Periodic Repolarization Dynamics Identifies ICD-responders in Non-ischemic Cardiomyopathy: A DANISH Substudy

Background: Identification of patients with non-ischemic cardiomyopathy who benefit from prophylactic implantation of a cardioverter-defibrillator (ICD) remains an unmet clinical need. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients that benefit from prophylactic ICD-implantation. Methods: Heart-failure (DANISH) study, in which patients with non-ischemic cardiomyopathy, left-ventricular ejection fraction (LVEF) ≤35% and elevated N-terminal pro-brain natriuretic peptides (NT-proBNP) were randomized to ICD-implantation or control group. Patients were included in the PRD-substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06.00 AM). PRD was assessed using wavelet analysis according to previously validated methods. Primary endpoint was all-cause mortality. Cox-regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes mellitus, cardiac resynchronization therapy and mean heart rate. We proposed PRD ≥10deg 2 as exploratory cut-off value for ICD-implantation. Results: Seven-hundred and forty-eight of the 1,116 DANISH patients qualified for the PRD-substudy. During a mean follow−up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (p−value=0.40). In Cox-regression analysis, PRD was independently associated with mortality (HR 1.28 [1.09−1.50] per SD increase; p−value = 0.003). Moreover, PRD was significantly associated with mortality in the control group (HR 1.51 [1.25−1.81]; p<0.001) but not in the ICD-group 1.04 [0.83−1.54]; p−value=0.71). There was a significant interaction between PRD and the effect of ICD−implantation on mortality (p−value 0.008), with patients with higher PRD having the greater benefit in terms of mortality reduction. ICD-implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10deg 2 (HR 0.54 [0.34-0.84]; p−value=0.006; number needed to treat 6), but not in the 468 patients with PRD<10deg 2 (HR 1.17 [0.77−1.78]; p−value=0.46; p−value for interaction 0.01). Conclusions: Increased PRD identified patients with non-ischemic cardiomyopathy, where prophylactic ICD-implantation led to significant mortality reduction.

Dinámica periódica de la repolarización como predictor de muerte súbita en pacientes con insuficiencia cardíaca crónica

Este trabajo evalúa la capacidad del índice Periodic Repolarization Dynamics (PRD) para predecir el riesgo de sufrir muerte súbita cardíaca (MSC) o muerte por fallo de bomba (MFB) en pacientes con insuficiencia cardíaca crónica (ICC).

Periodic repolarization dynamics for prediction of mortality: a systematic review and meta-analysis

Background Prediction of death is the philosopher's stone of arrhythmology. The electrophysiology has proven to be an important tool to predict the risk of death. Periodic repolarization dynamics (PRD) is a novel electrocardiographic marker that indicates the sympathetic effect on repolarization. PRD qualifies the low-frequency oscillations of cardiac repolarization instability using high-resolution 12 channel 24-h Holter recording. Several studies showed that PRD was an independent predictor of all-cause mortality and cardiac mortality. However, the prediction value of PRD has not been established. Purpose To evaluate the prediction value of PRD as an approach of risk stratification that selects patients at a higher risk of death. Methods We conducted electronic searches of MEDLINE (PubMed), Embase, Cochrane Register of Controlled Trials (CENTRAL), Science Citation Index Expanded, WHO International Clinical Trials Registry platform (ICTRP) and ClinicalTrials.gov from inception to January 9th, 2020. We also screened for relevant abstracts from conferences including ACC Annual Scientific Sessions, ESC Congress and Annual Congress of the EHRA for the last five years (2014–2019). The primary outcome was all-cause mortality and secondary outcome was cardiac mortality. We included study with large sample size while more than one study were found based on the same originated population. We extracted data from included studies and reported pooled outcomes as hazard ratios (HRs) with 95% confidential intervals (CI) for time-to-event outcomes using DerSimonian-Laird random-effects model. We did statistical analyses using Stata version 12.0 and R version 3.6.1. Results 5 studies including 6758 patients met all selection criteria for our meta-analysis. Follow-up period ranged from 20.4 to 75.1 months. Among 5 studies, 3 studies considered PRD as dichotomous variable and the cut-off value was 5.75 deg2, while 2 studies considered PRD as continuous variable and coefficient was expressed in standardized units (increase per standard deviation). We did subgroup analysis according to the type of variable because of heterogeneity. There was a significant higher risk of all-cause mortality in PRD ≥5.75 deg2 patients compared with PRD &lt;5.75 deg2 patients (HR 2.37, 95% CI 1.77–3.17). As for continuous variable, increased PRD was a predictor for all-cause death (HR 1.28, 95% CI 1.14–1.42) (Figure). The cardiac mortality was significantly increased in patients with PRD ≥5.75 deg2 vs PRD &lt;5.75 deg2 (HR 3.06, 95% CI 1.66–5.65). Increased PRD was associated with cardiac mortality in continuous variable subgroup (HR 1.34, 95% CI 1.21–1.48) (Figure). Conclusion Our findings suggest PRD is a significant predictor of all-cause mortality and cardiac mortality. PRD provides new additional electrophysiological indicator for risk stratification until further investigations are available. Funding Acknowledgement Type of funding source: None