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A role for inflammation in the development and progression of heart failure (HF) has been proposed for decades. Multiple studies have demonstrated the potential involvement of several groups of cytokines and chemokines in acute and chronic HF, though targeting these pathways in early therapeutic trials have produced mixed results. These studies served to highlight the complexity and nuances of how pro-inflammatory pathways contribute to the pathogenesis of HF. More recent investigations have highlighted how inflammation may play distinct roles based on HF syndrome phenotypes, findings that may guide the development of novel therapies. In this review, we propose a contemporary update on the role of inflammation mediated by the innate and adaptive immune systems with HF, highlighting differences that exist across the ejection fraction spectrum. This will specifically be looked at through the lens of established and novel biomarkers of inflammation. Subsequently, we review how improvements in inflammatory pathways may mediate clinical benefits of existing guideline-directed medical therapies for HF, as well as future therapies in the pipeline targeting HF and inflammation., (© 2024. The Author(s).)

Background: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF)., Methods: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves., Results: Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p < 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p < 0.05., Conclusion: Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes., Competing Interests: Declaration of Competing Interest MJ, AF, MTG, JL, MCP, CA, MW, GG, NR have no conflicts of interest to declare. DB: Moderator-presentation by Novartis. SdD: Grants-Pfizer, AstraZeneca, Roche Molecular Science, DalCor. NB: Personal fees-AstraZeneca (2019). SL: Research-Amgen and Novartis; Presentation-Bayer, Novartis, BI, Servier; Advisory board-Novartis, BI. ML: Speaker-Novartis. EOM: Consulting Fees/Honoraria-AstraZeneca, BI, BMS/Pfizer Alliance, Novartis, Amgen, Bayer, Merck; Funded grants/clinical trials-AstraZeneca, BI, BMS/Pfizer Alliance, Novartis, Amgen, Bayer, Merck, American Regent, Abbott, Cytokinetics, Eidos, Sanofi. PG: Research funding-Medtronic, Abbott Cardiovascular; Speaker-Abbott Cardiovascular. JLR: Consultant-Novartis, Bayer, Aventis, BMS, AstraZeneca. AD: Speaker bureau/adboard-Abbott, Akcea, Alnylam, AstraZeneca, Bayer BI, Novartis, Pfizer, Servier; Research support/grants-Abbott, AstraZeneca, Bayer, Corvia, Eidos, Novartis, Pfizer, Servier., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth factor levels were similar in CTL and patients with DM but were decreased in patients with HFpEF with/without DM (up to 94%; p ≤0.001). Circulating C-reactive protein, interleukin (IL)-8, IL-6, and IL-receptor antagonist increased in all patient groups with a maximum of 3.3-fold, 4.7-fold, 4.8-fold, and 1.6-fold, respectively, in patients with HFpEF and patients with DM. In vitro, lipopolysaccharide increased neutrophils IL-6 release from HFpEF with DM (3.7-fold; p ≤0.001), and IL-8 release from DM and HFpEF with DM versus CTL (2.8-fold and 10.1-fold, respectively; p ≤0.001). IL-1 receptor antagonist and vascular endothelial growth factor release from HFpEF neutrophils significantly decreased up to 87.0% and 92.2%, respectively, versus CTL. Neutrophils from patients with DM and HFpEF release more cytokines than CTL. This increase in pro-inflammatory status may explain the greater event rate in patients with HFpEF and DM., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Heart failure with reduced ejection fraction (HFrEF) is characterized by sub-clinical inflammation. Changes in selected biomarkers of inflammation concomitant with the release of pro-inflammatory and anti-inflammatory cytokines by neutrophils have not been investigated in patients with HFrEF., Methods and Results: Fifty-two patients, aged 68.8 ± 1.7 years, with HFrEF and left ventricular ejection fraction 28.7 ± 1.0%, and 21 healthy controls (CTL) were recruited. Twenty-five HF patients had type 2 diabetes. Venous blood samples from HF and CTL were collected once. Neutrophil-derived pro-inflammatory and anti-inflammatory cytokine levels were assessed in plasma by ELISA. Plasma biomarkers assessed included: C-reactive protein (CRP), vascular endothelial growth factor (VEGF), interleukins (IL)-6, -8, -1 receptor antagonist (-1RA), nitric oxide (NO), soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1) and E-Selectin (sE-Sel). Neutrophils were isolated and stimulated with various agonists to promote VEGF, IL-6, IL-8, and IL-1RA release. Compared with CTL, HFrEF patients showed a marked decrease in circulating VEGF [178.0 (interquartile range; IQR 99.6; 239.2) vs. 16.2 (IQR 9.3; 20.2) pg/mL, P ≤ 0.001] and NO [45.2 (IQR 42.1; 57.6) vs. 40.6 (IQR 30.4; 47.1) pg/mL, P = 0.0234]. All other circulating biomarkers were significantly elevated. Neutrophils isolated from patients with HFrEF exhibited a greater IL-8 release in response to LPS [1.2 ± 0.1 (CTL); 10.4 ± 1.6 ng/mL (HFrEF) and 12.4 ± 1.6 ng/mL (HFrEF and DM), P ≤ 0.001]. IL-6 release in response to LPS was not changed in HFrEF patients without diabetes, whereas it was significantly increased in patients with HFrEF and diabetes [46.7 ± 3.9 (CTL) vs. 165.8 ± 48.0 pg/mL (HFrEF), P = 0.1713 and vs. 397.7 ± 67.4 pg/mL (HFrEF and DM), P ≤ 0.001]. In contrast, the release of VEGF and IL-1RA was significantly reduced in HFrEF (VEGF; TNF-α: 38.6 ± 3.1 and LPS: 25.3 ± 2.6 pg/mL; IL1RA; TNF-α: 0.6 ± 0.04 and LPS: 0.3 ± 0.02 ng/mL) compared with CTL (VEGF; TNF-α: 60.0 ± 9.4 and LPS: 41.2 ± 5.9 pg/mL; IL1RA; TNF-α: 3.3 ± 0.2 and LPS: 2.3 ± 0.1 ng/mL)., Conclusions: Patients with HFrEF exhibit a significant decrease in circulating VEGF. The release of VEGF and both pro-inflammatory and anti-inflammatory cytokines from the stimulated neutrophils is markedly altered in these patients. The clinical significance of these findings deserves further investigation., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM., Results: Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin., Conclusions: Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis., (© 2021. The Author(s).)

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Background: International task force statements advocate telehealth programs to promote health-related quality of life for patients with chronic heart failure (CHF). To that end, we evaluated the efficacy and usability of an automated e-counseling program., Methods: This Canadian multi-site double-blind randomized trial assessed whether usual care plus either internet-based e-counseling (motivational and cognitive-behavioral tools for CHF self-care) or e-based conventional CHF self-care education (e-UC) improved 12-month Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS). Secondary outcomes included program engagement (total logon weeks, logons, and logon hours), total CHF self-care behaviors, diet (fruit and vegetable servings), 6-minute walk test, and 4-day step count. The association between program engagement and health-related quality of life was assessed using KCCQ-OS tertiles., Results: We enrolled 231 patients, median age =59.5 years, 22% female, and elevated median KCCQ-OS=83.0 (interquartile range, 68-93). KCCQ-OS increase ≥5 points was not more prevalent for e-counseling, n=29 (29.6%) versus e-UC, n=32 (34.0%), P =0.51. E-Counseling versus e-UC increased total logon weeks ( P =0.02), logon hours ( P =0.001), and logons ( P <0.001). Only e-counseling showed a positive association between 12-month KCCQ-OS tertile and logon weeks ( P =0.04) and logon hours ( P =0.004). E-Counseling increased CHF self-care behavior and diet but not 6-minute walk test or 4-day step count., Conclusions: The primary KCCQ-OS end point was negative for this trial. Only e-counseling showed a positive association between program engagement and 12-month KCCQ-OS tertile, and it improved CHF self-care behavior and diet. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01864369.

Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed-Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop-PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7-22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

We compared cognitive profiles in chronic heart failure patients (HF), heart transplant recipients (HT) and healthy controls (HC) and examined the relationship between cardiorespiratory fitness (V˙O 2peak ), peak cardiac output (CO peak ) and cognitive performance. Stable HT patients ( n = 11), HF patients ( n = 11) and HC ( n = 13) (61.5 ± 8.5 years) were recruited. Four cognitive composite scores targeting different cognitive functions were computed from neuropsychological tests: working memory, processing speed, executive functions and verbal memory. Processing speed and executive function scores were higher, which indicates lower performances in HF and HT compared to HC ( p < 0.05). V˙O 2peak and first ventilatory threshold (VT 1 ) were lower in HF and HT vs. HC ( p < 0.01). CO peak was lower in HF vs. HT and HC ( p < 0.01). Processing speed, executive function and verbal memory performances were correlated with V˙O 2peak , VT 1 and peak cardiac hemodynamics ( p < 0.05). Mediation analyses showed that V˙O 2peak and VT 1 mediated the relationship between group and processing speed and executive function performances in HF and HT. CO peak fully mediated executive function and processing speed performances in HF only. V˙O 2peak and CO peak were related to cognitive performance in the entire sample. In addition, V˙O 2peak and VT 1 fully mediated the relationship between group and executive function and processing speed performances.

Objectives: This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF)., Background: Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist., Methods: Medical records of all patients with HFrEF followed for at least 6 months at the authors' HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps., Results: Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p < 0.0001) and history of stroke or transient ischemic attack (TIA) (no vs. yes, OR: 0.264; p = 0.0336)., Conclusions: Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a "one-size-fits-all" approach may be required., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

C-reactive protein (CRP) is recognized as a biomarker of chronic, low-grade inflammation associated with vascular disorders. Lately, the role of neutrophils and neutrophil extracellular traps (NETs) has been investigated as a potential source of chronic inflammation and cardiovascular complications. This study investigated NETs as a marker of inflammation in patients with symptomatic heart failure (HF) with or without type 2 diabetes (T2DM) and examined the correlation between NETs and CRP. We performed a noninterventional study including patients with HF with or without T2DM, T2DM, and a healthy control (HC) group. NETs and other inflammatory markers in serum were measured by ELISA. The release of NETs (NETosis) in vitro under various stimuli was measured by confocal microscopy. The levels of NETs in the serum of HF patients were significantly higher compared with HC (112%). Serum CRP concentrations were significantly increased in HF and HF plus T2DM patients compared with HC, and a positive correlation was observed between serum CRP and NETs levels. Neutrophils from HF and HF plus T2DM patients underwent in vitro NETs release faster than T2DM and HC without any stimuli. In vitro, serum collected from the HF and the HF plus T2DM group induced NETosis in healthy neutrophils significantly more when compared with HC and T2DM, which was prevented by depletion from CRP. We confirmed in vitro that CRP induces a concentration-dependent NETs synthesis. This study proposes a mechanism by which CRP increases the risk of future cardiovascular events and supports mounting evidences on the role of neutrophils in chronic low-grade inflammation associated with HF., (Copyright © 2019 The Authors.)

Objectives: The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF)., Background: Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta 1 -adrenergic receptor (ADRB1) Arg389Arg genotype., Methods: A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period., Results: The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were <12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (n = 196), the HR was 0.54 (95% CI: 0.33 to 0.87; p = 0.011)., Conclusions: Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials., (Copyright © 2019. Published by Elsevier Inc.)

Background: National guidelines recommend that systolic blood pressure (SBP) in patients with heart failure with reduced ejection fraction (HFrEF) and hypertension be maintained below 130 mm Hg., Objectives: This study sought to determine associations of SBP <130 mm Hg with outcomes in patients with HFrEF., Methods: Of the 25,345 patients in the Medicare-linked OPTIMIZE-HF registry, 10,535 had an ejection fraction (EF) ≤40%. Of these, 5,615 had stable SBP (≤20 mm Hg admission to discharge variation), and 3,805 (68%) had a discharge SBP <130 mm Hg. Propensity scores for SBP <130 mm Hg, estimated for each of the 5,615 patients, were used to assemble a matched cohort of 1,189 pairs of patients with SBP <130 versus ≥130 mm Hg, balanced on 58 baseline characteristics (mean age 76 years; mean EF 28%, 45% women, 13% African American). This process was repeated in 3,946 patients, after excluding 1,669 patients (30% of 5,615) with a discharge SBP <110 mm Hg and assembled a second matched balanced cohort of 1,099 pairs of patients with SBP 110 to 129 mm Hg versus ≥130 mm Hg., Results: Thirty-day all-cause mortality occurred in 7% and 4% of matched patients with SBP <130 mm Hg versus ≥130 mm Hg, respectively (hazard ratio [HR]: 1.76; 95% confidence interval [CI]: 1.24 to 2.48; p = 0.001). HRs (95% CIs) for all-cause mortality, all-cause readmission, and HF readmission at 1 year, associated with SBP <130 mm Hg, were 1.32 (1.15 to 1.53; p < 0.001), 1.11 (1.01 to 1.23; p = 0.030), and 1.24 (1.09 to 1.42; p = 0.001), respectively. HRs (95% CIs) for 30-day and 1-year all-cause mortality associated with SBP 110 to 129 mm Hg (vs. ≥130 mm Hg) were 1.50 (1.03 to 2.19; p = 0.035), and 1.19 (1.02 to 1.39; p = 0.029), respectively., Conclusions: Among hospitalized older patients with HFrEF, SBP <130 mm Hg is associated with poor outcomes. This association persisted when the analyses were repeated after excluding patients with SBP <110 mm Hg. There is an urgent need for randomized controlled trials to evaluate optimal SBP reduction goals in patients with HFrEF., (Published by Elsevier Inc.)

Purpose: Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF)., Methods: Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents., Results: Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80-1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72-1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76-1.25; p = 0.8169)., Conclusion: We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.

The effect of third and second-generation type of beta-blocker on substrate oxidation especially during high-intensity exercises are scarce. The objective of the study is to explore differences of beta-blocker regimens (vasodilating vs. non-vasodilating beta-blockers) for substrate oxidation during in high-intensity intermittent exercise (HIIE) in chronic heart failure and reduced ejection fraction (HFrEF). Eighteen CHF males (58.8 ± 9 years), 8 under use of β1 specific beta-blockers+alfa 1-blocker and 10 using β1 non-specific beta-blockers, were randomly assigned to 4 different HIIE, in a cross-over design. The 4 protocols were: 30 seconds (A and B) or 90 seconds (C and D) at 100% peak power output, with passive (A and C) or active recovery (50% of PPO; B and D). Energy expenditure (EE; kcal/min), quantitative carbohydrate (CHO) and lipid oxidation (g/min) and qualitative (%) contribution were calculated. Two-way ANOVA and Bonferroni post-hoc test were used (p-value ≤ 0.05) to compare CHO and lipid oxidation at rest and at 10min. Total exercise time or EE did not show differences for beta-blocker use. The type of beta-blocker use showed impact in CHO (%) and lipid (g/min and %) for rest and 10 min, but absolute contribution of CHO (g/min) was different just at 10min (Interaction p = 0.029). Higher CHO oxidation was found in vasodilating beta-blockers when comparing to non-vasodilating. According to our pilot data, there is an effect of beta-blocker type on substrate oxidation during HIIE, but no influence on EE or exercise total time in HFrEF patients.

Although it is widely recognized that inflammation plays a critical role in the development and pathology of heart failure (HF), very little is known about the involvement of one of the most abundant immune cells in the blood, a primary immune response cell: the neutrophil. This review summarizes the current literature on the role of subclinical inflammation, with a focus on the neutrophil in the pathophysiology of the HF syndrome. Some emerging therapeutic strategies are also discussed., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials., Methods/design: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred., Conclusions: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure., Materials & Methods: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%., Results: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022)., Conclusion: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

Aims: To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial., Methods and Results: Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695)., Conclusion: In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Objectives: This study investigated temporal changes in the demographics and the prognosis of cardiac allograft vasculopathy (CAV) over 30 years following heart transplantation (HTx)., Background: Effects of the changing HTx demographics on CAV outcomes, based on International Society for Heart and Lung Transplantation (ISHLT) classification of CAV, have been incompletely investigated., Methods: Patients who underwent HTx at the Montreal Heart Institute were classified according to the severity of CAV (CAV 0 is no presence of CAV; CAV 1 is mild, CAV 2 to 3 is moderate to severe) and era of HTx (early: 1983 to 1998; recent: 1999 to 2011). We compared the risk of progression, survival, and independent predictors of outcomes among the groups., Results: A total of 298 patients were followed for 11.6 ± 6.6 years. Patients who received transplants in the early era exhibited a higher risk for progression from CAV 1 to a higher grade (adjusted odds ratio: 8.0; 95% confidence interval [CI]: 1.01 to 62.6). The presence of CAV was associated with a significantly increased risk for all-cause mortality in the early era (hazard ratio [HR]: 1.6; 95% CI: 1.1 to 2.5) but not in the recent era (HR: 1.1; 95% CI: 0.2 to 4.9). Regardless of the era, CAV classes 2 to 3 and CAV 1 were associated with a significantly increased risk for all-cause mortality compared to CAV 0 (HR: 6.5; 95% CI: 2.7 to 15.7; and HR: 1.750; 95% CI: 1.001 to 3.046, respectively)., Conclusions: The progression and prognosis of CAV have improved over 30 years. The ISHLT CAV classification accurately and independently predicts long-term outcome following HTx., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The SynCardia total artificial heart (TAH) provides complete circulatory support by replacing both native ventricles. Accepted indications include bridge to transplantation and destination therapy. We review our experience with TAH implantation during a period when axial flow pump became available., Methods: We retrospectively analyzed the demographics, clinical characteristics and survival of all patients receiving the TAH., Results: From September 2004 to November 2016, 13 patients (12 men, mean age 45 ± 13 yr) received the TAH for refractory cardiogenic shock secondary to idiopathic (56%) or ischemic (17%) cardiomyopathy and to other various causes (33%). Before implantation, mean ejection fraction was 14% ± 4%, 7 (54%) patients had previous cardiac surgery, 4 (31%) were on mechanical ventilation, and 3 (23%) patients were on dialysis. The mean duration of TAH support was 46 ± 40 days. Three (23%) patients died while on support after a mean of 15 days. Actuarial survival on support was 77% ± 12% at 30 days after implantation. Complications on support included stroke ( n = 1, 8%), acute respiratory distress syndrome requiring prolonged intubation ( n = 5, 38%) and acute renal failure requiring temporary dialysis ( n = 5, 38%). Ten (77%) patients survived to be transplanted after a mean of 52 ± 42 days of support. Actuarial survival rates after transplant were 67% ± 16% at 1 month and 56% ± 17% at 1 year after transplantation., Conclusion: The TAH provides an alternative with low incidence of neurologic events in extremely fragile and complex patients waiting for heart transplantation. Complex and unusual anatomic conditions explained the current use of TAH.

Background: A lower heart rate is associated with better outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Less is known about this association in patients with HF with preserved ejection fraction (HFpEF)., Objectives: The aims of this study were to examine associations of discharge heart rate with outcomes in hospitalized patients with HFpEF., Methods: Of the 8,873 hospitalized patients with HFpEF (EF ≥50%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 6,286 had a stable heart rate, defined as ≤20 beats/min variation between admission and discharge. Of these, 2,369 (38%) had a discharge heart rate of <70 beats/min. Propensity scores for discharge heart rate <70 beats/min, estimated for each of the 6,286 patients, were used to assemble a cohort of 2,031 pairs of patients with heart rate <70 versus ≥70 beats/min, balanced on 58 baseline characteristics., Results: The 4,062 matched patients had a mean age of 79 ± 10 years, 66% were women, and 10% were African American. During 6 years (median 2.8 years) of follow-up, all-cause mortality was 65% versus 70% for matched patients with a discharge heart rate <70 versus ≥70 beats/min, respectively (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93; p < 0.001). A heart rate <70 beats/min was also associated with a lower risk for the combined endpoint of HF readmission or all-cause mortality (HR: 0.90; 95% CI: 0.84 to 0.96; p = 0.002), but not with HF readmission (HR: 0.93; 95% CI: 0.85 to 1.01) or all-cause readmission (HR: 1.01; 95% CI: 0.95 to 1.08). Similar associations were observed regardless of heart rhythm or receipt of beta-blockers., Conclusions: Among hospitalized patients with HFpEF, a lower discharge heart rate was independently associated with a lower risk of all-cause mortality, but not readmission., (Published by Elsevier Inc.)

Background: Studies comparing biventricular (BiV) cardiac resynchronization therapy (CRT) and left ventricular (LV) pacing alone have yielded conflicting results. We recently reported the results of the Greater Evaluation of Resynchronization Therapy for Heart Failure (GREATER-EARTH) trial demonstrating similar clinical benefits of BiV and LV-CRT on exercise tolerance. We report the prespecified secondary outcomes of the GREATER-EARTH trial, comparing the impact of BiV vs LV-CRT on structural and biochemical cardiac remodelling., Methods: Patients with a LV ejection fraction (LVEF) ≤ 35% and a QRS duration ≥ 120 ms were randomized to BiV-CRT or LV-CRT for a 6-month period, followed by crossover. The primary end point was a change in LV end-systolic volume (LVESV). Secondary end points included changes in LVEF, right ventricular (RV) dimensions and function, mitral regurgitation (MR), indices of diastolic function, systolic pulmonary artery pressure (sPAP), and disease-specific biomarkers., Results: One hundred twenty patients (60.9 ± 8.8 years; 75.0% men; LVEF, 24.4% ± 6.3%) were enrolled. A similar reduction in LVESV was observed, from a baseline of 162.4 ± 57.2 mL to 130.4 ± 63.4 mL with BiV pacing and 130.3 ± 59.9 mL with LV pacing (P = 0.679, BiV pacing vs LV pacing). Improvements in LVEF, RV remodelling, and N-terminal pro b-type natriuretic peptide were similar between groups. BiV pacing yielded superior outcomes with respect to LV diastolic function, indexed left atrial volume, degree of MR, and sPAP (all P < 0.05), together with decreased N-terminal propeptide of type III collagen with LV-CRT., Conclusions: In this randomized double-blind crossover trial, BiV and LV pacing resulted in similar improvements in the primary LV remodelling end point (LVESV). Analyses of secondary end points revealed advantages of BiV pacing over LV pacing on several other features of cardiac remodelling, providing mechanistic insights to support the main finding of the GREATER-EARTH trial., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Isolated systolic hypertension and isolated diastolic hypotension are common in older adults and associated with a higher risk of incident heart failure (HF). However, little is known about the prevalence and impact of isolated diastolic hypertension in this population., Methods: In the Cardiovascular Health Study (CHS), of the 5776 community-dwelling older adults ≥65years who had data on baseline systolic and diastolic blood pressure (SBP and DBP), 28 had isolated diastolic hypertension (DBP ≥90mmHg and SBP <140mmHg). From the 5748 without isolated diastolic hypertension, we excluded those with SBP ≥120mmHg (n=4451), DBP 80-89mmHg (n=20), DBP <60mmHg (n=425), normal BP taking anti-hypertensive medications (n=311), normal BP taking no anti-hypertensive medications but with history of hypertension (n=38), and baseline HF (n=5). The final cohort of 524 participants included 27 with isolated diastolic hypertension., Results: Patients (n=524) had a mean (±SD) age of 71 (±5) years, 58% were women and 9% African American. There were no significant between-group age or sex differences; 37% of those with isolated diastolic hypertension (versus 7% without) were African American. Incident HF occurred in 19% and 7% of participants with and without isolated diastolic hypertension, respectively (multivariable-adjusted hazard ratio {HR}, 4.65; 95% confidence interval {CI}, 1.09-19.90; p=0.038). There was a trend toward higher cardiovascular mortality (HR, 4.59; 95% CI, 0.92-23.88; p=0.063)., Conclusion: Among community-dwelling older adults, isolated diastolic hypertension is rare and is associated with higher risk for incident HF and cardiovascular mortality., (Published by Elsevier B.V.)

Background: Isolated systolic hypertension (ISH) is common in older adults and is a risk factor for incident heart failure (HF). We examined the association of systolic-diastolic hypertension (SDH) with incident HF and other outcomes in older adults., Methods: In the Cardiovascular Health Study (CHS), 5776 community-dwelling adults≥65years had data on baseline systolic and diastolic blood pressure (SBP and DBP). We excluded those with DBP<60mmHg (n=821), DBP≥90 and SBP<140mmHg (n=28), normal BP, taking anti-hypertensive drugs (n=1138), normal BP, not taking anti-hypertensive drugs, history of hypertension (n=193), and baseline HF (n=101). Of the remaining 3495, 1838 had ISH (SBP≥140 and DBP<90mmHg) and 240 had SDH (SBP≥140 and DBP≥90mmHg). The main outcome was centrally-adjudicated incident HF over 13years of follow-up., Results: Participants had a mean (±SD) age of 73 (±6)years, 57% were women, and 16% African American. Incident HF occurred in 25%, 22% and 11% of participants with ISH, SDH and no hypertension, respectively. Compared to no hypertension, multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident HF associated with ISH and SDH were 1.86 (1.51-2.30) and 1.73 (1.23-2.42), respectively. Cardiovascular mortality occurred in 22%, 24% and 9% of those with ISH, SDH and no hypertension, respectively with respective multivariable-adjusted HRs (95% CIs) of 1.88 (1.49-2.37) and 2.30 (1.64-3.24)., Conclusion: Among older adults with hypertension, both SDH and ISH have similar associations with incident HF and cardiovascular mortality., (Published by Elsevier B.V.)

Background: Therapy with evidence-based heart failure (HF) medications has been shown to be associated with lower risk of 30-day all-cause readmission in patients with HF and reduced ejection fraction (HFrEF)., Methods: We examined the association of aldosterone antagonist use with 30-day all-cause readmission in this population. Of the 2443 Medicare beneficiaries with HF and left ventricular EF ≤35% discharged home from 106 Alabama hospitals during 1998-2001, 2060 were eligible for spironolactone therapy (serum creatinine ≤2.5 for men and ≤2mg/dl for women, and serum potassium <5mEq/L). After excluding 186 patients already receiving spironolactone on admission, the inception cohort consisted of 1874 patients eligible for a new discharge prescription for spironolactone, of which 329 received one. Using propensity scores for initiation of spironolactone therapy, we assembled a matched cohort of 324 pairs of patients receiving and not receiving spironolactone balanced on 34 baseline characteristics (mean age 72years, 42% women, 33% African American)., Results: Thirty-day all-cause readmission occurred in 17% and 19% of matched patients receiving and not receiving spironolactone, respectively (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.64-1.32; p=0.650). Spironolactone had no association with 30-day all-cause mortality (HR, 0.84; 95% CI, 0.38-1.88; p=0.678) or HF readmission (HR, 0.74; 95% CI, 0.41 1.31; p=0.301). These associations remained unchanged during 12months of post-discharge follow-up., Conclusion: A discharge prescription for spironolactone had no association with 30-day all-cause readmission among older, hospitalized Medicare beneficiaries with HFrEF eligible for spironolactone therapy., Competing Interests: Disclosures: None, (Published by Elsevier Ireland Ltd.)

Purpose: The long-term use of β-blockers has been shown to improve clinical outcomes among patients with heart failure (HF). However, a lack of data persists in assessing whether carvedilol or bisoprolol are superior to metoprolol tartrate in clinical practice. We endeavored to compare the effectiveness of β-blockers among older adults following a primary hospital admission for HF., Methods: We conducted a cohort study using Quebec administrative databases to identify patients who were using β-blockers, carvedilol, bisoprolol, or metoprolol tartrate after the diagnosis of HF. We characterized the patients by the type of β-blocker prescribed at discharge of their first HF hospitalization. An adjusted multivariate Cox proportional hazards model was used to compare the primary outcome of all-cause mortality. We also conducted analyses by matching for a propensity score for initiation of β-blocker therapy and assessed the effect on primary outcome., Results: Among 3197 patients with HF with a median follow-up of 2.8 years, the crude annual mortality rates (per 100 person-years) were at 16, 14.9, and 17.7 for metoprolol tartrate, carvedilol, and bisoprolol, respectively. Adjusted hazard ratios of carvedilol (hazard ratio 0.92; 0.78-1.09) and bisoprolol (hazard ratio 1.04; 0.93-1.16) were not significantly different from that of metoprolol tartrate in improving survival. After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate., Conclusions: Our evidence suggests no differential effect of β-blockers on all-cause mortality among older adults with HF. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Heart failure is the leading cause for 30-day all-cause readmission. We examined the impact of 30-day all-cause readmission on long-term outcomes and cost in a propensity score-matched study of hospitalized patients with heart failure., Methods: Of the 7578 Medicare beneficiaries discharged with a primary diagnosis of heart failure from 106 Alabama hospitals (1998-2001) and alive at 30 days after discharge, 1519 had a 30-day all-cause readmission. Using propensity scores for 30-day all-cause readmission, we assembled a matched cohort of 1516 pairs of patients with and without a 30-day all-cause readmission, balanced on 34 baseline characteristics (mean age 75 years, 56% women, 24% African American)., Results: During 2-12 months of follow-up after discharge from index hospitalization, all-cause mortality occurred in 41% and 27% of matched patients with and without a 30-day all-cause readmission, respectively (hazard ratio 1.68; 95% confidence interval 1.48-1.90; P <.001). This harmful association of 30-day all-cause readmission with mortality persisted during an average follow-up of 3.1 (maximum, 8.7) years (hazard ratio 1.33; 95% confidence interval 1.22-1.45; P <.001). Patients with a 30-day all-cause readmission had higher cumulative all-cause readmission (mean, 6.9 vs 5.1; P <.001), a longer cumulative length of stay (mean, 51 vs 43 days; P <.001), and a higher cumulative cost (mean, $38,972 vs $34,025; P = .001) during 8.7 years of follow-up., Conclusions: Among Medicare beneficiaries hospitalized for heart failure, 30-day all-cause readmission was associated with a higher risk of subsequent all-cause mortality, higher number of cumulative all-cause readmission, longer cumulative length of stay, and higher cumulative cost., (Published by Elsevier Inc.)

Background: Heart failure is the leading cause for 30-day all-cause readmission, the reduction of which is a goal of the Affordable Care Act. There is a growing interest in understanding the impact of evidence-based heart failure therapy on 30-day all-cause readmission. In the current study, we examined the impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI-ARBs) on 30-day all-cause readmission in heart failure., Methods: Of the 1384 hospitalized Medicare beneficiaries with heart failure and left ventricular ejection fraction <45% discharged alive from 106 Alabama hospitals (1998-2001) without prior ACEI-ARB use and without known contraindications to ACEI-ARB use; 734 received new predischarge prescriptions for these drugs. Using propensity scores for ACEI-ARB initiation, we assembled a matched cohort of 477 pairs of patients balanced on 32 baseline characteristics (mean age 75 years, 46% women, 26% African American)., Results: Thirty-day all-cause readmissions occurred in 18% and 24% of matched patients receiving and not receiving ACEI-ARBs, respectively (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.56-0.97; P = .030). ACEI-ARB use was also associated with lower risk of 30-day all-cause mortality (HR 0.56; 95% CI, 0.33-0.98; P = .041) and of the combined endpoint of 30-day all-cause readmission or 30-day all-cause mortality (HR 0.73; 95% CI, 0.56-0.94; P = .017). All associations remained significant at 1 year post discharge., Conclusions: Among hospitalized patients with heart failure and reduced ejection fraction, the use of ACEI-ARBs was associated with a significantly lower risk of 30-day all-cause readmission and 30-day all-cause mortality; both beneficial associations persisted during long-term follow-up., Competing Interests: None, (Published by Elsevier Inc.)

Background: According to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear., Methods and Results: Of the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28)., Conclusions: After >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers., (© 2015 American Heart Association, Inc.)

Objectives: The aim of this study was to investigate prognosis in patients with heart failure (HF) with preserved ejection fraction and the causes of hospitalization and post-hospitalization mortality., Background: Although hospitalizations in patients with HF with preserved ejection fraction are common, there are limited data from clinical trials on the causes of admission and the influence of hospitalizations on subsequent mortality risk., Methods: Patients (n = 4,128) with New York Heart Association functional class II to IV HF and left ventricular ejection fractions >45% were enrolled in I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction). A blinded events committee adjudicated cardiovascular hospitalizations and all deaths using predefined and standardized definitions. The risk for death after HF, any-cause, or non-HF hospitalization was assessed using time-dependent Cox proportional hazard models., Results: A total of 2,278 patients had 5,863 hospitalizations during the 49 months of follow-up, of which 3,585 (61%) were recurrent hospitalizations. For any-cause hospitalizations, 26.5% of patients died during follow-up, with an incident mortality rate of 11.1 deaths per 100 patient-years (PYs) and an adjusted hazard ratio of 5.32 (95% confidence interval: 4.21 to 6.23). Overall, 53.6% of hospitalizations were classified as cardiovascular and 43.7% as noncardiovascular, with 2.7% not classifiable. HF was the largest single cause of initial (17.6%) and overall (21.1%) hospitalizations, although, after HF hospitalization, a substantially higher proportion of readmissions were due to primary HF causes (40%). HF hospitalization occurred in 685 patients, with 41% deaths during follow-up, an incident mortality rate of 19.3 deaths per 100 PYs. The adjusted hazard ratio was 2.93 (95% confidence interval: 2.40 to 3.57) relative to patients who were not hospitalized for HF and was greater in those with longer durations of hospitalization. There were 1,593 patients with only non-HF hospitalizations, 21% of whom died during follow-up, with an incident mortality rate of 8.7 deaths per 100 PYs and an adjusted hazard ratio of 4.25 (95% confidence interval: 3.27 to 5.32). The risk for death was highest in the first 30 days and declined over time for all hospitalization categories. Patients not hospitalized for HF or for any cause had observed incident mortality rates of 3.8 and 1.3 deaths per 100 PYs, respectively., Conclusions: In I-PRESERVE, HFpEF patients hospitalized for any reason, and especially for HF, were at high risk for subsequent death, particularly early. The findings support the need for careful attention in the post-discharge time period including attention to comorbid conditions. Among those hospitalized for HF, the high mortality rate and increased proportion of readmissions due to HF (highest during the first 30 days), suggest that this group would be an appropriate target for investigation of new interventions., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides discussion on the management recommendations on 3 focused areas: (1) anemia; (2) biomarkers, especially natriuretic peptides; and (3) clinical trials that might change practice in the management of patients with heart failure. First, all patients with heart failure and anemia should be investigated for reversible causes of anemia. Second, patients with chronic stable heart failure should undergo natriuretic peptide testing. Third, considerations should be given to treat selected patients with heart failure and preserved systolic function with a mineralocorticoid receptor antagonist and to treat patients with heart failure and reduced ejection fraction with an angiotensin receptor/neprilysin inhibitor, when the drug is approved. As with updates in previous years, the topics were chosen in response to stakeholder feedback. The 2014 Update includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers to best manage patients with heart failure., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the association between baseline systolic blood pressure levels and mortality in patients with AF with or without LV dysfunction. Hypertension leads to cardiovascular disease but, in specific groups, low blood pressure has been associated with a paradoxical increase in mortality. In patients with AF and heart failure, the relationship between blood pressure and death remains largely unknown., Methods and Results: We conducted a post-hoc combined analysis on pooled data from AFFIRM and AF-CHF trials and assessed the relationship between baseline systolic blood pressure (SBP) and mortality and hospitalizations. Patients were classified according to LVEF (>40%, ≤40%) and baseline SBP (<120 mmHg, 120-140 mmHg, >140 mmHg). A total of 5436 patients with non-permanent AF were followed for 41 ± 16 months. In patients with LVEF >40%, baseline SBP was not related to mortality using multivariate Cox regression analyses to adjust for baseline differences (P = 0.563). In contrast, in patients with LVEF ≤40% (n = 1980), SBP <120 mmHg and SBP >140 mmHg were both associated with a significant increase in total mortality compared with SBP 120-140 mmHg [hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.41-2.17; and HR 1.40, 95% CI 1.04-1.90, respectively]. Hospitalizations were unrelated to SBP regardless of LVEF., Conclusions: Mortality is modulated by baseline SBP levels in patients with AF and depressed EF but not in patients with normal EF. Targeted therapy of AF patients based on SBP merits further prospective investigation., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Cardiac remodeling is associated with plasma biomarkers of fibrinogenesis, inflammation, and oxidative stress, and upregulation of mitogenic, pro-fibrotic, and apoptotic signaling pathways. Our primary objective was to evaluate biomarker and subcellular myocardial changes in pediatric heart transplant recipients. Fifty-two-week prospective, randomized (tacrolimus, Tac, vs. cyclosporine, CsA), open-label, parallel group study. Serial myocardial biopsies were probed for mitogenic and pro-inflammatory proteins. Plasma biomarkers of oxidative stress (F2α isoprostanes, nitrotyrosine), and inflammation and oxidation (hsCRP and cystatin-C) were measured. Nine of 11 randomized patients completed the study (four Tac, five CsA). Mean levels of F2α isoprostanes, hsCRP, and cystatin-C were maximal at Week 2. Peak activation of all MAP kinases in myocardial tissue was maximal at Week 10; no association was seen with rejection. Cardiac Bax/Bcl-2 levels (index of apoptosis) correlated negatively with F2α isoprostanes at Week 2 (r = -0.88) and with hsCRP at Week 52 (r = -0.67). At Week 52, hsCRP levels correlated positively with molecular indices of cardiac cell growth. We found evidence of systemic and myocardial oxidative damage and inflammation early posttransplant, which may be related to the remodeling process. Further study is needed to better understand the cardiac and systemic repair processes following pediatric heart transplantation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia., Methods and Results: In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia-HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF., Conclusions: Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00834691., (© 2014 American Heart Association, Inc.)

The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides focused discussions on the management recommendations on 2 topics: (1) exercise and rehabilitation; and (2) surgical coronary revascularization in patients with heart failure. First, all patients with stable New York Heart Association class I-III symptoms should be considered for enrollment in a tailored exercise training program, to improve exercise tolerance and quality of life. Second, selected patients with suitable coronary anatomy should be considered for bypass graft surgery. As in previous updates, the topics were chosen in response to stakeholder feedback. The 2013 Update also includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers manage their patients with heart failure., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the association of orthostatic hypotension with incident heart failure (HF) in older adults., Methods: Of the 5,273 community-dwelling adults aged 65 years and older free of baseline prevalent HF in the Cardiovascular Health Study, 937 (18%) had orthostatic hypotension, defined as ≥20 mmHg drop in systolic or ≥10 mmHg drop in diastolic blood pressure from supine to standing position at 3 minutes. Of the 937, 184 (20%) had symptoms of dizziness upon standing and were considered to have symptomatic orthostatic hypotension. Propensity scores for orthostatic hypotension were estimated for each of the 5,273 participants and were used to assemble a cohort of 3,510 participants (883 participants with and 2,627 participants without orthostatic hypotension) who were balanced on 40 baseline characteristics. Cox regression models were used to estimate the association of orthostatic hypotension with centrally adjudicated incident HF and other outcomes during 13 years of follow-up., Results: Participants (n = 3,510) had a mean (±standard deviation) age of 74 (±6) years, 58% were women, and 15% nonwhite. Incident HF occurred in 25% and 21% of matched participants with and without orthostatic hypotension, respectively (hazard ratio, 1.24; 95% confidence interval, 1.06-1.45; p = .007). Among matched participants, hazard ratios for incident HF associated with symptomatic (n = 173) and asymptomatic (n = 710) orthostatic hypotension were 1.57 (95% confidence interval, 1.16-2.11; p = .003) and 1.17 (95% confidence interval, 0.99-1.39; p = .069), respectively., Conclusions: Community-dwelling older adults with orthostatic hypotension have higher independent risk of developing new-onset HF, which appeared to be more pronounced in those with symptomatic orthostatic hypotension.

Background: In patients with heart failure and atrial fibrillation, the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial did not demonstrate the superiority of rhythm control (RhyC) over a rate control (RaC) strategy on cardiovascular mortality. Nevertheless, deleterious hemodynamic effects of atrial fibrillation can lead to further decrease in left ventricular (LV) function and progression of symptoms. This echocardiographic sub-study was designed to compare the effects of the two treatment strategies on LV ejection fraction (LVEF), chamber volumes and dimensions, valvular regurgitation and functional status., Methods and Results: A total of 59 patients (29 RhyC, 30 RaC) aged 67±8 years (14% women), enrolled in the AF-CHF trial at the Montreal Heart Institute underwent standardized echocardiograms at baseline and at 12 months. Mean LVEF at baseline was severely depressed (RhyC: 27.0±4.9% and RaC: 27.6±7.4%, p=0.73), and improved to a similar degree in both groups (RhyC: +8.0±10.4% and RaC: +4.5±10.6, both p<0.05; p=0.19 for RhyC versus RaC). Other echocardiographic parameters, such as LV end-systolic volume index and degree of mitral and tricuspid regurgitation, remained unchanged. New York Heart Association functional class and distance walked in 6 min improved significantly in both groups (RhyC: +48.9±78.7 m and RaC: +47.2±96.7 m, both p≤0.01), with no difference between RhyC and RaC strategies., Conclusions: Improvements in LVEF and functional status are observed after 12 months in patients with heart failure and atrial fibrillation, regardless of whether rate or rhythm control strategies are used., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aims: There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST)., Methods and Results: A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (β(1)389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤ 80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤ 80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤ 80 b.p.m., there were no treatment effects on events in either group. β(1)389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in β(1)389-Arg homozygotes., Conclusion: In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤ 80 b.p.m. and nominally in those with the β(1)389-Arg homozygous genotype.

Background: Although the benefits of cardiac resynchronization therapy are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated., Methods and Results: The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active and inactive cardiac resynchronization therapy in patients with severe left ventricular dysfunction and a QRS duration <120 milliseconds. The trial was interrupted prematurely by the Data Safety and Monitoring Board because of futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active cardiac resynchronization therapy (-0.7 minutes [95% confidence interval (CI), -2.9 to 1.5] versus 0.8 minutes [95% CI, -1.2 to 2.9]; P=0.31]. Similarly, no significant differences were observed in left ventricular end-systolic volumes (-6.4 mL [95% CI, -18.8 to 5.9] versus 3.1 mL [95% CI, -9.2 to 15.5]; P=0.28) and ejection fraction (3.3% [95% CI, 0.7-6.0] versus 2.1% [95% CI, -0.5 to 4.8]; P=0.52). Moreover, cardiac resynchronization therapy was associated with a significant reduction in the 6-minute walk distance (-11.3 m [95% CI, -31.7 to 9.7] versus 25.3 m [95% CI, 6.1-44.5]; P=0.01), an increase in QRS duration (40.2 milliseconds [95% CI, 34.2-46.2] versus 3.4 milliseconds [95% CI, 0.6-6.2]; P<0.0001), and a nonsignificant trend toward an increase in heart failure-related hospitalizations (15 hospitalizations in 5 patients versus 4 hospitalizations in 4 patients)., Conclusions: In patients with a left ventricular ejection fraction ≤35%, symptoms of heart failure, and a QRS duration <120 milliseconds, cardiac resynchronization therapy did not improve clinical outcomes or left ventricular remodeling and was associated with potential harm., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00900549.

Background: Randomized controlled trials (RCT) are limited by their generalizability to the broader nontrial population. To provide a context for Acute Study of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, we designed a complementary registry to characterize clinical characteristics, practice patterns, and in-hospital outcomes of acute heart failure patients., Methods and Results: Eligible patients for the registry included those with a principal diagnosis of acute heart failure (ICD-9-CM 402 and 428; ICD-10 I50.x, I11.0, I13.0, I13.2) from 8 sites participating in ASCEND-HF (n=697 patients, 2007-2010). Baseline characteristics, treatments, and hospital outcomes from the registy were compared with ASCEND-HF RCT patients from 31 Canadian sites (n=465, 2007-2010). Patients in the registry were older, more likely to be female, and have chronic respiratory disease, less likely to have diabetes mellitus: they had a similar incidence of ischemic HF, atrial fibrillation, and similar B-type natriuretic peptide levels. Registry patients had higher systolic blood pressure (registry: median 132 mm Hg [interquartile range 115-151 mm Hg]; RCT: median 120 mm Hg [interquartile range 110-135 mm Hg]) and ejection fraction (registry: median 40% [interquartile range 27-58%]; RCT: median 29% [interquartile range 20-40 mm Hg]) than RCT patients. Registry patients presented more often via ambulance and had a similar total length of stay as RCT patients. In-hospital mortality was significantly higher in the registry compared with the RCT patients (9.3% versus 1.3%,P<0.001), and this remained after multivariable adjustment (odds ratio 6.6, 95% CI 2.6-16.8, P<0.001)., Conclusions: Patients enrolled in a large RCT of acute heart failure differed significantly based on clinical characteristics, treatments, and inpatient outcomes from contemporaneous patients participating in a registry. These results highlight the need for context of RCTs to evaluate generalizability of results and especially the need to improve clinical outcomes in acute heart failure., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Background: Patients with heart failure (HF) and atrial fibrillation (AF) may differ from the larger HF population with respect to comorbidities, including renal impairment and overall prognosis. Associated cardiorenal interactions may mitigate the effects of pharmacological agents. Our primary objective was to assess the impact of mineralocorticoid receptor antagonists on cardiovascular mortality in patients with AF and HF enrolled in the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial., Methods and Results: All 1376 patients randomized in the AF-CHF trial were included. The median baseline creatinine was 105.2 (Q1 88.4, Q3 125.0) μmol/L, and the median estimated glomerular filtration rate was 62.3 (Q1 49.0, Q3 77.2) mL/min per 1.73 m(2). The renal function was moderately or severely impaired (ie, estimated glomerular filtration rate <60 mL/min per 1.73 m(2)) in 46.5% of patients. In multivariable analyses, increased creatinine was associated with worsening HF but not mortality. Mineralocorticoid receptor antagonists were prescribed in 44.8% and were independently associated with a 1.4-fold increase in total mortality (hazard ratio, 1.4; 95% CI [1.1-1.8]; P=0.005) and a 1.4-fold increase in cardiovascular mortality (hazard ratio, 1.4; 95% CI [1.1-1.9]; P=0.009). This was driven by an increased incidence of sudden cardiac death (hazard ratio, 2.0; 95% CI [1.3, 3.0]; P=0.001)., Conclusions: Renal dysfunction was highly prevalent in patients with AF and HF. Mineralocorticoid receptor antagonists were independently associated with an increased incidence of cardiovascular deaths, predominantly of presumed arrhythmic cause. Although these provocative findings merit prospective validation, they underscore the importance of careful monitoring of renal function and electrolytes in patients with AF and HF receiving mineralocorticoid receptor antagonists.

Background: Little is known about the association of rheumatic heart disease (RHD) with incident heart failure (HF) among older adults., Design: Cardiovascular Health Study, a prospective cohort study., Methods: Of the 4,751 community-dwelling adults ≥ 65 years, free of prevalent HF at baseline, 140 had RHD, defined as self-reported physician-diagnosed RHD along with echocardiographic evidence of left-sided valvular disease. Propensity scores for RHD, estimated for each of the 4,751 participants, were used to assemble a cohort of 720, in which 124 and 596 participants with and without RHD, respectively, were balanced on 62 baseline characteristics., Results: Incident HF developed in 33% and 22% of matched participants with and without RHD, respectively, during 13 years of follow-up (hazard ratio when RHD was compared to no-RHD 1.60; 95% confidence interval 1.13-2.28; P = 0.008). Pre-match unadjusted, multivariable-adjusted, and propensity-adjusted hazard ratios (95% confidence intervals) for RHD-associated incident heart failure were 2.04 (1.54-2.71; P < 0.001), 1.32 (1.02-1.70; P = 0.034), and 1.55 (1.14-2.11; P = 0.005), respectively. RHD was not associated with all-cause mortality (HR 1.09; 95% CI 0.82-1.45; P = 0.568)., Conclusion: RHD is an independent risk factor for incident HF among community-dwelling older adults free of HF, but has no association with mortality.

Background: There are little data on the optimization of high-intensity aerobic interval exercise (HIIE) protocols in patients with chronic heart failure (CHF). Therefore, we compared acute cardiopulmonary responses to 4 different HIIE protocols to identify the optimal one., Methods and Results: Twenty men with stable systolic CHF performed 4 different randomly ordered single HIIE sessions with measurement of gas exchange. For all protocols (A, B, C, and D) exercise intensity was set at 100% of peak power output (PPO). Interval duration was 30 seconds (A and B) or 90 seconds (C and D), and recovery was passive (A and C) or active (50% of PPO in B and D). Time spent above 85% of VO(2peak) and time above the ventilatory threshold were similar across all 4 HIIE protocols. Total exercise time was significantly longer in protocols with passive recovery intervals (A: 1,651 ± 347 s; C: 1,574 ± 382 s) compared with protocols with active recovery intervals (B: 986 ± 542 s; D: 961 ± 556 s). All protocols appeared to be safe, with exercise tolerance being superior during protocol A., Conclusion: Among the 4 HIIE protocols tested, protocol A with short intervals and passive recovery appeared to be superior., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension is highly prevalent in advanced heart failure (HF) despite optimal medical and device therapies. The objective of this investigation was to report on a single centre's experience of open-label chronic sildenafil therapy in patients with advanced HF., Methods: We conducted a retrospective systematic medical record review of all patients evaluated at our institution for heart transplantation who had also been treated with chronic sildenafil therapy. Baseline demographics, comorbidities, and concomitant medications, as well as the results of laboratory investigations and physiological testing, were abstracted from patient medical records. Change in systolic and mean pulmonary artery pressure (PAP), transpulmonary gradient, cardiac output and cardiac index, and selected laboratory parameters was analyzed by means of the Wilcoxon rank sum test. Outcomes of interest included New York Heart Association (NYHA) functional class after 6 months of therapy and adverse effects attributable to sildenafil., Results: The 16 patients undergoing evaluation for cardiac transplantation combined for 4166 patient-days on sildenafil, with a mean dose of 102.5 ± 54.0 mg/d. None discontinued because of side effects. At 6 months, there was an improvement in the cardiac index (P = 0.014) and systolic PAP (P = 0.049) without any significant change in other hemodynamic parameters. Ten patients (62.5%) experienced an improvement in their NYHA functional class, 8 (50%) received a heart transplantation, and 2 (12.5%) improved sufficiently to be removed from the transplant list., Conclusion: Chronic sildenafil therapy was well tolerated and associated with improved functional capacity and decreased systolic PAP. Properly controlled randomized studies of the long-term usefulness of sildenafil therapy in advanced HF populations are warranted., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The differences in concentrations of biomarkers between heart failure (HF) patients with a preserved left ventricular ejection fraction (LVEF), or HF-PEF, and patients with HF with reduced LVEF (HF-REF) have yet to be defined. The objectives of this study were to compare the concentrations and correlation of biomarkers of inflammation, extracellular matrix (ECM) turnover and neurohormonal activation between these populations., Methods: We performed a cross-sectional study of 29 subjects with symptomatic HF-REF (LVEF = 25.6 ± 5.1%) and 29 subjects with symptomatic HF-PEF (LVEF = 63.3 ± 5.3%). Concentrations of N-terminal proB-type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), procollagen type III amino-terminal peptide (PIIINP), matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of MMP (TIMP)-1 were measured., Results: Although NT-proBNP and PIIINP concentrations were higher in patients with HF-REF compared with patients with HF-PEF (both P < 0.05), the only significant difference between the groups remaining after adjusting for possible confounding variables was NT-proBNP (P = 0.02). In patients with HF-REF, NT-proBNP correlated with PIIINP (P < 0.05), TIMP-1 (P < 0.05), and MMP-2 (P = 0.002), while PIIINP correlated with TIMP-1 (P < 0.05) and MMP-2 (P < 0.0001). In patients with a HF-PEF, only high sensitivity C-reactive protein correlated significantly with MMP-2 (P = 0.002)., Conclusions: Patients with HF-REF or HF-PEF presenting similar symptoms and functional limitations exhibit similar concentrations of biomarkers of ECM and inflammation. However, patients with HF-REF exhibit significantly higher NT-proBNP concentrations than patients with HF-PEF. The differences in the correlations observed between the biomarkers between these 2 populations suggest some heterogeneity and differences in the mechanisms related to the release or clearance of biomarkers in HF-REF vs HF-PEF., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular (LV) pacing alone may theoretically avoid deleterious effects of right ventricular pacing., Methods and Results: In a multicenter, double-blind, crossover trial, we compared the effects of LV and biventricular (BiV) pacing on exercise tolerance and LV remodeling in patients with an LV ejection fraction ≤35%, QRS ≥120 milliseconds, and symptoms of heart failure. A total of 211 patients were recruited from 11 centers. After a run-in period of 2 to 8 weeks, 121 qualifying patients were randomized to LV followed by BiV pacing or vice versa for consecutive 6-month periods. The greatest improvement in New York Heart Association class and 6-minute walk test occurred during the run-in phase before randomization. Exercise duration at 75% of peak Vo(2) (primary outcome) increased from 9.3±6.4 to 14.0±11.9 and 14.3±12.5 minutes with LV and BiV pacing, respectively, with no difference between groups (P=0.4327). LV ejection fraction improved from 24.4±6.3% to 31.9±10.8% and 30.9±9.8% with LV and BiV pacing, respectively, with no difference between groups (P=0.4530). Reductions in LV end-systolic volume were likewise similar (P=0.6788). The proportion of clinical responders (≥20% increase in exercise duration) to LV and BiV pacing was 48.0% and 55.1% (P=0.1615). Positive remodeling responses (≥15% reduction in LV end-systolic volume) were observed in 46.7% and 55.4% (P=0.0881). Overall, 30.6% of LV nonresponders improved with BiV and 17.1% of BiV nonresponders improved with LV pacing., Conclusion: LV pacing is not superior to BiV pacing. However, nonresponders to BiV pacing may respond favorably to LV pacing, suggesting a potential role as tiered therapy., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00901212.