Introduction: Repeated remote ischaemic conditioning (RIC) significantly reduces the inflammatory response following a myocardial infarction (MI), and this improves left ventricular remodelling (Wei et al., 2011). However, it is unclear whether this is mediated directly by the reduction in the pro-inflammatory response or direct signalling to the myocardium by a blood borne agent. As the cardioprotective effect of acute RIC results from a blood borne agent, we hypothesised that RIC generates a blood borne signal capable of reducing the hypertrophic response by modulating gene expression associated with remodelling. Methods: Superfusate was collected from Langendorff perfused Wistar rat hearts during the reperfusion phase of conditioning ischaemia (RIC-superfusate). Blood was taken from healthy volunteers after 3 cycles of 5 minutes of upper arm conditioning by cuff inflation/deflation (RIC-serum). The RIC-superfusate/serum was applied to H9c2 cardiomyoblasts in culture treated with endothelin-1 (ET-1) to stimulate hypertrophy. Cell surface area was determined from fluorescence images of phalloidin-FITC/Hoechst stained cells. Expression of four genes: a marker of hypertrophy (BNP), the foetal genes (α-actin and βMHC) and the cardiac stress-related gene (ms-1), were determined using qRT-PCR. Response to RIC-superfusate/serum was compared to saline/serum collected immediately prior to RIC. Results:ET-1 (100ng/mL) caused a significant degree of cellular hypertrophy after 48 hours to 22.8±1.1×10-3 mm2 versus 16.4±0.7×10-3 mm2 in untreated cells (n=10 experiments/300 cells, p<0.01). Pre-treatment with either RIC-superfusate or RIC-serum significantly reduced the ET-1 induced hypertrophic response from 19.8±0.8×10-3 mm2 to 14.7±0.6×10-3 mm2 and 23.6±1.5×10-3 mm2 to 16.1±1.1×10-3 mm2 respectively (n=10/300 p<0.01). Rat RIC-superfusate caused a significant decrease in the ET-1 induced expression of α-actin (fold-change 8.0±0.4 to 1.7±0.1; n=4, p<0.01), βMHC (6.5±0.5 to 2.5±0.3; n=4, p<0.01), BNP (1.3±0.3 to 0.4±0.2; n=4, p<0.05) and ms-1 (31.6±2.7 to 13.0±1.4; n=4, p<0.01) determined after 48 hours. Human RIC-serum significantly reduced the ET-1 induced expression of βMHC (7.7±1.0 to 3.9±0.5; n=4, p<0.05) and ms-1 (15.4±2.7 to 7.0±0.7; n=4, p<0.05) after 48 hours. Conclusion: Our data supports the hypothesis that RIC initiated humoral signalling may also attenuate the deleterious process of cardiac remodelling. The findings identify a new therapeutic approach that may be beneficial in reducing adverse ventricular hypertrophy post-MI.