Ventricular Electrical Activation Delay and High-Frequency Electrocardiograms

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 11, No. 5Ventricular Electrical Activation Delay and High-Frequency Electrocardiograms Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBVentricular Electrical Activation Delay and High-Frequency ElectrocardiogramsHype or Hope? Ammar M. Killu, MBBS and Yong-Mei Cha, MD Ammar M. KilluAmmar M. Killu Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN. and Yong-Mei ChaYong-Mei Cha Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN. Originally published26 Apr 2018https://doi.org/10.1161/CIRCEP.118.006396Circulation: Arrhythmia and Electrophysiology. 2018;11:e006396See Article by Plesinger et alBetween too early and too late, there is never more than a moment.—Franz Werfel (novelist, playwright, poet)Cardiac resynchronization therapy (CRT) is undoubtedly an effective adjunctive therapy to the management of patients with symptomatic heart failure meeting certain guideline criteria. Numerous randomized clinical trials have shown improvements in heart failure hospitalization and mortality in select populations,1–5 with the suggestion that lifespan gain increases nonlinearly with time in both low- and high-risk individuals.Despite the overall gain noted in trials, a substantial proportion of patients do not derive the anticipated response. This occurs so frequently that, invariably, publications on CRT report approximately a 30% nonresponder rate. To improve patient selection for upstream CRT response, various investigators have worked to identify predictors of CRT response a priori.Reproducible clinical characteristics that predict a favorable likelihood of response form the basis for guideline recommendation and appropriate use criteria including heart failure symptoms, a reduced ejection fraction, a widened QRS complex, and left bundle branch block (LBBB); in addition, other advantageous factors include nonischemic substrate, female gender, and greater interventricular dyssynchrony.6,7The staple measure of dyssynchrony has been the longer QRS duration with LBBB morphology representative of a greater degree of interventricular dyssynchrony. Indeed, patients with a QRS duration ≥150 ms respond more favorably than those with durations between 120–149 ms.8 The lack of benefit in some individuals despite interventricular synchronization suggests that atrioventricular and intraventricular dyssynchrony should also be optimized if possible.9,10Given that the QRS morphology appearance is the summation of ventricular depolarization simply using the duration for measurement of interventricular dyssynchrony may be an oversimplification. As such, various echocardiographic parameters have been studied. Of these, the most frequently used are M-mode echocardiography, tissue Doppler imaging, strain imaging and, more recently, 3-dimensional echocardiography. Although data from the PROSPECT study (Results of the Predictors of Response to CRT) was underwhelming and regarded echocardiographic predictors as representing more hype, numerous prior studies demonstrated utility in this approach despite the nuance, especially on an individualized patient level. Certainly, methodological incongruences may have subjected the study to the suboptimal outcome. Other techniques to evaluate ventricular dyssynchrony include cardiac magnetic resonance imaging and nuclear imaging.11,12 However, these modalities are expensive, resource intensive, and have limited analytic ability of irregular beats. Ultra-high-frequency ECG analysis has recently been described and represents new hope for predicting CRT responders.13 High-frequency ECG possesses the ability to detect temporal (ultra-high-frequency oscillation distribution in time) and spatial (location via precordial ECG leads) distribution of ventricular electrical depolarization and correlates with the result obtained by speckle tracking echocardiography.13 The analysis using a higher frequency and dynamic range permits more accuracy in identifying the time-related distribution of electrical depolarization in each precordial lead: the high frequency permits a greater proportion of signals to be analyzed rather than filtered while the higher dynamic range permits a greater number of discrete levels that can be assigned to an instantaneous voltage.In this issue of Circulation: Arrhythmia and Electrophysiology, Plesinger et al14 performed a substudy on the effect of computational ventricular electrical activation delay (VED) using high-frequency ECG as measured from standard 12-lead Holter ECGs with respect to CRT response in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). Recall that the MADIT-CRT study enrolled 1820 patients with ischemic or nonischemic cardiomyopathy, ejection fraction ≤30%, New York Heart Association class 1 or 2 symptoms, and QRS duration of ≥130 ms in which they were randomized to either CRT-D or implantable cardioverter defibrillator alone. The trial showed that during an average follow-up of 2.4 years, the primary end point of death from any cause or a nonfatal heart failure event was 34% lower in favor of CRT-D recipients.4In this study, the authors analyzed 949 high-frequency ECG recordings at baseline (all patients from the CRT-D arm). Of these, 676 patients had LBBB, 113 had right bundle branch block, and 160 patients had nonspecific intraventricular conduction delay. They analyzed signals from the first 10 minutes of Holter recordings sampling only sinus rhythm QRS complexes at 1 KHz. The VED value was calculated as the average value across the maximal point, the center of mass point, and the average location of the center of mass and maximal points between septal (V1 and V2) and lateral (V5 and V6) precordial leads (Figure 1 of reference 14).14Several findings are worth highlighting:A widened QRS duration sets an important criterion for CRT indication in guidelines. VED provides additional information to QRS duration; as such it characterizes electrical septal-lateral conduction delay which could not be determined by a standard ECG. In patients who have LBBB with a similar QRS duration, the electrical spectrum of septal-lateral delay or VED may be different. A higher VED value was associated with better CRT-D outcomes—the C statistic score with a model for hazard ratio using dichotomized VED value was better when adjusting for QRS duration. Compared with VED<31.2 ms, VED≥31.2 ms was associated with a greater reduction in left ventricular end-systolic volume (−36.8±14.9% versus −28.8±13.1%, P<0.001), and a greater improvement in left ventricular ejection fraction (12.5±5.2% versus 9.8±4.5%, P<0.001).The improvement in hemodynamics translated into better primary clinical outcome: patients with a higher VED had lower mortality and heart failure admission rates than those with lower VED (14% versus 35%, P<0.001). Further, each 10 ms increase in VED value was associated with a 13% reduction in end point (10% in ischemic cardiomyopathy, P=0.067 and 17% in nonischemic cardiomyopathy, P=0.011).Interestingly, there was a lower occurrence of ventricular arrhythmias in patients with high VED values at baseline. This may be related to responder status as it has been shown patients with super-response to CRT have a reduced incidence of ventricular arrhythmias and appropriate implantable cardioverter defibrillator therapies.15When dichotomized by QRS duration at ≥150 ms and <150 ms, the hazard ratio for the primary outcome was similar among the higher VED groups which the authors interpreted as potentially meaning that VED may be a useful predictor of outcome in patients with QRS duration <150 ms. This will be important to verify in future studies as there is considerable data suggesting that the degree of benefit in patients with QRS duration between 120–149 ms is limited.8Despite the lack of response to CRT in non-LBBB patients in the MADIT-CRT study, the authors investigated the values of VED in patients with right bundle branch block and intraventricular conduction delay. The median VED value was −26.5 ms (interquartile range, 27.2) for right bundle branch block patients and 16.1 ms (interquartile range, 19.1) for intraventricular conduction delay patients, respectively. In opposite behavior to those with LBBB, lower absolute VED values were associated with a lower risk of combined end points, suggesting that CRT in non-LBBB patients has a limited effect which is consistent with current CRT guidelines.The retrospective analysis by Plesinger et al14 makes use of combining novel technology with a robust, prospective data set from which numerous substudies have been published all providing added insights into CRT. This technique of VED analysis has the advantage that standard 12-lead ECG electrode placements can be used. In addition, it permits analysis on various types of QRS complexes. However, it is not as simple as measuring the QRS duration: given the lower signal-to-noise ratio, a sufficient number of beats is required to permit averaging of signals. Certainly, improvements in technology permitting data acquisition from a standard 12-lead ECG would enhance efficiency. Further studies assessing whether or not VED measurement can assist in choosing the optimal LV lead position would be welcome. Finally, how it will perform with emerging resynchronizing pacing techniques including His-bundle and, especially, multipoint pacing as well as in patients with ejection fraction 35% to 50% and frequent right ventricular pacing, has yet to be determined.Evidently, the use of high-frequency ECG and VED assessment can assist in the optimal selection of patients for CRT therapy independent of other parameters. Additionally, preliminary data from this study suggests that it may help predict the risk of adverse outcome in non-LBBB recipients of CRT placing new hope on the tables of implanting physicians in appropriately selecting patients who do not perfectly fit current CRT guideline criteria.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circep.ahajournals.orgYong-Mei Cha, MD, Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. E-mail [email protected]References1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. 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