Search

Background: Most approaches to the creation of an interatrial shunt require placement of a permanent implant to maintain patency., Objectives: The goal of this study was to investigate the safety and efficacy of a no-implant interatrial shunt for patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF)., Methods: This was a multicenter, uncontrolled study of patients with HFpEF/HFmrEF and NYHA functional class ≥II, ejection fraction >40%, and pulmonary capillary wedge pressure (PCWP) during supine exercise ≥25 mm Hg with PCWP-to-right atrial gradient ≥5 mm Hg. Follow-up was through 6 months with imaging to assess shunt durability., Results: A total of 28 patients were enrolled: mean age was 68 ± 9 years, and 68% were female. Baseline resting and peak exercise PCWP were 19 ± 7 mm Hg and 40 ± 11 mm Hg, respectively. All procedures displayed technical success with confirmation of left-to-right flow (shunt diameter 7.1 ± 0.9 mm). At 1 month, peak exercise PCWP decreased 5.4 ± 9.6 mm Hg (P = 0.011) with no change in right atrial pressure. There were no serious device or procedure-related adverse events through 6 months. Mean 6-minute walk distance increased 101 ± 71 meters (P < 0.001); Kansas City Cardiomyopathy Questionnaire Overall Summary Score increased 26 ± 19 points (P < 0.001); N-terminal pro-B-type natriuretic peptide decreased 372 ± 857 pg/mL (P = 0.018); and shunt patency was confirmed with unchanged diameter., Conclusions: In these feasibility studies of a no-implant interatrial shunt, HFpEF/HFmrEF shunts exhibited stability with favorable safety and early efficacy signals. The results show promise toward this new approach for treating patients with HFpEF/HFmrEF and an appropriate hemodynamic profile. (Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-1]; NCT04583527; Evaluation of the Safety and Effectiveness of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-2]; NCT04838353)., Competing Interests: Funding Support and Author Disclosures These studies were funded by Alleviant Medical. Dr Udelson has received consulting fees from Alleviant Medical, Merck, Cardurion, Reprieve CV, Medtrace, and GE. Dr Barker has received consulting fees from and is an advisory board/board member to Alleviant Medical. Dr Gooley has received consulting fees from Boston Scientific, Medtronic, and Abbott Vascular; and is an advisory board member to Boston Scientific and Medtronic. Dr Potter has received research funding and consulting fees from Alleviant Medical; honoraria from Abbott; research funding from Bayer Canada, Boehringer Ingelheim Canada, and Novartis Canada; and has served as Principal Investigator of the ALLEVIATE-HF-2 study. Dr Meduri has received consulting fees from Alleviant Medical, Anteris Technologies, Boston Scientific, Medtronic, and VDyne; has received speaker fees from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic; is an advisory board member for Anteris Technologies and Cardiovalve; and is a proctor for Boston Scientific. Dr Fail has received consulting fees from BioVentrix and Alleviant Medical; speaker fees from Abbott Vascular, Boston Scientific, Medtronic; and has served as principal investigator of research studies for Ancora Heart and Corvia Medical. Dr Solet has received consulting fees from Abbott Medical and Alleviant Medical. Dr Felt has received consulting fees from Abbott Vascular, Alleviant Medical, Anteris Technologies, Pfizer Inc, and Orion Pharma. Dr Kriegel has received consulting fees from, is an advisory board/board member to, and serves as chief medical officer of Alleviant Medical. Dr Shaburishvili served as principal investigator of the ALLEVIATE-HF-1 study for Alleviant Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, a central committee of heart failure (HF) specialists optimized guideline-directed medical therapies (GDMT) and documented medication and goal dose intolerances before patient enrollment., Objectives: The authors sought to assess the rates, reasons, and predictors of GDMT intolerance in the COAPT trial., Methods: Baseline use, dose, and intolerances of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were analyzed in patients with left ventricular ejection fraction (LVEF) ≤40%, in whom maximally tolerated doses of these agents as assessed by an independent HF specialist were required before enrollment., Results: A total of 464 patients had LVEF ≤40% and complete medication information. At baseline, 38.8%, 39.4%, and 19.8% of patients tolerated 3, 2, and 1 GDMT classes, respectively (any dose); only 1.9% could not tolerate any GDMT. Beta-blockers were the most frequently tolerated GDMT (93.1%), followed by ACEIs/ARBs/ARNIs (68.5%), and then MRAs (55.0%). Intolerances differed by GDMT class, but hypotension and kidney dysfunction were most common. Goal doses were uncommonly achieved for beta-blockers (32.3%) and ACEIs/ARBs/ARNIs (10.2%) due to intolerances limiting titration. Only 2.2% of patients tolerated goal doses of all 3 GDMT classes., Conclusions: In a contemporary trial population with HF, severe mitral regurgitation, and systematic HF specialist-directed GDMT optimization, most patients had medical intolerances prohibiting 1 or more GDMT classes and achieving goal doses. The specific intolerances noted and methods used for GDMT optimization provide important lessons for the implementation of GDMT optimization in future clinical trials. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures Abbott Laboratories has provided funding for this paper. Dr Cox has received grants from AstraZeneca, and Cumberland Pharmaceuticals; and consulting fees from Roche. Dr Udelson has served on steering committees for Abiomed; and has received consulting fees from Imbria Pharmaceuticals. Dr Lim has received grants from Abbott, Edwards, Medtronic, and Gore; consulting fees from Abbott, Edwards, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; has served on advisory boards for Ancora and Venus; and holds equity in 510Kardiac and Venus. Dr Grayburn has received grant support and consulting fees from Edwards Lifesciences and Neochord; and grants from Boston Scientific, Medtronic, and Tendyne. Dr Mack has the following nonfinancial relationships: he has served as co-primary investigator for the PARTNER Trial for Edwards Lifesciences and COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Abraham has received grants and consulting fees from Abbott. Dr Stone has received honoraria from Terumo, Cook, and Infraredx; consulting fees from Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Reva, MAIA Pharmaceuticals, Vascular Dynamics, Shockwave, V-Wave, Cardiomech, and Gore; holds equity/options for Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and MedFocus family of funds. Dr Lindenfeld has received grants from AstraZeneca; and consulting fees from Abbott, CVRx, Edwards Lifesciences, RESMED, Relypsa, BI, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the increasing prevalence of comorbidities. While heart failure with reduced ejection fraction is dominated by left ventricular impairment, HFpEF results from a complex interplay of cardiac remodelling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes. In an important subset, however, HFpEF is subtended by specific diseases of the myocardium that are genetically determined, have distinct pathophysiology, and are increasingly amenable to targeted, innovative treatments. While each of these conditions is rare, they collectively represent a relevant subset within HFpEF cohorts, and their prompt recognition has major consequences for clinical practice, as access to dedicated, disease-specific treatments may radically change the quality of life and outcome. Furthermore, response to standard heart failure treatment will generally be modest for these individuals, whose inclusion in registries and trials may dilute the perceived efficacy of treatments targeting mainstream HFpEF. Finally, a better understanding of the molecular underpinnings of monogenic myocardial disease may help identify therapeutic targets and develop innovative treatments for selected HFpEF phenotypes of broader epidemiological relevance. The field of genetic cardiomyopathies is undergoing rapid transformation due to recent, groundbreaking advances in drug development, and deserves greater awareness within the heart failure community. The present review addressed existing and developing therapies for genetic causes of HFpEF, including hypertrophic cardiomyopathy, cardiac amyloidosis, and storage diseases, discussing their potential impact on management and their broader implications for our understanding of HFpEF at large., Competing Interests: Conflict of interest: I.O. is a consultant for Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Menarini International, Rocket Pharma, and Tenaya and has received research grants from BMS, Cytokinetics, Sanofi Genzyme, Shire Takeda, Amicus, Menarini International, Boston Scientific, Menarini International, and Bayer. J.E.U. serves as the Chair of a DMC for Cytokinetics and is a consultant to Cardurion, Bayer, Reprieve, Sequana, and Alleviant Medical. M.P. has received advisory board honoraria Myers Squibb and speaker fees from Sanofi Genzyme, Shire Takeda, Amicus Therapeutics, Pfizer, and Bristol Myers Squibb. C.R. has served as a speaker and has received consulting fees from Pfizer, Alnylam, and Eidos and has received research grants from Pfizer., (© The Author(s) 2022. 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.)

Background: Despite successful primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI), myocardial salvage is often suboptimal, resulting in large infarct size and increased rates of heart failure and mortality. Unloading of the left ventricle (LV) before primary PCI may reduce infarct size and improve prognosis., Study Design and Objectives: STEMI-DTU (NCT03947619) is a prospective, randomized, multicenter trial designed to compare mechanical LV unloading with the Impella CP device for 30 minutes prior to primary PCI to primary PCI alone without LV unloading. The trial aims to enroll approximately 668 subjects, with a potential sample size adaptation, with anterior STEMI with a primary end point of infarct size as a percent of LV mass evaluated by cardiac magnetic resonance at 3-5 days after PCI. The key secondary efficacy end point is a hierarchical composite of the 1-year rates of cardiovascular mortality, cardiogenic shock ≥24 hours after PCI, use of a surgical left ventricular assist device or heart transplant, heart failure, intra-cardiac defibrillator or chronic resynchronization therapy placement, and infarct size at 3 to 5 days post-PCI. The key secondary safety end point is Impella CP-related major bleeding or major vascular complications within 30 days. Clinical follow-up is planned for 5 years., Conclusions: STEMI-DTU is a large-scale, prospective, randomized trial evaluating whether mechanical unloading of the LV by the Impella CP prior to primary PCI reduces infarct size and improves prognosis in patients with STEMI compared to primary PCI alone without LV unloading., Competing Interests: Conflict of interest Dr Kapur has received research support from Abiomed, Cardiac Assist, and Maquet. and consulting fees/speaker honoraria from Abiomed, Cardiac Assist, Heartware, Maquet, and Thoratec. Dr Kim is a consultant for Abiomed. Dr Stone reports institutional research grants or contracts from Abbott, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics and V-wave; consulting fees from Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Reva, Shockwave, V-Wave, Cardiomech, Gore, and Vascular Dynamics; honoraria from Cook and Infraredx; and Stock (Equity) in Ancora, Cagent, Applied Therapeutics, Biostar Family of Funds, Spectra Wave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and MedFocus Family of Funds. Drs Ben-Yehuda and Redfors and Ms. Issever report institutional research contracts with Abiomed (no direct compensation). Dr Josephy and Dr Polak are employees of Abiomed. Dr O'Neill is a consultant to Abiomed, Boston Scientific, and Medtronic., (Copyright © 2022. Published by Elsevier Inc.)

Background: Decongestion is an important goal in the management of acute heart failure. Whether the rate of decongestion is associated with mortality and cardiovascular outcomes is unknown., Methods: Using data from 4133 patients from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between rates of in-hospital change in assessments of volume overload, including b-type natriuretic peptide (BNP), N-terminal pro b-type natriuretic peptide (NT-proBNP), as well as change in hemoconcentration, with risk of all-cause mortality and a composite outcome of cardiovascular mortality or heart failure hospitalization., Results: More rapid rates of in-hospital decongestion were associated with decreased risk of mortality and the composite outcome over a median 10-month follow-up. In reference to the quartile of slowest decline, the quartile with the fastest BNP and NT-proBNP decline had lower hazards of mortality (hazard rate [HR] = 0.43 [0.31, 0.59] and HR = 0.27 [0.19, 0.40], respectively) and composite outcome (HR = 0.49 [0.39, 0.60] and HR = 0.54 [0.42, 0.71], respectively). In reference to the quartile of slowest increase, the quartile with the fastest hematocrit increase had lower hazards of mortality (HR = 0.77 [0.62, 0.95]) and composite outcome (HR = 0.75 [0.64, 0.88]). Results were also consistent when models were repeated using propensity-score matching., Conclusions: Faster rates of decongestion are associated with reduced risk of mortality and a composite of cardiovascular mortality and heart failure hospitalization. It remains unknown whether more rapid decongestion provides cardiovascular benefit or whether it serves as a proxy for less treatment resistant heart failure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rationale & Objective: Achievement of decongestion in acute heart failure (AHF) is associated with improved survival and cardiovascular outcomes but can be associated with acute declines in estimated glomerular filtration rate (eGFR). We examined whether the rate of in-hospital decongestion is associated with longer term kidney function decline., Study Design: Post hoc analysis of trial data., Settings & Participants: Patients with ≥2 measures of kidney function (n = 3,500) from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial., Exposure: In-hospital rate of change in assessments of volume overload, including B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and clinical congestion score (0-12); and rate of change in hemoconcentration including measures of hematocrit, albumin, and total protein., Outcome: Incident chronic kidney disease GFR category 4 or worse (chronic kidney disease [CKD] categories G4-G5; defined by a new eGFR of <30 mL/min/1.73 m 2 ) and eGFR decline of >40%., Analytical Approach: Multivariable cause-specific hazards models., Results: Over median 10-month follow-up period, faster decreases in volume overload and more rapid increases in hemoconcentration were associated with a decreased risk of incident CKD G4-G5 and eGFR decline of >40%. In adjusted analyses, for every 6% faster decline in BNP per week, there was a 32% lower risk of both incident CKD G4-G5 (HR, 0.68 [95% CI, 0.58-0.79]) and eGFR decline of >40% (HR, 0.68 [95% CI, 0.57-0.80]). For every 1% faster increase per week in absolute hematocrit, there was a lower risk for both incident CKD G4-G5 (HR, 0.73 [95% CI, 0.64-0.84]) and eGFR decline of >40% (HR, 0.82 [95% CI, 0.71-0.95]), with results consistent for other biomarkers., Limitations: Possibility of residual confounding., Conclusions: These results provide reassurance that more rapid decongestion in patients with AHF does not increase the risk of adverse kidney outcomes in patients with heart failure., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) remains an elusive entity, due to its heterogeneous clinical profile and an arbitrarily defined nosology. Several pathophysiological mechanisms recognized as central for the development of HFpEF appear to be in common with the process of physiological aging of the heart. Both conditions are characterized by progressive impairment in cardiac function, accompanied by left ventricular hypertrophy, diastolic dysfunction, sarcomeric, and metabolic abnormalities. The neurological paradigm of dementia-intended as a progressive, multifactorial organ damage with decline of functional reserve, eventually leading to irreversible dysfunction-is well suited to represent HFpEF. In such perspective, certain phenotypes of HFpEF may be viewed as a maladaptive response to environmental modifiers, causing premature and pathological aging of the heart. We here propose that the 'HFpEF syndrome' may reflect the interplay of adverse structural remodelling and erosion of functional reserve, mirroring the processes leading to dementia in the brain. The resulting conceptual framework may help advance our understanding of HFpEF and unravel potential therapeutical targets., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Loop diuretics are the main treatment for patients with acute heart failure, but are associated with neurohormonal stimulation and worsening renal function and do not improve long-term outcomes. Antagonists to arginine vasopressin may provide an alternative strategy to avoid these effects. The AVANTI study will investigate the efficacy and safety of pecavaptan, a novel, balanced dual-acting V1a/V2 vasopressin antagonist, both as adjunctive therapy to loop diuretics after admission for acute heart failure, and later as monotherapy., Methods and Results: AVANTI is a double-blind, randomized phase II study in 571 patients hospitalized with acute heart failure and signs of persistent congestion before discharge. In part A, patients will receive either pecavaptan 30 mg/d or placebo with standard of care for 30 days. In part B, eligible patients will continue treatment or receive pecavaptan or diuretics as monotherapy for another 30 days. The primary end points for part A are changes in body weight and serum creatinine; for part B, changes in body weight and blood urea nitrogen/creatinine ratio., Conclusions: This study will provide the first evidence that a balanced V1a/V2 antagonist may safely enhance decongestion, both as an adjunct to loop diuretics and as an alternative strategy., Trial Registration Number: NCT03901729., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency., Objective: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF., Design, Setting, and Participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019., Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90)., Main Outcomes and Measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs)., Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group)., Conclusions and Relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT03254485.

Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. However, achieving complete decongestion can be challenging. Furthermore, residual congestion before discharge from hospital is associated with a high risk of early rehospitalization and death. An improved understanding of the pathophysiology of congestion is of great importance in finding better and more personalized therapies. In this Review, we describe the two different forms of congestion - intravascular congestion and tissue congestion - and hypothesize that differentiating between and specifically treating these two different forms of congestion could improve the outcomes of patients with acute decompensated heart failure. Although the majority of these patients have a combination of both intravascular and tissue congestion, one phenotype can dominate. Each of these two forms of congestion has a different pathophysiology and requires a different diagnostic approach. We provide an overview of novel and established biomarkers, imaging modalities and mechanical techniques for identifying each type of congestion. Treatment with loop diuretics, the current cornerstone of decongestive treatment, reduces circulating blood volume and thereby reduces intravascular congestion. However, the osmolality of the circulating blood decreases with the use of loop diuretics, which might result in less immediate translocation of fluid from the tissues (lungs, abdomen and periphery) to the circulation when the plasma refill rate is exceeded. By contrast, aquaretic drugs (such as vasopressin antagonists) predominantly cause water excretion, which increases the osmolality of the circulating blood, potentially improving translocation of fluid from the tissues to the circulation and thereby relieving tissue congestion.

Objectives: This study aimed to examine whether incorporation of a comprehensive set of measures of decongestion modifies the association of acute declines in kidney function with outcomes., Background: In-hospital acute declines in kidney function occur in approximately 20% to 30% of patients admitted with acute decompensated heart failure (ADHF) and may be associated with adverse outcomes., Methods: Using data from EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan), we used multivariable Cox regression models to evaluate the association between in-hospital changes in estimated glomerular filtration rate (eGFR) with death and a composite outcome of cardiovascular death and hospitalization for heart failure. We evaluated eGFR declines within the context of changes in markers of volume overload including b-type natriuretic peptide (BNP), N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and weight, as well as changes in measures of hemoconcentration including hematocrit, albumin, and total protein., Results: Among 3,715 patients over a median follow-up of 9.9 months, every 30% decline in eGFR was associated with higher risk of both death (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 1.07 to 1.31) and the composite outcome (HR: 1.09; 95% CI: 1.01 to 1.18) in adjusted models. The acute decline in eGFR was no longer associated with higher risk of either outcome as long as there was evidence of decongestion, either by declines in BNP, NT-proBNP, or weight or by increases in hematocrit, albumin or total protein. Interaction testing between decline in eGFR and changes in hematocrit, albumin, and total protein was statistically significant (p interaction of <0.01 for death and p interaction of ≤0.01 for composite for all 3 biomarkers). Interaction between change in eGFR and changes in BNP (p interaction = 0.07 for death; p interaction = 0.08 for composite), NT-proBNP (p interaction = 0.15 for death; p interaction = 0.18 for composite) and weight (p interaction = 0.13 for death; p interaction = 0.19 for composite) did not meet statistical significance., Conclusions: Overall, acute declines in eGFR are associated with adverse outcomes, with evidence of modification by changes in markers of decongestion, suggesting that they are no longer associated with adverse outcomes if these markers are concomitantly improving., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging., Methods: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days., Results: The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, -4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, -1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, -3.8 mL) (4 mg vs placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P  =  0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P  =  0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups., Conclusions: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo., (Copyright © 2020. Published by Elsevier Inc.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF., Methods: CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO 2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire., Conclusions: The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function., Methods: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score)., Conclusions: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.

Aims: To assess whether natriuretic peptides (NPs) can be used to reliably predict long-term therapeutic effect on clinical outcomes for patients with heart failure and reduced ejection fraction (HFrEF)., Methods and Results: HFrEF intervention trials with mortality data were identified. Subsequently, we identified trials assessing therapy-induced changes in NPs. We assessed the correlation between the average short-term placebo-corrected drug or device effect on NPs and the longer-term therapeutic effect on clinical outcomes. Of 35 distinct therapies with an identifiable mortality result (n = 105 062 patients), 20 therapies had corresponding data on therapeutic effect on NPs. No correlation was observed between therapy-induced placebo-corrected change in brain natriuretic peptide or N-terminal pro-brain natriuretic peptide and therapeutic effect on all-cause mortality (ACM) (Spearman r = -0.32, P = 0.18 and r = -0.20, P = 0.47, respectively). There was no correlation between therapy-induced placebo-corrected per cent change in NP and intervention effect on ACM or ACM-heart failure hospitalizations (r = -0.30, P = 0.11 and r = 0.10, P = 0.75, respectively)., Conclusions: Short-term intervention-induced changes in NP levels are not reliable predictors of therapeutic long-term effect on mortality or morbidity outcomes for patients with HFrEF., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Heart failure (HF) represents the most common cause of hypervolemic hyponatremia in current clinical practice. The presence of hyponatremia has been independently associated with worse outcomes in this patient population. The pathogenesis of hyponatremia in HF involves complex neurohormonal and cardio-renal interactions, including an increase in non osmotic secretion of arginine vasopressin (AVP) and insufficient tubular flow in the diluting segments of the nephron. The treatment of hyponatremia in HF involves decongestant therapy with diuretics, neurohormonal blockade and in certain occasions the use of AVP antagonists. The aim of this chapter is to summarize the pathophysiology, current evidence, and management recommendations for hyponatremia in patients with HF, with a specific focus on AVP homeostasis., (© 2019 S. Karger AG, Basel.)

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) and symptomatic secondary mitral regurgitation (SMR) have a poor prognosis, with morbidity and mortality directly correlated with MR severity. Correction of isolated SMR with surgery is not well established in this population, and medical management remains the preferred approach in most patients. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial was designed to determine whether transcatheter mitral valve (MV) repair with the MitraClip device is safe and effective in patients with symptomatic HF and clinically significant SMR., Study Design: The COAPT trial is a prospective, randomized, parallel-controlled, open-label multicenter study of the MitraClip device for the treatment of moderate-to-severe (3+) or severe (4+) SMR (as verified by an independent echocardiographic core laboratory) in patients with New York Heart Association class II-IVa HF despite treatment with maximally tolerated guideline-directed medical therapy (GDMT) who have been determined by the site's local heart team as not appropriate for MV surgery. A total of 614 eligible subjects were randomized in a 1:1 ratio to MV repair with the MitraClip plus GDMT versus GDMT alone. The primary effectiveness end point is recurrent HF hospitalizations through 24 months, analyzed when the last subject completes 12-month follow-up, powered to demonstrate superiority of MitraClip therapy. The primary safety end point is a composite of device-related complications at 12 months compared to a performance goal. Follow-up is ongoing, and the principal results are expected in late 2018., Conclusions: HF patients with clinically significant SMR who continue to be symptomatic despite optimal GDMT have limited treatment options and a poor prognosis. The randomized COAPT trial was designed to determine the safety and effectiveness of transcatheter MV repair with the MitraClip in symptomatic HF patients with moderate-to-severe or severe SMR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Among patients with heart failure with reduced ejection fraction, investigators have repeatedly identified a subgroup whose left ventricular ejection fraction and structural remodeling can improve to normal or nearly normal levels with or without medical therapy. This subgroup of patients with "heart failure with improved ejection fraction" has distinct clinical characteristics and a more favorable prognosis compared with patients who continue to have reduced ejection fraction. However, many of these patients also manifest clinical and biochemical signs of incomplete resolution of heart failure pathophysiology and remain at some risk of adverse outcomes, thus indicating that they may not have completely recovered. Although rigorous evidence on managing these patients is sparse, there are several reasons to recommend continuation of heart failure therapies, including device therapies, to prevent clinical deterioration. Notable exceptions to this recommendation may include patients who recover from peripartum cardiomyopathy, fulminant myocarditis, or stress cardiomyopathy, whose excellent long-term prognoses may imply true myocardial recovery. More research on these patients is needed to better understand the mechanisms that lead to improvement in ejection fraction and to guide their clinical management., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (≤40%) in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial. Multiple logistic regression analyses tested >30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p <0.10); however, this final model demonstrated poor discrimination (C-statistic 0.57). In conclusion, in the EVEREST trial, patients hospitalized for HFrEF faced risks of 1-year postdischarge SCD of 7%, which accrued gradually over time, and were balanced with high competing risks of nonsudden death (17%). Traditional clinical characteristics fail to adequately predict SCD risk. Further data are needed to identify patients at greatest relative risk for SCD (compared with non-SCD) after hospitalization for HFrEF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heart failure (HF), characterized by excessive exertional dyspnea, is a common complication within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM). HF has become an increasingly prominent management issue with the reduction in sudden deaths due to use of implantable defibrillators in this disease. Exertional dyspnea ranges in severity from mild to severe (New York Heart Association functional classes II to IV) and not uncommonly becomes refractory to medical management, leading to progressive disability, but largely in the absence of pulmonary congestion and volume overload requiring hospitalization. HCM-related HF is most commonly due to dynamic mechanical impedance to left ventricular outflow produced by mitral valve systolic anterior motion, leading to high intracavity pressures. Surgical septal myectomy with low operative mortality (<1%) produces HF reversal and symptom relief in 90% to 95% of patients, while also conveying a survival benefit. Exercise echocardiography has assumed an important role in the evaluation of patients with HCM, i.e., by identifying candidates for septal reduction therapy with refractory HF when outflow gradients are present only with physiological exercise, distinguishing highly symptomatic nonobstructive patients as heart transplant candidates, and predicting future development of progressive HF. Notably, mortality directly attributable to HF has become exceedingly uncommon in HCM (<0.5%/year) in contrast with HF in non-HCM diseases (by 20-fold). In conclusion, HF in HCM is associated with diverse and complex pathophysiology, but a substantially more favorable prognosis than conventional non-HCM HF, and highly amenable to effective treatment options in the vast majority of patients., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Stimulation of the V1a receptor for arginine vasopressin produces myocardial and vascular effects similar to those of angiotensin II while stimulation of the V2 receptor causes fluid retention. There are no data with sustained blockade of the V1a receptor while single-dose experiments suggest benefit. Acute and chronic administration of selective V2 receptor antagonists reliably relieves dyspnea and produces diuresis without adverse effects on renal function or neurohormonal stimulation, either as adjunctive or alternative therapy to loop diuretics, but has not been shown to improve outcomes as adjunctive therapy. Combined antagonism has been tried only in single-dose studies in stable patients or over the short-term in acute heart failure, with encouraging results. Based on the both the pathophysiologic rationale for additional neurohormonal blockade and these results, chronically blocking both receptors, particularly in more congested patients, may offer significant benefit either as adjunctive or alternative therapy to standard diuretics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction., Methods and Results: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg -1 ·h -1 ) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P =0.009) and end-systolic volume (-14 mL; P =0.005) occurred at end infusion in the highest dose cohort., Conclusions: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464., (© 2017 American Heart Association, Inc.)

Background: Heart failure clinical practice guidelines recommend applying validated clinical predictive models (CPMs) to support decision making. While CPMs are now widely available, the generalizability of heart failure CPMs is largely unknown., Methods and Results: We identified CPMs derived in North America that predict mortality for patients with acute heart failure and validated these models in different world regions to assess performance in a contemporary international clinical trial (N=4133) of patients with acute heart failure treated with guideline-directed medical therapy. We performed independent external validations of 3 CPMs predicting in-hospital mortality, 60-day mortality, and 1-year mortality, respectively. CPM discrimination decreased in all regional validation cohorts. The median change in area under the receiver operating curve was -0.09 (range -0.05 to -0.23). Regional calibration was highly variable (90th percentile of absolute difference between smoothed observed and predicted values range <1% to >50%). Calibration remained poor after global recalibrations; however, region-specific recalibration procedures significantly improved regional performance (recalibrated 90th percentile of absolute difference range <1% to 5% across all regions and all models)., Conclusions: Acute heart failure CPM discrimination and calibration vary substantially across different world regions; region-specific (as opposed to global) recalibration techniques are needed to improve CPM calibration., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions., (© 2017 American Heart Association, Inc.)

Background: In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments., Objectives: It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response., Methods: In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m 2 ; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach., Results: We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings., Conclusions: Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting., (© 2016 American Heart Association, Inc.)

Background: Dyspnea is the most common symptom among hospitalized patients with heart failure and represents a therapeutic target. However, the association between short-term dyspnea relief and postdischarge clinical outcomes and health-related quality of life (HRQOL) remains uncertain., Methods and Results: A post hoc analysis was performed of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which enrolled 4133 patients within 48 hours of admission for heart failure with an ejection fraction ≤40%. Physician-assessed dyspnea was recorded on a daily basis from baseline until discharge or day 7 as none, seldom, frequent, or continuous. Patient-reported dyspnea was measured using a 7-point Likert scale, and patients experiencing moderate or marked dyspnea improvement on day 1 were classified as early responders. The Kansas City Cardiomyopathy Questionnaire summary score, which ranges from 0 to 100, was collected postdischarge at week 1. The primary outcome was unfavorable HRQOL, defined a priori as a Kansas City Cardiomyopathy Questionnaire score <45. Secondary outcomes included 30-day all-cause mortality, and all-cause and cause-specific hospitalizations. The final analytic cohort included 1567 patients discharged alive with complete HRQOL data. Patients were 66.0±12.7 years old and had a mean ejection fraction of 25±8%. Physician-assessed dyspnea was rated as frequent or continuous in 1399 patients (90%) at baseline, which decreased to 250 patients (16%) by discharge, whereas patient-reported early dyspnea relief was reported by 610 patients (40%). The median Kansas City Cardiomyopathy Questionnaire score at week 1 was 50 (35, 65). All-cause mortality was 3.0%, and all-cause hospitalization was 20.5% within 30 days of discharge. Physician-assessed and patient-reported dyspnea was not independently associated with HRQOL, all-cause mortality, or all-cause or cause-specific hospitalization., Conclusions: In-hospital physician-assessed, and patient-reported dyspnea was not independently associated with postdischarge HRQOL, survival, or readmissions. Although dyspnea relief remains a goal of therapy for hospitalized patients with heart failure with reduced ejection fraction, this measure may not be a reliable surrogate for long-term patient-centered or hard clinical outcomes., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00071331., (© 2016 American Heart Association, Inc.)

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials., (© 2015 American Heart Association, Inc.)

Background: Despite considerable improvements in the medical management of patients with myocardial infarction (MI), patients with large MI still have substantial risk of developing heart failure. In the early post-MI setting, implantable cardioverter defibrillators have reduced arrhythmic deaths but have no impact on overall mortality. Therefore, additional interventions are required to further reduce the overall morbidity and mortality of patients with large MI., Methods: The Pacing Remodeling Prevention Therapy (PRomPT) trial is designed to study the effects of peri-infarct pacing in preventing adverse post-MI remodeling. Up to 120 subjects with peak creatine phosphokinase >3,000 U/L (or troponin T >10 μg/L) at time of MI will be randomized to either dual-site or single-site biventricular pacing with the left ventricular lead implanted in a peri-infarct region or to a nonimplanted control group. Those randomized to a device will be blinded to the pacing mode, but randomization to a device or control cannot be blinded. Subjects randomized to pacing will have the device implanted within 10 days of MI. The primary objective is to assess the change in left ventricular end-diastolic volume from baseline to 18 months. Secondary objectives are to assess changes in clinical and mechanistic parameters between the groups, including rates of hospitalization for heart failure and cardiovascular events, the incidence of sudden cardiac death and all-cause mortality, New York Heart Association functional class, 6-minute walking distance, and quality of life., Conclusions: The PRomPT trial will provide important evidence regarding the potential of peri-infarct pacing to interrupt adverse remodeling in patients with large MI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

(123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging is a tool for evaluating one of the fundamental pathophysiologic abnormalities seen in heart failure (HF), that of an upregulated sympathetic nervous system and its effect on the myocardium. Although this imaging technique offers information about prognosis for patients treated with contemporary guideline-based HF therapies and improves risk stratification, there are neither rigorous nor sufficient outcome data to suggest that this imaging tool can guide therapeutic decision making or better target subsets of patients with HF for particular therapies., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: In hypertrophic cardiomyopathy (HCM), heart transplant has been predominantly confined to patients with systolic dysfunction. An underappreciated HCM subset comprises patients with preserved left ventricular (LV) systolic function who may also require consideration for transplantation. Therefore, we sought to define the clinical profile and occurrence of advanced heart failure among patients with nonobstructive HCM and preserved systolic function., Methods and Results: Databases from 2 referral centers comprising 2100 HCM patients were interrogated. Forty-six nonobstructive HCM patients (2.2%) either received or were listed for heart transplant, including 20 with normal systolic function (ejection fraction ≥50%). At transplant listing, these 20 patients were 42±13 years old, each in New York Heart Association functional class III/IV with ejection fraction of 62±7%. LV was hypertrophied with maximum wall thickness of 22±4 mm and nondilated (end-diastolic dimension, 39±7 mm). Cardiovascular magnetic resonance in 10 (of 15) patients showed no or minimal fibrosis (≤5% LV mass). Elevated LV end-diastolic or pulmonary capillary wedge pressure, consistent with diastolic dysfunction, was present in 15 patients (75%). LV filling was impaired by echocardiographic measures in all patients, including a restrictive inflow pattern in 8 (40%). In 2 patients, traditional criteria for transplant were absent, including peak VO2 >14 mL/kg/min. Heart transplantation was performed in 12 patients with each alive and without cardiovascular symptoms, 2.3±1.7 years later., Conclusions: A previously under-recognized segment of the broad HCM clinical spectrum consists of nonobstructive patients with advanced heart failure, in the presence of preserved systolic function, for whom heart transplant is the sole definitive therapeutic option., (© 2014 American Heart Association, Inc.)

Objectives: This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort., Background: It is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM., Methods: In 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression., Results: At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m(2) and >30 kg/m(2), respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m(2)), compared with normal weight patients (BMI <25 kg/m(2); hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m(2) were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03)., Conclusions: In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.

Aims: Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized., Methods and Results: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up., Conclusion: Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.

Background: Hypertrophic cardiomyopathy (HCM) is prominently associated with risk for sudden death and disease progression, largely in young patients. Whether patients of more advanced age harbor similar risks is unresolved, often creating clinical dilemmas, particularly in decisions for primary prevention of sudden death with implantable defibrillators., Methods and Results: We studied 428 consecutive HCM patients presenting at ≥60 years of age and followed for 5.8±4.8 years; 53% were women. Of the 428 patients, 279 (65%) survived to 73±7 years of age (range, 61-96 years), most (n=245, 88%) with no/mild symptoms, including 135 with ≥1 conventional sudden death risk factors and 50 (37%) with late gadolinium enhancement. Over follow-up, 149 (35%) died at 80±8 years of age, mostly from non-HCM-related causes (n=133, 31%), including a substantial proportion from noncardiac disease (n=54). Sixteen patients (3.7%) had HCM-related mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3), postoperative complications (n=2), and arrhythmic sudden death events (n=5, 1.2% [0.20%/y]). All-cause mortality was increased in HCM patients ≥60 years of age compared with an age-matched US general population, predominantly as a result of non-HCM-related diseases (P<0.001; standard mortality ratio, 1.5)., Conclusions: HCM patients surviving into the seventh decade of life are at low risk for disease-related morbidity/mortality, including sudden death, even with conventional risk factors. These data do not support aggressive prophylactic defibrillator implantation at advanced ages in HCM. Other cardiac or noncardiac comorbidities have a greater impact on survival than HCM in older patients.

Aims: Data on the prognosis of heart failure (HF) patients with coronary artery disease (CAD) have been conflicting. We describe the clinical characteristics and mode-specific outcomes of HF patients with reduced ejection fraction (EF) and documented CAD in a large randomized trial., Methods and Results: EVEREST was a prospective, randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with worsening HF and reduced EF. Patients were classified as having CAD based on patient-reported myocardial infarction (MI) or coronary revascularization. We analysed the characteristics and outcomes [all-cause mortality and cardiovascular (CV) mortality/HF hospitalization] of patients with and without documented CAD. All events were centrally adjudicated. Documented CAD was present in 2353 patients (57%). Patients with CAD were older and had more co-morbidities compared with those without CAD. Patients with CAD were more likely to receive a beta-blocker, but less likely to receive an angiotensin-converting enzyme (ACE) inhibitor or aldosterone antagonist (P < 0.01). After risk adjustment, patients with documented CAD had similar mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.97-1.30], but were at an increased risk for CV mortality/HF hospitalization (HR 1.25, 95% CI 1.12-1.41) due to an increased risk for HF hospitalization (HR 1.26, 95% CI 1.10-1.44). Patients with CAD had increased HF- and MI-related events, but similar rates of sudden cardiac death., Conclusion: Documented CAD in patients hospitalized for worsening HF with reduced EF was associated with a higher burden of co-morbidities, lower use of HF therapies (except beta-blockers), and increased HF hospitalization, while all-cause mortality was similar.

Background: Although peak oxygen consumption (peak VO(2)), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction., Methods and Results: We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in VO(2), 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak VO(2) trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak VO(2) and the odds ratio for mortality (r=0.158, P=0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality (r=0.373, P=0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r=-0.065, P=0.82, NT-proBNP: r=-0.667, P=0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality., Conclusions: This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak VO(2), 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction.