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.

QT variability unrelated to RR variability during stress testing for identification of coronary artery disease

Stress test electrocardiogram (ECG) analysis is widely used for coronary artery disease (CAD) diagnosis despite its limited accuracy. Alterations in autonomic modulation of cardiac electrical activity have been reported in CAD patients during acute ischemia. We hypothesized that those alterations could be reflected in changes in ventricular repolarization dynamics during stress testing that could be measured through QT interval variability (QTV). However, QTV is largely dependent on RR interval variability (RRV), which might hinder intrinsic ventricular repolarization dynamics. In this study, we investigated whether different markers accounting for low-frequency (LF) oscillations of QTV unrelated to RRV during stress testing could be used to separate patients with and without CAD. Power spectral density of QTV unrelated to RRV was obtained based on time-frequency coherence estimation. Instantaneous LF power of QTV and QTV unrelated to RRV were obtained. LF power of QTV unrelated to RRV normalized by LF power of QTV was also studied. Stress test ECG of 100 patients were analysed. Patients referred to coronary angiography were classified into non-CAD or CAD group. LF oscillations in QTV did not show significant differences between CAD and non-CAD groups. However, LF oscillations in QTV unrelated to RRV were significantly higher in the CAD group as compared with the non-CAD group when measured during the first phases of exercise and last phases of recovery. ROC analysis of these indices revealed area under the curve values ranging from 61 to 73%. Binomial logistic regression analysis revealed LF power of QTV unrelated to RRV, both during the first phase of exercise and last phase of recovery, as independent predictors of CAD. In conclusion, this study highlights the importance of removing the influence of RRV when measuring QTV during stress testing for CAD identification and supports the added value of LF oscillations of QTV unrelated to RRV to diagnose CAD from the first minutes of exercise. This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.

ECG Ventricular Repolarization Dynamics during Exercise: Temporal Profile, Relation to Heart Rate Variability and Effects of Age and Physical Health

Periodic repolarization dynamics (PRD) is a novel electrocardiographic marker of cardiac repolarization instability with powerful risk stratification capacity for total mortality and sudden cardiac death. Here, we use a time-frequency analysis approach to continuously quantify PRD at rest and during exercise, assess its dependence on heart rate variability (HRV) and characterize the effects of age (young adults/middle-aged adults/older adults), body mass index (non-overweight/overweight) and cardiorespiratory fitness level (fit/unfit). Sixty-six male volunteers performed an exercise test. RR and dT variabilities (RRV, dTV), as well as the fraction of dT variability unrelated to RR variability, were computed based on time-frequency representations. The instantaneous LF power of dT (PdTV), representing the same concept as PRD, and of its RRV-unrelated component (PdTVuRRV) were quantified. dT angle was found to mostly oscillate in the LF band. Overall, 50–70% of PdTV was linearly unrelated to RRV. The onset of exercise caused a sudden increase in PdTV and PdTVuRRV, which returned to pre-exercise levels during recovery. Clustering analysis identified a group of overweight and unfit individuals with significantly higher PdTV and PdTVuRRV values at rest than the rest of the population. Our findings shed new light on the temporal profile of PRD during exercise, its relationship to HRV and the differences in PRD between subjects according to phenotypic characteristics.

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).

QT interval dynamicity during exercise test in adolescent athletes

In search of predictors of the life-threatening arrhythmias, the objective of this research was to study repolarization dynamics and reveal the signs of myocardial electrical instability in young athletes during exercise test (ET). Methods 124 young athletes including 78 boys 11–16 years old and 50 healthy untrained boys were enrolled into the study. All the children underwent ET with ECG recording and manually evaluated durations of QT interval and its derivatives –QTc interval, calculated by Basett and Fridericia formulas (QTc, FQTc), QTc and FQTc interval dispersion. Rate-dependent QT interval parameters (“QT dynamics”) were measured using of linear regression formula for determining slope, intercept, and correlation (r) between QT and RR intervals (Zareba W, Bayes de Luna A, 2005). Results Initially and on low and moderate loading (25–100 Wt) the athletes had lower heart rate (HR) than in untrained, and quicker (3 min) restoration to initial level (&lt;450 ms) during recovery. The athletes had higher absolute QT interval duration at rest due to bradycardia and myocardial hypertrophy. Beginning step II QTc and FQTc intervals and their dispersions shortening up to minimal in both athlete and untrained groups. Maximal QTc interval in athletes as well as in untrained was recorded at stage I (25 Wt) and did not exceed 460 ms in boys and 470 ms in girls versus 450 and 440 ms, respectively. Maximal QTc prolongation (δQTc) during ET (QTcmax − QTcmin) in athletes did not exceed 80 ms. A shorter FQTc duration compared to QTc was noted. More efficient rate-dependent QT interval reduction (“QT/RR hyperadaptation”) was noted in athletes at peak load: the upper limits of normal QTc, FQTc and dQTc were 400, 330 and 14 ms, respectively. These parameters increasing along with other (echocardiographic and biochemical) signs may serve as myocardial remodeling markers. Decreased (“flat”) slope QT/RR and lower level of QT/RR correlation (“hypoadaptation of QT to RR”) were recorded in athletes at rest and at the initial stages of load, probably due to a higher vagal tone. At the peak load increase both in slope (“steep slope”) and correlation QT/RR (“QT/RR hyper-adaptation”) was noted. Absence of this phenomenon was observed in athletes with cardiac remodeling. Conclusions Repolarization dynamics during ET test was similar in athletes and untrained children. Maximal QTc interval in athletes during ET was higher than in untrained and QTc shortening at peak load was more efficient. Complete restoration of HR and QTc intervals to the initial level in athletes occurred at an early recovery period (3 min). Absence of such dynamics gave evidence of myocardial remodeling. Funding Acknowledgement Type of funding source: None

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