The guinea pig has a similar electrophysiological and cardiac autonomic profile to human physiology and therefore could be a good model to investigate the effects of acute myocardial infarction. However, a previous report suggests that myocardial infarction cannot be induced in the guinea pig by ligation of either one or two coronary arteries due to high collateral vascularisation1. We have re-visited this model to determine whether it is possible to induce a significant myocardial infarction that results in an impaired cardiac neural phenotype. Guinea pigs (452±99g SD) (58 male and female) were anaesthetised using a protocol which involved induction with a mixture of oxygen and 4% isofluorane followed by intramuscular (IM) ketamine (30μg/g) and medetomidine (0.6μg/g). Anaesthesia was maintained using a mixture of oxygen and 2% isofluorane. A thoracotomy and pericardectomy was performed in the sham group (n=22) with continuation of surgery in another group to coronary artery ligation of the left anterior descending artery and its branches/collateral feeders using four discrete sutures (n=36). Once the thoracotomy was repaired buprenorphine was administered IM (1.2μg/gram) for post operative pain relief during intensive care management. All animals were killed 3 days post surgery. Post mortem histological analysis of the left ventricle and septum using Sirius Red staining confirmed 9.3±1.1% collagen deposition , n = 6 in the infarct group compared with 1.1±0.7%, n = 6 in the sham group (p<0.001, unpaired t test). Myocardial infarction caused 28% mortality in the infarct group (n=10) without evidence of cardiac rupture post mortem. Of the sham animals 9% (n=2) also died suddenly. Prior to histological profiling; seven infarct, sham and naïve guinea pigs were anaesthetised with isofluorane and in vivo vagal nerve stimulations were performed. The infarct group had a significant reduction (p<0.05, 1-way Anova, Tukey post-hoc analysis) in their chronotropic response to a 15 V, 3 Hz, 1 ms pulse, 30 s duration right vagal stimulation (-51±15 bpm) postbilateral vagotomy compared with both the sham (-91±41 bpm) and the naïve groups (-95±34 bpm). A further group of guinea pigs had right atrial 3H ACh measured in vitro. The infarct group had less 3H ACh release (1.8±0.7% increase from baseline, n = 8, p<0.01) compared to naïve animals (3.6±1.1%, n=11) but there was no difference compared to the shams (2.4±8%, n=6) suggesting the changes were secondary to surgical stress. In conclusion, we have successfully produced a guinea pig model of myocardial infarction that resulted in a sudden cardiac death phenotype associated with vagal dysfunction.