Non-invasive risk stratification of sudden cardiac death: Prospective evaluation of a novel ECG-based restitution biomarker in patients with ischaemic cardiomyopathy

Funding Acknowledgements: University of Leicester NIHR Biomedical Research Unit Purpose: Non-invasive risk stratification of sudden cardiac death (SCD) remains a challenge but has the potential to save lives while being safer and more cost-effective than invasive methods. The Regional Restitution Instability Index (R2I2) is a novel ECG biomarker developed for risk stratification of SCD due to ventricular arrhythmia (VA). It has previously identified patients with ischaemic cardiomyopathy (ICM) at high risk of VA and SCD and has been shown to be associated with VA/SCD in both retrospective and prospective studies of patients with ICM. However, the technology currently requires an invasive approach with catheters placed within the heart. Here, using exercise stress, we prospectively applied a modified, non-invasive form of R2I2 to a cohort of patients with ICM. Methods: 55 patients with ischaemic cardiomyopathy undergoing ICD implant underwent treadmill exercise testing. Digital 12-lead ECGs were recorded and custom software was used to develop semi-automated detection of ECG fiducial points which were manually verified. Q-wave onset to T-wave peak (QTpeak) and T-wave peak to Q-wave onset (TpQ) were used as surrogates for action potential duration (APD) and diastolic interval (DI) as previously reported and TpQ/QTp plots were taken. The raw exercise data plots were simplified using median TpQ-QTp intervals within specified ranges (Figure 1A and B). Non-invasive R2I2 (R2I2-NI) was then calculated. R2I2 quantifies inter-lead electrical restitution heterogeneity and is defined as the mean of the standard deviation of residuals from the mean gradient for each ECG lead at a range of diastolic intervals. Endpoints were VA/SCD. A predefined cut-off R2I2≥1.03, previously used in invasive studies was used to partition patients into "high" (R2I2≥1.03) and "low" (R2I2<1.03) risk groups for survival analysis. Results: Over a median follow-up of 30 months (range 14–44 months) 9/55 (16.4%) patients achieved endpoint. R2I2-NI was significantly higher in these patients compared with those without an event (mean±SD: 1.22±0.33 vs 0.84±0.32, p=0.0023) (Figure 1C). Cumulative survival analysis showed a significant separation of curves; patients with R2I2-NI≥1.03 had a significantly higher rate of VA/SCD than patients with R2I2-NI<1.03 (p=0.003, log rank) (Figure 1D). Patients with R2I2-NI≥1.03 had a VA/SCD hazard ratio 7.4 times that of of patients with R2I2-NI<1.03 (Cox regression, p=0.013). Receiver operating characteristic analysis found that R2I2-NI significantly discriminated between those experiencing VA/SCD and those without during follow-up (area under curve = 0.7995). Conclusions: Replicating earlier findings in invasive studies, R2I2-NI is significantly higher in patients with ICM experiencing VA/SCD. R2I2-NI≥1.03 is associated with reduced VA/SCD-free survival and a significantly higher risk of VA/SCD compared to a R2I2-NI<1.03. Non-invasive R2I2 represents a promising marker for SCD risk stratification and warrants further evaluation.