Periodic repolarization dynamics: Different methods for quantifying low-frequency oscillations of repolarization.

BACKGROUND: Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that quantifies low-frequency (LF) instabilities of repolarization. PRD is a strong predictor of mortality in patients with ischaemic and non-ischaemic cardiomyopathy. Until recently, two methods for calculating PRD have been proposed. The wavelet analysis has been widely tested and quantifies PRD in deg2 units by application of continuous wavelet transformation (PRDwavelet). The phase rectified signal averaging method (PRDPRSA) is an algebraic method, which quantifies PRD in deg. units. The correlation, as well as a conversion formula between the two methods remain unknown. METHOD: The first step for quantifying PRD is to calculate the beat-to-beat change in the direction of repolarization, called dT°. PRD is subsequently quantified by means of either wavelet or PRSA-analysis. We simulated 1.000.000 dT°-signals. For each simulated signal we calculated PRD using the wavelet and PRSA-method. We calculated the ratio between PRDwavelet and PRDPRSA for different values of dT° and RR-intervals and applied this ratio in a real-ECG validation cohort of 455 patients after myocardial infarction (MI). We finally calculated the correlation coefficient between real and calculated PRDwavelet. PRDwavelet was dichotomized at the established cut-off value of ≥5.75 deg2. RESULTS: The ratio between PRDwavelet and PRDPRSA increased with increasing heart-rate and mean dT°-values (p < 0.001 for both). The correlation coefficient between PRDwavelet and PRDPRSA in the validation cohort was 0.908 (95% CI 0.891-0.923), which significantly (p < 0.001) improved to 0.945 (95% CI 0.935-0.955) after applying the formula considering the ratio between PRDwavelet and PRDPRSA obtained from the simulation cohort. The calculated PRDwavelet correctly classified 98% of the patients as low-risk and 87% of the patients as high-risk and correctly identified 97% of high-risk patients, who died within the follow-up period. CONCLUSION: This is the first analytical investigation of the different methods used to calculate PRD using simulated and clinical data. In this article we propose a novel algorithm for converting PRDPRSA to the widely validated PRDwavelet, which could unify the calculation methods and cut-offs for PRD.

Periodic repolarization dynamics in patients with moderate to severe aortic stenosis.

BACKGROUND: Periodic repolarization dynamics (PRD) refers to low-frequency oscillations of cardiac repolarization, most likely related to phasic sympathetic activation. Increased PRD is a validated predictor of mortality after myocardial infarction and in ischemic heart disease, but has not been tested in aortic valve stenosis (AS). Here, we assessed PRD in patients with AS and tested its correlation with clinical and hemodynamic parameters as well as markers of heart rate variability (HRV). MATERIALS AND METHODS: We prospectively enrolled 139 consecutive patients with moderate to severe AS in sinus rhythm. In all patients we performed a 24-h Holter ECG in Frank-leads configuration. We assessed PRD according to previously published technologies from the nocturnal hours (0am-6am) and dichotomized PRD at the established cut-off value of ≥5.75deg2. In addition to clinical and hemodynamic markers, we also assessed deceleration capacity (DC) of heart rate, heart rate turbulence and standard HRV parameters. RESULTS: In the patients studied, PRD was 6.55±3.96deg2. Seventy-three patients (52.5%) had increased PRD. Among them, 36 (49.9%) patients were classified as being asymptomatic. There was no association between increased PRD and clinical or hemodynamic markers, including presence of symptoms, NYHA-classification, aortic valve area, and left-ventricular ejection fraction. Thirty-three of the 73 (45.2%) patients with PRD ≥5.75deg2 also suffered from decreased vagal tonic activity by means of abnormal DC (≤2.5ms) indicating severe autonomic dysfunction. CONCLUSION: Prevalence of increased PRD is high among patients with moderate to severe AS. Patients with increased PRD cannot be identified by clinical or hemodynamic markers Future studies should test the prognostic value of PRD in patients with AS.

Biomarker Periodic Repolarization Dynamics Indicates Enhanced Risk for Arrhythmias and Sudden Cardiac Death in Myocardial Infarction in Pigs.

BACKGROUND: Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. METHODS AND RESULTS: We investigated autonomic remodeling in pigs with myocardial infarction (MI)-related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre-MI versus post-MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P<0.05) reflecting pronounced autonomic alterations on the level of the ventricular myocardium. Pigs with MI-related ventricular fibrillation and SCD had significantly higher pre-MI PRD than pigs without tachyarrhythmias, suggesting a potential role for PRD as a predictive biomarker for ischemia-related arrhythmias (no ventricular fibrillation versus ventricular fibrillation: 1.50±0.39 deg2 versus 3.18±0.53 deg2 [P<0.05]; no SCD versus SCD: 1.67±0.32 deg2 versus 3.91±0.63 deg2 [P<0.01]). CONCLUSIONS: We demonstrate that ischemic heart failure leads to significant proarrhythmogenic autonomic remodeling. The concomitant elevation of PRD levels in pigs with ischemic heart failure and pigs with MI-related ventricular fibrillation/SCD suggests PRD as a biomarker for autonomic remodeling and as a potential predictive biomarker for ventricular arrhythmias/survival in the context of MI.

Large potassium shifts during dialysis enhance cardiac repolarization instability.

BACKGROUND: Patients with end-stage kidney disease are at high risk for the development of arrhythmias and sudden cardiac death (SCD). This has been especially attributed to large potassium shifts during hemodialysis (HD), and malignant arrhythmias are closely linked to dysfunction of the autonomic nervous system. Nevertheless, there is still a lack of methods for risk stratification in these patients. METHODS: In the present pilot study we investigated changes of the novel ECG-based biomarker periodic repolarization dynamics (PRD) mirroring the effect of efferent sympathetic nervous activity on the ventricular myocardium in 18 patients undergoing routine hemodialysis. High-resolution ECGs were recorded throughout the dialysis and PRD values were calculated out of 30 min intervals at the start and the end of dialysis. RESULTS: We detected a clear correlation between the intradialytic potassium shift and the increase in PRD levels (Spearman correlation coefficient R = 0.62, p = 0.006). Patients with a potassium shift > 1 mmol/l showed significantly increased levels of PRD at the end of dialysis when compared to patients with potassium shifts ≤ 1.0 mmol/l [delta PRD 2.82 (IQR 2.13) vs. - 2.08 (IQR 3.60), p = 0.006]. Spearman analysis showed no significant correlation between PRD changes and fluid removal (R = - 0.23, p = 0.36). CONCLUSIONS: We provide evidence that large potassium shifts during HD enhance sympathetic activity-associated repolarization instability. This could facilitate the occurrence of malignant arrhythmias, and PRD measurements might serve as a non-invasive monitoring tool in HD patients in future.

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.

Deceleration Capacity and Periodic Repolarization Dynamics As Predictors of Acute Mountain Sickness.

Hamm, Wolfgang, Sari Kassem, Lukas von Stülpnagel, Florian Maier, Mathias Klemm, Dominik Schüttler, Felix Grabher, Ludwig T. Weckbach, Bruno C. Huber, Axel Bauer, Konstantinos D. Rizas, and Stefan Brunner. Deceleration capacity and periodic repolarization dynamics as predictors of acute mountain sickness. High Alt Med Biol. 21:417-422, 2020. Background: The autonomic nervous system plays an important role in adaptive changes after acute altitude exposure. Periodic repolarization dynamics (PRD) and deceleration capacity (DC) of heart rate are advanced electrocardiogram (ECG)-based parameters reflecting sympathetic (PRD) and parasympathetic (DC) tone. These parameters have not been investigated in the context of acute mountain sickness (AMS) yet. Methods: In 23 healthy individuals (13 women), a high-resolution digital 30-minute ECG in Frank leads configuration was performed in a resting supine position at baseline (521 m altitude) and after a sojourn of 24 hours at the Environmental Research Station Schneefernerhaus (UFS) at Zugspitze (2,650 m altitude). PRD and DC were assessed using validated software. Symptoms of AMS were assessed with the Lake Louise Acute Mountain Sickness Score (LLS). Results: During altitude exposure, PRD significantly increased from 1.50 ± 1.01 (mean ± standard deviation) deg2 to 3.51 ± 4.46 deg2 (p = 0.03). DC significantly decreased from 11.48 ± 2.91 ms to 9.94 ± 2.78 ms (p = 0.001). An increase of PRD and/or a decrease of DC correlated significantly with the level of LLS. The combined finding of an increase of PRD and a decrease of DC had a sensitivity of 100% and a specificity of 76.5% to diagnose AMS (LLS ≥3). Receiver operating characteristic (ROC) analysis showed an AUC (area under the ROC curve) of 0.77. Linear regression analysis revealed a significant association between LLS and an increase in PRD during high-altitude exposure. Conclusions: Our findings show an increase of PRD and a decrease of DC during altitude exposure. Combined PRD and DC analysis may have potential for the diagnosis of AMS.

Effect of Hyperventilation on Periodic Repolarization Dynamics.

Heart and lung functions are closely connected, and the interaction is mediated by the autonomic nervous system. Hyperventilation has been demonstrated to especially activate its sympathetic branch. However, there is still a lack of methods to assess autonomic activity within this cardiorespiratory coupling. Periodic repolarization dynamics (PRD) is an ECG-based biomarker mirroring the effect of efferent cardiac sympathetic activity on the ventricular myocardium. Its calculation is based on beat-to-beat variations of the T wave vector (dT°). In the present study, we investigated the effects of a standardized hyperventilation maneuver on changes of PRD and its underlying dT° signal in 11 healthy subjects. In response to hyperventilation, dT° revealed a characteristic pattern and normalized dT° values increased significantly compared to baseline [0.063 (IQR 0.032) vs. 0.376 (IQR 0.093), p < 0.001] and recovery [0.082 (IQR 0.029) vs. 0.376 (IQR 0.093), p < 0.001]. During recovery, dT° remained on a higher level compared to baseline (p = 0.019). When calculating PRD, we found significantly increased PRD values after hyperventilation compared to baseline [3.30 (IQR 2.29) deg2 vs. 2.76 (IQR 1.43) deg2, p = 0.018]. Linear regression analysis revealed that the increase in PRD level was independent of heart rate (p = 0.63). Our pilot data provide further insights in the effect of hyperventilation on sympathetic activity associated repolarization instability.

Periodic repolarization dynamics as a risk predictor after myocardial infarction: Prospective validation study.

BACKGROUND: Periodic repolarization dynamics (PRD) is a novel electrocardiographic phenomenon that refers to sympathetic activity-associated low-frequency modulations of cardiac repolarization. Retrospective post-myocardial infarction (MI) studies revealed that increased PRD indicates an increased risk of subsequent death. OBJECTIVE: This is the first prospective study to validate PRD in patients after MI receiving up-to-date treatment. METHODS: Four hundred fifty-five survivors of MI (age ≤80 years) in sinus rhythm were enrolled. PRD was assessed from 20-minute electrocardiographic recordings (2048 Hz) and prospectively dichotomized at 5.75 deg2. Primary and secondary end points were total mortality and cardiovascular mortality, respectively. Multivariable analyses additionally included Global Registry of Acute Coronary Events score (dichotomized at >140), left ventricular ejection fraction (dichotomized at ≤35%), diabetes mellitus, and deceleration capacity of heart rate (dichotomized at ≤2.5 ms). The prognostic power of PRD was evaluated using receiver operating characteristic curve analysis, Cox regression analysis, and the integrated discrimination improvement index. RESULTS: During a median follow-up period of 27 months, 47 patients died. Twenty-three of these deaths were classified as cardiovascular. Increased PRD was significantly associated with both end points, yielding areas under receiver operating characteristic curves of 69.3% (60.2%-77.8%) and 79.1% (69.7%-86.7%) for total mortality and cardiovascular mortality, respectively (P < .001 for both). In multivariable analysis, increased PRD indicated a 2.2- and 9.5-fold risk of total mortality and cardiovascular mortality (P = .024 and P = .003, respectively). Addition of PRD to the models significantly improved the integrated discrimination improvement index for total (P = .047) and cardiovascular mortality (P = .007). CONCLUSION: PRD is a strong and independent predictor of total mortality and cardiovascular mortality in patients after MI treated with contemporary therapy.

Long-Term Microgravity Exposure Increases ECG Repolarization Instability Manifested by Low-Frequency Oscillations of T-Wave Vector.

Ventricular arrhythmias and sudden cardiac death during long-term space missions are a major concern for space agencies. Long-duration spaceflight and its ground-based analog head-down bed rest (HDBR) have been reported to markedly alter autonomic and cardiac functioning, particularly affecting ventricular repolarization of the electrocardiogram (ECG). In this study, novel methods are developed, departing from previously published methodologies, to quantify the index of Periodic Repolarization Dynamics (PRD), an arrhythmic risk marker that characterizes sympathetically-mediated low-frequency oscillations in the T-wave vector. PRD is evaluated in ECGs from 42 volunteers at rest and during an orthostatic tilt table test recorded before and after 60-day -6° HDBR. Our results indicate that tilt test, on top of enhancing sympathetic regulation of heart rate, notably increases PRD, both before and after HDBR, thus supporting previous evidence on PRD being an indicator of sympathetic modulation of ventricular repolarization. Importantly, long-term microgravity exposure is shown to lead to significant increases in PRD, both when evaluated at rest and, even more notably, in response to tilt test. The extent of microgravity-induced changes in PRD has been associated with arrhythmic risk in prior studies. An exercise-based, but not a nutrition-based, countermeasure is able to partially reverse microgravity-induced effects on PRD. In conclusion, long-term exposure to microgravity conditions leads to elevated low-frequency oscillations of ventricular repolarization, which are potentiated following sympathetic stimulation and are related to increased risk for repolarization instabilities and arrhythmias. Tested countermeasures are only partially effective in counteracting microgravity effects.

Risk prediction in post-infarction patients with moderately reduced left ventricular ejection fraction by combined assessment of the sympathetic and vagal cardiac autonomic nervous system.

AIM: Most deaths after myocardial infarction (MI) occur in patients with normal or moderately reduced left ventricular ejection fraction (LVEF >35%). Periodic repolarization dynamics (PRD) and deceleration capacity (DC) are novel ECG-based markers related to sympathetic and vagal cardiac autonomic nervous system activity. Here, we test the combination of PRD and DC to predict risk in post-infarction patients with LVEF >35%. METHODS AND RESULTS: We included 823 survivors of acute MI with LVEF >35%, aged ≤80years and in sinus rhythm. PRD and DC were obtained from 30-min ECG-recordings within the second week after index infarction and dichotomized at established cut-off values of ≥5.75deg2 and ≤2.5ms, respectively. Patients were classified as having normal (CAF 0), partly abnormal (DC or PRD abnormal; CAF 1) or abnormal cardiac autonomic function (DC and PRD abnormal; CAF 2). Primary endpoint was 5-year all-cause mortality. Within the first 5years of follow-up, 51 patients died (6.2%). PRD and DC effectively stratified patients into low-risk (CAF 0; n=562), intermediate-risk (CAF 1; n=193) and high-risk patients (CAF 2; n=68) with cumulative 5-year mortality rates of 2.9%, 9.4% and 25.2%, respectively (p<0.001). On multivariable analyses, CAF was independent from established risk factors (GRACE-score, diabetes mellitus, mean heart rate, heart rate variability). Addition of CAF significantly improved the model (increase of C-statistics from 0.732 (0.651-0.812) to 0.777 (0.703-0.850), p=0.047; continuous NRI (0.400, 95% CI 0.230-0.560, p<0.001); IDI (0.056, 95% CI 0.022-0.122, p<0.001)). CONCLUSION: CAF identifies new high-risk post-MI patients with LVEF >35% which might benefit from prophylactic strategies.