004; accepted May 27, 2004.

Background— We tested the hypothesis that intracoronary delivery of an adenovirus encoding adenylyl cyclase type VI (Ad.AC_VI) would be associated with increased left ventricular (LV) function in pigs with congestive heart failure.

Methods and Results— Pigs (52±6 kg; n=16) underwent placement of pacemakers, LV pressure transducers, and left atrial and aortic catheters. Physiological and echocardiographic studies were obtained from conscious animals 13 days later, and pacing was initiated (220 bpm). Seven days later, measures of LV function were reduced, documenting severe LV dysfunction and dilation. Pigs then received intracoronary Ad.AC_VI (1.4x10¹² vp; n=7) or saline (PBS; n=9) (randomized, blinded), with concomitant infusion of nitroprusside (50 µg/min, 6.4 minutes) to increase gene transfer. Pacing was continued for 14 days, and final studies were obtained. The a priori key end point was change in LV dP/dt during isoproterenol infusion (pre-Ad.AC_VI value minus value after 21 days of pacing). Pigs receiving Ad.AC_VI showed a smaller decrease in both LV +dP/dt (P=0.0014) and LV –dP/dt (P=0.0008). Serial echocardiography showed that Ad.AC_VI treatment was associated with increased LV function and reduced LV dilation and that end-systolic wall stress was reduced. AC-stimulated cAMP production was increased 1.7-fold in LV samples from Ad.AC_VI-treated pigs (P=0.006), and B-type natriuretic peptide was reduced (0.035). Gene transfer was confirmed by polymerase chain reaction.

Conclusions— AC_VI gene transfer increases LV function and attenuates deleterious LV remodeling in congestive heart failure.

Key Words: receptors, adrenergic, beta • genes • cAMP • nitroprusside

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