title: Prospective evaluation of two novel ECG-based restitution biomarkers for prediction of sudden cardiac death risk in ischaemic cardiomyopathy.
abstract: OBJECTIVE
  To improve prediction of sudden cardiac death (SCD) in patients with ischaemic cardiomyopathy (ICM). Electrical heterogeneity is known to contribute to risk of SCD. We have previously developed Regional Restitution Instability Index (R2I2), an ECG-based biomarker, which quantifies cardiac electrical instability by measuring heterogeneity in electrical restitution, and demonstrated its potential utility for risk stratification in a retrospective analysis of patients with ICM. Here, we examined R2I2 in a prospective ICM cohort and also tested the predictive value of another ECG-based biomarker, Peak ECG Restitution Slope (PERS).
  
  
  METHODS
  Prospective, blinded, observational study of 60 patients with ICM undergoing implantable cardioverter defibrillator risk stratification. R2I2 was calculated from an electrophysiological study (EPS) using ECG surrogates for action potential duration and diastolic interval. R2I2 quantifies inter-lead electrical restitution heterogeneity. PERS was the peak restitution curve slope taken as a mean across the 12 ECG leads. Endpoints were ventricular arrhythmia (VA)/SCD.
  
  
  RESULTS
  Over median follow-up of 22 months, 16 (26.6%) patients achieved endpoint. R2I2 was significantly higher in these patients compared with those without an event (mean ± SEM: 1.11 ± 0.09 vs 0.84 ± 0.04, p=0.003) as was PERS (median(IQR): 1.35(0.60) vs 1.08(0.52), p=0.014). R2I2≥1.03, the cut-off used in our previous study, identified patients with a significantly higher risk of VA/SCD independent of EPS result, LVEF or QRS duration with a relative risk of 6.5 (p=0.008). Patients positive for R2I2 and PERS had a relative risk of VA/SCD 21.6 times that of those negative for R2I2 and PERS (p<0.0001).
  
  
  CONCLUSIONS
  R2I2 and PERS each independently and in combination, identify patients with ICM that are at high risk of developing ventricular arrhythmias (VA). R2I2/PERS represent promising risk markers for SCD discrimination.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01944514.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: William B
authors.initials: WB
authors.lastname: Nicolson
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: Gerry P
authors.initials: GP
authors.lastname: McCann
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Smith
authors.affiliation: University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Sandilands
authors.affiliation: University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stafford
authors.affiliation: NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK Department of Engineering, University of Leicester, Leicester, UK.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Schlindwein
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: G André
authors.initials: GA
authors.lastname: Ng
mesh_terms: D000200:Action Potentials; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications* / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors