W.B. Nicolson

Prospective evaluation of two novel ECG-based restitution biomarkers for prediction of sudden cardiac death risk in ischaemic cardiomyopathy

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. Trial registration number ClinicalTrials.gov Identifier: NCT01944514.

A Novel Surface Electrocardiogram–Based Marker of Ventricular Arrhythmia Risk in Patients With Ischemic Cardiomyopathy

Background Better sudden cardiac death risk markers are needed in ischemic cardiomyopathy (ICM). Increased heterogeneity of electrical restitution is an important mechanism underlying the risk of ventricular arrhythmia (VA). Our aim was to develop and test a novel quantitative surface electrocardiogram–based measure of VA risk in patients with ICM: the Regional Restitution Instability Index (R2I2). Methods and Results R2I2, the mean of the standard deviation of residuals from the mean gradient for each ECG lead at a range of diastolic intervals, was measured retrospectively from high-resolution 12-lead ECGs recorded during an electrophysiology study. Patient groups were as follows: Study group, 26 patients with ICM being assessed for implantable defibrillator; Control group, 29 patients with supraventricular tachycardia undergoing electrophysiology study; and Replication group, 40 further patients with ICM. R2I2 was significantly higher in the Study patients than in Controls (mean ± standard error of the mean: 1.09±0.06 versus 0.63±0.04, P<0.001). Over a median follow-up period of 23 months, 6 of 26 Study group patients had VA or death. R2I2 predicted VA or death independently of demographic factors, electrophysiology study result, left ventricular ejection fraction, or QRS duration (Cox model, P=0.029). R2I2 correlated with peri-infarct zone as assessed by cardiac magnetic resonance imaging (r=0.51, P=0.024). The findings were replicated in the Replication group: R2I2 was significantly higher in 11 of 40 Replication patients experiencing VA (1.18±0.10 versus 0.92±0.05, P=0.019). In combined analysis of ICM cohorts, R2I2 ≥1.03 identified subjects with significantly higher risk of VA or death (43%) compared with R2I2 <1.03 (11%) (P=0.004). Conclusions In this pilot study, we have developed a novel VA risk marker, R2I2, and have shown that it correlated with a structural measure of arrhythmic risk and predicted risk of VA or death in patients with ICM. R2I2 may improve risk stratification and merits further evaluation. (J Am Heart Assoc. 2012;1:e001552 doi: 10.1161/JAHA.112.001552.)

New approach for T-wave peak detection and T-wave end location in 12-lead paced ECG signals based on a mathematical model

This paper presents an innovative approach for T-wave peak detection and subsequent T-wave end location in 12-lead paced ECG signals based on a mathematical model of a skewed Gaussian function. Following the stage of QRS segmentation, we establish search windows using a number of the earliest intervals between each QRS offset and subsequent QRS onset. Then, we compute a template based on a Gaussian-function, modified by a mathematical procedure to insert asymmetry, which models the T-wave. Cross-correlation and an approach based on the computation of Trapeziums area are used to locate, respectively, the peak and end point of each T-wave throughout the whole raw ECG signal. For evaluating purposes, we used a database of high resolution 12-lead paced ECG signals, recorded from patients with ischaemic cardiomyopathy (ICM) in the University Hospitals of Leicester NHS Trust, UK, and the well-known QT database. The average T-wave detection rates, sensitivity and positive predictivity, were both equal to 99.12%, for the first database, and, respectively, equal to 99.32% and 99.47%, for QT database. The average time errors computed for T-wave peak and T-wave end locations were, respectively, -0.38±7.12 ms and -3.70±15.46 ms, for the first database, and 1.40±8.99 ms and 2.83±15.27 ms, for QT database. The results demonstrate the accuracy, consistency and robustness of the proposed method for a wide variety of T-wave morphologies studied.

Regional fractionation and dominant frequency in persistent atrial fibrillation: effects of left atrial ablation and evidence of spatial relationship

AIMS The aim was to study regional fractionation and dominant frequency (DF) to determine if any relationship exists between the two parameters and also to assess the impact of limited left atrial ablation. METHODS AND RESULTS Patients undergoing catheter ablation of persistent AF using three-dimensional navigation were studied. Regional left atrial electrograms were analysed in the frequency domain by assessing DF and organization index (OI), and for degree of fractionation [using complex fractionated electrograms (CFE)-mean] before and after circumferential pulmonary vein and left atrial roof ablation. Twenty-three patients with persistent AF were studied. After ablation, global CFE-mean increased [100 ± 5 to 147 ± 11 ms (P= 0.0003)], DF decreased [6.1 ± 0.2 to 5.3 ± 0.2 Hz (P= 0.0003)], and OI was unchanged [0.27 ± 0.01 to 0.26 ± 0.02, (P= 0.70)]. Comparing sites close to and distant from ablation lines, percentage change in CFE-mean was 94 ± 10 vs. 37 ± 6% (P< 0.0001), DF change was -13 ± 3 vs.-12 ± 2% (P= 0.98), and OI change was 3 ± 6 vs. 10 ± 5% (P= 0.75), respectively. There was modest correlation between CFE-mean and DF points prior to ablation (r = -0.33, P< 0.0001) which was reduced following left atrial ablation (r = -0.24, P= 0.005). CONCLUSIONS Left atrial ablation reduces global left atrial DF and decreases the degree of fractionation. Complex fractionated electrograms-mean and DF appear to share only modest spatial correlation and are affected to different extents by ablation, suggesting that they are either separate entities or reflect different components of the same substrate.

Investigation of the relationship between two novel electrocardiogram-based sudden cardiac death risk markers and autonomic function

BACKGROUND Regional Restitution Instability Index (R2I2) and Peak ECG Restitution Slope (PERS) are promising sudden cardiac death (SCD) risk markers. R2I2 and PERS use the standard 12‑lead ECG to measure properties of electrical restitution implicated in ventricular arrhythmogenesis. We investigated the relationship between R2I2, PERS and autonomic function to inform future application of these risk markers. METHODS Blinded, prospective, observational study of 44 patients with ischaemic cardiomyopathy undergoing risk stratification for an ICD. Patients underwent an electrophysiological study for determination of R2I2 and PERS. 24-hour ambulatory ECG monitoring was carried out for determination of time-domain heart rate variability (HRV). RESULTS During median follow up of 22 months, 11 patients experienced ventricular arrhythmia (VA)/SCD. Weak inverse correlation was seen between R2I2 and HRV-i (rho: -0.36, p = 0.02). R2I2 and PERS were significantly higher in patients experiencing VA/SCD than those not (mean ± SEM:1.14 ± 0.11 vs 0.84 ± 0.05, p = 0.01) and (1.73 ± 0.27 vs 1.07 ± 0.08, p = 0.002) respectively. Patients with low HRV-i and high PERS had an incidence rate ratio for VA/SCD 14.5 times that of patients with high HRV-i and low PERS (p = 0.02). CONCLUSION This small study suggests that there is minimal correlation between R2I2, PERS and autonomic function as measured by HRV. Combining PERS with HRV identified patients at particularly high risk of ventricular arrhythmia/SCD. A combined PERS+HRV risk marker may improve SCD risk stratification in patients with ischaemic cardiomyopathy.

Recurrent valve obstruction in a patient with a pure carbon bileaflet metallic mitral valve: a case report

Abstract Background Despite overcoming the morbidity from severe native valve disease, prosthetic metallic valve replacement is not without its inherent morbidity, in particular from prosthetic valve thrombosis (PVT). The contemporary pure carbon bileaflet metallic valve confers reduced thrombogenicity. Case Summary We describe the case of a 45-year-old woman with a pure carbon bileaflet metallic mitral valve replacement (27/29 mm On-X) 6 months previously for severe rheumatic mitral stenosis, who presented with a rapid onset of dyspnoea, paroxysmal nocturnal dyspnoea, and haemoptysis. This was preceded by an interruption in therapeutic anticoagulation. On admission the patient was in cardiogenic shock. Transthoracic and transoesophageal (TOE) echocardiograms revealed increased transmitral gradients with disc hypomobility, suggestive of PVT, unexpected given the favourable safety profile of the On-X valve. Fluoroscopy confirmed the findings. The patient was thrombolysed successfully with alteplase, with restoration of normal transmitral gradients. A target international normalized ratio of 3.5–4.5 was chosen, in addition to aspirin 75 mg, to minimize thrombotic sequalae. Repeat TOE 6 weeks later revealed disc hypomobilty with a large adherent clot. Due to the high risks from thrombolysis, emergency redo-mitral bioprosthetic valve surgery was performed, to negate the need for long-term anticoagulation. Discussion Subtherapeutic anticoagulation and the rapid development of dyspnoea, should prompt the clinician to suspect PVT. Thorough clinical examination and immediate bedside echocardiography are critical for assessing prosthetic valve patients in cardiogenic shock. The treatment of PVT is complex, with considerable risks to the patient, irrespective of the strategy (thrombolysis/emergency valve replacement), necessitating the expertise of cardiologists and cardiac surgeons.

159 Pilot Study exploring the regional repolarisation instability index in relation to myocardial heterogeneity and prediction of ventricular arrhythmia and death

Introduction There is a need for better sudden cardiac death (SCD) risk markers. Mounting evidence suggests that the mechanism underlying risk of ventricular arrhythmia (VA) is increased heterogeneity of electrical restitution. We investigated a novel measure of action potential duration (APD) restitution heterogeneity: the Regional Repolarisation Instability Index (R2I2) and correlated it with peri-infarct zone (PIZ) a cardiac magnetic resonance (CMR) anatomic marker of VA risk. Methods Blinded retrospective study of 30 patients with ischaemic cardiomyopathy assessed for an implantable cardioverter defibrillator. The R2I2 was derived from high resolution 12 lead ECG recorded during programmed electrical stimulation (PES). ECG surrogates were used to plot APD as a function of diastolic interval; the R2I2 was the maximal value of the mean squared residuals of the mean points for anterior, inferior and lateral leads normalised to the mean value for the total population. PIZ was measured from late gadolinium enhanced CMR images using the full width half maximum technique. Results Seven patients reached the endpoint of VA/death (median follow-up 24 months). R2I2 > median was found to be predictive of VA/death independent of PES result, left ventricular ejection fraction and QRS duration (6/14 vs 1/15 p=0.031). Modest correlation was seen between the R2I2 and PIZ (r=0.41 p=0.057) (Abstract 159 figure 1).Abstract 159 Figure 1 Conclusions In this pilot study of ischaemic cardiomyopathy patients, the R2I2 was shown to be an electrical measure of VA/death risk with a moderately strong correlation with an anatomic measure of arrhythmic substrate, the extent of PIZ. The R2I2 may add value to existing markers of VA/death and merits further investigation.Abstract 159 Table 1 Variable Whole Group (n=30) No VA/death (n=23) VA/death (n=7) p Age (years) 67±9 65±9 72±8 0.055 Sex (% male) 97 96 100 QRSD(ms) 107±20 107±21 106±15 0.95 EF(%) 31±14 32.4±15 27±7.5 0.34 PES result (positive/total) 12/30 7/23 5/7 0.068 R2I2>median 14/29 8/22 6/7 0.031 EDV index (ml/cm) 1.48±0.41 1.49±0.41 1.45±0.45 0.84 SV index (ml/cm) 0.42±0.14 0.43±0.14 0.39±0.15 0.47 Follow-up (months) 24 (18) 24 (16) 16 (16) 0.088 PIZ % 7.8 (10.7) 7.5 (8.4) 13.6 (8.5) 0.093 Scar % 10.9 (16.5) 9.67 (13.5) 21.9 (17.8) 0.16