Non-invasive three-dimensional electrical activation mapping to predict cardiac resynchronization therapy response: site of latest left ventricular activation relative to pacing site.

AIMS: Pacing remote from the latest electrically activated site (LEAS) in the left ventricle (LV) may diminish response to cardiac resynchronization therapy (CRT). We tested whether proximity of LV pacing site (LVPS) to LEAS, determined by non-invasive three-dimensional electrical activation mapping [electrocardiographic Imaging (ECGI)], increased likelihood of CRT response. METHODS AND RESULTS: Consecutive CRT patients underwent ECGI and chest/heart computed tomography 6-24 months of post-implant. Latest electrically activated site and the distance to LVPS (dp) were assessed. Left ventricular end-systolic volume (LVESV) reduction of ≥15% at clinical follow-up defined response. Logistic regression probabilistically modelled non-response; variables included demographics, heart failure classification, left bundle branch block (LBBB), ischaemic heart disease (IHD), atrial fibrillation, QRS duration, baseline ejection fraction (EF) and LVESV, comorbidities, use of CRT optimization algorithm, angiotensin-converting enzyme inhibitor(ACE)/angiotensin-receptor blocker (ARB), beta-blocker, diuretics, and dp. Of 111 studied patients [64 ± 11 years, EF 28 ± 6%, implant duration 12 ± 5 months (mean ± SD), 98% had LBBB, 38% IHD], 67% responded at 10 ± 3 months post CRT-implant. Latest electrically activated sites were outside the mid-to-basal lateral segments in 35% of the patients. dp was 42 ± 23 mm [31 ± 14 mm for responders vs. 63 ± 24 mm non-responders (P < 0.001)]. Longer dp and the lack of use of CRT optimization algorithm were the only independent predictors of non-response [area under the curve (AUC) 0.906]. dp of 47 mm delineated responders and non-responders (AUC 0.931). CONCLUSION: The distance between LV pacing site and latest electrical activation is a strong independent predictor for CRT response. Non-invasive electrical evaluation to characterize intrinsic activation and guide LV lead deployment may improve CRT efficacy.

Comparison of the relation of the ESC 2021 and ESC 2013 definitions of left bundle branch block with clinical and echocardiographic outcome in cardiac resynchronization therapy.

INTRODUCTION: We aimed to investigate the impact of the 2021 European Society of Cardiology (ESC) guideline changes in left bundle branch block (LBBB) definition on cardiac resynchronization therapy (CRT) patient selection and outcomes. METHODS: The MUG (Maastricht, Utrecht, Groningen) registry, consisting of consecutive patients implanted with a CRT device between 2001 and 2015 was studied. For this study, patients with baseline sinus rhythm and QRS duration ≥ 130ms were eligible. Patients were classified according to ESC 2013 and 2021 guideline LBBB definitions and QRS duration. Endpoints were heart transplantation, LVAD implantation or mortality (HTx/LVAD/mortality) and echocardiographic response (LVESV reduction ≥15%). RESULTS: The analyses included 1.202, typical CRT patients. The ESC 2021 definition resulted in considerably less LBBB diagnoses compared to the 2013 definition (31.6% vs. 80.9%, respectively). Applying the 2013 definition resulted in significant separation of the Kaplan-Meier curves of HTx/LVAD/mortality (p < .0001). A significantly higher echocardiographic response rate was found in the LBBB compared to the non-LBBB group using the 2013 definition. These differences in HTx/LVAD/mortality and echocardiographic response were not found when applying the 2021 definition. CONCLUSION: The ESC 2021 LBBB definition leads to a considerably lower percentage of patients with baseline LBBB then the ESC 2013 definition. This does not lead to better differentiation of CRT responders, nor does this lead to a stronger association with clinical outcomes after CRT. In fact, stratification according to the 2021 definition is not associated with a difference in clinical or echocardiographic outcome, implying that the guideline changes may negatively influence CRT implantation practice with a weakened recommendation in patients that will benefit from CRT.

On-screen image-guided lead placement in cardiac resynchronization therapy: Feasibility and outcome in a multicenter setting.

Background: Image guidance to assist left ventricular (LV) lead placement may improve outcome after cardiac resynchronization therapy (CRT), but previous approaches and results varied greatly, and multicenter feasibility is lacking altogether. Objective: We sought to investigate the multicenter feasibility of image guidance for periprocedural assistance of LV lead placement for CRT. Methods: In 30 patients from 3 hospitals, cardiac magnetic resonance imaging was performed within 3 months prior to CRT to identify myocardial scar and late mechanical activation (LMA). LMA was determined using radial strain, plotted over time. Segments without scar but clear LMA were classified as optimal for LV lead placement, according to an accurate 36-segment model of the whole heart. LV leads were navigated using image overlay with periprocedural fluoroscopy. After 6 months, volumetric response and super-response were defined as ≥15% or ≥30% reduction in LV end-systolic volume, respectively. Results: Periprocedural image guidance was successfully performed in all CRT patients (age 66 ± 10 years; 59% men, 62% with nonischemic cardiomyopathy, 69% with left bundle branch block). LV leads were placed as follows: within (14%), adjacent (62%), or remote (24%) from the predefined target. According to the conventional 18-segment model, a remote position occurred only once (3%). On average, 86% of patients demonstrated a volumetric response (mean LV end-systolic volume reduction 36 ± 29%), and 66% of all patients were super-responders. Conclusion: On-screen image guidance for LV lead placement in CRT was feasible in a multicenter setting. Efficacy will be further investigated in the randomized controlled ADVISE (Advanced Image Supported Lead Placement in Cardiac Resynchronization Therapy) trial (NCT05053568).

Remodeling in the AV block dog is essential for tolerating moderate treadmill activity.

Background: A preclinical model standardized at different remodeling stages after AV block induction in awake state is suitable for the evaluation of improved cardiac devices. We studied exercise-induced cardiorespiratory parameters at three different timepoints after inducing AV block in dogs. Methods: Mongrel dogs (n = 12) were placed on a treadmill with a 10% incline and performed a moderate exercise protocol (10-minute run at 6 km/h). Dogs ran at sinus rhythm (SR), at two days (AVB2d, initiation of remodeling), three weeks (CAVB3) and six weeks (CAVB6, completed remodeling) after AV block. Results: All dogs completed the exercise protocol at SR, CAVB3 and CAVB6, while 6/12 dogs at AVB2d failed to complete the exercise protocol. The atrial rate was higher at all AV block timepoints (126 ± 20 to 141 ± 19 bpm at rest and 221 ± 10 to 231 ± 13 bpm during exercise) compared to SR (100 ± 29 bpm at rest and 162 ± 28 bpm during exercise, p < 0.05). Upon exercise, stroke volume increased from 66 ± 15 ml at SR, to 96 ± 21 ml at AVB2d (p < 0.05), 91 ± 13 ml at CAVB3 (p < 0.05) and 85 ± 24 ml at CAVB6 but failed to compensate for the AV block-induced bradycardia. Therefore, cardiac output was lower after AV block compared to SR. Exercising dogs at AVB2d showed most arrhythmic events, lowest VO2, and signs of desaturation and acidification in venous blood. Conclusion: Dogs with limited remodeling after AV block have a reduced exercise tolerance, which is reflected in changes in cardiorespiratory parameters.

Electrocardiogram-based deep learning improves outcome prediction following cardiac resynchronization therapy.

AIMS: This study aims to identify and visualize electrocardiogram (ECG) features using an explainable deep learning-based algorithm to predict cardiac resynchronization therapy (CRT) outcome. Its performance is compared with current guideline ECG criteria and QRSAREA. METHODS AND RESULTS: A deep learning algorithm, trained on 1.1 million ECGs from 251 473 patients, was used to compress the median beat ECG, thereby summarizing most ECG features into only 21 explainable factors (FactorECG). Pre-implantation ECGs of 1306 CRT patients from three academic centres were converted into their respective FactorECG. FactorECG predicted the combined clinical endpoint of death, left ventricular assist device, or heart transplantation [c-statistic 0.69, 95% confidence interval (CI) 0.66-0.72], significantly outperforming QRSAREA and guideline ECG criteria [c-statistic 0.61 (95% CI 0.58-0.64) and 0.57 (95% CI 0.54-0.60), P < 0.001 for both]. The addition of 13 clinical variables was of limited added value for the FactorECG model when compared with QRSAREA (Δ c-statistic 0.03 vs. 0.10). FactorECG identified inferolateral T-wave inversion, smaller right precordial S- and T-wave amplitude, ventricular rate, and increased PR interval and P-wave duration to be important predictors for poor outcome. An online visualization tool was created to provide interactive visualizations (https://crt.ecgx.ai). CONCLUSION: Requiring only a standard 12-lead ECG, FactorECG held superior discriminative ability for the prediction of clinical outcome when compared with guideline criteria and QRSAREA, without requiring additional clinical variables. End-to-end automated visualization of ECG features allows for an explainable algorithm, which may facilitate rapid uptake of this personalized decision-making tool in CRT.

Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy.

AIMS: Identifying heart failure (HF) patients who will benefit from cardiac resynchronization therapy (CRT) remains challenging. We evaluated whether virtual pacing in a digital twin (DT) of the patient's heart could be used to predict the degree of left ventricular (LV) reverse remodelling post-CRT. METHODS AND RESULTS: Forty-five HF patients with wide QRS complex (≥130 ms) and reduced LV ejection fraction (≤35%) receiving CRT were retrospectively enrolled. Echocardiography was performed before (baseline) and 6 months after CRT implantation to obtain LV volumes and 18-segment longitudinal strain. A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements. From each DT, baseline septal-to-lateral myocardial work difference (MWLW-S,DT) and maximum rate of LV systolic pressure rise (dP/dtmax,DT) were derived. Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location. Virtual pacing-induced changes ΔMWLW-S,DT and ΔdP/dtmax,DT were correlated with real-world LV end-systolic volume change at 6-month follow-up (ΔLVESV). The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02). CONCLUSION: Our results suggest that the reduction of septal-to-lateral work imbalance by virtual pacing in the DT can predict real-world post-CRT LV reverse remodelling. This DT approach could prove to be an additional tool in selecting HF patients for CRT and has the potential to provide valuable insights in optimization of CRT delivery.

Prognostic implications of invasive hemodynamics during cardiac resynchronization therapy: Stroke work outperforms dP/dtmax.

Background: Invasive measurements of left ventricular (LV) hemodynamic performance can evaluate acute response to cardiac resynchronization therapy (CRT). Objective: The study sought to determine which metric, maximum rate of LV pressure rise (LV dP/dtmax) or LV stroke work (LVSW), is more strongly associated with long-term prognosis. Methods: CRT patients were prospectively included from 3 academic centers. Invasive pressure-volume loop measurements during implantation were performed, and LV dP/dtmax and LVSW were determined at baseline and during biventricular pacing (BVP) as well as their relative increase (%Δ). Hazard ratios (HRs) for the primary outcome of 8-year all-cause mortality were derived using Cox proportional hazards. The secondary endpoint was echocardiographic response, defined as 6-month LV end-systolic volume reduction ≥15%. Results: Paired data from 82 patients were analyzed (67% male; age 66 ± 9 years; QRS duration 158 ± 22 ms, median survival time 72 months). Survival was better when LVSW during BVP was ≥4400 mL∙mm Hg (HR 0.21, 95% CI 0.08-0.58, P < .003) or when ΔLVSW% was ≥10% (HR 0.22, 95% CI 0.08-0.65, P = .006). In multivariate analysis, following direct comparison of continuous measures of acute ΔLV dP/dtmax% and ΔLVSW%, only ΔLVSW% remained associated with the primary endpoint (HR 0.982 per percentage point, P = .028). In contrast to LV dP/dtmax (all P > .05), significant associations with echocardiographic response were found for stroke work during BVP (area under the receiver-operating characteristic curve 0.745, P = .001) and ΔLVSW% (area under the receiver-operating characteristic curve 0.803, P < .001). Conclusion: Stroke work, but not LV dP/dtmax, is consistently associated with long-term prognosis and response after CRT. Our results therefore favor the use of stroke work as the hemodynamic parameter to predict long-term outcome after CRT.

Does recovery from submaximal exercise predict response to cardiac resynchronisation therapy?

BACKGROUND: Exercise parameters are not routinely incorporated in decision making for cardiac resynchronisation therapy (CRT). Submaximal exercise parameters better reflect daily functional capacity of heart failure patients than parameters measured at maximal exertion, and may therefore better predict response to CRT. We compared various exercise parameters, and sought to establish which best predict CRT response. METHODS: In 31 patients with chronic heart failure (61% male; age 68±7 years), submaximal and maximal cycling testing was performed before and 3 months after CRT. Submaximal oxygen onset (τVO2 onset) and recovery kinetics (τVO2 recovery), peak oxygen uptake (VO2 peak) and oxygen uptake efficiency slope (OUES) where measured. Response was defined as ≥15% relative reduction in end-systolic volume. RESULTS: After controlling for age, New York Heart Association and VO2 peak, fast submaximal VO2 kinetics were significantly associated with response to CRT, measured either during onset or recovery of submaximal exercise (area under the curve, AUC=0.719 for both; p<0.05). By contrast, VO2 peak (AUC=0.632; p=0.199) and OUES (AUC=0.577; p=0.469) were not associated with response. Among patients with fast onset and recovery kinetics, below 60 s, a significantly higher percentage of responders was observed (91% and 92% vs 43% and 40%, respectively). CONCLUSIONS: Impaired VO2 kinetics may serve as an objective marker of submaximal exercise capacity that is age-independently associated with non-response following CRT, whereas maximal exercise parameters are not. Assessment of VO2 kinetics is feasible and easy to perform, but larger studies should confirm their clinical utility.

Strain-based discoordination imaging during exercise in heart failure with reduced ejection fraction: Feasibility and reproducibility.

PURPOSE: Various parameters of mechanical dyssynchrony have been proposed to improve patient selection criteria for cardiac resynchronization therapy, but sensitivity and specificity are lacking. However, echocardiographic parameters are consistently investigated at rest, whereas heart failure (HF) symptoms predominately manifest during submaximal exertion. Although strain-based predictors of response are promising, feasibility and reproducibility during exercise has yet to be demonstrated. METHODS: Speckle-tracking echocardiography was performed in patients with HF at two separate visits. Echocardiography was performed at rest, during various exercise intensity levels, and during recovery from exercise. Systolic rebound stretch of the septum (SRSsept), systolic shortening, and septal discoordination index (SDI) were calculated. RESULTS: Echocardiography was feasible in about 70-80% of all examinations performed during exercise. Of these acquired views, 84% of the cine-loops were suitable for analysis of strain-based mechanical dyssynchrony. Test-retest variability and intra- and inter-operator reproducibility at 30% and 60% of the ventilatory threshold (VT) were about 2.5%. SDI improved in the majority of patients at 30% and 60% of the VT, with moderate to good agreement between both intensity levels. CONCLUSION: Although various challenges remain, exercise echocardiography with strain analysis appears to be feasible in the majority of patients with dyssynchronous heart failure. Inter- and intra-observer agreement of SRSsept and SDI up to 60% of the VT were comparable to resting values. During exercise, the extent of SDI was variable, suggesting a heterogeneous response to exercise. Further research is warranted to establish its clinical significance.

Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study. METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation. CONCLUSION: Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Does mechanical dyssynchrony in addition to QRS area ensure sustained response to cardiac resynchronization therapy?

AIMS: Judicious patient selection for cardiac resynchronization therapy (CRT) may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRSAREA, and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. To date, the relation between these measurements has not yet been investigated. METHODS AND RESULTS: A total of 240 CRT patients were prospectively enrolled from six centres. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6-month, and 12-month follow-up. QRSAREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥15% decrease in LVESVi, at both 6- and 12-month follow-up. QRSAREA and SRSsept were both strong, multivariable adjusted, variables associated with reverse remodelling. SRSsept was associated with response, but only in patients with QRSAREA ≥ 120 µVs (AUC = 0.727 vs. 0.443). Combined presence of SRSsept ≥ 2.5% and QRSAREA ≥ 120 µVs significantly increased reverse remodelling compared with high QRSAREA alone (ΔLVESVi 38 ± 21% vs. 22 ± 21%). As a result, 92% of left bundle branch block (LBBB)-patients with combined electrical and mechanical dysfunction were 'sustained' volumetric responders, as opposed to 51% with high QRSAREA alone. CONCLUSION: Parameters of mechanical dyssynchrony are better associated with response in the presence of a clear underlying electrical substrate. Combined presence of high SRSsept and QRSAREA, but not high QRSAREA alone, ensures a sustained response after CRT in LBBB patients.

Advanced image-supported lead placement in cardiac resynchronisation therapy: protocol for the multicentre, randomised controlled ADVISE trial and early economic evaluation.

INTRODUCTION: Achieving optimal placement of the left ventricular (LV) lead in cardiac resynchronisation therapy (CRT) is a prerequisite in order to achieve maximum clinical benefit, and is likely to help avoid non-response. Pacing outside scar tissue and targeting late activated segments may improve outcome. The present study will be the first randomised controlled trial to compare the efficacy of real-time image-guided LV lead delivery to conventional CRT implantation. In addition, to estimate the cost-effectiveness of targeted lead implantation, an early decision analytic model was developed, and described here. METHODS AND ANALYSIS: A multicentre, interventional, randomised, controlled trial will be conducted in a total of 130 patients with a class I or IIa indication for CRT implantation. Patients will be stratified to ischaemic heart failure aetiology and 1:1 randomised to either empirical lead placement or live image-guided lead placement. Ultimate lead location and echocardiographic assessment will be performed by core laboratories, blinded to treatment allocation and patient information. Late gadolinium enhancement cardiac magnetic resonance imaging (CMR) and CINE-CMR with feature-tracking postprocessing software will be used to semi-automatically determine myocardial scar and late mechanical activation. The subsequent treatment file with optimal LV-lead positions will be fused with the fluoroscopy, resulting in live target-visualisation during the procedure. The primary endpoint is the difference in percentage of successfully targeted LV-lead location. Secondary endpoints are relative percentage reduction in indexed LV end-systolic volume, a hierarchical clinical endpoint, and quality of life. The early analytic model was developed using a Markov-model, consisting of seven mutually exclusive health states. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee Utrecht (NL73416.041.20). All participants are required to provide written informed consent. Results will be submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05053568; Trial NL8666.

Optimizing lead placement for pacing in dyssynchronous heart failure: The patient in the lead.

Cardiac resynchronization therapy (CRT) greatly reduces morbidity and mortality in patients with dyssynchronous heart failure. However, despite tremendous efforts, response has been variable and can be further improved. Although optimizing left ventricular lead placement (LVLP) is arguably the cornerstone of CRT, the procedure of LVLP using the transvenous approach has remained largely unchanged for more than 2 decades. Improvements have been developed using scar location and electrical and/or mechanical mapping, and interest in conduction system pacing as an alternative to biventricular pacing has emerged recently. Conduction system pacing is promising but may not be suitable for all patients with dyssynchronous heart failure. This review underscores the importance of a patient-tailored approach and discusses the potential applications of both conduction system pacing and targeted biventricular CRT.

Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy.

PURPOSE: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT. METHODS: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dtmax,) during CRT-implantation. The acute change in dP/dtmax, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined. RESULTS: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dtmax 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination. CONCLUSION: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.

Reduction in the QRS area after cardiac resynchronization therapy is associated with survival and echocardiographic response.

INTRODUCTION: Recent studies have shown that the baseline QRS area is associated with the clinical response after cardiac resynchronization therapy (CRT). In this study, we investigated the association of QRS area reduction (∆QRS area) after CRT with the outcome. We hypothesize that a larger ∆QRS area is associated with a better survival and echocardiographic response. METHODS AND RESULTS: Electrocardiograms (ECG) obtained before and 2-12 months after CRT from 1299 patients in a multi-center CRT-registry were analyzed. The QRS area was calculated from vectorcardiograms that were synthesized from 12-lead ECGs. The primary endpoint was a combination of all-cause mortality, heart transplantation, and left ventricular (LV) assist device implantation. The secondary endpoint was the echocardiographic response, defined as LV end-systolic volume reduction ≥ of 15%. Patients with ∆QRS area above the optimal cut-off value (62 µVs) had a lower risk of reaching the primary endpoint (hazard ratio: 0.43; confidence interval [CI] 0.33-0.56, p < .001), and a higher chance of echocardiographic response (odds ratio [OR] 3.3;CI 2.4-4.6, p < .0001). In multivariable analysis, ∆QRS area was independently associated with both endpoints. In patients with baseline QRS area ≥109 µVs, survival, and echocardiographic response were better when the ∆QRS area was ≥62 µVs (p < .0001). Logistic regression showed that in patients with baseline QRS area ≥109 µVs, ∆QRS area was the only significant predictor of survival (OR: 0.981; CI: 0.967-0.994, p = .006). CONCLUSION: ∆QRS area is an independent determinant of CRT response, especially in patients with a large baseline QRS area. Failure to achieve a large QRS area reduction with CRT is associated with a poor clinical outcome.

The value of septal rebound stretch analysis for the prediction of volumetric response to cardiac resynchronization therapy.

AIMS: Patient selection for cardiac resynchronization therapy (CRT) may be enhanced by evaluation of systolic myocardial stretching. We evaluate whether systolic septal rebound stretch (SRSsept) derived from speckle tracking echocardiography is a predictor of reverse remodelling after CRT and whether it holds additive predictive value over the simpler visual dyssynchrony assessment by apical rocking (ApRock). METHODS AND RESULTS: The association between SRSsept and change in left ventricular end-systolic volume (ΔLVESV) at 6 months of follow-up was assessed in 200 patients. Subsequently, the additive predictive value of SRSsept over the assessment of ApRock was evaluated in patients with and without left bundle branch block (LBBB) according to strict criteria. SRSsept was independently associated with ΔLVESV (ß 0.221, P = 0.002) after correction for sex, age, ischaemic cardiomyopathy, QRS morphology and duration, and ApRock. A high SRSsept (≥optimal cut-off value 2.4) also coincided with more volumetric responders (ΔLVESV ≥ -15%) than low SRSsept in the entire cohort (70.0% and 56.4%), in patients with strict LBBB (83.3% vs. 56.7%, P = 0.024), and non-LBBB (70.7% vs. 46.3%, P = 0.004). Moreover, in non-LBBB patients, SRSsept held additional predictive information over the assessment of ApRock alone since patients that showed ApRock and high SRSsept were more often volumetric responder than those with ApRock but low SRSsept (82.8% vs. 47.4%, P = 0.001). CONCLUSION: SRSsept is strongly associated with CRT-induced reduction in left ventricular end-systolic volume and holds additive prognostic information over QRS morphology and ApRock. Our data suggest that CRT patient selection may be improved by assessment of SRSsept, especially in the important subgroup without strict LBBB. CLINICAL TRIAL REGISTRATION: The MARC study was registered at clinicaltrials.gov: NCT01519908.

Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart.

AIMS: Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Eighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR-133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR-133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR-199b and miR-155f, were not affected. CONCLUSIONS: In the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR-133a. Reduced miR-133a correlated with increased CTGF levels but not with SRF and NFATc4.