Heart failure and cardiac arrhythmias are known consequences of ventricular remodelling. Key signalling pathways responsible for such hypertrophic remodelling include the mitogen-activated protein (MAP) kinase cascade. MAP kinase kinase 7 (MKK7), positioned at a bottleneck of this stress-responsive pathway, is known to be vital for survival under hypertrophic stimulation (1,2). To assess the role of MKK7 in arrhythmogenesis, ventricular cardiomyocyte specific MKK7 knockout (MKK7CKO) and littermate wild-type mice (male, 8-12 wks old) were subjected to different stress stimuli. Chronic Angiotensin-II (Ang-II, 0.7μgm/kg/min) stimulation for 14-days using subcutaneous mini-osmotic pumps and transverse aortic constriction (TAC) for 3-days (3% Isoflurane or Ketamine-Xylazine anaesthesia, Buprenorphine 0.1mg/kg analgesia) were provided to mimic chronic hypertension and acute pressure overload, respectively. Mean (± S.E.M.) values were appropriately compared by ANOVA or paired T-tests. In both cases, MKK7CKO mice had augmented cardiac hypertrophy under stress, evidenced by increases in heart weight / tibia length ratios (n=9-16/group) and cardiomyocyte cross-sectional areas (n=3-4/group). Trans-thoracic echocardiography confirmed an associated comparative decrease in left ventricular contractile function (n=8-15/group). Masson’s trichrome staining revealed 3-4 folds increases in ventricular fibrosis in the MKK7CKO mice compared to wild-types receiving similar stimuli (n=3-4/group). A striking finding was the electrical remodelling featuring about 25-30% longer rate-corrected mean QT (Bazett’s) intervals in the stressed MKK7CKOs (n=8-12/group) in-vivo ECG recorded under terminal anaesthesia (Tribromoethanol, 200mg/kg). Programmed electrical stimulation induced more arrhythmias in MKK7CKOs than controls following stress. Between S1S2 delays of 100-40ms, 78% Ang-II treated MKK7CKOs generated ventricular arrhythmias or premature contractions, compared to 10% similarly treated wild-types and none of the untreated mice (n=8-10/group). Ventricular effective refractory periods increased after TAC, more so in MKK7CKOs, but without any statistical significance (n=8-12/group). Molecular analysis of whole ventricle extracts revealed, MKK7CKOs undergoing TAC had reduced versatile membrane-adapter Ankyrin-B and inward-rectifier potassium channel subunit Kir6.2 transcript (n=6-9/group) and protein levels (n=3-5/group) than similarly-treated wild-type mice. This study reveals the significant role of MKK7 in preserving the functional integrity and rhythmicity of the heart, as well as indicating novel and therapeutically promising signalling regulation of hearts electrical activities under hypertrophic stress.