Abstract 13209: Adenylyl Cyclase 6 Deletion Increases Mortality and Slows Atrio-Ventricular Conduction after Sustained Beta-Adrenergic Receptor Stimulation
Background: Chronic isoproterenol (Iso) infusion and associated excessive cAMP production reduces left ventricle (LV) function. Using our previously generated AC6 deletion line (AC6KO), which has impaired Iso-stimulated LV cAMP production (p<0.001), we tested the hypothesis that AC6 deletion, by limiting cAMP production, would reduce Iso-induced cardiomyopathy.
Methods & Results: AC6KO and control (CON) mice were infused (osmotic minipumps) with Iso (60 µg/g/d). After 7 days of infusion, AC6KO mice showed higher mortality (Figure). Echocardiography at day 4 showed that, compared to intact sibling control mice (CON), Iso infusion was associated with significant reductions in HR and EF of similar degrees in AC6KO-Iso and CON-Iso (Table). The similarity in degree of LV dysfunction makes progressive heart failure less likely and cardiac arrhythmia more likely to be the cause of increased mortality in AC6KO-Iso mice. Telemetry revealed Iso-induced PR interval prolongation in AC6KO mice only (Table). The PR interval lengthened even further to 63±4 ms 1 hr before death, and subsequently evolved to high grade AV block, the fatal rhythm in all instances.
Conclusions: 1) Limiting cAMP production does not prevent Iso-induced cardiomyopathy, indicating that its pathogenesis is not tightly linked with cAMP production; 2) Deletion of AC6 is associated with Iso-induced impairment of AV conduction, high grade AV block and increased mortality. We speculate that defects in AV node morphology in AC6KO mice may underlie Iso-induced PR prolongation, and that the mechanism for increased mortality is high grade AV block.
- © 2010 by American Heart Association, Inc.