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 < 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 (<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 <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

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)

Interaction of Left Ventricular Size and Sex on Outcome of Cardiac Resynchronization Therapy Among Patients With a Narrow QRS Duration in the EchoCRT Trial

Cardiolog

Controlled reduction of photobleaching in DNA origami gold nanoparticle hybrids

The amount of information obtainable from a fluorescence-based measurement is limited by photobleaching: Irreversible photochemical reactions either render the molecules nonfluorescent or shift their absorption and/or emission spectra outside the working range. Photobleaching is evidenced as a decrease of fluorescence intensity with time, or in the case of single molecule measurements, as an abrupt, single-step interruption of the fluorescence emission that determines the end of the experiment. Reducing photobleaching is central for improving fluorescence (functional) imaging, single molecule tracking, and fluorescence-based biosensors and assays. In this single molecule study, we use DNA self-assembly to produce hybrid nanostructures containing individual fluorophores and gold nanoparticles at a controlled separation distance of 8.5 nm. By changing the nanoparticles? size we are able to systematically increase the mean number of photons emitted by the fluorophores before photobleaching.Fil: Pellegrotti, Jesica Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Acuña, Guillermo. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; AlemaniaFil: Puchkova, Anastasiya. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; AlemaniaFil: Holzmeister, Phil. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; AlemaniaFil: Gietl, Andreas. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; AlemaniaFil: Lalkens, Birka. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; AlemaniaFil: Stefani, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Tinnefeld, Philip. Technische Universität Braunschweig. Institute for Physical and Theoretical Chemistry. NanoBioSciences Group; Alemani

Cardiac-resynchronization therapy in heart failure with a narrow QRS complex.

BACKGROUND: Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS: We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS: On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). CONCLUSIONS: In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, 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

Variability in the analysis of a single neuroimaging dataset by many teams

Data analysis workflows in many scientific domains have become increasingly complex and flexible. To assess the impact of this flexibility on functional magnetic resonance imaging (fMRI) results, the same dataset was independently analyzed by 70 teams, testing nine ex-ante hypotheses. The flexibility of analytic approaches is exemplified by the fact that no two teams chose identical workflows to analyze the data. This flexibility resulted in sizeable variation in hypothesis test results, even for teams whose statistical maps were highly correlated at intermediate stages of their analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Importantly, meta-analytic approaches that aggregated information across teams yielded significant consensus in activated regions across teams. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytic flexibility can have substantial effects on scientific conclusions, and demonstrate factors related to variability in fMRI. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for multiple analyses of the same data. Potential approaches to mitigate issues related to analytical variability are discussed

Variability in the analysis of a single neuroimaging dataset by many teams

Data analysis workflows in many scientific domains have become increasingly complex and flexible. To assess the impact of this flexibility on functional magnetic resonance imaging (fMRI) results, the same dataset was independently analyzed by 70 teams, testing nine ex-ante hypotheses. The flexibility of analytic approaches is exemplified by the fact that no two teams chose identical workflows to analyze the data. This flexibility resulted in sizeable variation in hypothesis test results, even for teams whose statistical maps were highly correlated at intermediate stages of their analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Importantly, meta-analytic approaches that aggregated information across teams yielded significant consensus in activated regions across teams. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytic flexibility can have substantial effects on scientific conclusions, and demonstrate factors related to variability in fMRI. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for multiple analyses of the same data. Potential approaches to mitigate issues related to analytical variability are discussed