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Background: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations., Objective: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD)., Methods: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality., Results: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m 2 vs 2.02 [1.89-2.16] m 2 ; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; P interaction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality., Conclusion: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: CL reports receiving research support from the Swedish Heart Lung Foundation, Swedish Royal Society of Science, and Stockholm County Council, consulting fees from AstraZeneca and Roche Diagnostics, speaker's honoraria from Novartis, AstraZeneca, Bayer, Vifor Pharma and Medtronic, and Impulse Dynamics, and CL serves on advisory boards for AstraZeneca.

Background: Whether conduction system pacing (CSP) is an alternative option for cardiac resynchronization therapy (CRT) in patients with heart failure remains an area of active investigation., Objective: The purpose of this study was to assess the echocardiographic and clinical outcomes of CSP compared to biventricular pacing (BiVP)., Methods: This multicenter retrospective study included patients who fulfilled CRT indications and received CSP. Patients with CSP were matched using propensity score matching and compared in a 1:1 ratio to patients who received BiVP. Echocardiographic and clinical outcomes were assessed. Response to CRT was defined as an absolute increase of ≥5% in left ventricular ejection fraction (LVEF) at 6 months post-CRT., Results: A total of 238 patients were included. Mean age was 69.8 ± 12.5 years, and 66 (27.7%) were female. Sixty-nine patients (29%) had His-bundle pacing, 50 (21%) had left bundle branch area pacing, and 119 (50%) had BiVP. Mean follow-up duration in the CSP and BiVP groups was 269 ± 202 days and 304 ± 262 days, respectively (P = .293). The proportion of CRT responders was greater in the CSP group than in the BiVP group (74% vs 60%, respectively; P = .042). On Kaplan-Meier analysis, there was no statistically significant difference in the time to first heart failure hospitalization (log-rank P = .78) and overall survival (log-rank P = .68) between the CSP and BiVP groups., Conclusion: In patients with heart failure and reduced ejection fraction, CSP resulted in greater improvement in LVEF compared to BiVP. Large-scale randomized trials are needed to validate these outcomes and further investigate the different options available for CSP., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Iron deficiency (ID) is associated with adverse prognosis in patients with heart failure. This study aims to investigate the relationship between ID and expression of genes involved in iron metabolism in human myocardium and skeletal muscle, focusing on Transferrin 1 receptor (TfR1), the main pathway of cellular iron uptake., Methods: Patients undergoing elective CABG were assessed prior to surgery with echocardiography and serum iron parameters. Core needle biopsies were collected from the left and right ventricle (LV, RV), the right atrium and intercostal skeletal muscle (SM). Gene expression analyses were done by mRNA sequencing., Results: Of 69 patients (median age 69 years, 91% men), 28% had ID. 26% had HFrEF, 25% had HFpEF physiology according to echocardiographic findings and NT-proBNP levels, and 49% had normal LV function. The expression of TfR1 was increased in patients with ID compared to patients without ID in ventricular tissue (p = 0.04) and in intercostal SM (p = 0.01). The increase in TfR1 expression in LV and RV was more pronounced when analysing patients with absolute ID (S-Ferritin<100 μg/L). Analysing the correlation between various iron parameters, S-Ferritin levels showed the strongest correlation with TfR1 expression. There was no correlation with NT-proBNP levels and no difference in TfR1 expression between different HF phenotypes., Conclusions: In patients undergoing elective CABG we found an association between ID and increased TfR1 expression in myocardium regardless of LV function, indicating physiologically upregulated TfR1 expression in the presence of ID to restore intracellular iron needs., Clinical Trial Registration: Clinicaltrials.govNCT03671122., Competing Interests: Declaration of Competing Interest CC: Speaker honoraria from Astra Zeneca and Boeringer Ingelheim. CF: None. UL: None. PL: Speaker honoraria from Novartis. CL: Research grants from Roche diagnostics. Consulting fees from Astra Zeneca, Medtronic. Honoraria from Vifor, Medtronic, Novartis, Bayer, Boeringer Ingelheim, Impulse Dynamics, Astra Zeneca. CH: Consulting fees from Novartis, Roche Diagnostics and AnaCardio. Research grants from Bayer. Speaker honoraria from MSD and Novartis. HP: Research grants from Astra Zeneca. Speaker honoraria from Novartis, AstraZeneca, Bayer. MJE: None. HW: Speaker honoraria from Bayer and Astra Zeneca. BP: None. ME: Research grants from Novartis Foundation for Medical-Biological Research., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional end points, as well as mortality, may better assess CRT efficacy and inform patient management. However, the association between LV remodeling and functional outcomes after CRT is not well understood., Objective: The purpose of this study was to evaluate long-term CRT outcomes by extent of LV remodeling., Methods: REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction (ClinicalTrials.gov identifier NCT00271154) was a prospective, double-blind, randomized trial of CRT. Subjects were classified on the basis of LV end-systolic volume (LVESV) change from baseline to 6 months post-CRT: worsened (increase), stabilized (0%-≤15% reduction), responder (>15%-<30% reduction), and super-responder (≥30% reduction). Subjects were evaluated annually for 5 years., Results: The analyses included 353 subjects randomized to CRT-ON arm. All-cause mortality was higher in the worsened group than in the other 3 response groups (29.8% vs 8.0%; P < .0001), with no difference in survival among those groups (P = .87). A significant interaction between the LVESV group and time was observed for health status and quality of life (P = .02 for both). The interaction was not significant for 6-minute hall walk (P = .79); however, super-responders had increased walk distance compared with the other 3 response groups (P = .03)., Conclusion: Preventing further increase in LVESV with CRT was associated with reduced mortality, whereas functional measure improvement was associated with LV remodeling magnitude. These results support the consideration of functional and mortality end points to assess CRT efficacy and provide further evidence that the dichotomous "responder and nonresponder" classification should be modified., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary., Objective: We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations., Methods: Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios., Results: Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders., Conclusion: Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Conflicting data exist about the relationship between cardiac resynchronization therapy (CRT) and diastolic function. Aims of the study are to assess diastolic patterns in patients undergoing CRT according to the 2016 recommendations of the American Society of Echocardiography/European Association of Cardiovascular Imaging and to evaluate the prognostic value of diastolic dysfunction (DD) in CRT candidates. METHODS AND RESULTS: One-hundred ninety-three patients (age: 67 ± 11 years, QRS width: 167 ± 21 ms) were included in this multicentre prospective study. Mitral filling pattern, mitral tissue Doppler velocity, tricuspid regurgitation velocity, and indexed left atrial volume were used to classify DD from grade I to III. CRT-response, defined as a reduction of left ventricular (LV) end-systolic volume > 15% at 6-month follow-up (FU), occurred in 132 (68%) patients. The primary endpoint was a composite of heart transplantation, LV assisted device implantation, or all-cause death during FU and occurred in 29 (15%) patients. CRT was associated with a degradation of DD in non-responders. At multivariable analysis corrected for clinical variables, QRS duration, mitral regurgitation, CRT-response and LV dyssynchrony, grade I DD was associated with a better outcome (HR 0.37, 95% CI: 0.14-0.96). Non-responders with grade II-III DD had the worse prognosis (HR 4.36, 95%CI: 2.10-9.06). CONCLUSIONS: The evaluation of DD in CRT candidates allows the prognostic stratification of patients, independently from CRT-response., Competing Interests: Declaration of Competing Interest Nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: In Australia and Sweden, orthodontic treatments may be performed by either a general dental practitioner (GDP) or a specialist orthodontist. Evidence suggests that the public may easily confuse a GDP who provides orthodontic treatment with a specialist orthodontist. We conducted a survey of people in Australia and Sweden to assess their understanding of the differences between a specialist orthodontist and a GDP who provides orthodontic treatments., Methods: The sample comprised 2006 Australian adults and 1010 Swedish adults who completed an online questionnaire. The survey examined the respondents' understanding of the difference between a GDP and a specialist orthodontist. Demographic data and the respondents' preference concerning future practitioner type were also collected., Results: Although most of the responses between the countries were different with statistical significance (P <0.001), many similarities in the responses were observed. More than 90% of the respondents in both countries did not know the difference between a GDP who provides orthodontic treatment and a specialist orthodontist. Almost 75% believed that a specialist orthodontist was the most qualified practitioner to perform orthodontic treatment. Fewer than 10% of the respondents preferred to see a GDP for orthodontic treatment over a specialist. These people tended to be male, have less education, and be younger. Cost was identified as an important factor in choosing an orthodontic practitioner, particularly in the Australian sample., Conclusions: The clear majority of both Australian and Swedish respondents were unable to identify the difference between a specialist orthodontic and a GDP who provides orthodontic treatments., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Objective: The aim was to assess sex-specific differences in N-terminal B-type natriuretic peptide (NT-proBNP) regarding concentrations, predictors of high concentrations, and prognostic role, in a large and unselected population with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF)., Methods and Results: In 9847 outpatients with HFpEF, HFmrEF, and HFrEF (49 vs. 35 vs. 25% females, respectively) from the Swedish HF Registry, median NT-proBNP concentrations were 1598 ng/L in females vs. 1310 ng/L in males in HFpEF, 1764 vs. 1464 ng/L in HFmrEF, and 2543 vs. 2226 ng/L in HFrEF (p < 0.05 for all). The differences persisted after multiple adjustment. The largest sex-difference in NT-proBNP levels was observed in HFpEF with sinus rhythm, where median concentrations were 1.4 folds higher in females (923 vs. 647 ng/L). Independent predictors of NT-proBNP levels (defined as above the different medians according to sex and HF phenotype) were overall consistent across sexes and EF. NT-proBNP levels were similarly associated with risk of all-cause death/HF hospitalization in both sexes regardless of EF., Conclusion: Concentrations of NT-proBNP were higher in females across the EF spectrum, with larger relative differences in HFpEF with sinus rhythm. However, similar predictors of high levels were observed in both sexes. There were no sex-differences in the prognostic role of NT-proBNP. These findings support the use of NT-proBNP for prognostic purposes in chronic HF, regardless of sex., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: To study prevalence and prognostic importance of diagnostic echocardiographic variables in patients with suspected heart failure with preserved ejection fraction (HFpEF) in the prospective KaRen register study., Methods and Results: KaRen patients were included following an acute HF-presentation, using Framingham criteria, B-type natriuretic peptide (BNP) >100 ng/L or N-terminal pro-BNP (NT-pro-BNP) >300 ng/L, and left ventricular (LV) ejection fraction ≥45%. Echocardiography was performed after 4-8 weeks and analyzed at a core laboratory. In this substudy HFpEF was diagnosed according to the ESC guidelines for heart failure 2016. A total of 539 patients were included with a follow-up after 4-8 weeks in 438 patients. Complete echocardiography and ECG were available in 356 patients. At least two abnormal echocardiographic criteria for HFpEF were found in 94% (n = 333). Echocardiographic signs of structural heart disease and diastolic dysfunction according to 4 criteria by ESC were found in 76% (n = 270). Diastolic dysfunction was graded as mild in 30% (n = 107), moderate in 27% (n = 97) or severe in 35% (n = 124). After multivariate analyses with adjustment for age, gender, EF and natriuretic peptides we found two independent predictors of worse prognosis: presence of moderate and severe diastolic dysfunction (HR 1.8, CI 1.2-2.7, p = 0.0037) and presence of a high number (≥4) of abnormal diastolic parameters (HR 2.0, CI 1.3-3.1, p = 0.0033)., Conclusion: The majority of KaRen patients with suspected HFpEF had diagnostic echocardiographic criteria for HFpEF according to ESC Guidelines. Our findings support using 2016 ESC HF guidelines for risk prediction in HFpEF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Electrochemical activation of carbon dioxide in aqueous solution is a promising way to use carbon dioxide as a C1 building block. Mechanistic studies in the gas phase play an important role to understand the inherent chemical reactivity of the carbon dioxide radical anion. Here, the reactivity of CO 2 •- (H 2 O) n with 3-butyn-1-ol is investigated by Fourier transform ion cyclotron (FT-ICR) mass spectrometry and quantum chemical calculations. Carbon-carbon bond formation takes places, but is associated with a barrier. Therefore, bond formation may require uptake of several butynol molecules. The water molecules slowly evaporate from the cluster due to the absorption of room temperature black-body radiation. When all water molecules are lost, butynol evaporation sets in. In this late stage of the reaction, side reactions occur including H • atom transfer and elimination of HOCO • .

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with poor quality of life (QoL), or patient reported outcome (PRO). Despite female predominance in HFpEF, sex-specific differences in PROs remain poorly studied. We assessed PRO measures and their association with HF-severity and outcome in HFpEF by sex., Methods and Results: In 378 patients with HFpEF from the KaRen study, EQ-5D-3L® and Minnesota Living with Heart Failure Questionnaire® (MLHFQ) were assessed. Characteristics and comorbidities were largely similar in women (n = 212, 57%) and men. Women expressed worse QoL in EQ-5D-3L®(EQ-VAS), independent of age and HF-severity, mean (SD), 57 (20) vs. 61 (19), p = 0.010. There was no difference in MLHFQ, 31 (21) vs. 29 (21), p = 0.269. Spearman's correlations with HF-severity (NYHA-class) were for MLHFQ in women r s 0.37 vs. men 0.41, p for both <0.001, and for EQ-VAS r s -0.28, p = 0.001 vs. -0.45, p < 0.001. Correlations with natriuretic peptides were for MLHFQ r s 0.21, p = 0.003 in women vs. men 0.27, p < 0.001, and for EQ-VAS r s -0.17 vs. -0.27, p both < 0.001. Associations between PRO and the composite of HF hospitalisation or all-cause death were present in men only, adjusted HR per 5 units increase in MLHFQ 1.06, 95% confidence interval (CI) 1.01-1.11, p = 0.02 and EQ-VAS, HR 0.93, 95% CI 0.88-0.98, p = 0.010., Conclusion: In HFpEF, women had worse general but similar disease specific QoL compared to men. QoL was more strongly associated with HF-severity in men, and associated with outcomes only in men. In women with HFpEF, QoL appears less determined by HF itself and potentially more by other unknown factors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: This study compares and contrasts the recommended indications for cardiac resynchronization therapy (CRT) according to the most recent guidelines from international cardiology societies., Background: CRT has been shown to reduce morbidity and mortality in selected patients with systolic heart failure. Cardiology societies provide guidelines regarding the indications for CRT. As evidence evolves, it is challenging for the guideline committees to review the impact of newer evidence in a timely fashion., Methods: Six of the most recent international guidelines providing recommendation concerning CRT implantation ranging from 2011 to 2017 were reviewed. These included guidelines from 2 European, 1 North American, 1 Canadian, and 1 Australian/New Zealand societies and the National Institute for Health and Care Excellence guidelines, specific to the United Kingdom., Results: Although international societies provide consistent recommendations for most CRT indications, differences are found in recommendations for several important patient populations. Specifically, divergent recommendations exist regarding QRS duration, bundle branch morphology, patients in atrial fibrillation, choice of device type (CRT pacemakers vs. CRT defibrillators), and selected patients who are likely to be dependent on right ventricular pacing. The timing of publication of specific guidelines appears to play an essential role in explaining these disparities., Conclusions: Despite general consistency in international guideline recommendations, there remain certain patient populations for whom there are variations in recommendations concerning eligibility for CRT and selection of the most appropriate device in the individual patient., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3-5, 2015., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the effects of abnormal left ventricular (LV) architecture on cardiac remodeling and clinical outcomes in mild heart failure (HF)., Background: Cardiac resynchronization therapy (CRT) is an established treatment for HF that improves survival in part by favorably remodeling LV architecture. LV shape is a dynamic component of LV architecture on which contractile function depends., Methods: Transthoracic 2-dimensional echocardiography was used to quantify changes in LV architecture over 5 years of follow-up of patients with mild HF from the REVERSE study. REVERSE was a prospective study of patients with large hearts (LV end-diastolic dimension ≥55 mm), LV ejection fraction <40%, and QRS duration >120 ms randomly assigned to CRT-ON (n = 419) and CRT-OFF (n = 191). CRT-OFF patients were excluded from this analysis. LV dimensions, volumes, mass index, and LV ejection fraction were calculated. LV architecture was assessed using the sphericity index, as follows: (LV end-diastolic volume)/(4/3 × π × r 3 ) × 100%., Results: LV architecture improved over time and demonstrated significant associations between LV shape, age, sex, and echocardiography metrics. Changes in LV architecture were strongly correlated with changes in LV end-systolic volume index and LV end-diastolic volume index (both p < 0.0001). Sphericity index emerged as a predictor of death and HF hospitalization in spite of the low adverse event rate. A decrease in LV end-systolic volume index >15% occurred in more than two-thirds of patients, which indicates considerable reverse remodeling., Conclusions: We demonstrated that change in LV architecture in patients with mild HF with CRT is associated with structural and functional remodeling. Mean LV filling pressure was elevated, and the inability to lower it was an additional predictor of HF hospitalization or death. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with reduced ejection fraction (HFrEF) exhibits a "reverse metabolic profile". Whether this profile exists in HF with preserved ejection fraction (HFpEF) is unknown. We tested the hypothesis that HFpEF and HFrEF are similar regarding concentrations of and prognostic impact of leptin and adiponectin., Methods: In patients with HFpEF(n=79), HFrEF(n=84), and controls(n=71), we analyzed serum leptin and adiponectin concentrations, their correlations, and associations with outcome., Results: Leptin levels in HFpEF and HFrEF were increased (p<0.05) compared to controls; with the highest levels in HFpEF, median (IQR), 23.1 (10.2-51.0), vs. HFrEF 15.0 (6.2-33.2), and vs. controls 10.8 (5.4-18.9) ng/mL.There was no difference between HFpEF and HFrEF p=0.125 (adjusted for gender, BMI and age). Leptin was inversely associated with NT-proBNP (r=-0.364 p=0.001) and associated with better outcome in HFrEF (HR per ln increase of leptin 0.76, 95% CI 0.58-0.99, p=0.044) but not in HFpEF. Crude levels of adiponectin were similar in HFpEF: 11.8 (7.9-20.1), HFrEF: 13.7 (7.0-21.1), and controls: 10.5 (7.4-15.1) μg/L. In men, adjusted similarly as leptin, there was no difference between HFpEF and HFrEF, p=0.310 but, compared to controls, higher levels in HFpEF (p=0.044) and HFrEF (p=0.001). Adiponectin correlated positively with NT-proBNP; r=0.396 p<0.001 and higher levels were associated with adverse outcome only in HFrEF (HR per ln increase 2.88 (95% CI 1.02-8.14, p=0.045)., Conclusion: HFpEF and HFrEF share elevated levels of leptin and adiponectin. However, the concept of reverse metabolic profile could not be confirmed in HFpEF, suggesting that HFpEF might have a conventional metabolic profile, rather than a distinct HF syndrome., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In acute decompensated heart failure (ADHF) with preserved ejection fraction (HFpEF) there are no surrogate endpoints for early phase trials. The aim of the current study was to evaluate whether a reduction in natriuretic peptides (NP) between acute hospital presentation to stable follow-up is associated with improved mortality and morbidity., Methods: Patients presenting acutely to the hospital for ADHF with HFpEF enrolled in the Karolinska Rennes (KaRen) study and reporting N-terminal pro-B-type NP or B-type NP assessment at baseline hospital presentation and at 4-8weeks follow-up were prospectively studied. Logistic regression analyses were performed to detect the predictors of baseline and changes in NPs. Cox regression models were performed to assess the impact of NP reductions on mortality and the composite of mortality and HF hospitalization., Results: Of 361 patients (median follow-up 585days), 267 (74%) reported an improvement in NPs, while 94 (26%) reported worsening. At baseline, the independent predictors of lower NPs were higher glomerular filtration rate (Odds Ratio [OR] per unit: 1.013; 95% Confidence Interval [CI]: 1.005-1.021) and younger age (OR per year: 0.972; CI: 0.947-0.998). Improvement in NPs at follow-up was predicted by higher heart rate at baseline (OR per bpm: 1.014; CI: 1.003-1.025). After adjustments, the hazard ratio for all-cause death was 0.730 (CI: 0.456-1.169) and for the composite outcome 0.814 (CI: 0.582-1.139) for patients who improved vs. worsened in NP levels., Conclusions: In patients presenting acutely to the hospital with HFPEF, an improvement in NP levels did not independently and significantly predict improved mortality and/or morbidity. NPs as surrogate endpoints in acute HFpEF require further study., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5-7, 2014., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The primary objective of the study was a change in left ventricular end-systolic volume index (LVESVi) from baseline to 6 months of spinal cord stimulation (SCS) therapy in the treatment arm compared to the control arm as measured by echocardiography. Secondary objectives were changes in peak oxygen uptake and N-terminal pro-B-type natriuretic peptide (NT-proBNP) between the treatment arm and control arm from baseline through 6 months., Background: Abnormal neurohormonal activation is often responsible for progression of heart failure (HF). Treatment has often included drug therapy to modulate the neurohormonal axis. The purpose of the DEFEAT-HF (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure) clinical study was to evaluate whether direct modulation of the nervous system through SCS improved HF metrics, including heart size, biomarkers, functional capacity, and symptoms., Methods: The DEFEAT-HF study was a prospective, multicenter randomized (3:2), parallel, single-blind, controlled study to investigate whether SCS was a feasible therapy for the treatment of systolic HF for patients with New York Heart Association functional class III HF, left ventricular ejection fraction (LVEF) ≤35%, QRS duration <120 ms, and left ventricular end-diastolic dimension ≥55 mm. The primary objective of the DEFEAT-HF study was to evaluate the reduction in LVESVi after 6 months of SCS therapy in the treatment arm compared to the control arm., Results: In total, 81 patients were enrolled, with 66 successfully randomized and implanted with the SCS device system. Seventy-six percent (50 of 66) had an implantable cardioverter-defibrillator at the baseline visit. Among randomized patients, the mean age was 61 years, 79% were male, mean LVEF was 27%, and mean QRS duration was 105 ms. The change in LVESVi over 6 months was not significantly different between randomization arms (SCS OFF: -2.2 [95% confidence interval: -9.1 to 4.6] vs., Scs on: 2.1 [95% confidence interval: -2.7 to 6.9]; p = 0.30). Analyses of secondary endpoints for the study were also not significantly different., Conclusions: The present study does not provide evidence to support a meaningful change in clinical outcomes for HF patients receiving SCS. (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure [DEFEAT-HF]; NCT01112579)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The benefits of CRT for symptomatic heart failure (HF) patients with a wide QRS and reduced left ventricular ejection fraction (LVEF≤35%), are well established .Post-hoc subgroup analyses suggest that CRT benefit may extend to patients with LVEF>35%., Methods: The MIRACLE EF was a prospective, randomized, controlled, double-blinded study to evaluate CRT-P in NYHA II-III HF patients with LBBB and with LVEF of 36%-50% and no previous pacing or ICD. The primary endpoint was a composite of time to first HF event or death. All patients were implanted with a CRT-P and randomized 2:1 to CRT-P ON or CRT-P OFF groups. The minimum follow up time was 24 months., Results: The MIRACLE EF study was stopped for enrollment futility after 13 months and enrolling only 44 patients. The main difficulties in recruiting patients were lack of eligible patients, previous ICD implants, and the reluctance of institutions, patients or physicians to enroll in the study which included a potential 5 year CRT OFF period., Conclusion: Despite a careful design, identification and randomization of eligible patients were challenging and a trial to assess morbidity and mortality trial was not feasible. The MIRACLE EF experience illustrates the difficulties of designing a scientifically robust but feasible study to assess potential new indications for implantable devices. Smaller randomized studies with surrogate endpoints may therefore be more reasonable, although the potential impact of such studies on clinical practice, guidelines, and reimbursement remain to be determined., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objectives: This study examined the time course of clinical events in cardiac resynchronization therapy (CRT) trials., Background: Recent randomized controlled trial results suggest that in heart failure with narrow QRS, biventricular pacing (CRT) may increase mortality. The authors proposed implant complications as the cause, rather than a progressive adverse physiological effect., Methods: The study identified all trials comparing CRT with no CRT, which reported Kaplan-Meier curves in groups defined by QRS: narrow, non-left bundle branch block (LBBB) broad, and LBBB broad. For each trial, the change in life span every 3 months up to 3.5 years (the longest time for which data are available) was calculated and a power law was fitted, that is, ∝ time(n)., Results: Four trials (MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure Trial], REVERSE [REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction], and EchoCRT [Echocardiography Guided Cardiac Resynchronization Therapy]), totaling 4,717 patients, reported curves for mortality or heart failure-related hospitalization, or for mortality. In patients with LBBB broad QRS (within MADIT-CRT), life span gain increased in proportion to time(1.94). In contrast, in patients with non-LBBB broad QRS (within MADIT-CRT) and patients with narrow QRS (EchoCRT), life span was lost in proportion to time(1.92) and time,(1.96) respectively. Hospitalization-free survival showed similar patterns., Conclusions: The nonlinear growth of life span gained when a CRT device is implanted in patients with LBBB broad QRS is unfortunately mirrored by a similarly progressive loss in life span in narrow QRS heart failure. This suggests the culprit is a progressive physiological effect of pacing rather than implant complications. If these data are not sufficient, a randomized controlled trial of deactivating CRT in patients with narrow QRS may now be needed, with a primary endpoint of increasing survival., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) reduces mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure (HF). The magnitude of reverse remodeling predicts survival with many HF medical therapies. However, there are few studies assessing the effect of remodeling on long-term survival with CRT., Objective: The purpose of this study was to assess the effect of CRT-induced reverse remodeling on long-term survival in patients with mildly symptomatic heart failure., Methods: The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial was a multicenter, double-blind, randomized trial of CRT in patients with mild HF. Long-term follow-up of 5 years was preplanned. The present analysis was restricted to the 353 patients who were randomized to the CRT ON group with paired echocardiographic studies at baseline and 6 months postimplantation. The left ventricular end-systolic volume index (LVESVi) was measured in the core laboratory and was an independently powered end point of the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial., Results: A 68% reduction in mortality was observed in patients with ≥15% decrease in LVESVi compared to the rest of the patients (P = .0004). Multivariable analysis showed that the change in LVESVi was a strong independent predictor (P = .0002), with a 14% reduction in mortality for every 10% decrease in LVESVi. Other remodeling parameters such as left ventricular end-diastolic volume index and ejection fraction had a similar association with mortality., Conclusion: The change in left ventricular end-systolic volume after 6 months of CRT is a strong independent predictor of long-term survival in mild HF., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background/objectives: In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized., Methods: We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression., Results: In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p < 0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p < 0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p < 0.001 overall and p = 0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not., Conclusions: Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

In this article an international group of CRT specialists presents a comprehensive classification system for present and future schemes for optimising CRT. This system is neutral to the measurement technology used, but focuses on little-discussed quantitative physiological requirements. We then present a rational roadmap for reliable cost-effective development and evaluation of schemes. A widely recommended approach for AV optimisation is to visually select the ideal pattern of transmitral Doppler flow. Alternatively, one could measure a variable (such as Doppler velocity time integral) and "pick the highest". More complex would be to make measurements across a range of settings and "fit a curve". In this report we provide clinicians with a critical approach to address any recommendations presented to them, as they may be many, indistinct and conflicting. We present a neutral scientific analysis of each scheme, and equip the reader with simple tools for critical evaluation. Optimisation protocols should deliver: (a) singularity, with only one region of optimality rather than several; (b) blinded test-retest reproducibility; (c) plausibility; (d) concordance between independent methods; and (e) transparency, with all steps open to scrutiny. This simple information is still not available for many optimisation schemes. Clinicians developing the habit of asking about each property in turn will find it easier to win now down the broad range of protocols currently promoted. Expectation of a sophisticated enquiry from the clinical community will encourage optimisation protocol-designers to focus on testing early (and cheaply) the basic properties that are vital for any chance of long term efficacy., (© 2013.)

Objectives: We sought a method for any reader to quantify the limit, imposed by variability, to sustainably observable R(2) between any baseline predictor and response marker. We then apply this to echocardiographic measurements of mechanical dyssynchrony and response., Background: Can mechanical dyssynchrony markers strongly predict ventricular remodeling by biventricular pacing (cardiac resynchronization therapy)?, Methods: First, we established the mathematical depression of observable R(2) arising from: 1) spontaneous variability of response markers; and 2) test-retest variability of dyssynchrony measurements. Second, we contrasted published R(2) values between externally monitored randomized controlled trials and highly skilled single-center studies (HSSCSs)., Results: Inherent variability of response markers causes a contraction factor in R(2) of 0.48 (change in left ventricular ejection fraction [ΔLVEF]), 0.50 (change in end-systolic volume [ΔESV]), and 0.40 (change in end-diastolic volume [ΔEDV]). Simultaneously, inherent variability of mechanical dyssynchrony markers causes a contraction factor of between 0.16 and 0.92 (average, 0.6). Therefore the combined contraction factor, that is, limit on sustainably observable R(2) between mechanical dyssynchrony markers and response, is ~0.29 (ΔLVEF), ~0.24 (ΔESV), and ~0.30 (ΔEDV). Many R(2) values published in HSSCSs exceeded these mathematical limits; none in externally monitored trials did so. Overall, HSSCSs overestimate R(2) by 5- to 20-fold (p = 0.002). Absence of bias-resistance features in study design (formal enrollment and blinded measurements) was associated with more overstatement of R(2)., Conclusions: Reports of R(2) > 0.2 in response prediction arose exclusively from studies without formally documented enrollment and blinding. The HSSCS approach overestimates R(2) values, frequently breaching the mathematical ceiling on sustainably observable R(2), which is far below 1.0, and can easily be calculated by readers using formulas presented here. Community awareness of this low ceiling may help resist future claims. Reliable individualized response prediction, using methods originally designed for group-mean effects, may never be possible because it has 2 currently unavailable and perhaps impossible prerequisites: 1) excellent blinded test-retest reproducibility of dyssynchrony; and 2) response markers reproducible over time within nonintervened individuals. Dispassionate evaluation, and improvement, of test-retest reproducibility is required before any further claims of strong prediction. Prediction studies should be designed to resist bias., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Over the last 10 years, several large, well-designed clinical trials have firmly established the role of cardiac resynchronization therapy (CRT) as a recommended treatment strategy for moderate-to-severe heart failure (HF). A review of the relevant results from the MUSTIC, MIRACLE, CONAK-CD, and MIRACLE ICD trials reveals that in patients with New York Heart Association (NYHA) class III-IV HF, CRT produces consistent improvements in quality of life, functional status, and exercise capacity while also providing strong evidence for reverse remodeling and diminished functional mitral regurgitation, resulting in reductions in both HF hospitalizations and all-cause morbidity and mortality. In patients with earlier NYHA class I-II HF, the benefit of CRT has been more controversial. The principal ongoing challenges addressed in this article include the substantial 30% of patients who receive a CRT device but fail to respond, the wide variations in how to define "response" vs "nonresponse," and how to identify patients who will benefit from CRT, especially narrow QRS (<120 ms), those with right bundle branch block, and those with mild-to-moderate (NYHA class I-II) HF. An important result of this uncertainty is the lack of a good sense of the optimal rate of CRT implantation, making consideration of the data reviewed in this article crucial for identifying important gaps of knowledge and mechanisms of action that need to be studied in the near future., (Copyright © 2012 Heart Rhythm Society. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular (LV) remodeling in selected populations. However, the effect of CRT on ventricular arrhythmias is controversial. This is particularly important among patients with mild heart failure (HF), in whom sudden death is a leading cause of mortality., Objective: This study sought to assess the impact of CRT on ventricular arrhythmias in mild HF., Methods: The REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study is a multicenter randomized, double-blind trial of CRT among patients with mild systolic HF. The time to first appropriate, treated ventricular tachycardia/ventricular fibrillation (VT/VF) episode or spontaneous sustained VT in cardiac resynchronization therapy plus defibrillation device (CRT-D) patients was compared between groups, as were predictors of VT/VF., Results: The study randomized 508 patients who received CRT-D devices. There were no significant demographic differences between groups. There were no differences in VT/VF episodes or VT storm between groups. Specifically, in the CRT ON group, the estimated event rate was 18.7% at 2 years, compared with 21.9% in the CRT OFF group (hazard ratio 1.05, P = .84). However, among CRT ON patients, those with reverse remodeling had a reduced incidence of VT/VF compared with those without remodeling (5.6% vs. 16.3%, hazard ratio 0.31, P = .001)., Conclusion: CRT for up to 2 years does not impact VT/VF in mild HF despite marked clinical and remodeling effects of pacing. This neutral effect may be attributable to competing antiarrhythmic effects of reverse remodeling and proarrhythmic effect of pacing., Clinical Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00271154., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Previously it was shown that the antimicrobial protein granulysin possesses potent membranolytic activity against Mycobacterium tuberculosis. Here we demonstrate that granF2 and G13, which are two short synthetic peptides derived from granulysin, inhibited the in vitro growth of clinical isolates of both multidrug resistant and drug susceptible strains of M. tuberculosis. Importantly, a particularly high activity against multidrug resistant M. tuberculosis correlated with a reduced growth rate compared to drug susceptible strains. A synergistic antibacterial effect of granF2 was further observed in combination with ethambutol, a compound with a documented effect on cell wall permeability. This finding suggests that granF2 and ethambutol exert their functions at different levels of the mycobacterial surface. Upon infection of macrophages in vitro, granF2 but not G13 efficiently reduced the intracellular growth of multidrug resistant M. tuberculosis in the presence of the pore-forming protein streptolysin O. The apoptotic function of granF2 apparently promoted destruction of host cells whereby the peptide gained access to and killed intracellular bacteria. Thus, a cost of resistance and a subsequent reduced fitness, measured as decreased growth among multidrug resistant strains of M. tuberculosis, could be associated with increased susceptibility to natural immune defense mechanisms, such as antimicrobial peptides of granulysin. However, a robust cell wall and the membrane of cells still provide physical shelter for the bacteria that may spare sensitive M. tuberculosis stains from being killed.

Objectives: The purpose of this study was to assess the temporal characteristics of cardiac memory in a human pacing model., Background: Cardiac memory is induced by periods of altered ventricular activation and in the canine pacing model develops in 2 to 3 weeks., Methods: Cardiac memory development (phase 1) and resolution (phase 2) was followed qualitatively (ECG) and quantitatively (vectorcardiography [VCG]) in 20 patients with symptomatic sinus bradycardia receiving DDD-R pacing at physiologic rates. During phase 1, maximum ventricular pacing in the right ventricular apical endocardium was achieved by short AV delay. ECG and VCG were recorded during normal ventricular activation prior to implantation (sinus rhythm), 1 day after and then weekly for 5 to 8 weeks during AAI pacing (n = 14, "long-term"), and daily during 1 week (n = 6, "short-term"). In phase 2, the remaining cardiac memory was related to the amount of ventricular pacing. A long AV delay was chosen to reduce ventricular pacing, and 14 patients were seen once after 4 to 5 weeks., Results: ECG and VCG showed marked changes in all patients within 1 week's pacing and remained stable during phase 1. Of the 14 long-term patients, 13 showed significant change in T vector azimuth (mean -150 degrees ) and 11 in T vector elevation (mean 63 degrees ). At the end of phase 2, a linear relation existed between remaining cardiac memory (%) and amount (%) of delivered ventricular pacing., Conclusions: Cardiac memory developed and reached steady state within 1 week of right ventricular endocardial pacing at physiologic rates in man, was preserved in proportion to delivered ventricular pacing, and completely resolved within 1 month in its absence.