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Background: Cardiac anatomy and function adapt in response to chronic cardiac resynchronization therapy (CRT). The effects of these changes on the optimal left ventricle (LV) lead location and timing delay settings have yet to be fully explored., Objective: To predict the effects of chronic CRT on the optimal LV lead location and device timing settings over time., Methods: Biophysical computational cardiac models were generated for 3 patients, immediately post-implant (ACUTE) and after at least 6 months of CRT (CHRONIC). Optimal LV pacing area and device settings were predicted by pacing the ACUTE and CHRONIC models across the LV epicardium (49 sites each) with a range of 9 pacing settings and simulating the acute hemodynamic response (AHR) of the heart., Results: There were statistically significant differences between the distribution of the AHR in the ACUTE and CHRONIC models (P < 0.0005 in all cases). The site delivering the maximal AHR shifted location between the ACUTE and CHRONIC models but provided a negligible improvement (<2%). The majority of the acute optimal LV pacing regions (76-100%) and device settings (76-91%) remained optimal chronically., Conclusion: Optimization of the LV pacing location and device settings were important at the time of implant, with a reduced benefit over time, where the majority of the acute optimal LV pacing region and device settings remained optimal with chronic CRT., (© 2016 Wiley Periodicals, Inc.)

Background: The high risk of ventricular arrhythmias in patients with heart failure remains despite the benefit of cardiac resynchronization therapy (CRT). An electromechanical interaction between regional myocardial strain patterns and the electrophysiological substrate is thought to be important., Objective: We investigated the in vivo relation between left ventricular activation recovery interval (ARI), as a surrogate measure of action potential duration (APD), and local myocardial strain patterns in responders and nonresponders to CRT., Methods: ARIs were recorded from the left ventricular epicardium in 20 patients with CRT 6 weeks and 6 months post implantation. Two-dimensional speckle tracking echocardiography was performed at the same time to assess myocardial strains. Patients with ≥15% reduction in end-systolic volume at 6 months were classified as responders., Results: ARI decreased in responders (263 ± 46 ms vs 246 ± 47 ms, P < .01) and increased in nonresponders (235 ± 23 ms vs 261 ± 20 ms; P < .01). Time-to-peak radial, circumferential, and longitudinal strains increased in responders (41 ± 27, 35 ± 25, 56 ± 37 ms; P < .01) and decreased in nonresponders (-58 ± 26, -47 ± 26, -64 ± 27 ms; P < .01). There was a nonlinear correlation between changes in time-to-peak strain and ARIs (Spearman correlation coefficient r ≥ 0.70; P < .01). Baseline QRS duration >145 ms and QRS duration shortening with biventricular pacing were associated with ARI shortening following CRT., Conclusion: Changes in ventricular wall mechanics predict local APD lengthening or shortening during CRT. Nonresponders have a worsening of myocardial strain and local APD. Baseline QRS duration >145 ms and QRS duration shortening with biventricular pacing identified patients who exhibited improvement in APD., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Many heart failure patients with dyssynchrony do not reverse remodel (RR) in response to cardiac resynchronization therapy (CRT). The presence of focal and diffuse interstitial myocardial fibrosis may explain this high nonresponse rate. T1 mapping is a new cardiac magnetic resonance imaging (CMR) technique that overcomes the limitations of conventional contrast CMR and provides reliable quantitative assessment of diffuse myocardial fibrosis. The study tested the hypothesis that focal and diffuse fibrosis quantification would correlate with a lack of left ventricular (LV) RR to CRT., Methods and Results: In a prospective study of 48 consecutive patients (27 ischemic cardiomyopathy, 21 dilated cardiomyopathy) LV scar burdens were quantified (scar core and gray zone using late gadolinium enhancement LGE CMR; interstitial fibrosis using T1 mapping) before CRT implant. LV RR was defined by a ≥ 15% reduction in LV end-systolic volume 6 months postimplant. Twenty-seven (56%) patients were responders with RR. Association between scar quantification and LV RR was assessed using the Poisson regression model. Univariate analysis showed that QRS duration/morphology, scar core, and gray zone volumes expressed as % of LV mass and extracellular volume index (ECV) (a measure of interstitial fibrosis from T1 mapping) to be significant predictors of LV RR. Multivariable-adjusted analyses demonstrated scar core quantification (≥ 13.7% LV mass) to be the only independent predictor of LV RR (prevalence ratio 0.40, P = 0.038)., Conclusions: Focal scar burden detected by LGE CMR is associated with a poor response to CRT. Diffuse interstitial fibrosis assessment by T1 mapping, however, is not independently predictive of CRT response., (© 2015 Wiley Periodicals, Inc.)

Cardiac resynchronisation therapy (CRT) improves mortality and symptoms in heart failure patients with electromechanically dyssynchronous ventricles. There is a 50% non-response rate and reproducible biomarkers to predict non-response have not been forthcoming. Therefore, there has been increasing interest in the pathophysiological effects of dyssynchrony particularly focusing on coronary flow, myocardial perfusion and metabolism. Studies suggest that dyssynchronous electrical activation effects coronary flow throughout the coronary vasculature from the epicardial arteries to the microvascular bed and that these changes can be corrected by CRT. The effect of both electrical and mechanical dyssynchrony on myocardial perfusion is unclear with some studies suggesting there is a reduction in septal perfusion whilst others propose that there is an increase in lateral perfusion. Better understanding of these effects offers the possibility for better prediction of non-response. CRT appears to improve homogeneity in myocardial perfusion where heterogeneity is described in the initial substrate. Novel approaches to the identification of non-responders via metabolic phenotyping both invasively and non-invasively have been encouraging. There remains a need for further research to clarify the interaction of coronary flow with perfusion and metabolism in patients who undergo CRT., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Cardiac resynchronization therapy has revolutionized the management of systolic heart failure in patients with prolonged QRS during the past 20 years. Initially, the use of this treatment in patients with shorter QRS durations showed promising results, which have since been opposed by larger randomized controlled trials. Despite this, some questions remain, such as, whether correction of mechanical dyssynchrony is the therapeutic target by which biventricular pacing may confer benefit in this group, or are there other mechanisms that need consideration? In addition, novel techniques of cardiac resynchronization therapy delivery such as endocardial and multisite pacing may reduce potential detrimental effects of biventricular pacing, thereby improving the benefit/harm balance of this therapy in some patients.

Background: New criteria to define strict left bundle branch block (LBBB) on the basis of pathophysiological principles predict response to cardiac resynchronization therapy (CRT). Heterogeneous activation and contraction patterns have been identified in patients with classical LBBB. Cardiac magnetic resonance (CMR) imaging has demonstrated that a U-shaped (type II) contraction predicts reverse remodeling post-CRT. A homogeneous spread of (type I) contraction is less predictive., Objectives: The purpose of this study was to investigate contraction patterns among patients with strict LBBB and to test whether a type II contraction pattern better predicts CRT response and super-response., Methods: Thirty-seven patients with strict LBBB (QRS duration ≥140 ms for men and ≥130 ms for women with mid-QRS notching or slurring in ≥2 contiguous leads) underwent cine CMR imaging pre-CRT with an analysis of their contraction patterns by using endocardial contour tracking software. Patients were evaluated for reverse remodeling 6 months postimplantation., Results: Nineteen patients (51%) had a type II contraction pattern. A total of 25 patients (68%) of the cohort reverse remodeled. In the type II contraction group, all 19 patients (100%) reverse remodeled as compared with 6 patients (33%) in the type I contraction group (P < .01). Super-response was achieved in 21 patients (57%) of the total cohort: 5 patients with a type I contraction pattern (28%) and 16 patients with a type II contraction pattern (84%) (P < .01)., Conclusion: Patients with strict LBBB who are guideline indicated for CRT have heterogeneous contraction patterns derived from cine CMR. A type II contraction pattern is strongly predictive for reverse remodeling and super-response. This questions whether strict LBBB criteria alone are sufficient to reliably predict a positive response to CRT., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with electrical dyssynchrony who undergo cardiac resynchronization therapy (CRT) do not obtain substantial benefit. Assessing mechanical dyssynchrony may improve patient selection. Results from studies using echocardiographic imaging to measure dyssynchrony have ultimately proved disappointing. We sought to evaluate cardiac motion in patients with heart failure and electrical dyssynchrony using cardiovascular magnetic resonance (CMR). We developed a framework for comparing measures of myocardial mechanics and evaluated how well they predicted response to CRT., Methods: CMR was performed at 1.5 Tesla prior to CRT. Steady-state free precession (SSFP) cine images and complementary modulation of magnetization (CSPAMM) tagged cine images were acquired. Images were processed using a novel framework to extract regional ventricular volume-change, thickening and deformation fields (strain). A systolic dyssynchrony index (SDI) for all parameters within a 16-segment model of the ventricle was computed with high SDI denoting more dyssynchrony. Once identified, the optimal measure was applied to a second patient population to determine its utility as a predictor of CRT response compared to current accepted predictors (QRS duration, LBBB morphology and scar burden)., Results: Forty-four patients were recruited in the first phase (91% male, 63.3 ± 14.1 years; 80% NYHA class III) with mean QRSd 154 ± 24 ms. Twenty-one out of 44 (48%) patients showed reverse remodelling (RR) with a decrease in end systolic volume (ESV) ≥ 15% at 6 months. Volume-change SDI was the strongest predictor of RR (PR 5.67; 95% CI 1.95-16.5; P = 0.003). SDI derived from myocardial strain was least predictive. Volume-change SDI was applied as a predictor of RR to a second population of 50 patients (70% male, mean age 68.6 ± 12.2 years, 76% NYHA class III) with mean QRSd 146 ± 21 ms. When compared to QRSd, LBBB morphology and scar burden, volume-change SDI was the only statistically significant predictor of RR in this group., Conclusion: A systolic dyssynchrony index derived from volume-change is a highly reproducible measurement that can be derived from routinely acquired SSFP cine images and predicts RR following CRT whilst an SDI of regional strain does not.

Background and Aims of Study: Septal flash (SF) describes early inward motion of the ventricular septum in patients with left bundle branch block (LBBB), and correction corresponds to increased response to cardiac resynchronization therapy (CRT). SF has traditionally been assessed by echocardiography. We sought to determine if cardiac magnetic resonance (CMR) imaging could identify SF and if the additional assessment of scar would improve the ability of CMR to predict CRT response., Methods: Fifty-two patients with LBBB and heart failure underwent prospective CMR scanning prior to CRT implantation. The presence of SF was assessed visually and by using endocardial contour-tracking software. Presence and extent of myocardial scar was assessed by delayed enhancement imaging during CMR. The association between SF, scar and reverse remodelling (RR) at 6 months was explored., Results: RR rate to CRT at 6 months was 52%. CMR-derived SF was identified in 24 (46%) patients. RR was seen in more patients with SF than those without (88% vs 21%; P < 0.001). The absence of scar combined with the presence of SF had 96% specificity for predicting RR. In a multivariate regression model, the presence of SF was the only independent predictor of RR., Conclusion: SF can be assessed by CMR and predicts increased response to CRT. The additional value of CMR is the assessment of scar. The presence of SF with no scar is a highly specific predictor of CRT response.

Cardiac resynchronization therapy (CRT) is a proven treatment adjunct for selected patients with heart failure and evidence of ventricular dyssynchrony. When applying most contemporary guidelines the accepted response rate has remained static with up to one-third of patients failing to respond. Empiric lateral/posterolateral lead positioning may not be the optimal strategy in all patients, particularly in those with extensive scar and there have been developments that suggest an approach whereby the latest mechanically activating segment is targeted for left ventricular (LV) lead placement may be of some benefit. Additionally, alternative means of delivering CRT, either by means of multi-site pacing or LV endocardial pacing, have similarly shown promise. At a time where novel predictors of response to CRT have proved disappointing in multi-center trials, a paradigm shift away from prediction towards better delivery of CRT may potentially be of most benefit to the significant minority who do not respond.

Background: We sought to compare left ventricular (LVepi) and biventricular epicardial pacing (BIVepi) with LV (LVendo) and BIV endocardial pacing (BIVendo) in patients with chronic heart failure with an emphasis on the underlying electrophysiological mechanisms and hemodynamic effects., Methods and Results: Ten patients with chronically implanted cardiac resynchronization devices underwent temporary LVendo and BIVendo pacing with an LV endocardial roving catheter. A pressure wire and noncontact mapping array were placed to the LV cavity to measure LVdP/dtmax and perform electroanatomical mapping. At the optimal endocardial position, the acute hemodynamic response (AHR) was superior to epicardial stimulation, the AHR to BIVendo pacing and LVendo pacing being comparable (21±15% versus 22±17%; P=NS). During intrinsic conduction, QRS duration was 185±30 ms, endocardial LV total activation time 92±27 ms, and trans-septal activation time 60±21 ms. With LVendo pacing, QRS duration (187±29 ms; P=NS) and endocardial LV total activation time (91±23 ms; P=NS) were comparable with intrinsic conduction. There was no significant difference in endocardial LV total activation time between LVendo and BIVendo pacing (91±23 versus 85±15 ms; P=NS). Assessment of isochronal maps identified slow trans-septal conduction with both LVendo and BIVendo pacing resulting in activation of almost the entire LV endocardium prior to septal breakout, thereby limiting any possible fusion with either pacing mode., Conclusions: The equivalent AHR to LVendo and BIVendo pacing may be explained by prolonged trans-septal conduction limiting fusion of electrical wavefronts. The optimal AHR was associated with predominantly LV pre-excitation and depolarization. Our results suggest that LV pacing alone may offer a viable endocardial stimulation strategy to achieve cardiac resynchronization.

Objectives: Type II activation describes the U-shaped electrical activation of the left ventricle (LV) with a line of block in patients with left bundle branch block (LBBB). We sought to determine if a corresponding pattern of contraction could be identified using cardiac magnetic resonance (CMR) cine imaging and whether this predicted response to cardiac resynchronization therapy (CRT)., Background: U-shaped LV electrical activation in LBBB has been shown to predict favorable response to CRT. It is not known if the degree of electromechanical coupling is such that the same is true for LV contraction patterns., Methods: A total of 52 patients (48% ischemic) scheduled for CRT implantation prospectively underwent pre-implantation CMR cine analysis using endocardial contour tracking software to generate time-volume curves and contraction propagation maps. These were analyzed to assess the contraction sequence of the LV. The effect of contraction pattern on CRT response in terms of reverse remodeling (RR) and clinical parameters (New York Heart Association functional class, 6-min walk distance and Heart Failure Questionnaire score) was assessed at 6 months., Results: Two types of contraction pattern were identified; homogenous spread from septum to lateral wall (type I, n = 27) and presence of block with a subsequent U-shaped contraction pattern (type II, n = 25). Rates of RR in those with a type 2 pattern were significantly greater at 6 months (80% vs. 26%, p < 0.001) as was mean increase in 6-min walk distance (126 ± 106 m vs. 55 ± 60 m; p = 0.004)., Conclusions: Cine CMR can identify a U-shaped pattern of contraction which predicts increased echocardiographic and clinical response rates to CRT in patients with LBBB., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A consistent feature of electrophysiological remodeling in heart failure is ventricular action potential duration (APD) prolongation. However, the effect of reverse remodeling on APD during cardiac resynchronization therapy (CRT) has not been determined in these patients. We hypothesized (1) that CRT may alter APD and (2) that the effect of CRT on APD may be different in patients who exhibit a good hemodynamic response to CRT compared with those with a poor response., Methods and Results: Left ventricular (LV) activation recovery intervals, as a surrogate for APD, were measured from the LV epicardium in 13 patients at day 0, 6 weeks, and 6 months after CRT implant. Responders to CRT were defined as those demonstrating a ≥15% reduction in LV end-systolic volume at 6 months. The responder group had a significant reduction in LV activation recovery interval (mean, -13±12 ms; median, -16 ms; interquartile range, -2 to -19 ms) during right ventricular pacing at 6 months (P<0.05). Conversely, the nonresponders showed a significant increase in activation recovery interval (mean, +22 ms±16; median, 17 ms; interquartile range, 8 to 35 ms; P<0.05). One patient in each group was on amiodarone., Conclusions: In patients with heart failure, LV epicardial APD (activation recovery interval) altered during CRT. The effect on APD was opposite in patients showing a good hemodynamic response compared with nonresponders. The findings may provide an explanation for the persistent high incidence of arrhythmias in some patients with CRT and the additional mortality benefit observed in responders of CRT.