Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling

Aims Chronic right ventricular (RV) pacing may impose ventricular dyssynchrony leading to LV remodelling and is associated with increased morbidity and mortality. Upgrading patients with chronic RV pacing to cardiac resynchronization therapy (CRT) may be considered to restore synchronicity and prevent these deleterious effects. Methods and results A total of 172 patients from two tertiary centres were analysed over a mean follow-up of 21.7 and 23.5 months after primary CRT implantation (n = 102) and CRT upgrade (n = 70), respectively. In the latter group, mean duration of RV pacing before CRT upgrade was 80.3 months, and ventricular stimulation was >95%. A significant improvement in left ventricular (LV) ejection fraction (10 and 11% absolute increase in primary CRT vs. upgrades, respectively), LV end-diastolic diameter index (−0.15 cm/m2 vs. −0.2 cm/m2), and LV end-systolic diameter (−6.0 vs. −7.0 mm) was observed in both groups, which did not differ between primary CRT recipients and CRT upgrades. Response to CRT upgrade was independent of the underlying rhythm, QRS duration, duration of prior RV pacing, or LV function and size at baseline. Of note, even seven of nine patients with RV pacing >12 years responded favourably to CRT. Conclusion The current study demonstrates that CRT reverses LV remodelling in heart failure patients with chronic RV pacing in a similar way as in primary CRT recipients, even after very long periods of RV pacing. Our data, therefore, may have important implications for the treatment of pacemaker-dependent patients with heart failure, and support the use of CRT in this settin

Effects of AV delay programming on ventricular resynchronisation: role of radionuclide ventriculography

Purpose: Optimal atrioventricular delay (AVD) setting for cardiac resynchronisation therapy, i.e. biventricular pacing in patients with heart failure, remains a formidable challenge. Thus, the purpose of this study was to evaluate the effects of different AVD on inter- and intra-ventricular resynchronisation using phase histograms of radionuclide ventriculography (RNV). Methods: In 17 consecutive patients (mean age 64 ± 6years), RNV was performed 236 ± 350days after pacemaker implantation for cardiac resynchronisation therapy. Images were acquired during atrial pacing at 80bpm and during biventricular pacing with AVD ranging from 80 to 160ms. Inter-ventricular dyssynchrony was measured by the delay between the mean phase angles of the left and right ventricles. Intra-ventricular dyssynchrony was measured by the standard deviation (SD) of left ventricular phase histograms. Results: Left ventricular (LV) ejection fraction (EF) was inversely correlated to LV dyssynchrony (SD of LV phase histogram, R = −0.82, p < 0.0001). However, the increase in LVEF by biventricular pacing (mean +4.4 ± 4%) showed only modest correlation to the resulting resynchronisation effect (characterised by a −13 ± 8° decrease in LV phase histogram SD, R = −0.38, p < 0.0001). Conclusion: RNV is helpful in optimising pacing parameters for resynchronisation therapy. Varying AVD did not have a major impact on intra- or inter-ventricular resynchronisation. Thus, the benefit of AVD-based LVEF optimisation seems to result from atrioventricular resynchronisatio

Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial

Aim: Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. Methods and results: Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4- and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2–10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04–1.17, P &lt; 0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (&lt;6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P = 0.009) whereas, no differences were observed in patients with LV GLS ≥6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P  = 0.62). Conclusion: Low LV GLS is associated with poor outcome in heart failure patients with QRS width &lt;130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes

Association of intraventricular mechanical dyssynchrony with response to cardiac resynchronization therapy in heart failure patients with a narrow QRS complex

Aims Current criteria for cardiac resynchronization therapy (CRT) are restricted to patients with a wide QRS complex (>120 ms). Overall, only 30% of heart failure patients demonstrate a wide QRS complex, leaving the majority of heart failure patients without this treatment option. However, patients with a narrow QRS complex exhibit left ventricular (LV) mechanical dyssynchrony, as assessed with echocardiography. To further elucidate the possible beneficial effect of CRT in heart failure patients with a narrow QRS complex, this two-centre, non-randomized observational study focused on different echocardiographic parameters of LV mechanical dyssynchrony reflecting atrioventricular, interventricular and intraventricular dyssynchrony, and the response to CRT in these patients. Methods and results A total of 123 consecutive heart failure patients with a narrow QRS complex (<120 ms) undergoing CRT was included at two centres. Several widely accepted measures of mechanical dyssynchrony were evaluated: LV filling ratio (LVFT/RR), LV pre-ejection time (LPEI), interventricular mechanical dyssynchrony (IVMD), opposing wall delay (OWD), and anteroseptal posterior wall delay with speckle tracking (ASPWD). Response to CRT was defined as a reduction ≥15% in left ventricular end-systolic volume at 6 months follow-up. Measures of dyssynchrony can frequently be observed in patients with a narrow QRS complex. Nonetheless, for LVFT/RR, LPEI, and IVMD, presence of predefined significant dyssynchrony is <20%. Significant intraventricular dyssynchrony is more widely observed in these patients. With receiver operator characteristic curve analyses, both OWD and ASPWD demonstrated usefulness in predicting response to CRT in narrow QRS patients with a cut-off value of 75 and 107 ms, respectively. Conclusion Mechanical dyssynchrony can be widely observed in heart failure patients with a narrow QRS complex. In particular, intraventricular measures of mechanical dyssynchrony may be useful in predicting LV reverse remodelling at 6 months follow-up in heart failure patients with a narrow QRS complex, but with more stringent cut-off values than currently used in ‘wide' QRS patient

The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial

Aims In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms. Methods and results The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160). Conclusions In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient populatio

Cardiac resynchronization therapy in patients with heart failure and narrow QRS complexes

Background: Cross correlation analysis (CCA) using tissue Doppler imaging has been shown to be associated with outcome after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with wide QRS. However, its significance in patients with narrow QRS treated with CRT is unknown. Objectives: The aim of the current study was to investigate the association of mechanical activation delay by CCA with study outcome in patients with HF enrolled in the EchoCRT trial. Methods: Baseline CCA could be performed from tissue Doppler imaging in the apical views in 807 of 809 (99.7%) enrolled patients, and 6-month follow-up could be performed in 610 of 635 (96%) patients with available echocardiograms. Patients with a pre-specified maximal activation delay ≥35 ms were considered to have significant delay. The study outcome was HF hospitalization or death. Results: Of 807 patients, 375 (46%) did not have delayed mechanical activation at baseline by CCA. Patients without delayed mechanical activation who were randomized to CRT-On compared with CRT-Off had an increased risk of poor outcome (hazard ratio: 1.70; 95% confidence interval: 1.13 to 2.55; p = 0.01) with a significant interaction term (p = 0.04) between delayed mechanical activation and device randomization for the endpoint. Among patients with paired baseline and follow-up data with no events before 6-month follow-up (n = 541), new-onset delayed mechanical activation in the CRT-On group showed a significant increase in unfavorable events (hazard ratio: 3.73; 95% confidence interval: 1.15 to 12.14; p = 0.03). Conclusions: In the EchoCRT population, absence of delayed mechanical activation by CCA was significantly associated with poor outcomes, possibly due to the onset of new delayed mechanical activation with CRT pacing. (Echocardiography Guided Cardiac Resynchronization Therapy [EchoCRT] Trial; NCT00683696)

Treatments targeting inotropy

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.Peer reviewe

Examining the generalizability of research findings from archival data

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples