Introduction: Ischaemic cardiomyopathy (ICM) is a condition characterised by left ventricular systolic dysfunction (ejection fraction<35% due to underlying coronary artery disease) that confers increased risk of sudden cardiac death (SCD). A promising new ECG based biomarker: Regional Restitution Instability Index (R2I2) has been shown to be an independent predictor of SCD in patients with ICM. R2I2 quantifies regional heterogeneity of APD restitution, an electrophysiological property of ventricular myocardium implicated in arrhythmogenesis. Regional heterogeneity of APD restitution has been shown to be influenced by direct modulation of sympathetic and parasympathetic input to the heart in an isolated heart model, however to our knowledge no attempts have been made to evaluate this relationship in-vivo. This study explores the relationship between autonomic function, reflected by the non-invasive measurement of heart rate variability (HRV) and R2I2 in patients with ICM. Methods: Blinded, prospective, observational study of 44 ICM patients undergoing risk stratification for an implantable cardioverter defibrillator. The R2I2 technique has been described previously: an electrophysiology study is performed and ECG surrogates for APD and diastolic interval are used to measure regional APD restitution heterogeneity. Patients underwent 24-hour ambulatory ECG monitoring to determine HRV (Schiller medilog®DARWIN). Time domain measures of HRV: standard deviation of ‘normal to normal’ RR intervals (SDNN) and HRV triangular index (HRV-i) were computed over the entire 24-hour period. Results: During median follow up of 22 months, 11 patients experienced ventricular arrhythmia (VA)/SCD. R2I2 was significantly higher in patients experiencing VA/SCD than those not (mean±S.E.M:1.14±0.11 vs 0.84±0.05, Students t-test: p=0.01). Patients with low HRV-i (<20) experienced a higher rate of VA/SCD than those with high HRV-i (42% vs. 19%, Fisher’s exact test: p=0.12). Weak negative correlation existed between R2I2 and HRV-i (Spearman’s rank correlation coefficient: -0.36, p<0.05). Patients with high R2I2 (≥1.03) had a significantly lower HRV-i (median [IQR}: 17.8[6.7] vs 31.9[15.4], Mann-Whitney U test: p<0.001) and SDNN (median [IQR}: 88.8[30] vs 118[47.4], Mann-Whitney U test: p<0.05) than patients with low R2I2 (<1.03). Conclusion: A weak inverse correlation between R2I2 and heart rate variability is seen. This finding suggests regional heterogeneity of APD restitution may be increased in the setting of autonomic dysfunction. Understanding this relationship will inform future application of R2I2 to patients without autonomic dysfunction and may reveal insight into the mechanisms underlying sudden cardiac death in these patients.