Background— To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC_VI) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC_VI. We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC_VI.

Methods and Results— Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC_VI (P<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC_VI, as documented by the ratio of ventricular weight to tibial length (Gq, 11.93±0.99 mg/mm, n=11; Gq/AC, 8.00±0.73 mg/mm, n=9; P<0.01) and by left ventricular cardiac myocyte size (Gq, 2800±254 μm², n=4; Gq/AC, 1721±166 μm², n=5; P<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20±0.15 mm, n=12; Gq/AC, 3.68±0.12 mm, n=7; P<0.05) and increased fractional shortening (Gq, 32±1%, n=12; Gq/AC, 41±2%, n=7; P<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8±1.3 fmol/cell, n=5; Gq/AC, 10.7±2.6 fmol/cell, n=6; P<0.02), documenting increased AC function.

Conclusions— Cardiac-directed expression of AC_VI restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.