Heart failure is one of the most common causes of morbidity and mortality in the human population. The number of patients suffering from heart failure is estimated to be up to 23 million worldwide. Cardiac hypertrophy is regarded as one of the most critical predisposing risk factors for the onset of heart failure. It has been reported that more than half of deaths from heart failure are caused by hypertrophy-associated ventricular arrhythmias. Yet, despite the enormity of this problem, the identification of the fundamental mechanisms underlying hypertrophy and its associated arrhythmias remain elusive. Over the past few years using genetically modified mouse models, mathematical simulations and pharmacological agents our group has investigated the roles of a number of intracellular signalling proteins in cardiac hypertrophy and associated ventricular arrhythmias. We recently discovered that p21-activated kinase-1 (Pak-1) and its downstream effecters, mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 are critical for controlling cardiac hypertrophy, and Pak1 activator, FTY-720 (a sphingosine-like analogue) is able to reserve existing hypertrophy through negative regulation of NFAT transcription activity. Furthermore, we have identified a new role for MKK4 in maintaining Cx43 expression/distribution, which are important for preservation of normal cardiac electrical function. Preliminary data from our ongoing projects also suggests that MKK7 likely plays a novel role for preventing ventricular arrhythmias by stabilising microtubule-associated protein and ankryrin, which are required for anchoring many membrane proteins including the Na+/K+ ATPase, the voltage gated Na+ channel and the Na+/Ca2+ exchanger. In summary, our research provides new insights into exploring upstream therapeutic targets for treating cardiac hypertrophy and stress-associated ventricular arrhythmias. Aforementioned experiments were carried out on murine hypertrophic models induced by transverse aortic constriction (TAC). 8-10 week old male mice were subjected to TAC or a sham operation under isoflurane anesthesia and artificial ventilation. 0.1mg/kg buprenorphine was given post operation.