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Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM)., Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation., Conclusions: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Background: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction)., Methods: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events., Results: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype., Conclusions: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711., Competing Interests: Dr Jhund reports receiving grant support from Boehringer Ingelheim and fees for serving on an advisory board from Cytokinetics. Dr Anand reports receiving fees for serving on a steering committee from AstraZeneca, ARCA biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end-point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. Dr Claggett received consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia Medical, Gilead Sciences, and MyoKardia. Dr Desai received consulting fees from Abbott, Boehringer Ingelheim, DalCor Pharmaceuticals, and Regeneron; grant support, paid to Brigham and Women’s Hospital, consulting fees, and fees for serving on an advisory board from Alnylam Pharmaceuticals and AstraZeneca; consulting fees and fees for serving on a steering committee from Biofourmis; consulting fees and fees for serving on a data and safety monitoring committee from Boston Scientific; fees for serving on an advisory board from Corvidia; and fees for serving on an advisory board and consulting fees from Relypsa. Drs Chiang, Gong, and Lefkowitz are employed by Novartis Pharmaceuticals. Dr Lam received grant support and fees for serving on an advisory board from Boston Scientific and Roche Diagnostics; grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer; grant support from Medtronics; grant support and fees for serving on a steering committee from Vifor Pharma; fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis; fees for serving on an advisory board from Amgen, Boehringer Ingelheim, and Abbott Diagnostics; consulting fees from Merck and Stealth BioTherapeutics; fees for serving on a steering committee from Janssen Research and Development; lecture fees and consulting fees from Menarini; and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure. Dr Maggioni received fees for serving on a study committee from Bayer and Fresenius. Dr Packer received consulting fees from AbbVie, Akcea Therapeutics, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead Sciences, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance Biopharma. Dr Rouleau received consulting fees from AstraZeneca. Dr van Veldhuisen received fees for serving on a steering committee and travel support from ARCA Biopharma and Corvia Medical. Dr Zannad received fees for serving on a steering committee from Janssen, Bayer, Boston Scientific, CVRx, and Boehringer Ingelheim; consulting fees from Amgen, Vifor Pharma–Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck; and consulting fees and fees for serving on a steering committee from AstraZeneca and serving as founder of cardiorenal and CVCT. Dr Zile received fees for serving on a steering committee from Abbott and Ironwood Pharma; consulting fees from Boston Scientific and MyoKardia; grant support and fees for serving on a steering committee from CVRx and Medtronic; fees for serving on an eligibility committee from EBR Systems and V-Wave; fees for serving on a clinical-events committee from Endotronics; and fees for serving on a data and safety monitoring board from Merck. Dr Solomon received grant support, paid to Brigham and Women’s Hospital, and consulting fees from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics; grant support, paid to Brigham and Women’s Hospital, from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; and fees for serving on a data and safety monitoring board from Janssen. Dr McMurray reports that his employer, Glasgow University, has been paid by Novartis for serving as an executive committee member and coprincipal investigator of ATMOSPHERE, PARADIGM-HF, and PARAGON-HF trials and executive/steering committee member of the PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan) and for meetings/presentations related to these trials, aliskiren, and sacubitril-valsartan. Novartis has also paid for his travel and accommodation for some of these meetings. Glasgow University has also been paid by Novartis for advisory board; by Bayer for serving as a steering committee member of the PANACHE trial using neladenoson bialanate (BAY 1067197); by Cardiorentis for serving as a steering committee member and end-point committee chair for the TRUE-AHF trial and attending meetings related to this trial; by Cardiorentis for travel and accommodation to attend some of these meetings; by Amgen for serving as steering committee member for the ATOMIC-HF and COSMIC-HF trials and attending meetings related to this trial; by Amgen for travel and accommodation for some of these meetings; by Oxford University (which received a grant from Bayer, which manufactures acarbose) for serving as a steering committee member for the ACE trial (using acarbose) and attending meetings related to this trial; by Theracos for serving as principal investigator for the BEST trial and attending meetings related to this trial; by Theracos for travel and accommodation to attend some of these meetings; by Abbvie (which manufactures atrasentan) for serving as steering committee member for the SONAR trial (using atrasentan) and to attend meetings related to this trial; by Abbvie for his travel and accommodation to attend some of these meetings; by DalCor Pharmaceuticals for serving as steering committee member for the Dal-GenE trial and to attend meetings related to this trial; by Pfizer for serving on the data safety monitoring committee for the SPIRE trial and to attend meetings related to this trial; by Merck for serving on the data safety monitoring committee for the MK-3102 program, for the VICTORIA trial, and to attend meetings related to these trials; by AstraZeneca (which markets dapagliflozin) for serving as principal investigator of DAPA-HF and coprincipal investigator of DELIVER (trials using dapagliflozin on heart failure) and to attend meetings related trial; by AstraZeneca for his travel and accommodation to attend meetings; by GSK for serving as coprincipal investigator and steering committee member for the Harmony-Outcomes trial (albiglutide) and the trials ASCEND-D and ASCEND-ND, using daprodustat, respectively, and to attend meetings related to these trials; by GSK for his travel and accommodation to attend some of the meetings; by BMS for serving as a steering committee member for the STAND-UP clinical trial (using an HNO donor) on heart failure and to attend meetings related to this trial; and by Kings College Hospital (which has received a grant from KRUK and Vifor-Fresenius, which manufactures intravenous iron) for serving as steering committee member for the PIVOTAL trial (using intravenous iron) and for running the end-point adjudication committee for this trial, to attend meetings related to PIVOTAL, and for his travel and accommodation for to attend some of the meetings. All payments were made through consultancies with Glasgow University, and Dr McMurray has not received any personal payments in relation to the trials or drugs. The other authors report no conflicts. The study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Aims: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF., Methods and Results: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m 2 , elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials., Conclusions: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329)., Methods: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil., Results: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2)., Conclusions: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI., Competing Interests: DISCLOSURES GMF has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. SDS reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women's Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly, Gilead Sciences,GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast,Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals. MM reports receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics. JJVM reports receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries. RD reports receiving grants from Amgen during the conduct of the study. BC reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis. DEL is supported in part by grants from the National Institutes of Health (P50MD017351, R01HL132154), has received research funding or support from Amgen, Astra Zeneca, Janssen, Eli Lilly, and Somalogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, and Otsuka. HV reports being a national leader of GALACTIC-HF and has received lecture fees and consultation fees from Amgen. RDL reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis and funding for educational activities or lectures from Pfizer and Daiichi Sankyo and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. S-IM reports being a national leader of GALACTIC-HF and has received lecture and consultation fees from Amgen. TB-S reports being a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur-financed NUDGE-FLU trial; chief investigator and steering committee chair of the Sanofi Pasteur-financed DANFLU-1 trial; steering committee member of LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System trial; is on the advisory boards of Sanofi Pasteur, Amgen and GSK; receives speaker honoraria from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. SBH, PHD, SK, and FIM are employees of Cytokinetics. JRT reports receiving grants from Amgen and Cytokinetics, personal fees from Amgen, Cytokinetics and Servier Laboratories, and nonfinancial support from Amgen and Cytokinetics during the conduct of the study; grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics; and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population., Methods and Results: We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02-1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction >0.1)., Conclusions: In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF., (© 2024 European Society of Cardiology.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain., Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis., Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups., Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.)., (Copyright © 2022 Massachusetts Medical Society.)

Importance: Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies., Objective: To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial., Design, Setting, and Participants: The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months., Interventions: Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo., Main Outcomes and Measures: The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability., Results: Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo., Conclusions and Relevance: In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited., Trial Registration: ClinicalTrials.gov Identifier: NCT02929329.

Background: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction., Methods: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events., Results: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P =0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P =0.005), whereas the primary outcome was no longer statistically significant., Conclusions: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients., Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime., Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months., Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy., Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause., Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival., Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF., Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.

Background Maximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction. Methods and Results We assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow-up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12-1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17-1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02-1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome ( P for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all P <0.05). Conclusions In patients with HF with preserved ejection fraction, LAVImin was more predictive of cardiovascular outcome than indexed maximal LA volume, suggesting this measure may be more physiologically relevant and might better identify patients at high risk for cardiovascular events. LA functional parameters provide prognostic information independent of LAVImin. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00094302.

Importance: Limited data exist regarding the association of subtle subclinical systolic dysfunction and incident heart failure (HF) in late life., Objective: To assess the independent associations of subclinical impairments in systolic performance with incident HF in late life., Design, Setting, and Participants: This study was a time-to-event analysis of participants without heart failure in the Atherosclerosis Risk in Communities (ARIC) study, a prospective, community-based cohort study, who underwent protocol echocardiography at the fifth study visit (January 1, 2011, to December 31, 2013). Findings were validated independently in participants in the Copenhagen City Heart Study (CCHS). Data analysis was performed from June 1, 2018, to February 28, 2020., Exposures: Left ventricular ejection fraction (LVEF), longitudinal strain (LS), and circumferential strain (CS) measured by 2-dimensional and strain echocardiography., Main Outcomes and Measures: Main outcomes were incident adjudicated HF and HF with preserved and reduced LVEF at a median follow-up of 5.5 years (interquartile range, 5.0-5.8 years). Cox proportional hazards regression models adjusted for demographics, hypertension, diabetes, obesity, smoking, coronary disease, estimated glomerular filtration rate, LV mass index, e', E/e', and left atrial volume index. Lower 10th percentile limits were determined in 374 participants free of cardiovascular disease or risk factors., Results: Among 4960 ARIC participants (mean [SD] age, 75 [5] years; 2933 [59.0%] female; 965 [19%] Black), LVEF was less than 50% in only 76 (1.5%). In the 3552 participants with complete assessment of LVEF, LS, and CS, 983 (27.7%) had 1 or more of the following findings: LVEF less than 60%, LS less than 16.0%, or CS less than 23.7%. Modeled continuously or dichotomized, worse LVEF, LS, and CS were each independently associated with incident HF. The adjusted hazard ratio (HR) per SD decrease in LVEF was 1.41 (95% CI, 1.29-1.55); the HR for LVEF less than 60% was 2.59 (95% CI, 1.99-3.37). Similar findings were observed for continuous LS (HR, 1.37; 95% CI, 1.22-1.53) and dichotomized LS (HR, 1.93; 95% CI, 1.46-2.55) and for continuous CS (HR, 1.39; 95% CI, 1.22-1.57) and dichotomized CS (HR, 2.30; 95% CI, 1.64-3.22). Although the magnitude of risk for incident HF or death associated with impaired LVEF was greater using guideline (HR, 2.99; 95% CI, 2.19-4.09) compared with ARIC-based limits (HR, 1.88; 95% CI, 1.58-2.25), the number of participants classified as impaired was less (104 [2.1%] based on guideline thresholds compared with 692 [13.9%] based on LVEF <60%). The population-attributable risk associated with LVEF less than 60% was 11% compared with 5% using guideline-based limits, a finding replicated in 908 participants in the CCHS., Conclusions and Relevance: These findings suggest that relatively subtle impairments of systolic function (detected based on LVEF or strain) are independently associated with incident HF and HF with reduced LVEF in late life. Current recommended assessments of LV function may substantially underestimate the prevalence of prognostically important impairments in systolic function in this population.

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood., Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF., Methods: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term., Results: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF., Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF., Competing Interests: Funding Support and Author Disclosures The TOPCAT study was supported by a contract from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200425207C). Dr. Beldhuis has received a research grant from the Dutch Heart Foundation. Dr. Myhre has received speaker fees from Novartis. Dr. Lewis has received research grants from Novartis, Amgen, and Sanofi; and has served as a consultant for and serves on the advisory boards of Modest and Novartis. Dr. Pitt has served as a consultant for Pfizer, Bayer, Relypsa, AstraZeneca, and KBP Biosciences; holds a pending patent related to site-specific delivery of eplerenone to the myocardium; and holds stock options in Relypsa and KBP Biosciences. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr. Vardeny has received research support from AstraZeneca. Dr. Voors has received consultancy fees from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Sanofi, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor; has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received research support from Singulex, Sphingotec, and Vifor. Dr. Pfeffer has received research support from Novartis; has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Solomon has received research support from the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis and Bayer. Dr. Desai has received consulting fees from Abbott, Amgen, AstraZeneca, Alnylam, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, Dalcor Pharma, Merck, Novartis, Relypsa, and Regeneron; and has received research grants from Novartis, Bayer, AstraZeneca, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction)., Methods: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope., Results: At randomization, eGFR was 63±19 mL·min -1 ·1.73 m - 2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P =0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min -1 ·1.73 m -2 ( P -interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min -1 ·1.73 m -2 per year)., Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF., Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF., Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions., Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men., Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Background: The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity., Objectives: The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies., Methods: Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors., Results: Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m 2 ; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm 2 ; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e' ratio, pulmonary artery systolic pressure, and event rates., Conclusions: Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The present study aimed to assess the association between left atrial (LA) structure and function and the risk for cardiovascular (CV) death or heart failure (HF) hospitalization in a population with atrial fibrillation (AF)., Methods and Results: In a prospective echocardiographic substudy of the Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study, 971 patients underwent transthoracic echocardiography. The associations between LA structure (LA volume index [LAVi]) and function (LA emptying fraction [LAEF] and LA expansion index [LAEi]) and risk for the composite endpoint of CV death or HF hospitalization, and its components, were assessed. Over a median follow-up of 2.5 years, 142 patients (14.6%) experienced CV death or HF hospitalization. Higher LAVi and lower LAEF and LAEi were each associated with a higher unadjusted risk for the composite outcome and its components. After adjustment for clinical and echocardiographic confounders, only measures of impaired LA function were predictive of the composite outcome (hazard ratio [HR] per 1 standard deviation [SD] decrease in LAEF: 1.35; 95% confidence interval [CI] 1.09-1.67 [P = 0.005]; HR per 1 SD decrease in LAEi: 1.34; 95% CI 1.06-1.69 [P = 0.012]). These findings were similar regardless of left ventricular ejection fraction, history of HF or whether patients were in AF or sinus rhythm at the time of the echocardiographic examination., Conclusions: In patients with AF, LA dysfunction was significantly associated with an increased risk for CV death or HF hospitalization and was more predictive of these outcomes than LA size. These parameters may help to identify AF patients at greatest risk for the development of HF., Clinical Trial Registration: ClinicalTrials.gov, NCT00781391., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Aims: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial., Methods and Results: Overall, 8399 patients with New York Heart Association class II-IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post-randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on-treatment analysis., Conclusion: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF)., Background: Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease., Methods: This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms., Results: The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function., Conclusions: Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and identify patients with beneficial response to cardiac resynchronization therapy (CRT)., Methods and Results: We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT-D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K-means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT-D on the primary outcome (all-cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT-D on the primary outcome [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19-0.64; P = 0.0005 and HR 0.36; 95% CI 0.19-0.68; P = 0.001] than observed in the other groups (interaction P = 0.02)., Conclusions: Our results serve as a proof-of-concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Aims: Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in cardiovascular (CV) and non-CV diseases. We evaluated the association of GDF-15 with CV and non-CV outcomes in the PARADIGM-HF trial., Methods and Results: In 1935 patients with heart failure and reduced ejection fraction (HFrEF) in PARADIGM-HF, median GDF-15 values were elevated and similar in sacubitril/valsartan and enalapril patients (1626 ng/L and 1690 ng/L, respectively). Diabetes, age, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class III/IV were most strongly associated with elevated GDF-15 values (all P < 0.001) (adjusted R 2 = 0.3857). Baseline GDF-15 and changes in GDF-15 at both 1 month and 8 months (log-transformed) were associated with subsequent mortality and CV events. Each 20% increment in baseline GDF-15 value was associated with a higher risk of mortality [adjusted hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.08-1.18, P < 0.001], the combined endpoint of CV death or hospitalization for heart failure (adjusted HR 1.09, 95% CI 1.05-1.14, P < 0.001) and heart failure death (adjusted HR 1.16, 95% CI 1.05-1.28, P < 0.001). Changes in GDF-15 were not influenced by assigned therapy (all P-values ≥ 0.1)., Conclusion: In patients with ambulatory HFrEF, GDF-15 is not modified by sacubitril/valsartan and is strongly associated with mortality and CV outcomes, suggesting that GDF-15 is a marker of poor outcomes in these patients., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01035255., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Aims: The impact of frailty on outcomes in randomized heart failure with preserved ejection fraction (HFpEF) trials has not been previously reported. This analysis sought to characterize frailty in a large contemporary HFpEF clinical trial cohort and to evaluate its impact on patient relevant outcomes., Methods and Results: Using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, a frailty index (FI) was constructed at baseline using 39 clinical, laboratory, and self-reported variables. The relationship between frailty and outcomes and the role of frailty in modulating the benefits of spironolactone were examined in a subset of 1767 TOPCAT patients. For the cohort as a whole (mean age 71.5 years, 49% female), the mean FI at baseline was 0.37 ± 0.11. Four frailty classes were defined ranging from FI < 0.3 to FI ≥ 0.5. Overall, 94% of subjects were considered frail (defined as a FI > 0.21). Mean age was lowest for the most frail class (69 ± 9 years for Class 4; 73 ± 10 years for Class 1; P < 0.001). Body mass index, systolic blood pressure, and pulse pressure all increased as FI increased. Both primary and secondary outcomes increased as frailty severity increased. There was no interaction between frailty class and treatment effect of spironolactone., Conclusions: Frailty was very common in TOPCAT HFpEF participants. Greater frailty was associated with a higher risk of cardiovascular outcomes and mortality. The benefit of spironolactone on outcomes in TOPCAT was not attenuated by frailty class., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Aims: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%]., Methods and Results: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient-years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79-1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%., Conclusion: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Aims: Systolic time intervals change in the progress of cardiac dysfunction. The usefulness of left ventricular ejection time (LVET) to predict cardiovascular morbidity, however, is unknown., Methods and Results: We studied middle-aged African-Americans from one of four cohorts of the Atherosclerosis Risk in Communities study (Jackson cohort, n=1980) who underwent echocardiography between 1993 and 1995. Left ventricular ejection time was measured by pulsed-wave Doppler of the left ventricular outflow tract and related to outcomes. A shorter LVET was associated with younger age, male sex, higher diastolic blood pressure, higher proportion of diabetes, higher heart rate, higher blood glucose levels and worse fractional shortening. During a median follow-up of 17.6 years, 384 (19%) had incident heart failure (HF), 158 (8%) had a myocardial infarction, and 587 (30%) died. In univariable analysis, a lower LVET was significantly associated with increased risk of all events (P<0.05 for all). However, after multivariable adjustment for age, sex, hypertension, diabetes, body mass index, heart rate, systolic and diastolic blood pressure, fractional shortening and left atrial diameter, LVET remained an independent predictor only of incident HF [hazard ratio 1.07 (1.02-1.14), P=0.010 per 10 ms decrease]. In addition, LVET provided incremental prognostic information to the known risk factors included in the Framingham risk score, in regard to predicting all outcomes except for myocardial infarction., Conclusion: Left ventricular ejection time is an independent predictor of incident HF in a community-based cohort and provides incremental prognostic information on the risk of future HF and death when added to known risk prediction models., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up., Methods: We defined the region-specific incidence of hypokalemia (potassium [K + ] <3.5 mmol/l) and hyperkalemia (K +  ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K + abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas., Results: In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K + , diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K + , younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models., Conclusions: Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K + and creatinine, particularly in high-risk groups., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Recent guidelines have advocated for stricter systolic blood pressure (SBP) control in heart failure with preserved ejection fraction (HFpEF), though data regarding the optimal SBP in HFpEF are sparse., Methods and Results: We analysed participants from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study with available baseline and 8-week visit SBP data (n = 1645). We related baseline SBP to several efficacy and safety outcomes. To determine whether blood pressure lowering was responsible for the potential beneficial effects of spironolactone observed in the Americas, we assessed the randomized treatment adjusting for baseline and change in 8-week SBP. The average age was 71.7 ± 9.7 years, 50% were women, and 79% were White. Patients in the lowest baseline SBP quartile were less often female, more often White, had lower body mass index, lower baseline diastolic blood pressure and pulse pressure, and more often had atrial fibrillation. After multivariable adjustment, there was no relationship observed between baseline SBP quartiles and any outcome. Spironolactone reduced SBP by 4.4 ± 0.6 mmHg compared with placebo (and consistently across baseline SBP quartiles). There was minimal change in the treatment effect for all outcomes after adjusting for baseline SBP and 8-week change in SBP., Conclusion: No relationship was observed between baseline SBP quartiles and outcomes in TOPCAT. The anti-hypertensive effects of spironolactone did not account for the potential benefit in cardiovascular outcomes in the Americas., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Black patients have been shown to have different baseline characteristics and outcomes compared with nonblack patients in cohort studies. However, few studies have focused on heart failure (HF) with preserved ejection fraction (HFpEF) patients. We aimed to determine the difference in cardiovascular outcomes in black and nonblack patients with HFpEF and to determine the relative efficacy and safety of spironolactone in black and nonblack patients., Methods and Results: Patients with HFpEF, randomized to spironolactone versus placebo in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in North and South America, were grouped according to self-described black and nonblack race. Black HFpEF patients (n=302) were younger and were more likely to have diabetes mellitus and hypertension than nonblack patients but had similar HFpEF severity. Black patients had higher risk for the primary outcome (hazard ratio [HR], 1.34; 95% confidence interval, 1.06-1.71; P =0.02) and first HF hospitalization (HR, 1.51; 95% confidence interval, 1.167-1.97; P =0.002)], but no significant difference in cardiovascular mortality risk (HR, 0.78; 95% confidence interval, 0.51-1.20; P =0.326). In black and nonblack patients, randomization to spironolactone conferred similar efficacy in the primary outcome (HR, 0.83 versus 0.79; P for interaction=0.49), HF hospitalization (HR, 0.67 versus 0.82; P for interaction=0.76), and cardiovascular mortality ( P for interaction=0.19). The risk of hyperkalemia and worsening renal function with spironolactone and study drug adherence were also similar., Conclusions: Black patients with HFpEF have a higher HF hospitalization risk than nonblack patients, but spironolactone is similarly effective and safe in both groups., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2018 American Heart Association, Inc.)

Aims: Patients with heart failure (HF) often have multiple co-morbidities that contribute to the risk of adverse cardiovascular (CV) and non-CV outcomes. We assessed the relative contribution of cardiac and extra-cardiac disease burden and demographic factors to CV outcomes in HF patients with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF)., Methods and Results: We utilized data from the CHARM trial, which enrolled HF patients across the ejection fraction spectrum. We decomposed the previously validated MAGGIC risk score into cardiac (LVEF, New York Heart Association class, systolic blood pressure, time since HF diagnosis, HF medication use), extra-cardiac (body mass index, creatinine, diabetes mellitus, chronic obstructive pulmonary disease, smoker), and demographic (age, gender) categories, and calculated subscores for each patient representing the burden of each component. Cox proportional hazards models were used to estimate the population attributable risk (PAR) associated with each component to the outcomes of death, CV death, HF, myocardial infarction, and stroke relative to patients with the lowest risk score. PARs for each component were depicted across the spectrum of LVEF. in 2675 chronic HF patients from North America [HFrEF (LVEF ≤40%): n = 1589, HFpEF (LVEF >40%): n = 1086] with data available for calculation of the MAGGIC score, the highest risk of death and CV death was attributed to cardiac burden. This was especially evident in HFrEF patients (PAR: 76% cardiac disease vs. 58% extra-cardiac disease, P < 0.05). Conversely, in HFpEF patients, extra-cardiac burden accounted for a greater proportion of risk for death than cardiac burden (PAR: 15% cardiac disease vs. 49% extra-cardiac disease, P < 0.05). For HF hospitalization, the contribution of both cardiac and extra-cardiac burden was comparable in HFpEF patients (PAR: 42% cardiac disease vs. 53% extra-cardiac disease, P = NS). In addition, demographic burden was especially high in HFpEF patients, with 62% of deaths attributable to demographic characteristics., Conclusion: In North American HF patients enrolled in the CHARM trials, the relative contribution of cardiac and extra-cardiac disease burden to CV outcomes and death differed depending on LVEF. The high risk of events attributable to non-cardiac disease burden may help explain why cardiac disease-modifying medication proven to be efficacious in HFrEF patients has not proven beneficial in HFpEF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Objectives: The aim of this study was to examine the relationship between baseline heart rate (HR), change in HR from a preceding visit, and time-updated HR with subsequent outcomes in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial., Background: Higher resting HR and increase in HR over time in patients with heart failure are associated with adverse outcomes. Whether these relationships between HR and prognosis are also observed in patients with HFpEF requires further assessment., Methods: In 1,767 patients enrolled in the TOPCAT trial from the Americas, the associations between baseline resting HR and change in HR from the preceding visit and clinical outcomes were examined using Cox proportional hazards models, along with the association between HR at each visit and outcome., Results: Both baseline HR (adjusted hazard ratio: 1.08; 95% confidence interval: 1.04 to 1.12) and change in HR from the preceding visit (adjusted hazard ratio: 1.09; 95% confidence interval: 1.05 to 1.14; p < 0.001 per 5 beats/min higher HR), after adjusting for covariates, were associated with a higher risk for the primary endpoint of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Time-updated resting HR at each visit was also associated with risk (adjusted hazard ratio: 1.11; 95% confidence interval: 1.07 to 1.15; p < 0.001 per 5 beats/min higher HR). Furthermore, a rise in resting HR of approximately 10 beats/min, beginning approximately 10 days prior to the primary endpoint, was observed., Conclusions: Baseline resting HR and change in HR over time predict outcomes in patients with HFpEF, as does time-updated HR during follow-up. These data suggest that frequent outpatient monitoring of HR, possibly with remote technologies, may identify patients with HFpEF who may be at increased risk for rehospitalization or death., (Copyright © 2017 American College of Cardiology Foundation. All rights reserved.)

Background: This study aimed to compare the independent and incremental prognostic value of peak oxygen consumption (VO 2 ) and minute ventilation/carbon dioxide production (VE/VCO 2 ) in heart failure (HF) with preserved (HFpEF), midrange (HFmEF), and reduced (HFrEF) ejection fraction (LVEF)., Methods and Results: In 195 HFpEF (LVEF ≥50%), 144 HFmEF (LVEF 40-49%), and 630 HFrEF (LVEF <40%) patients, we assessed the association of cardiopulmonary exercise testing variables with the composite outcome of death, left ventricular assist device implantation, or heart transplantation (256 events; median follow-up of 4.2 years), and 2-year incident HF hospitalization (244 events). In multivariable Cox regression analysis, greater association with outcomes in HFpEF than HFrEF were noted with peak VO 2 (HR [95% confidence interval]: 0.76 [0.67-0.87] versus 0.87 [0.83-0.90] for the composite outcome, P interaction =0.052; 0.77 [0.69-0.86] versus 0.92 [0.88-0.95], respectively for HF hospitalization, P interaction =0.003) and VE/VCO 2 slope (1.11 [1.06-1.17] versus 1.04 [1.03-1.06], respectively for the composite outcome, P interaction =0.012; 1.10 [1.05-1.15] versus 1.04 [1.03-1.06], respectively for HF hospitalization, P interaction =0.019). In HFmEF, peak VO 2 and VE/VCO 2 slope were associated with the composite outcome (0.79 [0.70-0.90] and 1.12 [1.05-1.19], respectively), while only peak VO 2 was related to HF hospitalization (0.81 [0.72-0.92]). In HFpEF and HFrEF, peak VO 2 and VE/VCO 2 slope provided incremental prognostic value beyond clinical variables based on the C-statistic, net reclassification improvement, and integrated diagnostic improvement, with models containing both measures demonstrating the greatest incremental value., Conclusions: Both peak VO 2 and VE/VCO 2 slope provided incremental value beyond clinical characteristics and LVEF for predicting outcomes in HFpEF. Cardiopulmonary exercise testing variables provided greater risk discrimination in HFpEF than HFrEF., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized., Methods: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models., Results: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28-3.28; HR, 1.95; 95% CI, 1.15-3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16-3.22; HR, 1.84; 95% CI, 1.02-3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37-13.83; HR, 4.05; 95% CI, 1.17-14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44-6.02; HR, 2.05; 95% CI, 0.90-4.67) after multivariable adjustment for potential confounders., Conclusions: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302., (© 2017 American Heart Association, Inc.)

Aims: Left ventricular mechanical dyssynchrony has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic significance is not known., Methods and Results: Of 3445 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, dyssynchrony analysis was performed on 424 patients (12%) by multiple speckle tracking echocardiography strain-based criteria. The primary dyssynchrony analysis was the standard deviation of the time to peak longitudinal strain (SD T2P LS). Cox proportional hazards models assessed the association of dyssynchrony with the composite outcome of cardiovascular death or heart failure hospitalization. Mean age was 70 ± 10 years, LVEF was 60 ± 8%, and QRS duration was 101 ± 27 ms. Worse dyssynchrony, reflected in SD T2P LS, was associated with wider QRS, prior myocardial infarction, larger LV volume and mass, and worse systolic (lower LVEF and global longitudinal strain) and diastolic (lower e' and higher E/e') function. During a median follow-up of 2.6 (interquartile range 1.5-3.8) years, 107 patients experienced the composite outcome. Worse dyssynchrony was associated with the composite outcome in unadjusted analysis [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01-1.07; P = 0.021, per 10 ms increase], but not after adjusting for clinical characteristics, or after further adjustment for LVEF, AF, NYHA class, stroke, heart rate, creatinine, haematocrit, and QRS duration (HR 1.03, 95% CI 0.99-1.06; P = 0.16, per 10 ms increase)., Conclusion: Worse LV mechanical dyssynchrony, assessed by speckle tracking echocardiography, is not an independent predictor of adverse outcomes in HFpEF, suggesting that mechanical dyssynchrony is unlikely to be an important mechanism underlying this syndrome. These findings warrant validation in an independent study specifically designed to assess the prognostic utility of mechanical dyssynchrony in HFpEF., Trial Registration: NCT00094302., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Left ventricular dysfunction is a known predictor of ventricular arrhythmias. We hypothesized that measures of regional longitudinal deformation by speckle-tracking echocardiography predict ventricular tachyarrhythmias and provide incremental prognostic information over clinical and conventional echocardiographic characteristics., Methods and Results: We studied 1064 patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior, and inferior myocardial walls at baseline. The end point was the first event of ventricular tachycardia (VT) or fibrillation (VF). During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower left ventricular ejection fraction (28.3% versus 29.5%; P<0.001) and longitudinal strain in all myocardial walls compared with patients without VT/VF (anterior-strain, -7.7% versus -8.8%; P<0.001; lateral-strain, -7.3% versus -7.9%; P=0.022; inferior-strain, -8.3% versus -9.9%; P<0.001; septal-strain, -9.1% versus -10.0%; P<0.001). After multivariate adjustment, only anterior and inferior longitudinal strain remained independent predictors of VT/VF (anterior: hazard ratio, 1.08 [1.03-1.13]; P=0.001; inferior: hazard ratio, 1.08 [1.04-1.12]; P<0.001; per 1% absolute decrease for both). When including B-type natriuretic peptide in the model, only a decreasing myocardial function in the inferior myocardial wall predicted VT/VF (hazard ratio, 1.05 [1.00-1.11]; P=0.039). Only strain obtained from the inferior myocardial wall provided incremental prognostic information for VT/VF over clinical and echocardiographic parameters (C statistic 0.71 versus 0.69; P=0.005)., Conclusions: Assessment of regional longitudinal myocardial deformation in the inferior region provided incremental prognostic information over clinical and echocardiographic risk factors in predicting ventricular tachyarrhythmias., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271., (© 2016 American Heart Association, Inc.)

Background: Atrial fibrillation (AF) is associated with increased risk for thromboembolism and death; however, the relationships between cardiac structure and function and adverse outcomes among individuals with AF are incompletely understood., Methods: The Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 study tested the once-daily oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke (ischemic or hemorrhagic) or systemic embolism in 21,105 subjects with nonvalvular AF and increased risk for thromboembolic events (CHADS2 score ≥ 2). In a prospective substudy of 971 subjects who underwent transthoracic echocardiography at baseline, Cox proportional hazards models were used to evaluate associations between cardiac structure and function and the risks for death and thromboembolism (ischemic stroke, transient ischemic attack, or systemic embolism)., Results: Over a median follow-up period of 2.5 years, 89 deaths (9.2%) and 48 incident thromboembolic events (4.9%) occurred in 971 subjects. In models adjusted for CHADS2 score, aspirin use, and randomized treatment, larger left ventricular (LV) end-diastolic volume index (hazard ratio per 1 SD [12.9 mL/m(2)], 1.49; 95% CI, 1.16-1.91) and higher LV filling pressures measured by E/e' ratio (hazard ratio per 1 SD [4.6], 1.32; 95% CI, 1.08-1.61) were independently associated with increased risks for death. E/e' ratio > 13 significantly improved the prediction of death beyond clinical factors alone. No features of cardiac structure and function were independently associated with thromboembolism in this population. Findings were similar when adjusted for CHA2DS2-VASc score in place of CHADS2 score., Conclusions: In a contemporary population of patients with AF at increased risk for thromboembolic events, larger LV size and higher filling pressures were significantly associated with increased risk for death, but neither left atrial nor LV measures were associated with thromboembolic risk. LV size and filling pressures may help identify patients with AF at increased risk for death., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Left atrial (LA) size is an established marker of risk for adverse outcomes in heart failure with preserved ejection fraction (HFpEF). However, the independent prognostic importance of LA function in HFpEF is not known., Methods and Results: We assessed LA function measured by speckle-tracking echocardiography in 357 patients with HFpEF enrolled in the Treatment Of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial who were in sinus rhythm at the time of echocardiography. Lower peak LA strain, indicating LA dysfunction, was associated with older age, higher prevalence of atrial fibrillation and left ventricular (LV) hypertrophy, worse LV and right ventricular systolic function, and worse LV diastolic function. At a mean follow-up of 31 months (interquartile range, 18-43months), 91 patients (25.5%) experienced the primary composite end point of cardiovascular death, HF hospitalization, and aborted sudden death. Lower peak LA strain was associated with a higher risk of the composite end point (hazard ratio, 0.96 per unit of reduction in strain; 95% confidence interval, 0.94-0.99; P=0.009) and of HF hospitalization alone (hazard ratio, 0.95 per unit of reduction in strain; 95% confidence interval, 0.92-0.98; P=0.003). The association of LA strain with incident HF hospitalization remained significant after adjustment for clinical confounders, but not after further adjustment for LV global longitudinal strain and the E/E' ratio, parameters of LV systolic and diastolic function, respectively., Conclusions: LA dysfunction in HFpEF is associated with a higher risk of HF hospitalization independent of potential clinical confounders, but not independent of LV strain and filling pressure. Impairment in LV systolic and diastolic function largely explains the association between impaired LA function and higher risk of HF hospitalization in HFpEF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2016 American Heart Association, Inc.)

Background: The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril., Methods and Results: Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95)., Conclusions: In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2016 American Heart Association, Inc.)

Background: Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL., Methods and Results: Patients ≥50 years of age, with symptomatic HF and left ventricular ejection fraction ≥45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change scores. Paired KCCQ data were available for 91.7% of 3445 TOPCAT patients. By 4 months, the mean change in KCCQ was 7.7±16 and mean change in EQ5D visual analog scale was 4.7±16. Adjusted mean changes in KCCQ for the spironolactone group were significantly better than those for the placebo group at 4-month (1.54 better; P=0.002), 12-month (1.35 better; P=0.02), and 36-month (1.86 better; P=0.02) visits. No between-group differences in EQ5D visual analog scale change scores or McMaster Overall Treatment Evaluation were noted. Older age, obesity, current smoking, New York Heart Association class III/IV, and comorbid illnesses were associated with declines in KCCQ scores. Use of spironolactone was an independent predictor of improved KCCQ scores., Conclusions: In symptomatic HF with preserved ejection fraction patients, use of spironolactone was associated with an improvement in HF-specific HRQL. Several modifiable risk factors were associated with HRQL deterioration., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2016 American Heart Association, Inc.)

Background: Impairment in left ventricular systolic function has been described in heart failure (HF) with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether left ventricular longitudinal strain (LS) is predictive of cardiovascular outcomes in HFpEF beyond clinical and conventional echocardiographic measures., Methods and Results: LS was assessed by 2-dimensional speckle-tracking echocardiography at baseline in 447 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 years (interquartile range, 1.5-3.9 years), 115 patients experienced the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Impaired LS, defined as an absolute LS <15.8%, was present in 52% of patients and was predictive of the composite outcome (adjusted hazard ratio, 2.14; 95% confidence interval, 1.26-3.66; P=0.005), cardiovascular death alone (adjusted hazard ratio, 3.20; 95% confidence interval, 1.44-7.12; P=0.004), and HF hospitalization alone (adjusted hazard ratio, 2.23; 95% confidence interval, 1.16-4.28; P=0.016) after adjustment for clinical and conventional echocardiographic variables. LS was the strongest echocardiographic predictor of the composite outcome. Exploratory analysis in a subset of 131 patients with follow-up LS assessed after 12 to 18 months demonstrated a trend toward improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia., Conclusions: Impaired left ventricular systolic function is a powerful predictor of HF hospitalization, cardiovascular death, or aborted cardiac arrest in HFpEF independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify patients with HFpEF at particularly high risk for cardiovascular morbidity and mortality., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2015 American Heart Association, Inc.)

Background: Increases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed., Methods and Results: A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016)., Conclusion: In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas)., Methods and Results: To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone., Conclusions: This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2014 American Heart Association, Inc.)

Aims: Left atrial (LA) enlargement is present in the majority of heart failure with preserved ejection fraction (HFpEF) patients and is a marker of risk. However, the importance of LA function in HFpEF is less well understood., Methods and Results: The PARAMOUNT trial enrolled HFpEF patients (LVEF ≥45%, NT-proBNP >400 pg/mL). We assessed LA reservoir, conduit, and pump function using two-dimensional volume indices and speckle tracking echocardiography in 135 HFpEF patients in sinus rhythm at the time of echocardiography and 40 healthy controls of similar age and gender. Systolic LA strain was related to clinical characteristics and measures of cardiac structure and function. Compared with controls, HFpEF patients had worse LA reservoir, conduit, and pump function. The differences in systolic LA strain (controls 39.2 ± 6.6% vs. HFpEF 24.6 ± 7.3%) between groups remained significant after adjustments and even in the subsets of HFpEF patients with normal LA size or without a history of AF. Among HFpEF patients, lower systolic LA strain was associated with higher prevalence of prior HF hospitalization and history of AF, as well as worse LV systolic function, and higher LV mass and LA volume. However, NT-proBNP and E/E' were similar across the quartiles of LA function., Conclusions: In this HFpEF cohort, we observed impairment in all phases of LA function, and systolic LA strain was decreased independent of LA size or history of AF. LA dysfunction may be a marker of severity and play a pathophysiological role in HFpEF., Trial Registration: NCT00887588., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality., Methods and Results: Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16-2.00), elevated left ventricular filling pressure (E/E'; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02-1.07), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02-1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E'., Conclusions: Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2014 American Heart Association, Inc.)

Background: Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between previous HF hospitalization and randomization in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) trials on clinical outcomes in patients with both reduced and preserved ejection fraction., Methods and Results: CHARM enrolled 7599 patients with New York Heart Association class II to IV HF, of whom 5426 had a history of previous HF hospitalization. Cox proportional hazards regression models were used to assess the association between time from previous HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF during a median of 36.6 months. For patients with HF and reduced or preserved ejection fraction, rates of cardiovascular mortality and HF hospitalization were higher among patients with previous HF hospitalization than those without. The risk for mortality and hospitalization varied inversely with the time interval between hospitalization and randomization. Rates were higher for patients with HF and reduced ejection fraction within each category. Event rates for those with HF with preserved ejection fraction and a HF hospitalization in the 6 months before randomization were comparable with the rate in patients with HF and reduced ejection fraction with no previous HF hospitalization., Conclusions: Rates of cardiovascular death or HF hospitalization are greatest in those who have been previously hospitalized for HF. Independent of EF, rates of death and readmission decline as time from HF hospitalization to trial enrollment increased. Recent HF hospitalization identifies a high-risk population for future clinical trials in HF and reduced ejection fraction and HF with preserved ejection fraction., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00634400., (© 2014 American Heart Association, Inc.)

Objectives: This study sought to determine the frequency and magnitude of impaired systolic deformation in heart failure with preserved ejection fraction (HFpEF)., Background: Although diastolic dysfunction is widely considered a key pathophysiologic mediator of HFpEF, the prevalence of concomitant systolic dysfunction has not been clearly defined., Methods: We assessed myocardial systolic and diastolic function in 219 HFpEF patients from a contemporary HFpEF clinical trial. Myocardial deformation was assessed using a vendor-independent 2-dimensional speckle-tracking software. The frequency and severity of impaired deformation was assessed in HFpEF, and compared to 50 normal controls free of cardiovascular disease and to 44 age- and sex-matched hypertensive patients with diastolic dysfunction (hypertensive heart disease) but no HF. Among HFpEF patients, clinical, echocardiographic, and biomarker correlates of left ventricular strain were determined., Results: The HFpEF patients had preserved left ventricular ejection fraction and evidence of diastolic dysfunction. Compared to both normal controls and hypertensive heart disease patients, the HFpEF patients demonstrated significantly lower longitudinal strain (LS) (-20.0 ± 2.1 and -17.07 ± 2.04 vs. -14.6 ± 3.3, respectively, p < 0.0001 for both) and circumferential strain (CS) (-27.1 ± 3.1 and -30.1 ± 3.5 vs. -22.9 ± 5.9, respectively; p < 0.0001 for both). In HFpEF, both LS and CS were related to LVEF (LS, R = -0.46; p < 0.0001; CS, R = -0.51; p < 0.0001) but not to standard echocardiographic measures of diastolic function (E' or E/E'). Lower LS was modestly associated with higher NT-proBNP, even after adjustment for 10 baseline covariates including LVEF, measures of diastolic function, and LV filling pressure (multivariable adjusted p = 0.001)., Conclusions: Strain imaging detects impaired systolic function despite preserved global LVEF in HFpEF that may contribute to the pathophysiology of the HFpEF syndrome. (LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction; NCT00887588)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)