DISCUSSION
In this paper, we report the first data for use of R2I2 and PERS as markers of VA/death in patients with non-ischemic cardiomyopathy and we also report the first data for PERS values in a normal control population. As has been found previously, combining R2I2+PERS offered the greatest discrimination of endpoint in this study population, predicting VA/death (p=0.02) with a hazard ratio per positive component marker of 3.2.11 R2I2 and PERS separately show trends towards significantly higher values in patients reaching the endpoint of VA/death than those not. This replicates the findings of our previous work in ischemic cardiomyopathy using the same technique and cut-offs for R2I2/PERS analysis and the same endpoints.11,12R2I2 and PERS appear to perform favourably compared to other surface ECG markers, such as T wave alternans, QRS fragmentation, signal averaged ECG and QRS-T angle, all of which have been shown to have a poor positive predictive value.15
The underlying aetiology of the cohort was heterogeneous and significantly more endpoints occurred in the ‘other conditions’ subgroup compared to the dilated cardiomyopathy subgroup. Combined R2I2+PERS, was independent of aetiology in predicting VA/death (p=0.04) with a hazard ratio of 2.7 per positive component. This suggests that R2I2+PERS are applicable to both dilated cardiomyopathy patients and patients with ‘other conditions’ but larger studies are needed to confirm the relationship. In Kaplan Meier analysis (Figure 3) the rate of VA/death at 5 years in patients positive for both R2I2≥1.03+PERS≥1.21 was 41%, compared with 23% for patients positive for either, and 0% for patients negative for both.
R2I2 was developed to quantify heterogeneity in APD restitution as a measure of electrical instability. In silico modelling has shown that heterogeneity of APD restitution leads to increased dispersion of depolarisation and repolarisation times leading to wavebreak and the substrate for ventricular arrhythmogenesis.5Heterogeneity in APD restitution has been clinically demonstrated with both endocardial and epicardial approaches; using intracardiac catheters and also with an epicardial sock of electrodes in patients undergoing cardiac surgery, with significant differences seen between patients with ischemic heart disease and aortic valve disease.16–18PERS is based on the original ‘restitution hypothesis’: a maximum APD restitution curve gradient >1 magnifies oscillations of APD/DI leading to wavebreak and ventricular fibrillation. Steep APD restitution curves have been shown in silico and in animal studies to convey increasing risk of VA.8,19,20
It is important and expected that R2I2 and PERS could be applied successfully to patients without ischemic heart disease. Differences in APD restitution heterogeneity have been demonstrated in studies in cohorts of hypertrophic cardiomyopathy, Brugada syndrome, dilated cardiomyopathy, valvular heart disease, cardiac sarcoidosis and ARVC when compared to healthy controls.21–23 The successful application to a non-ischemic population suggests that R2I2 and PERS measure a common underlying arrhythmogenic mechanism (i.e. electrical restitution) rather than, for example, the effect of infarction on ECG morphology.
R2I2 was found to be significantly higher in the study cohort compared to the controls. PERS showed a non-significant trend to higher values in the study group compared to controls. Both the DCM and the ‘other conditions’ subgroups also had a significantly higher mean R2I2 than controls with trends to higher PERS values. The study was underpowered to test for a difference in R2I2/PERS values in relation to VA/death in the study group aetiology subgroups but found trends to higher values. Moderate positive correlation was seen between R2I2 and PERS values in control patients. No correlation was seen between R2I2 and PERS values in study patients.
It is of interest that correlation was seen between R2I2 and PERS in the control group but not in the study group. Our previous study of R2I2 and PERS found no correlation between the two parameters in an ischemic cardiomyopathy population and this is anticipated since they are intended to measure different APD restitution properties.11 The R2I2 calculation uses mean and standard deviations; it is a staple of the APD restitution research to calculate mean and standard deviations of APD restitution slopes. However, as the gradient of a slope steepens it increases exponentially and hence the standard deviation of a steep slope is likely to be higher than that of a shallow slope. It is possible that in a control population with homogenous APD restitution this effect leads to a relationship between PERS and R2I2 while in a population with high APD restitution heterogeneity the heterogeneity effect predominates over the standard deviation effect.
This study provides proof-of-principle that clinically relevant biomarkers of electrical restitution curve heterogeneity and peak electrical restitution curve slope can be measured using the 12 lead ECG and be applied to a broad spectrum of patients at risk of sudden cardiac death with a range of underlying etiologies. The annual incidence of VA/death in patients with either/both R2I2≥1.03/PERS≥1.21 was over 7% and all patients experiencing VA/death were positive for either R2I2/PERS/both. A current limitation to wider use of R2I2 and PERS is that their measurement requires a 5 min programmed stimulation protocol delivered by transvenous pacing at the right ventricular apex, limiting its use to patients in whom such a protocol can be instigated. Although in the majority of patients, this currently requires an invasive study, R2I2 and PERS can be investigated non-invasively in patients with ICDs or pacemakers. This is currently being tested in a large prospective multicentre trial of patients with ischaemic cardiomyopathy (ClinicalTrials.gov Identifier: NCT03022487). We are also exploring fully non-invasive methods of obtaining a spectrum of heart rates, such as exercise and chronotropic medication to see if these methods provide the same information as that from pacing.24
Amongst the limitations of this study was that the aetiology of the study group was heterogeneous containing patients with dilated cardiomyopathy and a range of other conditions. Importantly R2I2≥1.03+PERS≥1.21 were independent of aetiology in predicting VA/death but larger studies of homogenous populations are needed to support the application of R2I2 and PERS in specific cohorts. This study was marginally underpowered to find a difference in R2I2, reflected in the non-significant trends seen; the results fit expectations from previous work.11 Also, VA/death does not equate to SCD, the combined endpoint is heterogeneous. The study is a single-centre study, and before any clinical application, the association of the ECG markers with VA/death should be replicated in a broader multicentre clinical trial.
This study offers the first evidence to support application of two novel electrical restitution markers R2I2≥1.03+PERS≥1.21 in assessment of sudden cardiac death risk in patients with non-ischemic heart disease. R2I2 and PERS have the potential to play an important role in SCD risk stratification but their validity should be confirmed in a larger multi-centre study before clinical trials are undertaken.