The Popeye domain containing (Popdc) gene family encode membrane proteins with a high-affinity cAMP-binding domain. Single null mutants for Popdc1 and Popdc2 display stress-induced bradycardia, implicating Popdc genes in the cardiac response to β-adrenergic signalling1. Here we report our preliminary telemetric ECG analysis of the Popdc1/2 double mutants (heterozygous, dHET and homozygous null, dKO) at rest and after swimming exercise, or isoproterenol injection (2mg/kg body weight was administered intraperitoneally under isoflurane anaesthesia). Telemetry devices were implanted under isoflurane anaesthesia with vetergesic analgesia, a minimum of 10 days prior to stress testing to allow for sufficient recovery. As previously published, average heart rate for Popdc1 mutant mice was reduced during forced swimming (6 minutes) and recovery (30 minutes) compared to age matched (5.5 months) wild type (WT) males (Popdc1KO: 604±98bpm swim, 632±63bpm recovery vs. WT: 692±53bpm swim, 729±19bpm recovery). Preliminary data indicate that the average heart rate for Popdc1/2dKO (631±74bpm swim, 572±68bpm recovery) is similarly reduced compared to age-matched controls. Further analysis of ECG data shows an increased incidence of sinus pauses during forced swimming (Popdc1/2dKO: 119 pauses, WT: 49 pauses) and recovery (Popdc1/2dKO: 273 pauses vs. WT: 0 pauses). Consistently, the averaged heart rate increase following isoproterenol treatment was decreased in the Popdc1/2dHET (3%, n=3) and Popdc1/2dKO (-11%, n=1) male mice aged 5.5 to 8 months compared to age matched controls (10%, n=2). This impaired stress response was also observed in ventricular cardiac myocytes (isolated from 3 month age matched male mice) treated with increasing concentrations of isoproterenol (10-10M to 10-4M). Popdc1/2dHET ventricular cardiac myocytes displayed an increase in delayed after depolarisations and spontaneously generated action potentials compared to WT controls (spontaneously generated action potentials at 3Hz, p<0.05 at 10-4M). Together these data indicate that deficiency of Popdc1 and Popdc2 results in an impaired response to β-adrenergic signalling. By further analysing the single and double Popdc1/2 mutants at the organ and cellular level, we aim to define the role of Popdc proteins in cardiac stress response.