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(Circulation. 2006;114:388-396.)
© 2006 American Heart Association, Inc.

Heart Failure

Increased Cardiac Adenylyl Cyclase Expression Is Associated With Increased Survival After Myocardial Infarction

Toshiyuki Takahashi, MD, PhD; Tong Tang, PhD; N. Chin Lai, PhD; David M. Roth, PhD, MD; Brian Rebolledo, BA; Miho Saito, MD; Wilbur Y.W. Lew, MD; Paul Clopton, MS; H. Kirk Hammond, MD

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

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

Received April 6, 2006; revision received May 23, 2006; accepted May 26, 2006.

Background— Cardiac-directed expression of adenylyl cyclase type VI (AC_VI) in mice results in structurally normal hearts with normal basal heart rate and function but increased responses to catecholamine stimulation. We tested the hypothesis that increased left ventricular (LV) AC_VI content would increase mortality after acute myocardial infarction (MI).

Methods and Results— Transgenic mice with cardiac-directed AC_VI expression and their transgene-negative littermates (control) underwent coronary ligation, and survival, infarct size, and LV size and function were assessed 1 to 7 days after MI. Mice with increased AC_VI expression had increased survival (control 41%, AC_VI 74%; P=0.004). Infarct size and myocardial apoptotic rates were similar in AC_VI and control mice; however, AC_VI mice had less LV dilation (P<0.001) and increased ejection fractions (P<0.03). Three days after MI, studies in isolated perfused hearts showed that basal LV +dP/dt was similar, but graded dobutamine infusion was associated with a more robust LV contractile response in AC_VI mice (P<0.05). Increased LV function was associated with increases in cAMP generation (P=0.0002), phospholamban phosphorylation (P<0.04), sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) affinity for calcium (P<0.015), and reduced AV block (P=0.04).

Conclusions— In acute MI, increased cardiac AC_VI content attenuates adverse LV remodeling, preserves LV contractile function, and reduces mortality.

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CLINICAL PERSPECTIVE

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