Clinical and Experimental Evidence for a Strain-Based Classification of Left Bundle Branch Block-Induced Cardiac Remodeling.

BACKGROUND: Septal strain patterns measured by echocardiography reflect the severity of left bundle branch block (LBBB)-induced left ventricular (LV) dysfunction. We investigated whether these LBBB strain stages predicted the response to cardiac resynchronization therapy in an observational study and developed a sheep model of LBBB-induced cardiomyopathy. METHODS: The clinical study enrolled cardiac resynchronization therapy patients who underwent echocardiographic examination with speckle-tracking strain analysis before cardiac resynchronization therapy implant. In an experimental sheep model with pacing-induced dyssynchrony, LV remodeling and strain were assessed at baseline, at 8 and 16 weeks. Septal strain curves were classified into 5 patterns (LBBB-0 to LBBB-4). RESULTS: The clinical study involved 250 patients (age 65 [58; 72] years; 79% men; 89% LBBB) with a median LV ejection fraction of 25 [21; 30]%. Across the stages, cardiac resynchronization therapy resulted in a gradual volumetric response, ranging from no response in LBBB-0 patients (ΔLV end-systolic volume 0 [-12; 15]%) to super-response in LBBB-4 patients (ΔLV end-systolic volume -44 [-64; -18]%) (P<0.001). LBBB-0 patients had a less favorable long-term outcome compared with those in stage LBBB≥1 (log-rank P=0.003). In 13 sheep, acute right ventricular pacing resulted in LBBB-1 (23%) and LBBB-2 (77%) patterns. Over the course of 8-16 weeks, continued pacing resulted in progressive LBBB-induced dysfunction, coincident with a transition to advanced strain patterns (92% LBBB-2 and 8% LBBB-3 at week 8; 75% LBBB-3 and 25% LBBB-4 at week 16) (P=0.023). CONCLUSIONS: The strain-based LBBB classification reflects a pathophysiological continuum of LBBB-induced remodeling over time and is associated with the extent of reverse remodeling in observational cardiac resynchronization therapy-eligible patients.

Relationship of Mechanical Dyssynchrony and LV Remodeling With Improvement of Mitral Regurgitation After CRT.

OBJECTIVES: The aim of this study was to explore the association between mechanical dyssynchrony of the left ventricle before cardiac resynchronization therapy (CRT) and improvement of mitral regurgitation (MR) after CRT. BACKGROUND: MR is very frequent among patients with dilated cardiomyopathy and conduction delay. METHODS: Echocardiograms (pre-CRT and 12 ± 3.8 months thereafter) of 314 patients with dilated cardiomyopathy and any degree of MR, who underwent CRT device implantation according to guidelines, were analyzed. Left ventricular (LV) mechanical dyssynchrony was assessed by apical rocking (ApRock) and septal flash (SF), while MR severity was graded from I to IV on the basis of vena contracta width, regurgitation jet size, and proximal isovelocity surface area. RESULTS: At baseline, 30% of patients presented with severe MR (grade III or IV). In 62% of patients, MR decreased after CRT, and these patients more frequently had left bundle branch block, had more severe MR, had more dilated left ventricles, had lower ejection fractions, and more often had ApRock and SF. Reverse remodeling was more frequent among patients with MR reduction (ΔLV end-systolic volume -35.5% ± 27.2% vs -4.1% ± 33.2%; P < 0.001). In a multivariable logistic stepwise regression, only ApRock (odds ratio [OR]: 3.8; 95% CI: 1.7-8.5; P = 0.001), SF (OR: 3.6; 95% CI: 1.6-7.9; P = 0.002), and baseline MR (OR: 1.4; 95% CI: 1.0-1.9; P = 0.046) remained significantly associated with MR reduction. CONCLUSIONS: ApRock, SF, and severity of MR at baseline are strongly associated with MR reduction after CRT, while LV reverse remodeling is its underlying mechanism. Therefore, in patients with heart failure with LV dyssynchrony on optimal medical treatment, CRT should be the primary treatment attempt for relevant MR.

The association of mechanical dyssynchrony and resynchronization therapy with survival in heart failure with a wide QRS complex: a two-world study.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35-0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups-they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17-0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22-0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25-0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

Sex-specific difference in outcome after cardiac resynchronization therapy.

AIMS: Observation of better outcome in women after cardiac resynchronization therapy (CRT) has led to controversies about a potential sex-specific response. In this study, we investigated to which extent this sex-specific difference in CRT outcome could be explained by differences in baseline characteristics between both sexes. METHODS AND RESULTS: We retrospectively analysed data from a multicentre registry of 1058 patients who received CRT. Patients were examined by echocardiography before and 12 ± 6 months after implantation. Response was defined as ≥15% reduction of left ventricular end-systolic volume at follow-up. Patient's characteristics at baseline, including New York Heart Association class, ejection fraction, QRS width and morphology, ischaemic aetiology of cardiomyopathy (ICM), number of scarred segments, age at implantation, atrial fibrillation, and mechanical dyssynchrony (Dyss) were analysed. Patients were followed for a median duration of 59 months. Primary end point was all-cause mortality. Women (24% of the population) had less ICM (23% vs. 49%, P < 0.0001), less scarred segments (0.4 ± 1.3 vs. 1.0 ± 2.1, P < 0.0001), more left bundle branch block (LBBB; 87% vs. 80%, P = 0.01), and more Dyss at baseline (78% vs. 57%, P < 0.0001). Without matching baseline differences, women showed better survival (log rank P < 0.0001). After matching, survival was similar (log rank P = 0.58). In multivariable analysis, female sex was no independent predictor of neither volumetric response (P = 0.06) nor survival (P = 0.31). CONCLUSION: Our data suggest that the repeatedly observed better outcome in women after CRT is mainly due to the lower rate ICM and smaller scars. When comparing patients with similar baseline characteristics, the response of both sexes to CRT is similar.

Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy.

Aim: To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results: Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37-86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion: Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony.

Timing of myocardial shortening determines left ventricular regional myocardial work and regional remodelling in hearts with conduction delays.

Aims: The interaction between asynchronous regional myocardial activation and left ventricular (LV) wall remodelling has not been well established. We investigated the relationship between time of onset of longitudinal shortening (Tonset), regional myocardial work, and segmental LV wall thickness (SWT) in patients treated with cardiac resynchronization therapy (CRT). Methods and results: We analysed 26 patients with sinus rhythm, non-ischaemic cardiomyopathy (63 ± 9 years, 69% male, QRS duration 174 ± 18 ms) and positive response to CRT (15% reduction in end-systolic volume). Longitudinal strain was obtained by 2D speckle-tracking echocardiography before and after [14.5 (7-29) months] CRT. Tonset and SWT were measured in 18 segments per LV. Segmental myocardial work was calculated from non-invasive segmental stress-strain loop area. Before CRT, Tonset was the shortest in septal and anteroseptal and the longest in lateral and posterior walls (P < 0.001) and not different after CRT (P = 0.733). Before CRT, septal and anteroseptal walls were significantly thinner than lateral and posterior. After CRT, reverse remodelling increased thickness in septal and anteroseptal and thinned lateral and posterior segments (P < 0.001). Before CRT, non-uniformity in work distribution with reduced work in septal and anteroseptal and increased work in lateral and posterior walls (P < 0.001) was observed. After CRT, distribution of myocardial work was uniform (P = 0.215). Conclusion: Dys-synchronous myocardial shortening is related to thinning of early and thickening of late activated segments in heart failure with conduction delay. Correction of dys-synchrony leads to regression of inhomogeneity towards more evenly distributed wall thickness. Regional differences in myocardial work load that are homogenized by successful CRT are considered as the underlying pathophysiological mechanism.

The association of volumetric response and long-term survival after cardiac resynchronization therapy.

AIMS: Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT. METHODS AND RESULTS: In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 ± 3 months post-implantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 ± 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction ≥15%), and LV volume expansion (ESV increase ≥5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P < 0.001). CONCLUSION: Volumetric response assessed at 1-year after CRT is strongly associated with long-term mortality. However, an optimal cut-off cannot be established. The association of the correction of mechanical dyssynchrony with survival was stronger than that of any volumetric cut-off.

Long-Term Outcome After CRT in the Presence of Mechanical Dyssynchrony Seen With Chronic RV Pacing or Intrinsic LBBB.

OBJECTIVES: The aim of this study was to compare the volumetric response and the long-term survival after cardiac resynchronization therapy (CRT) in patients with intrinsic left bundle branch block (LBBB) versus chronic right ventricular pacing (RVP) with respect to the presence of mechanical dyssynchrony (MD). BACKGROUND: Chronic RVP induces an iatrogenic LBBB and asynchronous left ventricular contraction that is potentially reversible by upgrading to CRT. METHODS: A total of 914 patients eligible for CRT (117 with conventional pacemakers and 797 with intrinsic LBBB) were included in the study. MD was visually assessed before CRT and was defined as the presence of either apical rocking and/or septal flash on baseline echocardiograms. Patients with a left ventricular end-systolic volume decrease of ≥15% during the follow-up were considered responders. Patients were followed for all-cause mortality during the median follow-up of 48 months (interquartile range: 29 to 66 months). RESULTS: MD was observed in 51% of patients with RVP versus 77% in patients with intrinsic LBBB (p < 0.001). Patients with RVP and MD had a similar likelihood of volumetric response as did patients with intrinsic LBBB and MD (adjusted odds ratio: 0.71; 95% confidence interval: 0.33 to 1.53; p = 0.385). There was no significant difference in long-term survival between patients with RVP and intrinsic LBBB (adjusted hazard ratio: 1.101; 95% confidence interval: 0.658 to 1.842; p = 0.714). Patients with visual MD and either intrinsic LBBB or RVP had a more favorable survival than those without MD (p < 0.001). CONCLUSIONS: The likelihood of volumetric response and a favorable long-term survival of patients with RVP was similar to those of patients with intrinsic LBBB and were mainly determined by the presence of MD and not by the nature of LBBB.

The Impact of Infarct Location and Extent on LV Motion Patterns: Implications for Dyssynchrony Assessment.

OBJECTIVES: This study sought to investigate the influence of scar extent and location on the motion pattern of the left ventricle (LV) and its interaction with LV conduction delays. BACKGROUND: Different echocardiographic parameters have been proposed to identify responders to cardiac resynchronization therapy based on the detection of LV mechanical dyssynchrony. However, the impact of infarct scar on the diagnostic performance of these parameters remains unknown. METHODS: We included 11 healthy volunteers and 122 patients with normal and severely reduced function, wide and narrow QRS, as well as with and without infarct scar. Location and extent of infarct scar was defined by contrast-enhanced cardiac magnetic resonance. Influence of infarct scar on the motion pattern of the LV was examined by measuring direction and amplitude of apical rocking. The influence of scar on different echocardiographic dyssynchrony parameters was investigated. RESULTS: Scar in the absence of conduction delay caused most apical rocking in the presence of 3 to 4 infarct segments. Pure apical infarction caused no rocking. In wide QRS patients without infarct scar, apical rocking was mainly dominated by the conduction delay, whereas in wide QRS patients with ischemic cardiomyopathy, this pattern was modulated by the scar. Apical rocking was inversely related to scar extent (r = -0.54, p < 0.05). Apical rocking was better associated with cardiac resynchronization therapy response than conventional dyssynchrony measurements. CONCLUSIONS: LV motion patterns are mainly dominated by conduction delays, but they are also modulated by infarct scar. Higher scar burden resulted in less pronounced apical rocking. Apical rocking is more strongly associated with cardiac resynchronization therapy response than with conventional echocardiographic parameters and may therefore be used as a screening parameter.

Relationship of visually assessed apical rocking and septal flash to response and long-term survival following cardiac resynchronization therapy (PREDICT-CRT).

AIMS: Apical rocking (ApRock) and septal flash (SF) are often observed phenomena in asynchronously contracting ventricles. We investigated the relationship of visually assessed ApRock and SF, reverse remodelling, and long-term survival in cardiac resynchronization therapy (CRT) candidates. METHODS AND RESULTS: A total of 1060 patients eligible for CRT underwent echocardiographic examinations before and 12 ± 6 months after device implantation. Three blinded physicians were asked to visually assess the presence of ApRock and SF before device implantation and also their correction by CRT 12 ± 6 months post-implantation. Patients with a left ventricular (LV) end-systolic volume decrease of ≥15% during the first year of follow-up were regarded as responders. Patients were followed for a median period of 46 months (interquartile range: 27-65 months) for the occurrence of death of any cause. If corrected by CRT, visually assessed ApRock and SF were associated with reverse remodelling with a sensitivity of 84 and 79%, specificity of 79 and 74%, and accuracy of 82 and 77%, respectively. ApRock (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.30-0.53, P < 0.0001) and SF (HR 0.45 [CI 0.34-0.61], P < 0.001) were independently associated with lower all-cause mortality after CRT and had an incremental value over clinical variables and QRS width for identifying CRT responders. Both the absence of ApRock/SF and unsuccessful correction of ApRock/SF despite CRT were associated with a high risk for non-response and an unfavourable long-term survival. CONCLUSION: A specific LV mechanical dyssynchrony pattern, characterized by ApRock and SF, is associated with a more favourable long-term survival after CRT. Both parameters are also indicators of an effective therapy.

Dynamic relationship of left-ventricular dyssynchrony and contractile reserve in patients undergoing cardiac resynchronization therapy.

AIMS: Contradicting reports have been published regarding the relation between a dobutamine-induced increase in either cardiac dyssynchrony or left-ventricular ejection fraction (LVEF) and the response to cardiac resynchronization therapy (CRT). Using apical rocking (ApRock) as surrogate dyssynchrony parameter, we investigated the dobutamine stress echocardiography (DSE)-induced changes in left-ventricular (LV) dyssynchrony and LVEF and their potential pathophysiological interdependence. METHODS AND RESULTS: Fifty-eight guideline-selected CRT candidates were prospectively enrolled for low-dose DSE. Dyssynchrony was quantified by the amplitude of ApRock. An LVEF increase during stress of >5% was regarded significant. Scar burden was assessed by magnetic resonance imaging. Mean follow-up after CRT implantation was 41 ± 13 months for the occurrence of cardiac death. ApRock during DSE predicted CRT response (AUC 0.88, 95% CI 0.77-0.99, P < 0.001) and correlated inversely with changes in EF (r = -0.6, P < 0.001). Left-ventricular ejection fraction changes during DSE were not associated with CRT response (P = 0.082). Linear regression analysis revealed an inverse association of LVEF changes during DSE with both, total scar burden (B = -2.67, 95CI -3.77 to -1.56, P < 0.001) and the DSE-induced change in ApRock amplitude (B = -1.23, 95% CI -1.53 to -0.94, P < 0.001). Kaplan-Meier analysis revealed that DSE-induced increase in ApRock, but not LVEF, was associated with improved long-term survival. CONCLUSION: During low-dose DSE in CRT candidates with baseline dyssynchrony, myocardial contractile reserve predominantly results in more dyssynchrony, but less in an increase in LVEF. Dyssynchrony at baseline and its dobutamine-induced changes are predictive of both response and long-term survival following CRT.

Peak oxygen uptake during cardiopulmonary exercise testing determines response to cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment modality for advanced heart failure (HF) but 20-30% of patients treated with CRT do not experience clinical improvement. Hence, in this study we aimed to investigate whether baseline cardiopulmonary exercise testing (CPX) can help improve the prediction of a positive functional CRT response. METHODS: This prospective observational study included 76 HF patients undergoing elective CRT implantation and clinical CPX and echocardiographic assessment were performed at baseline, 6, and 12 months. RESULTS: Peak VO2 increased from 11.0±2.5 ml/min/kg to 12.0±4.1 ml/min/kg and 12.2±3.5 ml/min/kg at 6 and 12 months after CRT, respectively. The number of patients classified as "CRT-responders" (Δ peak VO2≥1 ml/kg/min) was 33 (46%) and 36 (52%) at 6 and 12 months after CRT, respectively. Patients with baseline peak VO2<40% of predicted (lowest tertile) demonstrated a 68% and 69% response rate at 6 and 12 months, respectively, as compared to a 35% and 42% response rate among patients with baseline peak VO2≥40% of predicted (p=0.01 and p=0.02, respectively). In multivariate analysis patients with baseline peak VO2<40% of predicted had an adjusted odds ratio of 4.4 (95% CI 1.6-12.5; p<0.01) and 3.1 (95% CI 1.1-8.8; p=0.03) for positive CRT response at 6 and 12 months, respectively. CONCLUSIONS: Treatment with CRT improves exercise capacity but this increase is most substantial among patients with a lower baseline peak VO2 (% of predicted). Baseline CPX can, therefore, be utilized to identify patients more likely to exhibit a functional improvement after CRT.

Prognostic value of cardiac troponin T in patients with moderate to severe heart failure scheduled for cardiac resynchronization therapy.

BACKGROUND: Predicting response to cardiac resynchronization therapy (CRT) is challenging. Highly sensitive cardiac troponin T (hsTnT) might predict response to CRT and identify patients at a high risk of experiencing severe cardiovascular events. We investigated whether baseline levels of hsTnT were associated with response to CRT and with severe cardiovascular events after long-term follow-up. METHODS: Eighty-one consecutive patients were included according to the current guidelines for CRT. Biochemical, functional, and clinical parameters were assessed at baseline and at 3, 6, and 12 months of follow-up; and mortality/cardiac transplantation after 46 ± 6 months of follow-up was investigated. Cardiac magnetic resonance imaging and echocardiography were used to assess left ventricular function including viability and remodeling. RESULTS: Seventy-five patients completed 12 months of follow-up; and after a follow-up of 46 ± 6 months, a total of 15 patients died, 13 of these from cardiovascular causes, and 7 underwent heart transplantation. Baseline hsTnT <15 ng/L predicted response to CRT and was associated with a more favorable outcome with regard to severe cardiovascular events. Multivariate analysis found that presence of transmural scar tissue/fibrosis on magnetic resonance imaging and use of statins were independently associated with higher concentrations of hsTnT at baseline. There was a strong correlation between hsTnT and N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS: Highly sensitive TnT levels were elevated in the majority of heart failure patients who were scheduled for CRT. The HsTnT levels predicted response to CRT as well as long-time survival.