{'fraction_non_alphanumeric': 0.031652230227475105, 'fraction_numerical': 0.017607059014004695, 'mean_word_length': 5.09898790422118, 'pattern_counts': {'":': 0, '<': 18, '<?xml version=': 0, '>': 3, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Changes in QRS Area and QRS Duration After Cardiac Resynchronization Therapy Predict Cardiac Mortality, Heart Failure Hospitalizations, and Ventricular Arrhythmias

Background Predicting clinical outcomes after cardiac resynchronization therapy (CRT) and its optimization remain a challenge. We sought to determine whether pre‐ and postimplantation QRS area (QRS area) predict clinical outcomes after CRT. Methods and Results In this retrospective study, QRS area, derived from pre‐ and postimplantation vectorcardiography, were assessed in relation to the primary end point of cardiac mortality after CRT with or without defibrillation. Other end points included total mortality, total mortality or heart failure (HF) hospitalization, total mortality or major adverse cardiac events, and the arrhythmic end point of sudden cardiac death or ventricular arrhythmias with or without a shock. In patients (n=380, age 72.0±12.4 years, 68.7% male) undergoing CRT over 7.7 years (median follow‐up: 3.8 years [interquartile range 2.3–5.3]), preimplantation QRS area ≥102 μVs predicted cardiac mortality (HR: 0.36; P<0.001), independent of QRS duration (QRSd) and morphology (P<0.001). A QRS area reduction ≥45 μVs after CRT predicted cardiac mortality (HR: 0.19), total mortality (HR: 0.50), total mortality or heart failure hospitalization (HR: 0.44), total mortality or major adverse cardiac events (HR: 0.43) (all P<0.001) and the arrhythmic end point (HR: 0.26; P<0.001). A concomitant reduction in QRS area and QRSd was associated with the lowest risk of cardiac mortality and the arrhythmic end point (both HR: 0.12, P<0.001). Conclusions Pre‐implantation QRS area, derived from vectorcardiography, was superior to QRSd and QRS morphology in predicting cardiac mortality after CRT. A postimplant reduction in both QRS area and QRSd was associated with the best outcomes, including the arrhythmic end point.

C ardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure (HF), impaired left ventricular (LV) function, and a wide QRS complex. 1 As with any medical therapy, its treatment effect is variable. "Nonresponder" rates range from 9% to 68%, depending on the criteria used to define response. 2 Although no medical therapy can be expected to be 100% effective, there is a consensus view that response to CRT can be improved. 3 Manifold imaging studies explored mechanical dyssynchrony in relation to patient selection and optimization but, ultimately, no single measure of mechanical dyssynchrony has been adopted by clinical guidelines. 4 In this context, we should consider CRT is an electrical treatment and that its substrate should be electrical rather than mechanical. In this respect, QRS duration (QRSd) has been adopted as a surrogate of electrical dyssynchrony in randomized, controlled trials, 1 and a reduction in QRSd has been shown to predict better long-term outcomes after CRT. 5,6 Evidence has recently emerged in support of vectorcardiography in the field of CRT. In this respect, QRS area (QRS area ) has been shown to correlate with LV lateral wall activation time, 7 the maximum rate of rise of LV pressure (DLV dP/ dt max ), 8,9 and LV reverse remodeling 10 after CRT. Crucially, pre-implantation QRS area has also been shown to be superior to pre-implantation QRSd and QRS morphology in predicting total mortality after CRT. 11,12 Although QRS area and QRSd duration relate to depolarization in a global sense, QRS area also yields the dominant axis of the activation sequence. 13 Given that the objective of CRT is to make depolarization more synchronous, both the pacing location and timing between LV and right ventricular pacing can be used to manipulate activation sequence. In this study, we explored pre-and postimplantation QRS area and QRSd in relation to long-term cardiac mortality, HF hospitalization, and major adverse cardiac events (MACEs) after CRT.

Methods
Patients referred for CRT implantation at the University Hospitals Birmingham, Queen Elizabeth, United Kingdom, were retrospectively evaluated. The study was approved by the local Ethics Committee and local Clinical Audit Department, both of which waived patient consent on the basis that all study tests and interventions had already been undertaken. The study conforms with the Declaration of Helsinki.

Study Population
Patients undergoing CRT implantation from November 2011 to June 2018 were identified. Implantation practice adhered to the United Kingdom's National Institute of Clinical Excellence guidelines, which before 2007 recommended CRT with defibrillation (CRFT-D) only in the context of secondary prevention. After 2014, National Institute of Clinical Excellence recommended cardiac resynchronization therapy with defibrillation rather than CRT-pacing in nonischemic cardiomyopathy. 14 Inclusion criteria were the following: indications for CRT according to National Institute of Clinical Excellence guidance and availability of a digitizable 12-lead ECG before and after implantation. Exclusion criteria were the following: subjects with technically unsuitable ECGs and patients with congenital heart disease.

Device Therapy
Device implantation was undertaken using standard transvenous techniques with patients under local anesthesia and the QRS complex, in the form of "loops," which are determined from vectors representing successive, instantaneous mean electrical forces throughout the cardiac cycle. A, A representation of the 3 vectorcardiogram leads (X, Y, and Z), according to Frank's orthogonal lead system. B, Two-dimensional vector loops in the frontal (X-Y leads), sagittal (Y-Z leads), and transverse (X-Z leads) planes from a patient with a left bundle branch block. The QRS area is calculated as the integral sum of the area bound by the QRS complex and the isoelectric baseline in each vectorcardiogram lead (X, Y, and Z).

Clinical Perspective
What Is New?
• Pre-implantation QRS area was superior to QRSd and QRS morphology in predicting cardiac and total mortality after cardiac resynchronization therapy. • Concomitant reductions in QRS area and QRSd after cardiac resynchronization therapy were associated with the best survival and the lowest risk of heart failure hospitalization, major adverse cardiac events as well as ventricular arrhythmias.
What Are the Clinical Implications?
• Reductions in QRS area and QRSd could be a focus for optimization after cardiac resynchronization therapy implantation. intravenous sedation. Following implantation, patients were followed up in combined cardiac device therapy/HF clinics. Devices were programmed according to physician discretion. Generally, backup atrial pacing was set at 60 beats/min, and the pacing mode was set to DDDR. The atrioventricular delay was set at 90 ms and the interventricular delay to between 0 and À20 ms (LV first). In patients in permanent atrial fibrillation, right ventricular and LV leads were deployed, a CRT generator was implanted, and devices were programmed to a ventricular triggered mode. Atrioventricular junction ablation was undertaken according to physicians' discretion. Targeted echocardiographic optimization was only undertaken in symptomatic nonresponders.

Lead positions
The anteroposterior, as well as the left anterior and right anterior oblique fluoroscopic views from coronary sinus venography taken at the time of implantation were used retrospectively to assess the LV lead tip position, as previously described. 15 All LV lead positions were assessed retrospectively by an experienced implanter (F.L.) who was blinded to clinical outcome data.

ECG
Pre-implantation, standard supine 12-lead ECGs (25 mm/s, 10 mm/mV) were used for analysis. A left bundle branch block (LBBB) was defined as a QRSd >120 ms, rS or QS in lead V 1 , notched or slurred R-waves in leads I, aVL, V 5 or V 6 , with absent q waves in leads V 5 and V 6 . 16 We used this definition rather than "strict" Strauss criteria, as the latter is not predictive of clinical outcomes after CRT. 12 Right bundle branch block was defined as a QRS ≥120 ms, with a wide, positive R-wave deflection in lead V 1 and a slurred S wave in leads I and V 6 . A nonspecific intraventricular conduction delay was defined as nonpaced QRS >120 ms not fitting these criteria. Postimplantation ECGs were undertaken within 3 months after implantation.

Vectorcardiography
Standard 12-lead ECGs were first converted to an Extensible Markup Language (XML) format using ECGScan (AMPS LLC, New York, USA), a commercially available program approved by the US Food and Drug Administration. A custom-made program was used for generation of 2 vectorcardiographies according to Frank's orthogonal lead system using the Kors transformation. The latter was used given previous evidence that it is superior to other vectorcardiography transformations in predicting clinical outcomes after CRT. 12 The start and end of the QRS complex were defined semi-automatically using digital calipers at 200% magnification. For paced rhythms, the onset and end of the QRS complex was measured manually, excluding the pacing spike. Digitization of ECGs and generation of vectorcardiographies were undertaken by a single investigator (O.O.) who was blinded to clinical outcomes collected by another investigator (A.Z.). The QRS area was calculated as the integral between the ventricular deflection curve and the isoelectric line in each the 3 orthogonal leads (X, Y, and Z), according to the formula: Figure 1).

End points
The primary end point was cardiac mortality, which included cardiac transplantation or implantation of a ventricular assist device. The secondary end point was total mortality. Ancillary end points included total mortality or unplanned HF hospitalization; total mortality or unplanned hospitalization for MACE; and the combined end point of sudden cardiac death, ventricular tachycardia, ventricular fibrillation, or shock. MACE included unplanned hospitalization for HF, myocardial infarction, acute coronary syndrome, ventricular arrhythmias, and atrial fibrillation. A HF hospitalization was defined as an unplanned admission related to worsening dyspnea, in association with peripheral edema, pulmonary edema on chest radiography, and requirement for intravenous diuretic therapy. Device-treated arrhythmias (appropriately treated with shocks or antitachycardia pacing) not leading to an unplanned hospitalization were not regarded as a hospitalization for MACE. Stroke and pulmonary embolism were not regarded as MACE. In composite end points, the first event was included in statistical analyses. Mortality data were collected through medical record and cross-checked with a national mortality database. Data were collected retrospectively from medical records and entered into an electronic database every 6 months by investigators who were blinded to clinical and imaging data. Events were adjudicated by blinded investigators on a 6-monthly basis.

Mode of death
Sudden cardiac death was defined as a natural, unexpected death because of cardiac causes, heralded by an abrupt loss of consciousness within 1 hour of the onset of acute symptoms. Death from pump failure was defined as "death after a period of clinical deterioration in signs and symptoms of HF despite medical treatment". 17

Statistical Analysis
Continuous variables are expressed as meanAE SD. Normality was tested using the Shapiro-Wilk test. Comparisons between normally distributed continuous variables were made using the Student t test. Categorical variables were analyzed using v 2 tests. Receiver operating characteristic curves were created to assess the predicted probabilities of ECG and vectorcardiography variables in relation to cardiac mortality. A 10-fold cross-validation was used as the model validation technique for assessing performance, and the average was calculated over 10 repetitions. The measure with largest area under the receiver operating characteristic (area under the curve [AUC]) was used for subsequent analyses. The Liu method was also applied to estimate nonparametrically the optimal cutoffs for ECG and vectorcardiography measures. 18 Kaplan-Meier curves and the log-rank test were used to assess cumulative survival and Cox proportional hazard models were used to assess relative risks. Proportionality hypotheses were verified by visual examination of log (survival) and Schoenfeld residuals. Variables reaching P<0.10 as univariate predictors of cardiac mortality were entered in multivariate models. Statistical analyses were undertaken by a biostatistician (T.Q.) who did not partake in data collection. The Stata15 (StataCorp, TX) statistical package was used. The package "cvauroc" was used for cross-validation of the areas under the receiver operating characteristic curve, and package "cutpt" was used for empirical estimation of optimal cutoffs. A 2-sided P<0.05 was considered statistically significant.

Baseline Characteristics
The analytic sample consisted of 380 patients. As shown in  Table 2). The cause of death was unknown in 34/380 (9%). The AUC for predicting cardiac mortality was higher for QRS area than for QRSd or QRS morphology (0.71, 0.60, and 0.53, respectively; P<0.001 for comparison) ( Figure 2) and for QRSd and QRS morphology combined (AUC: 0.66; P=0.002).
In Kaplan-Meier survival analyses, QRS area ≥102 lVs was associated with a lower cardiac mortality (P<0.001), total mortality (P=0.001), total mortality or HF hospitalization, and total mortality or MACE (both P<0.001) ( Table 2 and Figure 3). In univariable Cox proportional hazards analyses, QRS area predicted cardiac mortality, total mortality, total mortality or HF hospitalization, and total mortality or MACE (all P<0.001) (

Post-CRT QRS area
The QRS area decreased by 41.0 lVs (interquartile range: À79 to À4) after CRT (Figure 4). The cutoff of DQRS area derived from Liu method was À45 lVs ([À60] to [À31] lVs). As shown in Table 5, the DQRS area groups were well matched for age, New York Heart Association class, hypertension and diabetes mellitus status, device type, left ventricular ejection fraction, and medical therapy (Table 5). A QRS area reduction ≥45 lVs group had a lower proportion of men (P<0.001), and most had nonischemic cardiomyopathy (P<0.001). As expected from the DQRS area grouping, there were significant differences in ECG and vectorcardiography variables.

Interaction of DQRS area and DQRSd
As shown in Figures 2 and 5, DQRS area and DQRSd were comparable predictors of cardiac mortality. In Cox proportional hazard analyses, a significant interaction between DQRS area and DQRSd emerged with respect to cardiac mortality (HR: 0.12, 96% CI 0.06-0.26). A similar trend was observed for total mortality, total mortality or HF hospitalization, and total mortality or MACE ( Figure 6).

Lead Positions
Most LV leads were deployed in a lateral or posterolateral position ( Table 5). As shown in Figure 7, there was considerable interindividual variability in DQRS area and DQRSd within each LV lead position, but no significant differences emerged in DQRS area or DQRSd between the different LV lead positions.

Arrhythmic events
As shown in Table 3 and Figure 8, both QRSd and QRS area predicted the combined end point of sudden cardiac death, ventricular tachycardia/ventricular fibrillation or shock, but no

Discussion
This is the first study to explore both pre-and postimplantation QRS area in relation to long-term, cause-specific mortality, as well as long-term HF hospitalization, MACE, and ventricular arrhythmias after CRT. Several findings have emerged. First, pre-implantation QRS area was superior to QRSd and QRS morphology in predicting cardiac mortality after CRT. Second, a QRS area reduction after CRT was associated with favorable outcomes, independent of baseline QRSd or QRS morphology. Third, the best outcomes after CRT were observed in patients exhibiting concomitant reductions in QRS area and QRSd.

Pre-CRT QRS area
This study provides an external validation of the findings of 2 observational studies showing that QRS area is superior to QRSd and QRS morphology in predicting total mortality after CRT. 11,12 We found that QRS area (<102 lVs) predicted total mortality, with an AUC of 0.71, which is higher than the AUC of 0.61 identified by van Stipdonk et al using a cutoff of 109 lVs. 11 Emerek et al found that a QRS area ≤95 lVs was associated with a higher total mortality than a QRS area >95 lVs, with an unadjusted HR of 2.11 (P<0.001). 12 Using a cutoff of 102 lVs, we have found an unadjusted HR of 1.73 (P=0.002) for total mortality and 2.77 for cardiac mortality (P<0.001).
Previous studies on QRS area 11,12 did not address causespecific mortality and only 1 year follow-up data were provided with respect to HF hospitalization. 11 We found that, in addition to predicting total mortality, QRS area predicted cardiac mortality, total mortality or HF hospitalization, and total mortality or MACE. The relation between a high QRS area and better clinical outcomes after CRT is not unexpected, because QRS area correlates with electrical dyssynchrony, 8 the natural substrate of CRT.

Post-CRT DQRS area
In an acute hemodynamic study of 25 patients with LBBB, De Pooter et al showed that DQRS area correlated with DLV dP/ dt max . 8 This is consistent with our finding that a reduction in QRS area was associated with a lower cardiac mortality, as well as other end points. While De Pooter et al 8 found that DQRS area after CRT was a stronger correlate of DLV dP/dt max than DQRSd, we found that both DQRSd and DQRS area were comparable in predicting long-term clinical outcomes. Importantly, the combination of DQRSd and DQRS area had additive effects in predicting cardiac mortality: patients who exhibited reductions in both variables experienced the best outcomes after CRT, whereas patients who did not exhibit reductions in either experienced the worst outcomes.

QRSd
Randomized, controlled trials of CRT 19,20 adopted a QRSd ≥120 ms as an indication for CRT. In COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure), patients without LBBB and those with QRSd ≤147 ms did not derive a benefit. 19 Similarly, in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial- Cardiac Resynchronization Therapy) trial, patients with a QRSd <150 ms derived no survival benefit from CRT. 21,22 In the present study, we found that a QRSd ≥150 ms was associated with a lower cardiac mortality, compared with a QRSd <150 ms. The ability of QRSd to predict cardiac mortality, however, was relatively weak (AUC: 0.60). Meta-analyses of observational studies have shown an inconsistent relationship between post-CRT DQRSd 23,24 and "clinical response." In these meta-analyses, however, "clinical response" was defined in terms of symptoms, echocardiographic variables, and/or hard end points, assuming that these are identical, interchangeable measures. On the other hand, studies focusing on hard end points do indeed support a relationship between a QRSd reduction and better outcomes after CRT. The REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) study, the only randomized controlled trial to address DQRSd after CRT, explored acute DQRSd in the CRT-treated group in relation to the primary end point of the clinical composite score, as well as LV reverse remodeling. 25 Although not designed to address hard end points, REVERSE reported an association between DQRSd and total mortality or HF hospitalization over a relatively short follow-up (12 months in North America and for 24 months in Europe) on univariate analyses, but not in a multivariate model that corrected for baseline QRSd. Importantly, however, the CRT-treated group in REVERSE only had 4 deaths over 24 months, raising the possible play of statistical underpowering. In contrast, in an observational study, Appert et al showed that a lack of postoperative QRSd reduction was independently associated with an increased risk of total mortality over a median follow-up period of 48 months. 6 In a similar study, Jastrzebski et al showed that a QRSd reduction predicted death from any cause or urgent heart transplantation and death from any cause/urgent heart transplantation or hospital admission for HF over an average follow-up period of 46 months. 5 In the present study, in which 135 deaths occurred over a median follow-up of 3.8 years, a QRSd  reduction below baseline predicted cardiac mortality, total mortality, total mortality or HF hospitalization, and total mortality or MACE.

QRS Morphology
Observational studies 26,27 as well as large registries 28 and subanalyses of randomized, controlled trials 19,22,25,29 have shown that patients with a LBBB morphology derive the most benefit from CRT. While some studies have suggested that a LBBB defined using "strict" criteria, with notching and/or slurring of the QRS complex, is associated with a better left ventricular ejection fraction response to CRT, 10,27 this is not a consistent finding. 30,31 Moreover, Emerek et al found that "strict" (Strauss) criteria of LBBB was not predictive of clinical outcomes after CRT. 12 In the present study, a conventionally defined LBBB did not predict cardiac mortality after CRT (AUC: 0.53).

Lead Position
We have observed a considerable interindividual variability in QRS area at a given LV lead position. In this regard, De Pooter et al also found a similar interindividual variability in QRS area in CRT recipients with a LBBB. 8 Crucially, they also found that QRS area and the acute hemodynamic response to CRT in a given patient could be improved by changing the LV lead position. Together, these findings make the case for optimization of QRS area in CRT recipients. To date, however, no studies have prospectively explored this issue.

Arrhythmic events
Several studies have suggested that QRSd predicts sudden cardiac death. 32  implantation QRS area did not predict this end point, its reduction was associated with a 74% reduction in the end point. Moreover, concomitant with QRS area reduction, a QRd reduction was associated with an 88% lower risk of the combined end point. This novel finding, which was not anticipated, could speculatively relate to a greater dispersion of depolarization in relation to arrhythmic events. The physiological basis for this empirical finding requires further study.

Clinical Perspectives
Attention has recently focused on ECG imaging using body surface mapping as a tool for identifying electrical dyssynchrony and to predict response to CRT. 34,35 Although there is a proof-of-principle and encouraging clinical data to support the use of this technique in CRT, it requires specialized acquisition. Importantly, data on body surface mapping in relation to long-term outcomes after CRT are lacking. In contrast, QRS area can be readily derived from the standard 12lead ECG and crucially, is now known to predict long-term clinical outcomes. The role of QRS area in patient selection and CRT optimization requires further investigation.

Limitations
This study has all the limitations of an observational study. Although we have corrected for potential confounders using    statistical means, unobserved variables may have contributed to outcomes. Importantly, vectorcardiographies were derived retrospectively from 12-lead ECGs undertaken before implantation. Inconsistencies in electrode position could conceivably influence vectorcardiography analysis. 36 Notwithstanding, all ECGs were acquired by trained cardiac technicians using a standardized operating procedure in routine clinical practice. Consequently, our results should be generalizable to a "real-world" environment. Unfortunately, we did not systematically collect data on device programming. In this respect, variable programming at implantation and follow-up could account for variations in ECG and vectorcardiography variables, as well as outcomes. Although the AUCs for pre-implant QRS area and DQRS area did not exceed 0.74, these values are comparable to those found in other studies 11 and exceed the AUCs for QRSd and LBBB.

Conclusions
Pre-implantation QRS area was superior to QRSd and QRS morphology in predicting clinical outcomes after CRT. A concomitant reduction in QRSd and QRS area after CRT was associated with the lowest risk of cardiac and total mortality, as well as ventricular arrhythmias. These findings add support for the use of QRS area and QRSd in the risk stratification and optimization of CRT recipients.

Sources of Funding
Okafor was supported by an unrestricted educational grant from Medtronic Plc.