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Background: Monitoring supine pulmonary artery pressures to guide heart failure (HF) management has reduced HF hospitalizations in select patients., Objectives: The purpose of this study was to evaluate the effect of managing seated mean pulmonary artery pressure (mPAP) with the Cordella Pulmonary Artery sensor on outcomes in patients with HF., Methods: Following GUIDE-HF (Hemodynamic-GUIDEd Management of Heart Failure Trial), with U.S. Food and Drug Administration input, PROACTIVE-HF (A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial) was changed from a randomized to a single-arm, open label trial, conducted at 75 centers in the USA and Europe. Eligible patients had chronic HF with NYHA functional class III symptoms, irrespective of the ejection fraction, and recent HF hospitalization and/or elevated natriuretic peptides. The primary effectiveness endpoint at 6 months required the HF hospitalization or all-cause mortality rate to be lower than a performance goal of 0.43 events/patient, established from previous hemodynamic monitoring trials. Primary safety endpoints at 6 months were freedom from device- or system-related complications or pressure sensor failure., Results: Between February 7, 2020, and March 31, 2023, 456 patients were successfully implanted in modified intent-to-treat cohort. The 6-month event rate was 0.15 (95% CI: 0.12-0.20) which was significantly lower than performance goal (0.15 vs 0.43; P < 0.0001). Freedom from device- or system-related complications was 99.2% and freedom from sensor failure was 99.8% through 6 months., Conclusions: Remote management of seated mPAP is safe and results in a low rate of HF hospitalizations and mortality. These results support the use of seated mPAP monitoring and extend the growing body of evidence that pulmonary artery pressure-guided management improves outcomes in heart failure. (Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial [PROACTIVE-HF]; NCT04089059)., Competing Interests: Funding Support and Author Disclosures This work was supported by Endotronix Inc. Drs Miranda, Shah, Macaluso, and Hickey were on the Eligibility Committee of PROACTIVE-HF. Prof Sharif is funded by the Science Foundation Ireland SFI 17/RI/5353. Drs Hiivala, Owens, Sauerland, and Forouzan are employees of Endotronix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines recommend that intravenous iron should be considered to improve symptoms of heart failure (HF) and reduce the risk for HF admissions in patients after acute HF., Objectives: This study sought to analyze the effect of intravenous iron on cardiovascular (CV) death and HF admissions in a broad population of HF patients with iron deficiency and the relation with baseline transferrin saturation (TSAT)., Methods: A systematic review of all published randomized controlled trials assessing the effect of intravenous iron in patients with iron deficiency and HF between January 1, 2000, and August 26, 2023, was performed. The overall treatment effect was estimated using a fixed effect model for: 1) CV death; 2) CV death and HF admission; 3) first HF admission; and 4) total HF admissions. Metaregression through a mixed effect model was used to explore the impact of baseline TSAT in case of heterogeneity among trial results., Results: A total of 14 randomized controlled trials were identified in the systematic review and retained in the meta-analysis. Aggregate-level data were included on 6,624 HF patients, 3,407 of whom were randomized to intravenous iron and 3,217 to placebo. Treatment with intravenous iron resulted in a lower risk for CV death (OR: 0.867 [95% CI: 0.755-0.955]; P = 0.0427), combined CV death and HF admission (OR: 0.838 [95% CI: 0.751-0.936]; P = 0.0015), first HF admission (OR: 0.855 [95% CI: 0.744-0.983]; P = 0.0281), and total HF admissions (rate ratio: 0.739 [95% CI: 0.661-0.827]; P < 0.0001). Significant heterogeneity among trial results was observed for first and total HF admissions. Metaregression suggested that some of the heterogeneity was related to the baseline TSAT of the enrolled population, with trials enrolling patients with lower TSAT exhibiting a large effect size on HF-related events., Conclusions: The totality of data suggests that treatment with intravenous iron reduces both CV death and HF-related events in a broad population with HF. A lower baseline TSAT might be important for the effect on HF-related events., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is scarce evidence supporting the clinical utility of congestive intrarenal venous flow (IRVF) patterns in patients with acute heart failure., Objectives: This study aims to: 1) investigate the association between IRVF patterns and the odds of worsening renal function (WRF); 2) track the longitudinal changes of serum creatinine (sCr) across IRVF at predetermined points and its association with decongestion; and 3) explore the relationship between IRVF/WRF categories and patient outcomes., Methods: IRVF was assessed at baseline (pre-decongestive therapy), 72 hours, and 30 and 90 days postdischarge. Changes in sCr trajectories across dynamic IRVF variations and parameters of decongestion were assessed using linear mixed effect models. The association between IRVF/WRF categories and outcomes was evaluated using univariable/multivariable models., Results: In this prospective, multicenter study with 188 participants, discontinuous IRVF patterns indicated higher odds of WRF (OR: 3.90 [95% CI: 1.24-12.20]; P = 0.020 at 72 hours; and OR: 5.76 [95% CI: 1.67-19.86]; P = 0.006 at 30 days) and an increase in sCr (Δ-72 hours 0.14 mg/dL [95% CI: 0.06-0.22]; P = 0.001; Δ-discharge 0.13 mg/dL [95% CI: 0.03-0.23]; P = 0.007). However, the diuretic response and decongestion significantly influenced the magnitude of these changes. Patients exhibiting both WRF and discontinuous IRVF at 30 days experienced an increased hazard of adverse events (HR: 5.96 [95% CI: 2.63-13.52]; P < 0.001)., Conclusions: Discontinuous IRVF identifies patients with higher odds of WRF during admission and postdischarge periods. Nonetheless, adequate diuretic response and decongestion could modify this association. Patients showing both WRF and discontinuous IRVF at 30 days had increased rates of adverse events., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the Ministry of Economy and Competitiveness, Instituto Carlos III (PI20/00392), CIBER Cardiovascular (16/11/00420 and 16/11/00403), and Heart Failure Association of the Spanish Society of Cardiology (2019). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Continuous automatic optimisation of cardiac resynchronisation therapy (CRT), stimulating only the left ventricle to fuse with intrinsic right bundle conduction (synchronised left ventricular stimulation), might offer better outcomes than conventional CRT in patients with heart failure, left bundle branch block, and normal atrioventricular conduction. This study aimed to compare clinical outcomes of adaptive CRT versus conventional CRT in patients with heart failure with intact atrioventricular conduction and left bundle branch block., Methods: This global, prospective, randomised controlled trial was done in 227 hospitals in 27 countries across Asia, Australia, Europe, and North America. Eligible patients were aged 18 years or older with class 2-4 heart failure, an ejection fraction of 35% or less, left bundle branch block with QRS duration of 140 ms or more (male patients) or 130 ms or more (female patients), and a baseline PR interval 200 ms or less. Patients were randomly assigned (1:1) via block permutation to adaptive CRT (an algorithm providing synchronised left ventricular stimulation) or conventional biventricular CRT using a device programmer. All patients received device programming but were masked until procedures were completed. Site staff were not masked to group assignment. The primary outcome was a composite of all-cause death or intervention for heart failure decompensation and was assessed in the intention-to-treat population. Safety events were collected and reported in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02205359, and is closed to accrual., Findings: Between Aug 5, 2014, and Jan 31, 2019, of 3797 patients enrolled, 3617 (95·3%) were randomly assigned (1810 to adaptive CRT and 1807 to conventional CRT). The futility boundary was crossed at the third interim analysis on June 23, 2022, when the decision was made to stop the trial early. 1568 (43·4%) of 3617 patients were female and 2049 (56·6%) were male. Median follow-up was 59·0 months (IQR 45-72). A primary outcome event occurred in 430 of 1810 patients (Kaplan-Meier occurrence rate 23·5% [95% CI 21·3-25·5] at 60 months) in the adaptive CRT group and in 470 of 1807 patients (25·7% [23·5-27·8] at 60 months) in the conventional CRT group (hazard ratio 0·89, 95% CI 0·78-1·01; p=0·077). System-related adverse events were reported in 452 (25·0%) of 1810 patients in the adaptive CRT group and 440 (24·3%) of 1807 patients in the conventional CRT group., Interpretation: Compared with conventional CRT, adaptive CRT did not significantly reduce the incidence of all-cause death or intervention for heart failure decompensation in the included population of patients with heart failure, left bundle branch block, and intact AV conduction. Death and heart failure decompensation rates were low with both CRT therapies, suggesting a greater response to CRT occurred in this population than in patients in previous trials., Funding: Medtronic., Competing Interests: Declaration of interests BLW reports participating in physician advisory committees of Medtronic, Abbott, Boston Scientific, Biotronik, and Philips, and receiving honoraria from Medtronic, Abbott, Boston Scientific, Biotronik, Philips, and Cook. GF reports receiving lecture fees, participating in committees of trials sponsored by Bayer, Boehringer Ingelheim, Novartis, Servier, Vifor, Impulse Dynamics, and Medtronic, and receiving research grants from the European Union. CL reports participating in a Medtronic advisory board and receiving honoraria from Medtronic, Biotronik, LivaNova, Boston Scientific, and Abbott. MRG reports being a consultant for Medtronic and Boston Scientific and receiving honoraria from Medtronic, Boston Scientific, and EBR Systems. KK reports receiving speaker's honoraria and research grants from Medtronic Japan and Biotronik Japan. GMF reports receiving research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, Bristol Myers Squibb, Merck, Cytokinetics, and CSL-Behring, acting as a consultant for Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Regeneron, Reprieve, Myovant, Sequana, Windtree Therapuetics, Rocket Pharma, and Whiteswell, and serving on clinical endpoint committees or data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, and LivaNova. MFE-C reports consultancy work for Medtronic and Boston Scientific. VE reports receiving support from a Clinical Research Scholar Award from the Fonds de recherche du Québec-Santé (FRQS) and honoraria from Abbott, Boston Scientific, and Medtronic. BP reports consultancy work for Abbott, Biotronik, Boston Scientific, and Microport, and receiving honoraria from Medtronic. FP reports receiving research grants from Medtronic, Boston Scientific, and Abbott. ESC reports consultancy work for Medtronic, Abbott, Intershunt, and Cardionomic, and serving on data safety monitoring boards and clinical events committees for LivaNova, EBR, and Abbott. BB reports consultancy work for Medtronic, Boston Scientific, and Pfizer. HHE reports receiving research grants from Medtronic. NV reports consultancy work for Medtronic, Abbott, Biotronik, Boston Scientific, EP Solutions, Implicity, and Pacemate. JvW, BG, DES, and DHF report being employees of Medtronic. DB reports being a mid-career investigator (supported by the Heart and Stroke Foundation of Ontario and the University of Ottawa Chair in Electrophysiology Research) and receiving research funding from Medtronic, Boston Scientific, Boehringer Ingelheim, Bayer, Biotronik, Pfizer, and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified., (Copyright © 2023 The Heart Rhythm Society, the European Heart Rhythm Association, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the effect of congestion and decongestive therapy on left atrial (LA) mechanics and to determine the relationship between LA improvement after decongestive therapy and clinical outcome in immediate or chronic heart failure with reduced ejection fraction (HFrEF)., Background: LA mechanics are affected by volume/pressure overload in decompensated HFrEF., Methods: A total of 31 patients with HFrEF and immediate heart failure (age 64 ± 15 years, 74% male, left ventricular ejection fraction 20 ± 12%) underwent serial echocardiography during decongestive therapy with simultaneous hemodynamic monitoring. LA function was assessed by strain (rate) imaging. Patients were re-evaluated 6 weeks after discharge and prospectively followed up for the composite endpoint of heart failure readmission and all-cause mortality., Results: LA reservoir function was markedly reduced at baseline and improved with decongestion (peak atrial longitudinal strain from 6.4 ± 2.2% to 8.8 ± 3.0% and strain rate from 0.29 ± 0.11 s -1 to 0.38 ± 0.13 s -1 ), independent of changes in left ventricular global longitudinal strain, LA end-diastolic volume, and mitral regurgitation severity (p < 0.001). Both measures continued to rise at 6 weeks (up to 13.4 ± 6.1% and 0.50 ± 0.19 s -1 , respectively; p < 0.001). LA pump strain rate only increased 6 weeks after discharge (-0.25 ± 0.12 s -1 to -0.55 ± 0.29 s -1 ; p < 0.010). Changes in LA mechanics correlated with changes in wedge pressure (r = -0.61; p < 0.001). Lower peak atrial longitudinal strain values after decongestion were associated with increased risk for the composite endpoint of heart failure and mortality (p < 0.019)., Conclusions: LA reservoir and booster function, while severely impaired during immediate decompensation, significantly improve during and after decongestive therapy. Poor LA reservoir function after decongestion is associated with worse outcome., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed the impact of right-atrial (RA) pacing on left-atrial (LA) physiology and clinical outcome., Background: Data for the effects of RA pacing on LA synchronicity, function, and structure after cardiac resynchronization therapy (CRT) are scarce., Methods: The effect of RA pacing on LA function, morphology, and synchronicity was assessed in a prospective imaging cohort of heart failure (HF) patients in sinus rhythm with a guideline-based indication for CRT. Additionally, in a retrospective outcome cohort of consecutive HF patients undergoing CRT implantation, the relationship to RA pacing was assessed using various outcome endpoints. High versus low atrial pacing burden was defined as atrial pacing above or below 50% in both cohorts., Results: A total of 36 patients were included in the imaging cohort (68 ± 11 years of age). Six months after CRT, patients with high RA pacing burden showed less improvement in LA maximum and minimum volumes and total emptying fraction (p < 0.05). Peak atrial longitudinal strain and reservoir and booster strain rates but not conduit strain rate improved after CRT in patients with low RA pacing burden but worsened in patients with high RA pacing burden (p < 0.05 for all). A high RA pacing burden induced significant intra-atrial dyssynchrony (maximum opposing wall delay: 44 ± 13 ms vs. 97 ± 17 ms, respectively; p = 0.022). A total of 569 patients were included in the outcome cohort. After covariate adjustments were made, a high RA pacing burden was associated with reduced LV reverse remodeling (β = 8.738; 95% confidence interval [CI]: 3.101 to 14.374; p = 0.002) and new-onset or recurrent atrial fibrillation (41% vs. 22%, respectively, at a median of 31 months [range 22 to 44 months follow-up]; p < 0.001). There were no differences in time to first HF hospitalization or all-cause mortality (p = 0.185) after covariate adjustment. However, in a recurrent event analysis, HF readmissions were more common in patients exposed to a high RA pacing burden (p = 0.003)., Conclusions: RA pacing in CRT patients negatively influences LA morphology, function, and synchronicity, which is associated with worse clinical outcome, including diminished LV reverse remodeling, increased risk for new-onset or recurrent AF and heart failure readmission. Strategies reducing RA pacing burden may be warranted., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate real world safety and efficacy of hypertonic saline therapy in cases of refractory acute decompensated heart failure (ADHF) at a large U.S. academic medical center., Background: Hypertonic saline therapy has been described as a potential management strategy for refractory ADHF, but experience in the United States is limited., Methods: A retrospective analysis was performed in all patients receiving hypertonic saline for diuretic therapy-resistant ADHF at the authors' institution since March 2013. The primary analytic approach was a comparison of the trajectory of clinical variables prior to and after administration of hypertonic saline, with secondary focus on predictors of treatment response., Results: A total of 58 hypertonic saline administration episodes were identified across 40 patients with diuretic-therapy refractory ADHF. Prior to hypertonic saline administration, serum sodium, chloride, and creatinine concentrations were worsening but improved after hypertonic saline administration (p < 0.001, all). Both total urine output and weight loss significantly improved with hypertonic saline (p = 0.01 and <0.001, respectively). Diuretic efficiency, defined as change in urine output per doubling of diuretic dose, also improved over this period (p < 0.01). There were no significant changes in respiratory status or overcorrection of serum sodium with the intervention., Conclusions: In a cohort of patients who were refractory to ADHF, hypertonic saline administration was associated with increased diuretic efficiency, fluid and weight loss, and improvement of metabolic derangements, and no adverse respiratory or neurological signals were identified. Additional study of hypertonic saline as a diuretic adjuvant is warranted., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to describe sodium excretion in acute decompensated heart failure (ADHF) clearly and to evaluate the prognostic ability of urinary sodium and fluid-based metrics., Background: Sodium retention drives volume overload, with fluid retention largely a passive, secondary phenomenon. However, parameters (urine output, body weight) used to monitor therapy in ADHF measure fluid rather than sodium balance. Thus, the accuracy of fluid-based metrics hinges on the contested assumption that urinary sodium content is consistent., Methods: Patients enrolled in the ROSE-AHF (Renal Optimization Strategies Evaluation-Acute Heart Failure) trial with 24-h sodium excretion available were studied (n = 316). Patients received protocol-driven high-dose loop diuretic therapy., Results: Sodium excretion through the first 24 h was highly variable (range 0.12 to 19.8 g; median 3.63 g, interquartile range: 1.85 to 6.02 g) and was not correlated with diuretic agent dose (r = 0.06; p = 0.27). Greater sodium excretion was associated with reduced mortality in a univariate model (hazard ratio: 0.80 per doubling of sodium excretion; 95% confidence interval: 0.66 to 0.95; p = 0.01), whereas gross urine output (p = 0.43), net fluid balance (p = 0.87), and weight change (p = 0.11) were not. Sodium excretion of less than the prescribed dietary sodium intake (2 g), even in the setting of a negative net fluid balance, portended a worse prognosis (hazard ratio: 2.02; 95% confidence interval: 1.17 to 3.46; p = 0.01)., Conclusions: In patients hospitalized with ADHF who were receiving high-dose loop diuretic agents, sodium concentration and excretion were highly variable. Sodium excretion was strongly associated with 6-month mortality, whereas traditional fluid-based metrics were not. Poor sodium excretion, even in the context of fluid loss, portends a worse prognosis., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study sought to determine the relationship between urinary sodium (U na ) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization., Background: No data are available on the longitudinal dynamics of U na concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization., Methods: Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot U na samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in U na concentration. Patients were followed for the development of the clinical endpoint of AHF., Results: A total of 80 chronic HF patients (71 ± 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 ± 7%) prospectively submitted weekly pre-diuretic first void morning U na samples for 30 weeks. A total of 1,970 U na samples were collected, with mean U na concentration of 81.6 ± 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l U na [n = 39]) and low (73 mmol/l U na [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 ± 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower U na concentrations (F [1.80]  = 24.063; p < 0.001). The discriminating capacity of U na concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, U na concentration dropped (U na  = 46 ± 16 mmol/l vs. 70 ± 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (U na  = 71 ± 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation., Conclusions: Overall, U na concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower U na  concentration and exhibited a further drop in U na concentration during the week preceding hospitalization. Ambulatory U na sample collection is feasible and may offer additional prognostic and therapeutic information., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Lower serum chloride (Cl) is associated with mortality in heart failure patients and may be more prognostically relevant than sodium. However, the association of hemodynamics and Cl levels is unknown., Methods: 438 sequential patients with advanced chronic heart failure (ACHF) underwent invasive hemodynamic assessment with measured serum Cl levels during an evaluation for ACHF. Patients were followed for death, heart transplant (HT), or ventricular assist device placement (VAD). A backwards regression model determined hemodynamic predictors of Cl (removal, P<0.1) with candidate variables: Fick cardiac index (FCI), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), mean arterial pressure (MAP), heart rate (HR), and pulmonary artery systolic pressure (PASP). All models were also adjusted for serum sodium and bicarbonate., Results: In this cohort, the median Cl level was 102 [98-104]meq/L (range 86-113meq/L). Chloride was weakly correlated with FCI (rho 0.12, P=0.01) and MAP (rho 0.21, P<0.001); but not PCWP, RAP, HR or PASP (P>0.05 for all). In the multivariable model, FCI (beta 0.73meq/L/L/min/m 2 , P=0.002) but not RAP (P=0.3) or MAP (P=0.2), remained associated with Cl. Lower Cl was associated with increased risk of death, HT, or VAD placement (HR 0.94/meq/L, 95% CI 0.89-0.99, P=0.01). However, this association was attenuated after additional adjustment for BUN (P=0.27) and PCWP and FCI (0.48)., Conclusions: Lower FCI, not lower MAP or higher cardiac filling pressures, was associated with lower chloride. Although lower chloride was associated with poor long-term outcomes, this risk attenuates with adjustment for more conventional clinical parameters., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: An ischemic etiology of heart failure (HF) has been associated with reduced left ventricular reverse remodeling after cardiac resynchronization therapy (CRT)., Objective: The purpose of this study was to assess the relationship between the etiology of HF and reverse remodeling and outcome after CRT., Methods: Consecutive patients undergoing CRT implantation between October 1, 2008 and August 14, 2015 were retrospectively evaluated. Coronary angiography classified ischemic vs nonischemic etiology. Reverse remodeling was defined as the changes in left ventricular ejection fraction (LVEF) after 6 months. Clinical outcome was assessed 1 year after implantation using a combined end point of all-cause mortality and HF readmission., Results: A total of 685 patients were included (300/385 for ischemic/nonischemic etiology). Compared with patients with ischemic cardiomyopathy, patients with nonischemic cardiomyopathy exhibited a greater degree of improvement in LVEF (8.4% ± 10.4% vs 15.8% ± 12.3%; P < .001). After correcting for differences, an ischemic etiology of HF predicted less reverse remodeling (P < .001) and a higher rate of mortality or HF readmission (hazard ratio 1.63; 95% confidence interval [CI] 1.12-2.73; P = .011). Nevertheless, in comparison to a greater degree of improvement in LVEF, a lesser degree of improvement in LVEF (0%-5%) was associated with a higher risk of all-cause mortality and HF hospitalization in patients with nonischemic cardiomyopathy (odds ratio 9.78; 95% CI 1.95-49.04; P = .006) but not in patients with ischemic cardiomyopathy (odds ratio 3.58; 95% CI 0.85-15.18; P = .083). The most accurate cutoff for improvement in LVEF predicting good clinical outcome was 5.5% in ischemic cardiomyopathy vs 10.5% in nonischemic cardiomyopathy., Conclusion: CRT results in reverse remodeling in both patients with ischemic and nonischemic cardiomyopathy, but to a lesser extent in the former. Patients with an ischemic etiology are at an intrinsically higher risk of mortality and HF hospitalization, but derive benefit on outcome at a lesser degree of reverse remodeling., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Guidelines advocate down-titration of loop diuretics in chronic heart failure (CHF) when patients have no signs of volume overload. Limited data are available on the expected success rate of this practice or how routine diagnostic tests might help steering this process., Methods and Results: Fifty ambulatory CHF-patients on stable neurohumoral blocker/diuretic therapy for at least 3months without any clinical sign of volume overload were prospectively included to undergo loop diuretic down-titration. All patients underwent a similar pre-down-titration evaluation consisting of a dyspnea scoring, physical examination, transthoracic echocardiography (diastolic function, right ventricular function, cardiac filling pressures and valvular disease), blood sample (serum creatinine, plasma NT-pro-BNP and neurohormones). Loop diuretic maintenance dose was subsequently reduced by 50% or stopped if dose was ≤40mg furosemide equivalents. Successful down-titration was defined as a persistent dose reduction after 30days without weight increase >1.5kg or new-onset symptoms of worsening heart failure. At 30-day follow-up, down-titration was successful in 62% (n=31). In 12/19 patients exhibiting down-titration failure, this occurred within the first week. Physical examination, transthoracic echocardiography and laboratory analysis had limited predictive capability to detect patients with down-titration success/failure (positive likelihood-ratios below 1.5, or area under the curve [AUC] non-statically different from AUC=0.5)., Conclusion: Loop diuretic down-titration is feasible in a majority of stable CHF patients in which the treating clinician felt continuation of loops was unnecessary to sustain euvolemia. Importantly, routine diagnostics which suggest euvolemia, have limited diagnostic impact on the post-test probability., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Untreated and preclinical heart failure patients with reduced ejection fraction (HFrEF) have an impaired ability to alleviate excess intravascular volume., Objectives: To investigate 1) the renal response to intravascular volume expansion in euvolemic and optimally treated HFrEF patients and 2) loop diuretic efficiency., Methods: 14 healthy and 28 HFrEF patients underwent intravascular volume expansion with 1l hydroxyl ethyl starch 6% during 3h after which a loop diuretic was administered. Clinical parameters, neurohormones and urine were hourly measured., Results: In response to intravascular volume expansion (+0.6±0.2L; p<0.001 vs baseline) HFrEF patients demonstrated significantly lower natriuresis compared to healthy subjects (0.9±0.5 versus 1.7±0.6g/3h; p<0.001). However, natriuresis varied substantially with half of HFrEF patients exhibiting a response within the range of healthy and the other half demonstrating a significantly decreased response (1.4±0.4 vs 0.5±0.2g/3h; p<0.001). Natriuresis was associated with glomerular filtration function (eGFR), NT-proBNP and tubular fractional sodium excretion (FE Na ). Loop diuretic efficiency was significantly lower in HFrEF patients compared to healthy subjects (3.4±0.7 vs 2.6±1.1g/2h; p=0.044) but was only related to eGFR (R 2 =0.47; p<0.001) and independent of FE Na (R 2 =0.07; p=0.20). Loop diuretics increased FE Na similarly in healthy subjects and HFrEF patients (9.1±2.4 vs 9.3±3.3%; p=0.64)., Conclusion: The ability of the kidneys to remove excess intravascular volume is decreased in a substantial amount of euvolemic and optimally treated HFrEF patients. Renal response relates to filtration function and tubular sodium handling. In contrast, loop diuretics can surmount decreased renal tubular sodium excretion but remain dependent on eGFR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The goal of this study was to assess: 1) the intrarenal flow in heart failure (HF) patients during the transition from euvolemia to intravascular volume overload; and 2) the relationship between intrarenal flow and diuretic efficiency., Background: Intrarenal blood flow alterations may help to better understand impaired volume handling in HF., Methods: Resistance index (RI) and venous impedance index (VII) were assessed in 6 healthy subjects, 40 euvolemic HF patients with reduced ejection fraction (HFrEF), and 10 HF patients with preserved ejection fraction (HFpEF). Assessments were performed by using Doppler ultrasonography at baseline, during 3 h of intravascular volume expansion with 1 l of hydroxyethyl starch 6%, and 1 h after the administration of a loop diuretic. Clinical parameters, echocardiography, and biochemistry were assessed. Urine output was collected after 3 and 24 h., Results: In response to volume expansion, VII increased significantly in HFrEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p < 0.001) and in HFpEF patients (0.4 ± 0.3 to 0.7 ± 0.2; p = 0.002) but not in healthy subjects (0.2 ± 0.2 to 0.3 ± 0.1; p = 0.622). This outcome was reversed after loop diuretic administration. In contrast, RI did not change significantly after volume expansion. Echocardiographic-estimated filling pressures did not change significantly. VII during volume expansion was significantly correlated with diuretic response in HF patients independent of baseline renal function (R 2  = 0.35; p < 0.001)., Conclusions: In HF patients, intravascular volume expansion resulted in significant blunting of venous flow before a significant increase in cardiac filling pressures could be demonstrated. The observed impaired renal venous flow is correlated with less diuretic efficiency. Intrarenal venous flow patterns may be of interest for evaluating renal congestion., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with heart failure, the degree of intraventricular mechanical dyssynchrony (intra-VMD) at baseline may predict reversal of cardiac remodeling with cardiac resynchronization therapy (CRT)., Objective: The purpose of this study was to determine the prevalence and clinical significance of intra-VMD in patients admitted for advanced decompensated heart failure (ADHF)., Methods: We prospectively enrolled 50 patients with ADHF without previous CRT implantation who had been admitted to a specialized heart failure intensive care unit because of hemodynamic derangements. All patients underwent comprehensive echocardiographic evaluation within 12 hours of admission and after 48 hours from baseline evaluation after intensive medical therapy. Intra-VMD was assessed by the opposing wall time-to-peak myocardial velocity intervals in a four-segment model using color-tissue Doppler imaging., Results: In our study cohort (mean age 57 +/- 11 years, left ventricular ejection fraction 26 +/- 10%, QRS width 127 +/- 31 ms, cardiac index 2.0 +/- 0.6 L/min/m(2)), significant intra-VMD (>or=65 ms) was present in 44% of subjects at baseline, and 56% of patients presented with QRS >120 ms. There was no correlation between QRS width and extent of intra-VMD. Intensive medical therapy was associated with a significant reduction in intra-VMD (85 +/- 23 ms vs. 39 +/- 19 ms; P <.001). Significant hemodynamic improvement in cardiac index, filling pressures, and systemic and pulmonic vascular resistance was seen only in patients with intra-VMD., Conclusion: A substantial subset of patients admitted with ADHF and hemodynamic derangements demonstrate evidence of intra-VMD, which is reduced at follow-up and independent of underlying QRS width. Nevertheless, the presence of significant intra-VMD is associated with a more reversible hemodynamic profile.

Background: Heart failure is associated with a reduction in left ventricular (LV) contractility as evidenced by a blunted force-frequency response (FFR) and downregulation of contractility regulating genes., Objective: This study sought to investigate whether cardiac resynchronization therapy (CRT) is capable of reversing the blunted FFR and the downregulation of contractility regulating genes., Methods: Twenty heart failure patients underwent echocardiographic examination during incremental AAI and DDD-CRT pacing at 70, 90, and 110 beats/min, immediately after and 4 months after CRT implantation. The FFR was determined from the ratio of the LV systolic pressure/end systolic volume index at given heart rate. In a subgroup of 6 patients with idiopathic dilated cardiomyopathy, serial LV dP/dtmax was invasively measured during both pacing modes and serial LV endomyocardial biopsies were taken to measure sarcoplasmatic reticulum calcium ATPase 2alpha (SERCA2alpha), phospholamban (PLN), sarcolemmal sodium calcium exchanger (NCX), beta1-adrenoreceptor (beta1-AR), and apelin (APL) gene expression using reverse-transcriptase polymerase chain reaction., Results: Acutely, DDD-CRT pacing was associated with a decrease in dyssynchrony (P <.01) and increase in diastolic filling time (P <.01) at all heart rates paralleled by an upward shift of the FFR (P <.01) without force-frequency amplification. A greater upward shift of the FFR was noticed during DDD-CRT as compared with AAI (P <.01) after 4 months. In addition, CRT was associated with a significant force-frequency amplification at follow-up as evidenced from the steeper slope of the FFR relationship (P = .039). This was associated with a significant upregulation of SERCA2alpha P = .01), PLN (P = .01), their ratio (P = .01), ratio of SERCA/NCX (P = .02), beta1-AR (P = .03), and APL (P = .01) mRNA levels., Conclusion: CRT is associated with an acute upward shift in the FFR without force-frequency amplification related to restored synchronicity and increased filling time of the LV. Only chronic CRT is associated with force-frequency amplification in parallel to upregulation of contractility regulating genes.