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Background: The optimal treatment of atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (HFrEF) remains unsettled., Objective: The purpose of this study was to assess the efficacy of catheter ablation (CA) and medical therapy compared to medical therapy alone in patients with AF and HFrEF., Methods: We performed a systematic review of randomized controlled trials (RCTs) comparing CA with guideline-directed medical therapy for AF in patients with HFrEF (left ventricular ejection fraction [LVEF] ≤ 40%). We systematically searched PubMed, Embase, and Cochrane for eligible trials. A random effects model was used to calculate the risk ratios (RRs) and mean differences (MDs), with 95% confidence intervals (CIs)., Results: Six RCTs comprising 1055 patients were included, of whom 530 (50.2%) were randomized to CA. Compared with medical therapy, CA was associated with a significant reduction in heart failure (HF) hospitalization (RR 0.57; 95% CI 0.45-0.72; P < .01), cardiovascular mortality (RR 0.46; 95% CI 0.31-0.70; P < .01), all-cause mortality (RR 0.53; 95% CI 0.36-0.78; P < .01), and AF burden (MD -29.8%; 95% CI -43.73% to -15.90%; P < .01). Also, there was a significant improvement in LVEF (MD 3.8%; 95% CI 1.6%-6.0%; P < .01) and quality of life (Minnesota Living with Heart Failure Questionnaire; MD -4.92 points; 95% CI -8.61 to -1.22 points; P < .01) in the ablation group., Conclusion: In this meta-analysis of RCTs of patients with AF and HFrEF, CA was associated with a reduction in HF hospitalization, cardiovascular mortality, and all-cause mortality as well as a significant improvement in LVEF and quality of life., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Importance: Readmissions after an index heart failure (HF) hospitalization are a major contemporary health care problem., Objective: To evaluate the feasibility and efficacy of an intensive telemonitoring strategy in the vulnerable period after an HF hospitalization., Design, Setting, and Participants: This randomized clinical trial was conducted in 30 HF clinics in Brazil. Patients with left ventricular ejection fraction less than 40% and access to mobile phones were enrolled up to 30 days after an HF admission. Data were collected from July 2019 to July 2022., Intervention: Participants were randomly assigned to a telemonitoring strategy or standard care. The telemonitoring group received 4 daily short message service text messages to optimize self-care, active engagement, and early intervention. Red flags based on feedback messages triggered automatic diuretic adjustment and/or a telephone call from the health care team., Main Outcomes and Measures: The primary end point was change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 180 days. A hierarchical win-ratio analysis incorporating blindly adjudicated clinical events (cardiovascular deaths and HF hospitalization) and variation in NT-proBNP was also performed., Results: Of 699 included patients, 460 (65.8%) were male, and the mean (SD) age was 61.2 (14.5) years. A total of 352 patients were randomly assigned to the telemonitoring strategy and 347 to standard care. Satisfaction with the telemonitoring strategy was excellent (net promoting score at 180 days, 78.5). HF self-care increased significantly in the telemonitoring group compared with the standard care group (score difference at 30 days, -2.21; 95% CI, -3.67 to -0.74; P = .001; score difference at 180 days, -2.08; 95% CI, -3.59 to -0.57; P = .004). Variation of NT-proBNP was similar in the telemonitoring group compared with the standard care group (telemonitoring: baseline, 2593 pg/mL; 95% CI, 2314-2923; 180 days, 1313 pg/mL; 95% CI, 1117-1543; standard care: baseline, 2396 pg/mL; 95% CI, 2122-2721; 180 days, 1319 pg/mL; 95% CI, 1114-1564; ratio of change, 0.92; 95% CI, 0.77-1.11; P = .39). Hierarchical analysis of the composite outcome demonstrated a similar number of wins in both groups (telemonitoring, 49 883 of 122 144 comparisons [40.8%]; standard care, 48 034 of 122 144 comparisons [39.3%]; win ratio, 1.04; 95% CI, 0.86-1.26)., Conclusions and Relevance: An intensive telemonitoring strategy applied in the vulnerable period after an HF admission was feasible, well-accepted, and increased scores of HF self-care but did not translate to reductions in NT-proBNP levels nor improvement in a composite hierarchical clinical outcome., Trial Registration: ClinicalTrials.gov Identifier: NCT04062461.

Aims: Few reports have examined the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) or their relationship with mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF)., Methods and Results: Data from the PARAGON-HF, TOPCAT, I-Preserve, and CHARM-Preserved trials were merged. VT/VF, reported as adverse events, were identified. Patients who experienced VT/VF were compared with patients who did not. The relationship between VT/VF and mortality was examined in time-updated Cox proportional hazard regression models. Variables associated with VT/VF were examined in Cox proportional hazard regression models. The rate of VT/VF in patients with HFmrEF compared with patients with HFpEF was examined in a Cox proportional hazards regression model. Of 13 609 patients, over a median follow-up of 1170 days (interquartile range: 966-1451), 146 (1.1%) experienced an investigator-reported VT/VF (incidence rate 0.3 per 100 person-years). Patients who experienced VT/VF were more likely to be male, have had a myocardial infarction, poorer renal function, more adverse left ventricular remodelling, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) than patients who did not. Occurrence of VT/VF was associated with NT-proBNP, history of atrial fibrillation/flutter, male sex, lower ejection fraction, and history of hypertension. VT/VF was associated with all-cause death [adjusted hazard ratio (HR): 3.95, 95% confidence interval (CI): 2.80-5.57; P < 0.001] and cardiovascular death, driven by death from heart failure and not sudden death. Patients with HFmrEF had a higher rate of VT/VF than patients with HFpEF (adjusted HR: 2.19, 95% CI: 1.77-2.71)., Conclusion: VT/VF was uncommon in patients with HFmrEF and HFpEF. However, such events were strongly associated with mortality and appear to be a marker of disease severity rather than risk of sudden death., Clinical Trial Registration: ClinicalTrials.gov unique identifier: NCT01920711(PARAGON-HF); NCT00094302 (TOPCAT); NCT00095238 (I-Preserve); NCT00634712 (CHARM-Preserved)., Competing Interests: Conflicts of interest: F.Z. reports personal fees from Boerhinger Ingelheim, Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera. J.L.R. reports grants and consulting fees from Novartis and consulting fees from AstraZeneca. M.P. has received consulting fees from Abbvie, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; has received payment for expert testimony from Actavis; and has received support for attending meetings and/or travel from Boehringer Ingelheim. I.S.A. has received fees for serving on a steering committee from ARCA Biopharma, Amgen, LivaNova, and Novartis; fees for serving on an end point committee from Boehringer Ingelheim; and fees for serving as chair of a data and safety monitoring board from Boston Scientific. M.R.Z. has received grants, consulting fees, and participation on a data safety monitoring board or advisory board as part of the committees for the PARAGON-HF and PARADIGM-HF trials. A.S.D. received institutional research grant support from Abbott, AstraZeneca, Alnylam, Bayer and Novartis; and has received personal consulting fees from Abbott, Alnylam, Amgem, AstraZeneca, Biofourmis, Boerhinger Ingelheim, Boston Scientific Cytokinetics, DalCor Pharma, Lupin Pharma, Lexicon, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. M.P.L. is an employee of Novartis. T.K. received lecture fees from Abbott Medical Japan LLC, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., AstraZeneca K.K., Bristol Myers Squibb Co., and Abiomed Japan K.K. L.K. has received speakers honorarium from Novo, Novartis, AstraZeneca, Boehringer Ingelheim and Bayer. L.E.R. has been a consultant or served on advisory boards for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis and Pfizer. J.B. has received advisory board honoraria from Bayer. M.C.P. reports compensation from Bayer for end point committee services; compensation from Boehringer Ingelheim for end point committee services; compensation from AstraZeneca for consultant services; compensation from Novo Nordisk for consultant services; compensation from Takeda California Inc for end point review committee services; grants from Boehringer Ingelheim; compensation from Novo Nordisk for end point review committee services; compensation from Novartis for consultant services; grants from Novartis to other; grants from SQ Innovation to other; compensation from SQ Innovation for consultant services; and grants from AstraZeneca to other. P.S.J. reports speakers and advisory board fees from AstraZeneca, Boehringer Ingelheim and Novartis; and reports research funding from Boehringer Ingelheim and Analog Devices. S.D.S. received grants to his institution from Actelion, Alnylam, Amgem, AstraZenaca, Belleerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinectics, Eidos, Gilead, GlaxoSmithKline, IONIS, Lilly, Mesoblast, MyoKardia, National Institute of Health National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; received fees for consultancy from Abbott, Action, Akros, Alnylam, Amgem, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokenetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta; and received honoraria for lectures from Novartis and AstraZeneca. J.J.V.M. has received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology Servier, and the Corpus; and reports steering committee and travel fees from Amgen, steering committee fees from Bayer, investigator and travel fees from Theracos, consultancy and travel fees from IONIS, steering committee fees from DalCor, investigator, steering committee and travel fees from Novartis, investigator, steering committee and travel fees from GlaxoSmithKline, steering committee fees from Bristol Myers Squibb, consultancy fees from Boehringer Ingelheim, advisory board fees from Cardurion, and advisory board fees from Alnylam all paid to the University of Glasgow. All other authors report no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Heart failure (HF) treatment recommendations are centered on New York Heart Association (NYHA) classification, such that most apparently asymptomatic patients are not eligible for disease-modifying therapies., Objectives: To assess within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide [NT-proBNP] level), and their association with long-term prognosis in the PARADIGM-HF trial., Design, Setting, and Participants: All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan during a 6- to 10-week run-in period before randomization. Patients classified as NYHA class I, II, and III in PARADIGM-HF were compared at randomization., Exposures: NYHA class at randomization after 6 to 10 weeks of the run-in period., Main Outcomes and Measures: Primary outcome was cardiovascular death or first HF hospitalization. Logistic regression models, areas under the receiver operating characteristic curve (AUC), kernel density estimation overlaps, and Cox proportional hazards models were used., Results: The analysis included 8326 patients with known NYHA classification at randomization. Of 389 patients in NYHA class I, 228 (58%) changed functional class during the first year after randomization. Level of NT-proBNP was a poor discriminator of NYHA classification: for NYHA class I vs II, the AUC was 0.51 (95% CI, 0.48-0.54). For NT-proBNP level, estimated kernel density overlap was 93% between NYHA class I vs II, 79% between NYHA I vs III, and 83% between NYHA II vs III. Patients classified as NYHA III displayed a distinctively higher rate of cardiovascular events (NYHA III vs I, hazard ratio [HR], 1.84; 95% CI, 1.44-2.37; NYHA III vs II, HR, 1.49; 95% CI, 1.35-1.64). Patients in NYHA class I and II revealed lower event rates (NYHA II vs I, HR, 1.24; 95% CI, 0.97-1.58). Stratification by NT-proBNP level (<1600 pg/mL or ≥1600 pg/mL) identified subgroups with distinctive risk, such that NYHA class I patients with high NT-proBNP levels (n = 175) had a numerically higher event rate than patients with low NT-proBNP levels from any NYHA class (vs I, HR, 3.43; 95% CI, 2.03-5.87; vs II, HR, 2.12; 95% CI, 1.58-2.86; vs III, HR, 1.37; 95% CI, 1.00-1.88)., Conclusions and Relevance: In this study, patients in NYHA class I and II overlapped substantially in objective measures and long-term prognosis. Physician-defined "asymptomatic" functional class concealed patients who were at substantial risk for adverse outcomes. NYHA classification might be limited to differentiate mild forms of HF., Trial Registration: ClinicalTrials.gov Identifier: NCT01035255.

Background: Heart failure (HF) is a growing problem for healthcare systems worldwide. Sodium and fluid restriction are non-pharmacological treatments recommended for patients with HF by several guidelines over the years, even without consensus., Objective: To evaluate the effects of sodium and fluid restriction in patients with HF., Methods: We searched MEDLINE, Embase, and Cochrane CENTRAL databases up to June 2020 and screened the reference lists of relevant articles. We included randomized controlled trials evaluating sodium and/or fluid restriction in patients with HF. We assessed three independent comparisons: (a) sodium restriction versus control; (b) fluid restriction versus control; and (c) sodium and fluid restriction versus control. Main outcomes of interest were all-cause mortality and hospitalization. Two independent reviewers selected studies and extracted data. We pooled the results using random-effects meta-analysis. We used the RoB 2.0 and the GRADE framework to assess risk of bias and quality of evidence., Results: We included 16 studies totaling 3545 patients in our meta-analysis. Daily sodium intake was 1.5-2.4 g for the intervention group and >2.7 g for the control group, and daily fluid intake was 0.8-1.5 L for the intervention group and free oral fluid intake for the control group. Sodium restriction increased mortality (relative risk 1.92, 95% confidence interval 1.51 to 2.45, moderate quality of evidence) and hospitalization (relative risk 1.63, 1.11 to 2.40, low quality of evidence). Fluid restriction reduced mortality (relative risk 0.32, 0.13 to 0.82, low quality of evidence) and hospitalization (relative risk 0.46, 0.27 to 0.77, n = 331, low quality of evidence). The combination of sodium and fluid restriction did not significantly affect the risk of mortality (relative risk 0.92, 0.49 to 1.73, low quality of evidence) or the risk of hospitalization (relative risk 0.94, 0.75 to 1.19, low quality of evidence)., Conclusion: The combination of sodium and fluid restriction in clinical trials resulted in a null effect although results in the opposite direction were observed for each intervention independently. Combined sodium and fluid restriction are usually recommended for patients with HF. Our findings of sodium restriction harm, risk of mortality and hospitalization are consistent with publications from several clinical trial and physiologic explanations. A well-designed clinical trial nested by an implementation study is urgent for definitive sodium range recommendation, specially considering the change of currently guidelines, pushing up the cut-off of sodium restriction range., Competing Interests: Declaration of competing interest The methodological coordination for the development of these study was funded by the Institutional Development Program of the Brazilian Unified Health System (PROADI-SUS) together with Hospital Moinhos de Vento., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Aims: Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias., Methods and Results: Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65-0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020)., Conclusions: Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: To evaluate a telemonitoring strategy based on automated text messaging and telephone support after heart failure (HF) hospitalization., Methods and Results: The MESSAGE-HF study is a prospective multicentre, randomized, nationwide trial enrolling patients from 30 clinics in all regions of Brazil. HF patients with reduced left ventricular ejection fraction (<40%) and access to mobile phones are eligible after an acute decompensated HF hospitalization. Patients meeting eligibility criteria undergo an initial feasibility text messaging assessment and are randomized to usual care or telemonitoring intervention. All patients receive a HF booklet with basic information and recommendations about self-care. Patients in the intervention group receive four daily short text messages (educational and feedback) during the first 30 days of the protocol to optimize self-care; the feedback text messages from patients could trigger diuretic adjustments or a telephone call from the healthcare team. After 30 days, the frequency of text messages can be adjusted. Patients are followed up after 30, 90, and 180 days, with final status ascertained at 365 days by telephone. Our primary endpoint is the change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels after 180 days. Secondary endpoints include changes in NT-proBNP after 30 days; health-related quality of life, HF self-care, and knowledge scales after 30 and 180 days; and a composite outcome of HF hospitalization and cardiovascular death, adjudicated by a blinded and independent committee., Conclusions: The MESSAGE-HF trial is evaluating an educational and self-care promotion strategy involving a simple, intensive, and tailored telemonitoring system. If proven effective, it could be applied to a broader population worldwide., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: New York Heart Association (NYHA) functional class plays a central role in heart failure (HF) assessment but might be unreliable in mild presentations. We compared objective measures of HF functional evaluation between patients classified as NYHA I and II in the Re de B rasileira de Estudos em I nsuficiência C ardíaca (ReBIC)-1 Trial., Methods: The ReBIC-1 Trial included outpatients with stable HF with reduced ejection fraction. All patients had simultaneous protocol-defined assessment of NYHA class, 6 min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patient's self-perception of dyspnoea using a Visual Analogue Scale (VAS, range 0-100)., Results: Of 188 included patients with HF, 122 (65%) were classified as NYHA I and 66 (35%) as NYHA II at baseline. Although NYHA class I patients had lower dyspnoea VAS Scores (median 16 (IQR, 4-30) for class I vs 27.5 (11-49) for class II, p=0.001), overlap between classes was substantial (density overlap=60%). A similar profile was observed for NT-proBNP levels (620 pg/mL (248-1333) vs 778 (421-1737), p=0.015; overlap=78%) and for 6MWT distance (400 m (330-466) vs 351 m (286-408), p=0.028; overlap=64%). Among NYHA class I patients, 19%-34% had one marker of HF severity (VAS Score >30 points, 6MWT <300 m or NT-proBNP levels >1000 pg/mL) and 6%-10% had two of them. Temporal change in functional class was not accompanied by variation on dyspnoea VAS (p=0.14)., Conclusions: Most patients classified as NYHA classes I and II had similar self-perception of their limitation, objective physical capabilities and levels of natriuretic peptides. These results suggest the NYHA classification poorly discriminates patients with mild HF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment., Methods and Results: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (P interaction  < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05)., Conclusions: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure., (© 2021 European Society of Cardiology.)

Introduction: The aim of this study was to evaluate the effectiveness of a diuretic adjustment algorithm (DAA) in maintaining clinical stability and reducing HF readmissions using telemonitoring technologies., Methods: Randomized clinical trial of patients with an indication for furosemide dose adjustment during routine outpatient visits. In the intervention group (IG), the diuretic dose was adjusted according to the DAA and the patients received telephone calls for 30 days. In the control group (CG), the diuretic dose was adjusted by a physician at baseline only. Co-primary outcomes were hospital readmission and/or emergency department visits due to decompensated HF within 90 days, and a 2-point change in the Clinical Congestion Score and/or a deterioration in New York Heart Association functional class within 30 days., Results: A total of 206 patients were included. Most patients were male ( n =119; 58%), with a mean age of 62 (SD 13) years. Four patients (2%) in the IG and 14 (7%) in the CG were hospitalized for HF (odds ratio (OR) 0.31 (0.10-0.91); p =0.04). Multivariate analysis showed a reduction of 67% in readmissions and/or emergency department visits due to decompensated HF in the IG compared with the CG (95% CI 0.13-0.88; p =0.027). Regarding the combined outcome of HF readmission and/or emergency department visits or clinical instability, the IG had 20% fewer events than the CG within 30 days (IG: n =48 (23%), CG: n =70 (34%); OR 0.80 (0.63-0.93); p =0.03)., Discussion: Using DAA improved the combined outcome in these outpatients, with favorable and significant results that included a reduction in HF admissions and in clinical instability. (NCT02068937).

Background: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction., Methods: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality., Results: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P <0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P <0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain ( P <0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes ( P <0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P <0.05 for both outcomes)., Conclusions: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

Objectives: The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause., Background: SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF)., Methods: Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis., Results: At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers)., Conclusions: Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy., (Copyright © 2020. Published by Elsevier Inc.)

Aims: Although loop diuretics are widely used to treat heart failure (HF), there is scarce contemporary data to guide diuretic adjustments in the outpatient setting., Methods and Results: In a prospective, randomized and double-blind protocol, we tested the safety and tolerability of withdrawing low-dose furosemide in stable HF outpatients at 11 HF clinics in Brazil. The trial had two blindly adjudicated co-primary outcomes: (i) symptoms assessment quantified as the area under the curve (AUC) of a dyspnoea score on a visual-analogue scale evaluated at 4 time-points (baseline, Day 15, Day 45, and Day 90) and (ii) the proportion of patients maintained without diuretic reuse during follow-up. We enrolled 188 patients (25% females; 59 ± 13 years old; left ventricular ejection fraction = 32 ± 8%) that were randomized to furosemide withdrawal (n = 95) or maintenance (n = 93). For the first co-primary endpoint, no significant difference in patients' assessment of dyspnoea was observed in the comparison of furosemide withdrawal with continuous administration [median AUC 1875 (interquartile range, IQR 383-3360) and 1541 (IQR 474-3124), respectively; P = 0.94]. For the second co-primary endpoint, 70 patients (75.3%) in the withdrawal group and 77 patients (83.7%) in the maintenance group were free of furosemide reuse during follow-up (odds ratio for additional furosemide use with withdrawal 1.69, 95% confidence interval 0.82-3.49; P = 0.16). Heart failure-related events (hospitalizations, emergency room visits, and deaths) were infrequent and similar between groups (P = 1.0)., Conclusions: Diuretic withdrawal did not result in neither increased self-perception of dyspnoea nor increased need of furosemide reuse. Diuretic discontinuation may deserve consideration in stable outpatients with no signs of fluid retention receiving optimal medical therapy., Clinicaltrials.gov Identifier: NCT02689180., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Furosemide is commonly prescribed for symptom relief in heart failure (HF) patients. Although few data support the continuous use of loop diuretics in apparently euvolemic HF patients with mild symptoms, there is concern about safety of diuretic withdrawal in these patients. The ReBIC-1 trial was designed to evaluate the safety and tolerability of withdrawing furosemide in stable, euvolemic, chronic HF outpatients. This multicenter initiative is part of the Brazilian Research Network in Heart Failure (ReBIC) created to develop clinical studies in HF and composed predominantly by university tertiary care hospitals., Methods: The ReBIC-1 trial is currently enrolling HF patients in NYHA functional class I-II, left ventricular ejection fraction ≤45%, without a HF-related hospital admission within the last 6 months, receiving a stable dose of furosemide (40 or 80 mg per day) for at least 6 months. Eligible patients will be randomized to maintain or withdraw furosemide in a double-blinded protocol. The trial has two co-primary outcomes: (1) dyspnea assessment using a visual-analogue scale evaluated at 4 time points and (2) the proportion of patients maintained without diuretics during the follow-up period. Total sample size was calculated to be 220 patients. Enrolled patients will be followed up to 90 days after randomization, and diuretic will be restarted if clinical deterioration or signs of congestion are detected. Pre-defined sub-group analysis based on NT-proBNP levels at baseline is planned., Perspective: Evidence-based strategies aiming to simplify HF pharmacotherapy are needed in clinical practice. The ReBIC-1 trial will determine the safety of withdrawing furosemide in stable chronic HF patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Risk stratification of serious arrhythmic events in patients with nonischemic heart failure (HF), beyond estimates of left ventricular ejection fraction (LVEF), remains an important clinical challenge. This study aims to determine the clinical value of different noninvasive and invasive tests as predictors of serious arrhythmic events in patients with nonischemic HF., Methods: A prospective observational study was conducted including 106 nonischemic HF patients who underwent a comprehensive clinical and laboratory evaluation including two-dimensional echocardiography, 24-h Holter monitoring, cardiopulmonary exercise testing (CPX), and an invasive electrophysiological study. The study's primary end-point was either syncope, appropriate therapy by implantable cardioverter-defibrillators, or sudden cardiac death., Results: During a mean follow-up of 704 ± 320 days, the primary end-point occurred in 15 patients (14.2%). In multivariable analysis, LV end-diastolic diameter >73 mm (hazard ratio [HR] 3.7; p = 0.016), exercise periodic breathing (EPB) on CPX (HR 2.88; p = 0.045), and non-sustained ventricular tachycardia (NSVT) ≥10 beats (HR 8.2; p < 0.01) remained independently associated with serious arrhythmic events. The positive predictive value of the presence of two of these predictors ranged from 44 to 100%. The absence of all three factors (n = 65, 61% of the sample) identified a subset of patients with low risk of future arrhythmic events, with a negative predictive value of 96.9%., Conclusions: In this cohort study of nonischemic HF patients, LV dimension, EPB, and NSVT ≥10 beats were independent predictors of serious arrhythmic events. The presence or absence of these characteristics identified sub-groups of high and low risk of serious arrhythmic events, respectively.

Importance: The presumed proarrhythmic action of caffeine is controversial. Few studies have assessed the effect of high doses of caffeine in patients with heart failure due to left ventricular systolic dysfunction at high risk for ventricular arrhythmias., Objective: To compare the effect of high-dose caffeine or placebo on the frequency of supraventricular and ventricular arrhythmias, both at rest and during a symptom-limited exercise test., Design, Setting, and Participants: Double-blinded randomized clinical trial with a crossover design conducted at the heart failure and cardiac transplant clinic of a tertiary-care university hospital. The trial included patients with chronic heart failure with moderate-to-severe systolic dysfunction (left ventricular ejection fraction <45%) and New York Heart Association functional class I to III between March 5, 2013, and October 2, 2015., Interventions: Caffeine (100 mg) or lactose capsules, in addition to 5 doses of 100 mL decaffeinated coffee at 1-hour intervals, for a total of 500 mg of caffeine or placebo during a 5-hour protocol. After a 1-week washout period, the protocol was repeated., Main Outcomes and Measures: Number and percentage of ventricular and supraventricular premature beats assessed by continuous electrocardiographic monitoring., Results: We enrolled 51 patients (37 [74%] male; mean [SD] age, 60.6 [10.9] years) with predominantly moderate-to-severe left ventricular systolic dysfunction (mean [SD] left ventricular ejection fraction, 29% [7%]); 31 [61%] had an implantable cardioverter-defibrillator device. No significant differences between the caffeine and placebo groups were observed in the number of ventricular (185 vs 239 beats, respectively; P = .47) and supraventricular premature beats (6 vs 6 beats, respectively; P = .44), as well as in couplets, bigeminal cycles, or nonsustained tachycardia during continuous electrocardiographic monitoring. Exercise test-derived variables, such as ventricular and supraventricular premature beats, duration of exercise, estimated peak oxygen consumption, and heart rate, were not influenced by caffeine ingestion. We observed no increases in ventricular premature beats (91 vs 223 vs 207 beats, respectively) in patients with higher levels of plasma caffeine concentration compared with lower plasma levels (P = .91) or with the placebo group (P = .74)., Conclusions and Relevance: Acute ingestion of high doses of caffeine did not induce arrhythmias in patients with systolic heart failure and at high risk for ventricular arrhythmias., Trial Registration: clinicaltrials.gov Identifier: NCT02045992.

Circulating levels of matrix metalloproteinase-2 (MMP-2) predict mortality and hospital admission in heart failure (HF) patients. However, the role of MMP-2 gene polymorphisms in the susceptibility and prognosis of HF remains elusive. In this study, 308 HF outpatients (216 Caucasian- and 92 African-Brazilians) and 333 healthy subjects (256 Caucasian- and 77 African-Brazilians) were genotyped for the -1575G>A (rs243866), -1059G>A (rs17859821), and -790G>T (rs243864) polymorphisms in the MMP-2 gene. Polymorphisms were analyzed individually and in combination (haplotype), and positive associations were adjusted for clinical covariates. Although allele frequencies were similar in HF patients and controls in both ethnic groups, homozygotes for the minor alleles were not found among African-Brazilian patients. After a median follow-up of 5.3 years, 124 patients (40.3%) died (54.8% of them for HF). In Caucasian-Brazilians, the TT genotype of the -790G>T polymorphism was associated with a decreased risk of HF-related death as compared with GT genotype (hazard ratio [HR] = 0.512, 95% confidence interval [CI] 0.285-0.920). However, this association was lost after adjusting for clinical covariates (HR = 0.703, 95% CI 0.365-1.353). Haplotype analysis revealed similar findings, as patients homozygous for the -1575G/-1059G/-790T haplotype had a lower rate of HF-related death than those with any other haplotype combination (12.9% versus 28.5%, respectively; P = 0.010). Again, this association did not remain after adjusting for clinical covariates (HR = 0.521, 95% CI 0.248-1.093). Our study does not exclude the possibility that polymorphisms in MMP-2 gene, particularly the -790G>T polymorphism, might be related to HF prognosis. However, due to the limitations of the study, our findings need to be confirmed in further larger studies., Competing Interests: The authors have declared that no competing interests exist.

Background: Although half of all patients with heart failure (HF) have a normal or near-normal ejection fraction and their prognosis differs little from that of patients with a reduced ejection fraction, the pathophysiology of HF with preserved ejection fraction (HF-PEF) is still poorly understood, and its management poorly supported by clinical trials. Sodium and fluid restriction is the most common self-care measure prescribed to HF patients for management of congestive episodes. However, its role in the treatment of HF-PEF remains unclear. This trial seeks to compare the effects of a sodium- and fluid-restricted diet versus an unrestricted diet on weight loss, neurohormonal activation, and clinical stability in patients admitted for decompensated HF-PEF., Methods/design: This is a randomized, parallel trial with blinded outcome assessment. The sample will include adult patients (aged ≥18 years) with a diagnosis of HF-PEF admitted for HF decompensation. The patients will be randomized to receive a diet with sodium and fluid intake restricted to 0.8 g/day and 800 mL/day respectively (intervention group) or an unrestricted diet, with 4 g/day sodium and unlimited fluid intake (control group), and followed for 7 days or until hospital discharge. The primary outcome shall consist of weight loss at 7 days or discharge. The secondary outcome includes assessment of clinical stability, neurohormonal activation, daily perception of thirst and readmission rate at 30 days., Discussion: Assessment of the effects of sodium and fluid restriction on neurohormonal activation and clinical course of HF-PEF can promote a deeper understanding of the pathophysiology and progression of this complex syndrome., Trial Registration Number: ClinicalTrials.gov identifier: NCT01896908 (date of registration: 8 August 2013).

Background: QRS duration is considered to be an indicator of adverse outcome in patients with heart failure (HF), and genetic polymorphisms may be involved in this conductivity impairment. We studied the prognostic impact of the QRS widening rate (QRS-WR) on patients with HF and the influence of the matrix metalloproteinases gene polymorphisms on the QRS-WR., Methods: This prospective cohort study included 184 patients with left ventricular (LV) systolic dysfunction (LV ejection fraction [LVEF] < 45%). The QRS-WR was calculated as the difference between 2 electrocardiogram assessments (in ms) divided by the time elapsed between each evaluation (months). The MMP-1 -1607 1G/2G, MMP-2 -790G/T and -1575G/A, MMP-3 -1171 5A/6A, MMP-9 -1562 C/T and R279Q, and MMP-12 -82A/G polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism., Results: Patients were predominantly white (68%) men (67%) in New York Heart Association functional classes I and II (77%). Patients with HF with a QRS-WR ≥ 0.5 ms/month had more HF-related deaths and more combined clinical events than those with a QRS-WR < 0.5 ms/month (P = 0.03 and P = 0.01, respectively). After adjusting for other covariates, the QRS-WR remained an independent predictor of combined clinical events (hazard ratio, 1.6; 95% confidence interval, 1.1-2.5; P = 0.02). The MMP-1 2G2G genotype was associated with nearly a 2-fold increase in QRS-WR (P = 0.03). Conversely, patients with the MMP-3 5A5A genotype and a nonischemic cause of HF were protected against QRS enlargement (P = 0.03)., Conclusions: QRS-WR retains prognostic value in patients with chronic HF receiving guideline-based pharmacologic treatment. MMP gene polymorphisms can influence the rate of QRS enlargement over time., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Context: Elevated plasmatic microRNAs (miRs) are observed in heart failure (HF). However, the cardiac origin of these miRs remains unclear., Objective: We calculated transcoronary gradients of miR-29b, miR-133a and miR-423-5p in 17 outpatients with stable systolic HF and in controls without structural cardiac disease., Materials and Methods: MicroRNAs were measured by quantitative real-time polymerase chain reaction., Results: Positive transcoronary miR gradients were observed in patients with HF but not in controls (p = 0.03). B-type natriuretic peptide (BNP) moderately correlated with the transcoronary gradients of miR-133a and miR-423-5p., Discussion and Conclusions: The difference in transcoronary gradients between HF outpatients and controls suggests that miR-423-5p has a cardiac origin. The positive correlation between miR-423-5p and BNP transcoronary gradients supports this hypothesis.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Management of HF involves accurate diagnosis and implementation of evidence-based treatment strategies. Costs related to the care of patients with HF have increased substantially over the past 2 decades, partly owing to new medications and diagnostic tests, increased rates of hospitalization, implantation of costly novel devices and, as the disease progresses, consideration for heart transplantation, mechanical circulatory support, and end-of-life care. Not surprisingly, HF places a huge burden on health-care systems, and widespread implementation of all potentially beneficial therapies for HF could prove unrealistic for many, if not all, nations. Cost-effectiveness analyses can help to quantify the relationship between clinical outcomes and the economic implications of available therapies. This Review is a critical overview of cost-effectiveness studies on key areas of HF management, involving pharmacological and nonpharmacological clinical therapies, including device-based and surgical therapeutic strategies.

Background: Cardiac resynchronization therapy (CRT) improves symptoms and survival in patients with heart failure (HF). However, the devices used to deliver it are costly and can impose a significant burden to the relatively constrained health budgets of middle-income countries such as Brazil., Methods: A Markov model was constructed, representing the follow-up of a hypothetical cohort of HF patients, with a 20-year time horizon. Input data were based on information from a Brazilian cohort of 316 HF patients, as well as meta-analyses of data on devices' effectiveness and risks. Stochastic and probabilistic sensitivity analyses were performed for all important variables in the model. Costs were expressed as International Dollars (Int$), by application of current purchasing power parity conversion rate., Results: In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of CRT over medical therapy was Int$ 15,723 per quality-adjusted life years (QALYs) gained. For CRT combined with an implantable cardioverter-defibrillator (ICD), ICER was Int$ 36,940/QALY over ICD alone, and Int$ 84,345/QALY over CRT alone. Sensitivity analyses showed that the model was generally robust, though susceptible to the cost of the devices, their impact on HF mortality, and battery longevity., Conclusions: CRT is cost-effective for HF patients in the Brazilian public health system scenario. In patients eligible for CRT, upgrade to CRT+ICD has an ICER above the World Health Organization willingness-to-pay threshold of three times the nation's Gross Domestic Product per Capita (Int$ 31,689 for Brazil). However, for ICD eligible patients, upgrade to CRT+ICD is marginally cost-effective., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Background: Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction., Methods and Results: We conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African-Brazilians (p=0.043). African-Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value=0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR=0.11; 95% CI=0.01-0.83; p=0.03)., Conclusions: The -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African-Brazilian patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: The purpose of this study is to compare clinical assessment of congestion performed by a nurse to that performed by cardiologist and correlate them with NT-ProBNP levels., Background: The nurses' role in heart failure has been strongly focused in therapeutic, educational and self-care interventions. The diagnostic performance of nurses in heart failure outpatients is not well explored. N-terminal pro-B-type natriuretic peptide is a cardiac marker that reflects elevated filling pressures., Design: Cross-sectional contemporaneous study., Methods: Heart failure outpatients underwent a systematic clinical assessment of clinical congestion score performed by cardiologist and nurse during the same visit. Assessments were performed independently and N-terminal pro-B-type natriuretic peptide levels obtained. The nurses' ability to classify patients in hemodynamic profile was compared to the cardiologist's., Results: Eighty-nine assessments were performed in 63 patients with heart failure. The correlation of clinical congestion scores obtained by nurse with those obtained by cardiologist was rs=0.86; p<0.001. The correlation of clinical congestion scores from nurse and cardiologist with levels of N-terminal pro-B-type natriuretic peptide were as follows: rs=0.45; p<0.0001 and rs=0.51, respectively, p<0.0001. Patients with clinical congestion score≥3 had levels of NT-ProBNP significantly higher than those with clinical congestion score<3, in the assessment performed by the cardiologist (1866 SD 1151 vs. 757 SD 988 pg/ml; p<0.0001) and by the nurse (1720 SD 1228 vs. 821 SD 914 pg/ml; p<0.0001). The nurse and cardiologist had similar capacity in classifying patients in congested quadrants (p=0.027) or in dry quadrants (p=0.03), according to the levels of N-terminal pro-B-type natriuretic peptide. Area under the receiver-operating characteristic curve of the nurse and cardiologist to detect congestion was, respectively, 0.77 and 0.72., Conclusions: Our data suggests that nurses trained in heart failure may have a similar performance to that of the cardiologist for the clinical detection of congestion and assessment of the hemodynamic profile in patients with chronic heart failure., Relevance to Clinical Practice: Considering that consistent clinical assessment can identify congested or hypovolemic patients with reasonable reliability, as well as patients with low or normal cardiac output, our results may help confirm nurses' capability in performing reliable clinical assessment in heart failure patients. While nurses' led heart failure programmes are usually focused on the management of patients, nurses' ability to perform accurate assessment would expand nurses' role in these programmes. As many institutions now focus on home visits by heart failure nurses, accurate assessment would benefit patients and improve their clinical outcomes., (© 2010 Blackwell Publishing Ltd.)

Aims: We investigated whether the combination of beta(1)-Gly389Arg and GNB3 C825T, two genetic polymorphisms strictly related to adrenergic system modulation, could act as predictors of appropriate therapies in patients with heart failure (HF) using implantable cardioverter-defibrillators (ICDs)., Methods and Results: Patients with HF and ICD implantation for primary and secondary prevention were studied. All ICD therapies were registered and classified as appropriate (secondary to ventricular tachycardia) or inappropriate (others). Genetic analysis was performed by polymerase chain reaction and restriction fragment length polymorphism methods. Seventy-three patients with mean left ventricular ejection fraction of 35 +/- 11% were evaluated. Overall, 35 ICD therapies occurred during follow-up in 31 (42.5%) patients. Twenty-four therapies (33%) were appropriate, and 11 (15%) were inappropriate. Individual analysis of each polymorphism only identified T825 carriers of GNB3 C825T as predictor of appropriate shocks. The combined presence of risk genotypes (Arg389 of the beta(1)-Gly389Arg and T825 of the GNB3 C825T) identified patients with higher risk of appropriate shocks. Patients with two at-risk genotypes had a survival rate free of appropriate shocks lower than those with none or only one of these markers (87 vs. 54%, respectively; log-rank statistic = 0.006). Using a Cox regression model, each at-risk genotype was associated with an increment of risk of appropriate ICD shocks (odds ratio = 3.9, 95% confidence interval of 1.3-12.0; P = 0.02)., Conclusion: Genetic polymorphisms of the adrenergic system may help to identify HF patients who are more likely to receive appropriate ICD therapies. Further studies are necessary to determine the clinical applicability of these polymorphisms as predictors of arrhythmias.

Elevated filling pressures are associated with heart failure deterioration, but mechanisms underlying this association remain poorly understood. We sought to investigate whether or not elevated filling pressures are associated with increased collagen turnover, evaluated by procollagen type III aminoterminal peptide (PIIINP) levels, in stable systolic heart failure. Eighty patients with heart failure with severe systolic dysfunction (ejection fraction 26 +/- 7%) were included. Patients underwent simultaneous echocardiogram with evaluation of haemodynamic parameters and blood sampling for PIIINP measurement. Mean PIIINP level was 6.11 +/- 2.62 microg l(-1). PIIINP was positively associated with estimated right atrial pressure (RAP) (r = 0.36; p = 0.001). Mean PIIINP values were 5.04 +/- 2.42 microg l(-1) in patients with estimated RAP < or = 5 mmHg, and 7.59 +/- 2.54 microg l(-1) in those with RAP > 15 mmHg (p < 0.01). In conclusion, elevated right-side filling pressures are associated with evidence of active extracellular matrix turnover, as indicated by elevated PIIINP levels, in stable systolic heart failure. Activation of extracellular matrix turnover may be implicated in the accelerated progression of heart failure syndromes seen in patients with persistent congestion.

Beta1-adrenergic receptor polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). The impact of 2 functional polymorphisms (beta1-Arg389Gly and beta1-Ser49Gly) on HF susceptibility, arrhythmogenesis, and prognosis was evaluated in Brazilian outpatients. Genotyping at codons 389 and 49 was performed using polymerase chain reaction with restriction fragment length polymorphism analysis in 201 outpatients with systolic HF and 141 apparently healthy controls. Enrolled patients were followed up at the HF clinic, and vital status was evaluated using electronic hospital records, telephone contact, and a local death certificate database. Allele frequencies were similar between patients with HF and controls, with neither polymorphism related to HF susceptibility. The beta1-389Gly homozygotes had significantly less nonsustained ventricular tachycardia on Holter monitoring (17% vs 48% for Arg/Arg patients; p = 0.015) and improved HF-related survival, with no events after a median follow-up of 40 months (log-rank statistics = 0.025). The negative impact of beta1-389Arg allele on HF-related survival was substantially reduced using high-dose beta-blocker therapy (80% survival for high-dose vs 42% for low-dose beta blockers or nonusers; log-rank statistics = 0.0003). The beta1-Ser49Gly polymorphism was not associated with nonsustained ventricular tachycardia or HF prognosis. In conclusion, beta1-Arg389Gly and beta1-Ser49Gly polymorphisms had no influence on HF susceptibility. However, the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better HF-related survival. A pharmacogenetic interaction is suggested because beta blockers were more effective in beta1-389Arg allele carriers.

Background: Endothelial function has been extensively evaluated at the arterial bed in several cardiovascular scenarios. Venous endothelial dysfunction, however, has not been thoroughly explored particularly in heart failure (HF)., Aims: To characterize venous endothelial function in severe HF., Methods and Results: Venous endothelial function was evaluated by the dorsal hand vein technique using a tripod holding a linear variable differential transformer. Dorsal hand veins were pre-constricted with phenylephrine and dose-response curves were constructed after acetylcholine and sodium nitroprusside administration. Maximum vasodilator response to acetylcholine, a marker of endothelium-dependent venodilation, was significantly lower (47+/-53% versus 102+/-54%, respectively, p=0.0004) in HF (n=27) patients compared to healthy controls (n=20). No difference in the endothelium-independent venodilator response was observed (p=0.87). Maximum vasodilator response to acetylcholine was also significantly lower on admission compared to the response immediately before hospital discharge in patients with acute decompensated HF (p<0.01). Improvement in venous endothelial function paralleled weight loss (mean difference of -3.8 kg, p<0.01) and improvement in the 6-minute walk test (mean difference of 107 m, p<0.01). There was no significant change in angiotensin-converting enzyme inhibitor or beta-blocker use during hospital stay., Conclusions: HF patients experience marked endothelium-dependent venous dysfunction with partial recovery during in-hospital management.

Background: The effects of chronic inhibition of 5'-phosphodiesterase with sildenafil on functional capacity, ventilatory efficiency, oxygen uptake, pulmonary hypertension, and endothelial function in chronic heart failure (CHF) are unknown., Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess the acute (1 hour after 50 mg by mouth) and chronic (4 weeks after 50 mg 3 times per day by mouth) effects of sildenafil in outpatients with CHF. The outcomes were cardiopulmonary exercise test parameters (chronic effect), echocardiographic-derived pulmonary artery systolic pressure, and plethysmography-derived forearm blood flow (acute and chronic effects)., Results: Nineteen patients with CHF (48 +/- 12 years) with an ejection fraction of 28% +/- 6% were studied. Patients who received sildenafil (n = 11) showed improved maximal oxygen uptake, ventilatory efficiency, and oxygen uptake kinetics. Sildenafil decreased pulmonary artery systolic pressure levels at 60 minutes and at 4 weeks compared with changes after placebo (P = .004 for group and time interaction). Improvement in ventilatory efficiency was positively associated with reductions in pulmonary artery systolic pressure. Patients allocated to placebo demonstrated a trend toward decreased forearm blood flow after reactive hyperemia, whereas this remained unchanged in patients allocated to sildenafil., Conclusions: Sildenafil administration for 4 weeks in stable outpatients with CHF improves functional capacity, ventilatory efficiency, oxygen uptake kinetics, and pulmonary hypertension. These effects may be mediated in part by improvements in endothelial function.

Anemia is common among patients with heart failure (HF) and has been associated with worse prognosis. To date, it is not well known whether correction of anemia in these patients can improve outcome. Proposed modalities for correction of anemia have been either administration of erythropoiesis-stimulating proteins, which appears plausible in patients with concomitant renal failure (so-called cardiorenal syndrome), or iron supplementation, which is particularly attractive in patients with no overt renal failure and chronic disease anemia with some degree of iron deficiency. This article reviews the rationale for anemia correction and the latest randomized clinical trial assessing clinical utility of erythropoiesis-stimulating proteins and/or iron supplementation through oral or intravenous administration in anemic HF patients.

Background: The therapeutic applicability of echocardiographic evaluations remains poorly defined in heart failure (HF). We hypothesized that an individualized echocardiography-guided strategy would be feasible and significantly reduce morbidity compared with the conventional clinically oriented treatment., Methods and Results: We conducted a single-center clinical trial comparing an echocardiography-guided strategy aimed at achieving a near-normal hemodynamic profile and a conventional clinically oriented strategy for HF management. The echocardiography-guided strategy was based on sequential echocardiograms to evaluate hemodynamically derived parameters. Pharmacologic therapy was guided according to a predefined protocol. The primary efficacy end point was time to the first event of combined all-cause mortality and all-cause hospitalization or emergency department visit up to 1 year of follow-up. We studied 96 outpatients with HF, enrolled from 1999 to 2003, with predominantly nonischemic cause and a mean left ventricular ejection fraction of 26% +/- 6%. Event-free survival at a mean follow-up of 230 days was 58.5% with the echocardiography-guided strategy and 36.5% with the clinically based strategy (relative risk = 0.54, 95% confidence interval = 0.31-0.97, P = .04). More patients in the echocardiography-based group received high-dose loop diuretics (absolute difference of 19%, P = .02) and hydralazine (absolute difference of 30%, P < .001). Significant reductions of estimates of pulmonary artery systolic pressure (mean difference of -9 mm Hg, P = .02) and systemic vascular resistance index (mean difference of -700 dyn x sec x m2 x cm5, P = .02) were observed in the echocardiography-guided group., Conclusion: A hemodynamically oriented echocardiography-based strategy is feasible and decreases HF morbidity. This benefit could be attributed in part to the rational and individualized use of higher doses of diuretics and vasodilators.

The hemodynamic profile of heart failure (HF) patients may be critical to their clinical outcome, whereby congestion emerges as a particularly important aspect to define therapeutic goals, optimize HF treatment, and determine prognosis. Accordingly, individualized HF management must include several strategies to detect congestion, which might easily be underestimated in chronic HF patients. Therefore, it is important to recognize the true reliability of traditional HF signs and symptoms. The contemporary understanding of HF has brought new value to some aspects of physical examination. Natriuretic peptides have emerged as potential new tools in the diagnosis of congestion in patients with HF, and echocardiography has gained renewed importance in HF management when it is used to investigate hemodynamic profile. The aim of this article is to review and integrate these 3 ways of assessing and monitoring HF patients: clinical findings, natriuretic peptides, and echocardiography.

Background: Scarce data are available to predict in-hospital mortality for decompensated heart failure (HF) in South American populations., Methods and Results: We evaluated 779 consecutive HF admissions defined by the Boston criteria in a tertiary care hospital. Stepwise logistic regression was used to determine independent correlates of in-hospital mortality, derived from 83 potential predictors collected on hospital admission. A clinical score rule (HF Revised Score) was created using the regression coefficient estimates derived from multivariate modeling. During hospital stay, 77 (10%) deaths occurred and 6 clinical characteristics were independently associated with in-hospital mortality: presence of cancer (P < .001), systolic blood pressure < or =124 mm Hg (P < .001), serum creatinine >1.4 mg/dL (P = .02), blood urea nitrogen >37 mg/dL (P = .03), serum sodium <136 mEq/L (P = .03), and age >70 years old (P = .03). Both the Acute Decompensated Heart Failure National Registry stratification algorithm and the proposed HF Revised Score performed adequately to predict in-hospital mortality ("c" statistics = 0.71 and 0.76, respectively). The newly proposed score, however, discriminated a very low-risk group (101 [13%]) in whom all patients were discharged home, representing patients admitted with none of the 6 predictors of risk., Conclusion: HF risk stratification can be accurately accomplished during the first day of admission with simple and easily obtained clinical variables.

Background: Few international studies prospectively compared evidence-based practices and health outcomes among congestive heart failure (CHF) cohorts from countries with different cultural and economic backgrounds., Methods: Patients consecutively admitted with congestive heart failure to tertiary care teaching hospitals in Brazil and in the United States (U.S.) were systematically evaluated using a structured data form. Follow-up data 3 months after discharge were obtained using chart review and telephone interviews., Results: U.S. patients were older (p < 0.01), had higher prevalence of ischemic etiology (p < 0.01) and less previous hospitalizations for congestive heart failure (p = 0.03) than Brazilian patients, but similar Charlson comorbidity scores (p = 0.54) and left ventricular (LV) function (p = 0.45). Prescription of angiotensin-converting enzyme inhibitors at discharge was lower at the U.S. hospital (57% vs. 68%; p = 0.03), but beta-blockers prescription was higher (37% vs. 10%; p < 0.01). Length-of-stay was significantly shorter (5 [interquartile range, 3-9] vs. 11 [6-19] days; p < 0.001) and in-hospital mortality was lower (2.4% vs. 13%; p < 0.001) in the U.S. cohort, but fewer clinical events within 3 months after discharge were observed in Brazilian patients (42% vs. 54%; p = 0.02). Combined clinical outcomes within 3 months, including overall mortality and hospital readmission, were similar between cohorts (57% vs. 55%; p = 0.80). In multivariate analysis, hospital site remained significantly associated with health outcomes., Conclusions: Medical practice and health-related outcomes were different between U.S. and Brazilian congestive heart failure patients. In order to improve management worldwide, potential factors (structural, cultural or disease-related) that might be associated with these differences need to be evaluated in future studies.

Background: Increased ventricular arrhythmia density and reduced heart rate variability are associated with risk of death in patients with heart failure. Cholinesterase inhibition with pyridostigmine bromide increases heart rate variability in normal subjects, but its effect on patients with heart failure is unknown. In this study, we tested the hypothesis that short-term administration of pyridostigmine bromide, a cholinesterase inhibitor, reduces ventricular arrhythmia density and increases heart rate variability in patients with congestive heart failure., Methods: Patients with heart failure and in sinus rhythm participated in a double-blind, cross-over protocol, randomized for placebo and pyridostigmine (30 mg orally 3 times daily for 2 days). Twenty-four hour electrocardiographic recordings were performed for arrhythmia analysis and for the measurement of time domain indices of heart rate variability. Patients were separated into 2 groups, according to their ventricular arrhythmia density. The arrhythmia group (n = 11) included patients with >10 ventricular premature beats (VPBs) per hour (VPBs/h), and the heart rate variability group (n = 12) included patients with a number of VPBs in 24 hours not exceeding 1% of the total number of R-R intervals., Results: For the arrhythmia group, pyridostigmine resulted in a 65% reduction of ventricular ectopic activity (placebo 266 +/- 56 VPBs/h vs pyridostigmine 173 +/- 49 VPBs/h, P =.03). For the heart rate variability group, pyridostigmine administration increased mean R-R interval (placebo 733 +/- 22 ms vs pyridostigmine 790 +/- 33 ms, P =.01), and in the time domain indices of heart rate variability root-mean-square of successive differences (placebo 21 +/- 2 ms vs pyridostigmine 27 +/- 3 ms, P =.01) and percentage of pairs of adjacent R-R intervals differing by >50 ms (placebo 3% +/- 1% vs pyridostigmine 6% +/- 2%, P =.03)., Conclusion: In patients with heart failure, pyridostigmine reduced ventricular arrhythmia density and increased heart rate variability, most likely due to its cholinomimetic effect. Long-term trials with pyridostigmine in heart failure should be conducted.

Introduction: Cardiac biomarkers have been proposed as a new tool to improve risk stratification of serious arrhythmic events in patients with heart failure (HF) beyond estimates of left ventricular ejection fraction. Growth differentiation factor (GDF)-15, a stress-induced cytokine, has been found to correlate with markers of myocardial fibrosis and adverse clinical outcomes, but its role as a predictor of arrhythmic events in patients with nonischemic HF is uncertain.Methods and Results: A prospective observational study was conducted in 148 nonischemic patients with HF who underwent comprehensive clinical and laboratory evaluation, including measurement of serum GDF-15. The study endpoints were serious arrhythmic events (which included appropriate implantable cardioverter-defibrillator therapy and sudden cardiac death) and all-cause mortality. Mean age of the cohort was 54.8 ± 12.7 years, and mean left ventricular ejection fraction (LVEF) was 27.4% ± 7.5%. During a mean follow-up time of 42 months, arrhythmic events occurred in 28 patients (19%), and 40 patients (27%) died. An increase in serum GDF-15 (log-transformed) correlated linearly with a higher risk of serious arrhythmic events (HR 1.14, 95% CI 1.01-1.28, p = 0.03) even after adjustment for other potential clinical predictors (HR 1.16, 95% CI 1.02-1.32, p = 0.02). GDF-15 was also strongly and independently associated with all-cause mortality (HR 1.17, 1.05-1.31, p = 0.004).Conclusion: In this cohort of nonischemic HF patients on optimized medical treatment, serum GDF-15 levels were independently associated with major arrhythmic events and overall mortality. This biomarker may add prognostic information to better stratify the risk of sudden death in this particular population. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRs) are a class of small non-coding RNAs that regulate gene expression. Studies of transgenic mouse models have indicated that deregulation of a single miR can induce pathological cardiac hypertrophy and cardiac failure. The roles of miRs in the genesis of physiological left ventricular hypertrophy (LVH), however, are not well understood. Objective: To evaluate the global miR expression in an experimental model of exercise-induced LVH. Methods: Male Balb/c mice were divided into sedentary (SED) and exercise (EXE) groups. Voluntary exercise was performed on an odometer-monitored metal wheels for 35 days. Various tests were performed after 7 and 35 days of training, including a transthoracic echocardiography, a maximal exercise test, a miR microarray (miRBase v.16) and qRT-PCR analysis. Results: The ratio between the left ventricular weight and body weight was increased by 7% in the EXE group at day 7 (p<0.01) and by 11% at day 35 of training (p<0.001). After 7 days of training, the microarray identified 35 miRs that were differentially expressed between the two groups: 20 were up-regulated and 15 were down-regulated in the EXE group compared with the SED group (p = 0.01). At day 35 of training, 25 miRs were differentially expressed: 15 were up-regulated and 10 were decreased in the EXE animals compared with the SED animals (p<0.01). The qRT-PCR analysis demonstrated an increase in miR-150 levels after 35 days and a decrease in miR-26b, miR-27a and miR-143 after 7 days of voluntary exercise. Conclusions: We have identified new miRs that can modulate physiological cardiac hypertrophy, particularly miR-26b, -150, -27a and -143. Our data also indicate that previously established regulatory gene pathways involved in pathological LVH are not changed in physiological LVH. [ABSTRACT FROM AUTHOR]

Abstract: Background: Peripartum cardiomyopathy is a rare but significant cause of maternal morbidity and mortality. Identification of silent forms of ventricular dysfunction associated with the peripartum period is challenging, yet necessary to establish specific counseling and therapeutic measures to prevent progression to overt heart failure. Our aims were to determine the prevalence of asymptomatic left ventricular systolic dysfunction in puerperium and compare its progression with that of cases of peripartum cardiomyopathy occurring in the same study period. Methods: Cross-sectional study conducted from September 2002 to April 2005 to determine by echocardiography the prevalence of asymptomatic ventricular dysfunction in early puerperium and a nested cohort study from November 2007 to January 2008 to obtain clinical and echocardiography follow-up data of positively screened patients. All clinically diagnosed cases of peripartum cardiomyopathy occurring in the same study period were also examined. Results: We screened 1182 puerperal women; ten cases (0.85%) of asymptomatic ventricular dysfunction were detected characterized by either decreased left ventricular systolic function and/or increased end-diastolic diameter. Incidence of peripartum cardiomyopathy was 6 cases/10,866 deliveries (1/1811 live births) in the same period. An echocardiogram-based follow-up study performed after a mean of 4.0years (2.9–5.2years), showed significant and similar improvement in parameters of left ventricular function in both groups (p >0.05). Conclusions: Asymptomatic left ventricular dysfunction in puerperal women shows a high prevalence and a pattern of long term echocardiographic changes similar to those found in overt peripartum cardiomyopathy. [Copyright &y& Elsevier]

Abstract: Background: The role of matrix metalloproteinases (MMPs) polymorphisms on heart failure (HF) susceptibility, phenotypic characteristics, and prognosis has been poorly explored. Methods and Results: We studied 313 HF patients with left ventricular systolic dysfunction and 367 healthy control subjects. Genotyping of MMP-1 (−1607 1G/2G), MMP-3 (−1171 5A/6A), and MMP-9 (−1562 C/T) polymorphisms was performed by polymerase chain reaction. Allelic and genotypic frequencies of MMP-1, -3, and -9 were similar in HF patients and controls. MMP1 2G allele carriers were positively associated to ischemic etiology and history of myocardial infarction (all P values <.05). Patients were followed-up for a median of 40 months and 58 HF-related deaths occurred during this period. HF-related survival was significantly better in MMP1 2G allele carriers (71% versus 42% for 1G/1G patients, P = .002) and in MMP-3 6A allele carriers (70% versus 61% for 5A/5A patients, P = .064), particularly in non-ischemic patients (P = .039). MMP1 2G allele was independently associated to HF survival after adjustment for several other predictors of risk (hazard ratio 0.47, 95% confidence interval 0.27 to 0.82; P = .008). Conclusions: MMP-1, -3, and -9 polymorphisms were not associated to HF susceptibility. However, MMP1 2G allele carriers were related to a higher prevalence of ischemic etiology among patients with systolic HF and better HF-related prognosis. [Copyright &y& Elsevier]

Aims: We investigated whether the combination of β1-Gly389Arg and GNB3 C825T, two genetic polymorphisms strictly related to adrenergic system modulation, could act as predictors of appropriate therapies in patients with heart failure (HF) using implantable cardioverter-defibrillators (ICDs). [ABSTRACT FROM PUBLISHER]

Anemia is common among patients with heart failure (HF) and has been associated with worse prognosis. To date, it is not well known whether correction of anemia in these patients can improve outcome. Proposed modalities for correction of anemia have been either administration of erythropoiesis-stimulating proteins, which appears plausible in patients with concomitant renal failure (so-called cardiorenal syndrome), or iron supplementation, which is particularly attractive in patients with no overt renal failure and chronic disease anemia with some degree of iron deficiency. This article reviews the rationale for anemia correction and the latest randomized clinical trial assessing clinical utility of erythropoiesis-stimulating proteins and/or iron supplementation through oral or intravenous administration in anemic HF patients. [ABSTRACT FROM AUTHOR]