Maladaptive cardiac hypertrophic remodeling can lead to heart failure and cardiac arrhythmias. Role of mitogen-activated protein (MAP) kinase pathway members in intracellular signal transduction is important for such remodeling. MAP kinase kinase 7 (MKK7), positioned at a bottleneck of the MAP kinase pathway, is essential for survival in response to pressure overload (1,2). Ventricular cardiomyocyte specific knockout (MKK7CKO) and littermate wild-type mice were subjected to chronic Angiotensin-II (Ang-II, 0.7μgm/kg/min) or vehicle stimulation for 2 weeks using subcutaneous osmotic pumps inserted under anesthesia (2.5-4% isoflurane, intraperitoneal Buprenorphine 0.1mg/kg analgesia). This resulted in significantly higher heart wt. gain in Ang-II treated MKK7CKO mice compared to similarly treated controls (heart wt/tibia length 6.60 ± 0.17 vs. 5.79 ± 0.10mg/mm, respectively; n=10-12, paired t test, p<0.001). Associated similar increase in cardiomyocyte cross-sectional areas (296.22 ± 5.11 vs. 222.41 ± 2.89, n=3, p<0.0005) defined this hypertrophy. Rise of average systolic (20-23%) & diastolic (24-31%) blood pressure after Ang-II treatment was alike. In terminally anesthetised (Tribromoethanol, 200mg/kg) mice, trans-thoracic echocardiography showed significant functional impairment of MKK7CKO hearts. Compared to Ang-II treated wild-type mice, similarly treated MKK7CKO hearts had lower ejection fraction (%, 76.39 ± 2.23 vs. 53.5 ± 2.90, n=7-9, p<0.001) and fraction shortening (%, 38.73 ± 2.05 vs. 22.8 ± 1.62, n=7-9, p<0.001). Alongside, the drug treated MKK7CKO mice had significantly increased QTc interval than the wild-type mice (ms, 85 ± 4.56 vs. 65 ± 3.85, n=8-10, p<0.005). Electrical programmed stimulation using S1S2 protocol discovered an increase in mean ventricular effective refractory period (VERP) from about 40ms in vehicle treated mice to 51ms in Ang-II treated wild types. Most (89%) Ang-II treated knockout mice developed ventricular tachycardia (VT) or ventricular premature contractions (VPC) before reaching VERP, obliterating a mean calculation. While S1S2 delay was gradually reduced from 100ms to 40ms, 78% Ang-II treated mutants generated VT/VPCs, compared to 10% similarly treated wild types and none of the untreated controls (n=8-10). Masson’s trichrome staining revealed 9.96% interstitial fibrosis in the Ang-II treated knockouts compared to 2.86% in wild types and <0.5% in untreated controls (n=3, p<0.05). Although total connexin 43 protein levels were not significantly altered, its distribution in cardiomyocytes was altered as a result of Ang-II treatment in MKK7CKO mice (n=3-4). These data support the essential role of MKK7 for maintenance of functional integrity and rhythmicity of the heart in hypertrophic stress. Subsequent investigations will help unveil the specific role of MKK7 absence in ventricular arrhythmogenesis following different hypertrophic stress.