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Background: Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and has few treatments. The molecular mechanisms and resultant signaling pathways that underlie the development of HFpEF are poorly defined. It has been proposed that activation of proinflammatory pathways plays a role in the development of cardiac fibrosis. The signature of gene expression (transcriptome) of previously validated left ventricular biopsies obtained from patients with HFpEF and matched referent controls allows for an unbiased assessment of proinflammatory and profibrotic signaling pathways and genes., Methods: Epicardial left ventricular biopsies from stringently selected HFpEF patients (HFpEF, n=16) and referent control patients (CTR, n=14) were obtained during aortocoronary bypass surgery. The subepicardial myocardium was flash-frozen to build a repository that was parallel-processed for RNA sequencing to allow for an unsupervised in-depth comparison of the left ventricular transcriptome., Results: The average patient age was 67±10 years. When compared with controls, patients with HFpEF were hypertensive with a higher body mass index (kg/m 2 : 30±5 versus 37±6; P <0.01) and elevated NT-proBNP levels (pg/mL: 155 [89-328] versus 1554 [888-2178]; P <0.001). The transcriptome analysis revealed differential expression of 477 genes many of which were involved in profibrotic pathways including extracellular matrix production and posttranslational modification but no proinflammatory signature., Conclusions: The transcriptome analysis of left ventricular myocardial samples from patients with HFpEF confirms an overabundant extracellular matrix gene expression, the basis of myocardial fibrosis, without a signature of activated proinflammatory pathways or genes., Competing Interests: Disclosures None.

Background: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients., Methods: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level., Results: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17-2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06-4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68-0.91) and a simple score could be created from the model., Conclusions: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT00095238 and NCT01920711., Competing Interests: Disclosures Dr Kondo received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, and Abiomed. Dr Jering is supported by National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604. Dr Jhund’s employer the University of Glasgow has been remunerated by AstraZeneca, personal fees from Novartis and Cytokinetics, and grants from Boehringer Ingelheim. 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 Desai has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Maggioni has received fees for serving on a study committee from Bayer, Novartis, and Fresenius. Dr Martinez has received research grants or honoraria from Novartis, AstraZeneca, Bayer, Pfizer, Bristol Myers Squibb, Gador, Baliarda, and Boehringer Ingelheim. Dr Packer reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. M.C. Petrie is supported by the British Heart Foundation (BHF) Center of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217þ); has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served as a consultant and on Clinical Trials Committees for Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Siemens, and Takeda. Dr Pfeffer reports research grant support through Brigham and Women’s Hospital from Novartis; and consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute (NHLBI) CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. Dr Rouleau reports grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. Dr van Veldhuisen has received fees for serving on a steering committee and travel support from ARCA Biopharma and Corvia Medical. Dr Zannad has served on the advisory board/steering committee/executive committee for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, Ceva Santé Animale, CVRx, GE Healthcare, Janssen, KBP biosciences, LivaNova, Novartis, Novo Nordisk, Merck, Mundipharma, Quantum Genomics, Relypsa, Roche, Vifor Fresenius; and is cofounder of CardioRenal, CardioVascular Clinical Trialists, and Eshmoun. Dr Zile reports research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR Systems Inc, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, DalCor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos and personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP).

Background: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides., Methods: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death., Results: Compared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline ( P interaction =0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes ( P interaction ≥0.31)., Conclusions: In patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio., Registration: URL: https://www., Clinicaltrials: gov; Unique Identifier: NCT01035255.

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial., Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region., Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P >0.05)., Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Background: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)., Methods: Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction ≤40%, and elevated natriuretic peptides: BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (for patients with HF hospitalization within 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate <30 mL/min per 1.73 m 2 was a key exclusion criterion., Results: The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217-4003) and BNP 318 (Q1, Q3: 207-559), and the ratio, calculated from the raw data, was ≈6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33-1.49) per 1 SD increase, P <0.0001; NT-proBNP, 1.45 (1.36-1.54); P <0.0001., Conclusions: The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction.

Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction., Methods: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial)., Results: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73-0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62-0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82-1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43-0.65]; P <0.001). E/A ratio was lower in women (1.1 versus 1.2)., Conclusions: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and preserved ejection fraction, with and without atrial fibrillation (AF). Methods and Results Among 3835 HF with preserved ejection fraction patients enrolled in the I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function trial) or TOPCAT trial (Treatment of Preserved Cardiac Function in Heart Failure With an Aldosterone Antagonist), 719 (19%) patients had AF on their baseline ECG. Median (Q1-Q3) levels of NT-proBNP were 1286 pg/mL (778-2072) in those with AF and 288 pg/mL (122-704) in those without ( P<0.001). We analyzed patients using 4 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, and ≥2000 pg/mL. The event rates for the primary composite outcome of cardiovascular death or HF hospitalization were higher in patients with AF versus patients without or those without without AF in the lowest NT-proBNP band (<400 pg/mL; 8.0 versus 3.2 per 100 patient-years), whereas for the higher bands the opposite was true (1000-1999 pg/mL; 11.4 versus 13.2 per 100 patient-years and ≥2000 pg/mL; 17.4 versus 25.6 per 100 patient-years). In adjusted analyses, higher NT-proBNP levels were less predictive of HF hospitalization than mortality in patients with AF compared with those without. Conclusions Event rates in HF with preserved ejection fraction patients without AF and with NT-proBNP <400 pg/mL are low. Among patients with NT-proBNP ≥400 pg/mL, the relationship between NT-proBNP and outcomes differs with lower absolute risk in patients who have AF compared with those who do not have AF. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00094302 and NCT00095238.

Background: Increased activity of IGFBP7 (insulin-like growth factor-binding protein-7) is associated with cellular senescence, tissue aging, and obesity. IGFBP7 may be related to heart failure with preserved ejection fraction, a disease of elderly obese people., Methods and Results: In a subset of patients with heart failure with preserved ejection fraction (N=228) randomized to receive sacubitril/valsartan versus valsartan, IGFBP7 concentrations were measured at baseline, 12 weeks, and 36 weeks. Patient characteristics and echocardiographic measures including left atrial (LA) size and volume, ratio of early mitral inflow velocity/annular diastolic velocity, and ratio of early diastole/peak late diastolic velocity were assessed as a function of IGFBP7 concentration. Effect of sacubitril/valsartan on IGFBP7 concentrations was analyzed. With increasing baseline IGFBP7 quartiles, LA size and LA volume index (LAVi) were higher (both P<0.001); modest association between IGFBP7 and higher early mitral inflow velocity/annular diastolic velocity ( P=0.03) and early diastole/peak late diastolic velocity ratio ( P=0.04) was also seen. IGFBP7 concentrations were higher in those with LAVi ≥34 mL/m 2 compared with lower LAVi at all time points (all P<0.01). IGFBP7 independently predicted LAVi at baseline even in the presence of NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentrations; highest LAVi was seen in those with elevation in both biomarkers. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations over 36 weeks compared with valsartan (adjusted treatment effect, -7%; P<0.001)., Conclusions: Among patients with heart failure with preserved ejection fraction, concentrations of the cellular senescence biomarker IGFBP7 were associated with abnormalities in diastolic filling and LA dilation. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations compared with valsartan., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00887588.

Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality., Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease., Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711., (© 2018 American Heart Association, Inc.)

Background: Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined., Methods and Results: Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes ( P =0.001, 0.012, and 0.009 for the 3 outcomes, respectively)., Conclusions: Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2018 American Heart Association, Inc.)

Background: In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients., Methods and Results: We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan ( P <0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events ( P interaction>0.90)., Conclusions: Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension., (© 2018 American Heart Association, Inc.)

Background: Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction caused by Chagas' disease, with other etiologies, in the era of modern HF therapies., Methods and Results: This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94; P =0.003) and Chagasic versus ischemic: 1.55 (1.18-2.04; P =0.002). The rates of all-cause mortality were also higher., Conclusions: Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies., Clinical Trial Registration: PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658., (© 2017 American Heart Association, Inc.)

Background: Patients with heart failure (HF) and atrial fibrillation (AF) have higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) than HF patients without AF. There is uncertainty about the prognostic importance of a given concentration of NT-proBNP in HF patients with and without AF. We investigated this question in a large cohort of patients with HF and reduced ejection fraction., Methods and Results: We studied 14 737 patients with HF and reduced ejection fraction and a measurement of NT-proBNP at time of screening, enrolled in either the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) or the ATMOSPHERE trial (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure), of whom 3575 (24%) had AF on their baseline ECG. Median (Q1, Q3) levels of NT-proBNP were 1817 pg/mL (1095-3266 pg/mL) in those with AF and 1271 pg/mL (703-2569 pg/mL) in those without ( P <0.0001). Patients with AF were older (67 versus 62 years), had worse New York Heart Association class (III/IV; 36% versus 24%), and experienced fewer previous HF hospitalizations (52% versus 61%) or myocardial infarction (30% versus 46%); all P <0.001. We categorized patients with and without AF into 5 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, 2000 to 2999, and ≥3000 pg/mL. For the primary composite outcome of cardiovascular death or HF hospitalization, event rates differed for patients with and without AF in the lowest band (<400 pg/mL; 8.2 versus 5.0 per 100 patient-years), but not for the higher bands (400-999 pg/mL, 7.4 versus 7.7 per 100 patient-years; 1000-1999 pg/mL, 9.8 versus 11.4 per 100 patient-year; 2000-2999 pg/mL, 13.5 versus 13.4 per 100 patient-years; ≥3000 pg/mL, 22.7 versus 23.0 per 100 patient-years). These findings were consistent whether NT-proBNP was examined as a categorical or continuous variable and before and after adjustment for other prognostic variables. We found similar results for the components of the composite outcome and all-cause mortality., Conclusions: HF and reduced ejection fraction patients with AF had higher NT-proBNP than those without AF. However, above a concentration of 400 pg/mL (representing most patients in each group), NT-proBNP had similar predictive value for adverse cardiovascular outcomes, irrespective of AF status., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier NCT00853658 (ATMOSPHERE) and NCT01035255 (PARADIGM-HF)., (© 2017 American Heart Association, Inc.)

Background: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only., Methods and Results: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P =0.008) and KCCQ overall summary score (+1.13 versus -0.14; P <0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%; P =0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months., Conclusions: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2017 American Heart Association, Inc.)

Background: The purpose of this analysis was to examine whether implantable hemodynamic monitor-derived baseline estimated pulmonary artery diastolic pressure (ePAD) and change from baseline ePAD were independent predictors of all-cause mortality in patients with chronic heart failure., Methods and Results: Retrospective analysis used data from 3 studies (n=790 patients; 216 deaths). Baseline ePAD was related to mortality using a multivariable model including baseline and demographic data. Changes in ePAD defined as change from baseline to 6 months and from baseline to 14 days before death or exit from study were related to subsequent mortality, and analysis was adjusted for baseline ePAD. Area under the pressure versus time curve during 180 days before death or exit from study was related to mortality. Baseline ePAD, independent of other covariates, was a significant predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05-1.09; P<0.0001). Change in ePAD was an independent predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05-1.100; P=0.0008). Increased ePAD of 3, 4, or 5 mm Hg from baseline to 6 months was associated with increased mortality risk of 23.8%, 32.9%, or 42.8%. Change in ePAD from baseline to 14 days before death or exit from study was higher in patients who died (3.0±8 versus 1.7±10 mm Hg; P=0.003). Area under the pressure versus time curve in the final 180 days before death or exit from study was higher in patients who died versus those alive at end of study (185±668 versus 17±482 mm Hg.days; P=0.006)., Conclusions: Implantable hemodynamic monitor-derived baseline ePAD and change from baseline ePAD were independent predictors of mortality in chronic heart failure patients., (© 2017 American Heart Association, Inc.)

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

Background: In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitorenalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy., Methods and Results: We examined the effect of study treatment in the following subgroups: diuretics (yes/no), digitalis glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no),and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399)were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval,0.73-0.87;P<0.001) and for cardiovascular death was0.80 (0.71-0.89;P<0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death rangedfrom 0.75 to 0.89, with no treatment-by-subgroup interaction., Conclusions: The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previouscoronary revascularization or β-blocker dose., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2016 American Heart Association, Inc.)

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: Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction., Methods and Results: Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6-48.1] ng/mL) and galectin 3 (17.8 [14.1-22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5-230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3-6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E', and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time., Conclusions: In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588., (© 2016 American Heart Association, Inc.)

Background: The prevalence of pre-diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these 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: We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: < 6.0% [< 42 mmol/mol], 6.0%-6.4% [42-47 mmol/mol; pre-diabetes mellitus], and ≥ 6.5% [≥ 48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n = 2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52; P < 0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre-diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, > 6.5%) and known diabetes mellitus compared with those with HbA1c < 6.0% was 1.39 (1.17-1.64); P < 0.001 and 1.64 (1.43-1.87); P < 0.001, respectively. Patients with pre-diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10-1.47]; P < 0.001) compared with those with HbA1c < 6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial., Conclusions: In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre-diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c < 6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255., (© 2016 The Authors.)

Background: Intrathoracic impedance-derived OptiVol fluid index calculated using implanted devices has been shown to predict mortality; direct measurements of impedance have not been examined. We hypothesized that baseline measured impedance predicts all-cause mortality; changes in measured impedance result in a change in the predicted mortality; and the prognostic value of measured impedance is additive to the calculated OptiVol fluid index., Methods and Results: A retrospective analysis of 146,238 patients within the Medtronic CareLink database with implanted devices was performed. Baseline measured impedance was determined using daily values averaged from month 6 to 9 after implant and were used to divide patients into tertiles: group L = low impedance, ≤ 65 ohms; group M = medium impedance, 66 to 72 ohms; group H = high impedance, ≥ 73 ohms. Change in measured impedance was determined from values averaged from month 9 to 12 post implant compared with the 6- to 9-month values. OptiVol fluid index was calculated using published methods. All-cause mortality was assessed beginning 9 months post implant; changes in mortality was assessed beginning 12 months post implant. Baseline measured impedance predicted all-cause mortality; 5-year mortality for group L was 41%, M was 29%, and H was 25%, P < 0.001 among all groups. Changes in measured impedance resulted in a change in the predicted mortality; the prognostic value of measured impedance was additive to the OptiVol fluid index., Conclusions: Direct measurements of intrathoracic impedance using an implanted device can be used to stratify patients at varying mortality risk., (© 2015 American Heart Association, Inc.)

Background: MicroRNAs (miRNAs) and histone deacetylases (HDACs) serve a significant role in the pathogenesis of a variety of cardiovascular diseases. The transcriptional regulation of miRNAs is poorly understood in cardiac hypertrophy. We investigated whether the expression of miR-133a is epigenetically regulated by class I and IIb HDACs during hypertrophic remodeling., Methods and Results: Transverse aortic constriction (TAC) was performed in CD1 mice to induce pressure overload hypertrophy. Mice were treated with class I and IIb HDAC inhibitor (HDACi) via drinking water for 2 and 4 weeks post TAC. miRNA expression was determined by real-time polymerase chain reaction. Echocardiography was performed at baseline and post TAC end points for structural and functional assessment. Chromatin immunoprecipitation was used to identify HDACs and transcription factors associated with miR-133a promoter. miR-133a expression was downregulated by 0.7- and 0.5-fold at 2 and 4 weeks post TAC, respectively, when compared with vehicle control (P<0.05). HDAC inhibition prevented this significant decrease 2 weeks post TAC and maintained miR-133a expression near vehicle control levels, which coincided with (1) a decrease in connective tissue growth factor expression, (2) a reduction in cardiac fibrosis and left atrium diameter (marker of end-diastolic pressure), suggesting an improvement in diastolic function. Chromatin immunoprecipitation analysis revealed that HDAC1 and HDAC2 are present on the miR-133a enhancer regions., Conclusions: The results reveal that HDACs play a role in the regulation of pressure overload-induced miR-133a downregulation. This work is the first to provide insight into an epigenetic-miRNA regulatory pathway in pressure overload-induced cardiac fibrosis., (© 2015 American Heart Association, Inc.)

Background: The aim of our study was to investigate the relationship between coronary artery disease (CAD), angina, and clinical outcomes in patients with heart failure and preserved ejection fraction enrolled in the irbesartan in patients with heart failure and preserved systolic function (I-Preserve) trial., Methods and Results: The mean follow-up period for the 4128 patients enrolled in I-Preserve was 49.5 months. Patients were divided into 4 mutually exclusive groups according to history of CAD and angina: patients with no history of CAD or angina (n=2008), patients with no history of CAD but a history of angina (n=649), patients with a history of CAD but no angina (n=468), and patients with a history of CAD and angina (n=1003); patients with no known CAD or angina were the reference group. After adjustment for other prognostic variables using Cox proportional-hazard models, patients with CAD but no angina were found to be at higher risk of all-cause mortality (hazard ratio [HR], 1.58 [1.22-2.04]; P<0.01) and sudden death (HR, 2.12 [1.33-3.39]; P<0.01), compared with patients with no CAD or angina. Patients with CAD and angina were also at higher risk of all-cause mortality (HR, 1.29 [1.05-1.59]; P=0.02) and sudden death (HR, 1.83 [1.24-2.69]; P<0.01) compared with the same reference group and had the highest risk of unstable angina or myocardial infarction (HR, 5.84 [3.43-9.95]; P<0.01)., Conclusions: Patients with heart failure and preserved ejection fraction and CAD are at higher risk of all-cause mortality and sudden death when compared with those without CAD., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238., (© 2015 American Heart Association, Inc.)

Background: Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown., Methods and Results: Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients)., Conclusions: A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral., (© 2015 American Heart Association, Inc.)

Background: Characteristics and outcomes of patients with heart failure and reduced ejection fraction receiving care at Veterans Affairs (VA) versus non-VA hospitals have not been previously reported., Methods and Results: In the randomized controlled Beta-blocker Evaluation of Survival Trial (BEST; 1995-1999), of the 2707 (bucindolol=1353; placebo=1354) patients with heart failure and left ventricular ejection fraction ≤35%, 918 received care at VA hospitals, of which 98% (n=898) were male. Of the 1789 receiving care at non-VA hospitals, 68% (n=1216) were male. Our analyses were restricted to these 2114 male patients. VA patients were older with higher symptom and comorbidity burdens. There was no significant between-group difference in unadjusted primary end point of 2-year all-cause mortality (35% VA versus 32% non-VA; hazard ratio associated with VA hospitals, 1.09; 95% confidence interval, 0.94-1.26), which remained unchanged after adjustment for age and race (hazard ratio, 1.00; 95% confidence interval, 0.86-1.16) or multivariable adjustment, including cardiovascular morbidities (hazard ratio, 0.94; 95% confidence interval, 0.80-1.10). There was no between-group difference in cause-specific mortalities or hospitalizations. Chronic kidney disease, pulmonary edema, left ventricular ejection fraction <20%, and peripheral arterial disease were significant predictors of mortality for both groups. African America race, New York Heart Association class IV symptoms, atrial fibrillation, and right ventricular ejection fraction <20% were associated with higher mortality among non-VA hospital patients only; however, these differences from VA patients were not significant., Conclusions: Patients with heart failure and reduced ejection fraction receiving care at VA hospitals were older and sicker; yet their risk of mortality and hospitalization was similar to younger and healthier patients receiving care at non-VA hospitals., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00000560., (© 2014 American Heart Association, Inc.)

Background: Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction., Methods and Results: We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 μg/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P=0.05) and at 36 weeks (14% reduction; P=0.03) compared with valsartan., Conclusions: Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N-terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00887588., (© 2014 American Heart Association, Inc.)

Background: Atrial fibrillation (AFib) is common in heart failure (HF) with preserved ejection fraction (HFpEF). Current AFib stroke risk prediction models include the presence of HF but do not specifically include HFpEF as a risk factor. Whether a history of AFib should be used to identify patients with HFpEF who are at risk has not been established., Methods and Results: Baseline characteristics and outcomes of patients with HFpEF in the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial were analyzed in relation to AFib. At baseline, 1209 (29.3%) had a history of AFib. Of these 557 (13.5%) had history of AFib alone, whereas 670 (16.2%) had both a history and AFib on ECG; 2901 (70.3%) had neither. There were no significant differences in the risk of stroke between the 2 groups with a history of AFib who did or did not have AFib present on baseline ECG. During a median follow-up of 53 months, a fatal or nonfatal stroke occurred in 6.5% (79/1209) patients with history of AFib compared with 3.9% (114/2901) with no AFib. Having a history of AFib was independently associated with higher risk of stroke (hazard ratio, 2.2; 95% confidence interval, 1.6-3.2; P<0.0001) compared with those with no history of AFib., Conclusions: In patients with HFpEF, a history of AFib was common and independently associated with increased risk of stroke, regardless of whether AFib was present on ECG. Patients with HFpEF and a history of AFib should be considered at risk. Further studies are needed to determine whether this risk can be safely reduced., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT000095238., (© 2014 American Heart Association, Inc.)

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: Although matrix metalloproteinases (MMPs) were initially thought to result primarily in extracellular matrix degradation, certain MMP types, such as membrane type-1 (MT1) MMP, may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor-binding protein (LTBP-1) and activation of transforming growth factor-dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus., Methods and Results: Wild-type (WT) and transgenic mice with cardiac-restricted MT1-MMP overexpression or MT1-MMP reduced expression underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass/volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP-mediated LTBP-1 hydrolysis and a 190% increase in collagen content in WT mice. Although LV mass was similar among WT, MT1-MMP overexpression, and MT1-MMP reduced expression after PO, significant differences in LV function, MT1-MMP-mediated LTBP-1 hydrolysis, and collagen content occurred. PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and left atrial dimension (19%; indicative of LV diastolic dysfunction) when compared with WT. PO in MT1-MMP reduced expression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when compared with both WT., Conclusions: Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix-dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to PO.

Background: The purpose of the current study was to define exercise-induced changes in indices of left ventricular (LV) systolic and diastolic properties in patients with chronic heart failure (HF), compare these changes in patients with HF and a reduced ejection fraction (EF) versus HF and a preserved EF, and compare the hemodynamic responses to activities of daily living with symptom-limited upright exercise., Methods and Results: Subjects with HF and a preserved EF (n=8) and subjects with HF and a reduced EF (n=5) underwent symptom-limited Naughton protocol treadmill exercise tests. Implantable hemodynamic monitor data and echocardiographic data were obtained before exercise and at peak exercise. Implantable hemodynamic monitor data were obtained during activities of daily living during a 24-hour time period. In patients with HF and a reduced EF, limited exercise time (639±164 seconds) was associated with a marked rise in right ventricular systolic, diastolic, and estimated pulmonary artery diastolic (ePAD) pressures and an increase in LV end diastolic volume (EDV). LV systolic properties, namely EF, end systolic elastance, stroke work, and preload recruitable stroke work, all decreased. The ePAD/EDV ratio increased; to a large extent, this was dependent on an increase in EDV. By contrast, in HF and a preserved EF, limited exercise time (411±128 seconds) and the marked rise in right ventricular systolic, diastolic, and ePAD pressures were associated with no change in LV EDV. LV systolic properties increased or were unchanged; ePAD/EDV ratio increased during exercise, but the increase was independent of a change in EDV. The ranges of right ventricular systolic, diastolic, and ePAD pressures during activities of daily living were higher than the ranges of these values during the exercise stress test., Conclusions: Although exercise limitations were similar between HF and a reduced EF and HF and a preserved EF, there were significant differences in exercise-induced changes in LV systolic and diastolic properties. These differences likely reflect the different pathophysiologies of these clinical syndromes of HF.

Background: There are few sex-specific outcome data in heart failure with preserved ejection fraction., Methods and Results: We assessed sex differences in baseline characteristics and outcomes among 4128 patients with heart failure with preserved ejection fraction in the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial. Women (n=2491) with heart failure with preserved ejection fraction were ≈1 year older (72±7 years versus 71±7 years) and more likely to be obese (46% versus 35%) and have chronic kidney disease (34% versus 26%) and hypertension (91% versus 85%) than men but less likely to have an ischemic cause (19% versus 34%), atrial fibrillation (27% versus 33%), or chronic obstructive pulmonary disease (8% versus 13%) (all P<0.001). During a mean of 49.5 months, there were 881 deaths (447 in women, 434 in men; risk ratio, 0.64; 95% CI, 0.56-0.74) and 5776 hospitalizations (3239 in women, 2537 in men; risk ratio, 0.80; 95% CI, 0.76-0.84). Women had lower risk of all-cause events (deaths and hospitalizations), even after adjusting for baseline characteristics (adjusted hazards ratio, 0.81; 95% CI, 0.73-0.89). However, the sex-related difference in risk of all-cause events was modified in the presence or absence of atrial fibrillation, renal dysfunction, stable angina pectoris, or advanced New York Heart Association class symptoms., Conclusions: In patients with typical heart failure with preserved ejection fraction, there were prominent sex differences in baseline characteristics and outcomes. Women had better overall prognosis, although the presence of 4 common baseline characteristics seemed to moderate this finding.

Background: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used in a large, multinational, randomized, placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction (HF-PEF) on patients' lives and the effects of irbesartan., Methods and Results: Patients with symptomatic HF-PEF were randomly assigned to irbesartan (up to 300 mg daily) or placebo. The MLHFQ was administered at baseline (n=3605), month 6 (n=3137), month 14 (n=2904), and the end of study (median, 56 months, n=2205). Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects. Estimated retest reliability was 0.80. Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms, signs of congestion, cardiac structure, and time to hospitalizations or deaths attributed to heart failure. Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores (-5.9 and -5.0, P<0.0001). Compared with placebo, further improvement in MLHFQ scores was not observed with irbesartan after 6 months (mean adjusted difference, 0.4; 95% confidence interval, -0.8 to 1.7), 14 months (0.5; 95% confidence interval, -0.9 to 1.8), or the end of study (2.0; 95% confidence interval, -4.1 to 0.01)., Conclusions: The MLHFQ scores are a reliable, valid, and sensitive measure of the adverse impact of HF-PEF on patients' lives. Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels., Methods and Results: N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10; P<0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47; P<0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (P=0.005), all-cause mortality (P=0.05), and the HF composite outcome (P<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90; P=0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99; P=0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80; P=0.001) in patients with NT-proBNP below the median., Conclusions: The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined., Methods and Results: This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-μg/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-μg/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185)., Conclusions: Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Obesity is a major risk factor for incident heart failure (HF). Paradoxically, in HF with reduced left ventricular ejection fraction (HFREF), a high body mass index (BMI) appears to be beneficial. Approximately 50% of HF patients have a preserved left ventricular ejection fraction (HFPEF). However, there are few data regarding the relationship between BMI and outcomes in HFPEF., Methods and Results: Baseline characteristics and cardiovascular outcomes were assessed in the 4109 patients (mean age, 72 years; mean follow-up, 49.5 months) in the Irbesartan in HF with Preserved Ejection Fraction (I-PRESERVE) trial. Based on the BMI distribution, 5 BMI categories were defined: <23.5, 23.5 to 26.4, 26.5 to 30.9, 31 to 34.9, and ≥35 kg/m(2). Most patients (71%) had a BMI ≥26.5, 21% had a BMI between 23.5 and 26.4, and 8% had a BMI <23.5 kg/m(2). Patients with higher BMI were younger, more often women, and more likely to have hypertension and diabetes and higher left ventricular ejection fraction. Patients with BMI of 26.5 to 30.9 kg/m(2) had the lowest rate for the primary composite outcome (death or cardiovascular hospitalization) and were used as reference group. After adjustment for 21 risk variables including age, sex, and N-terminal pro-brain natriuretic peptide, the hazard ratio for the primary outcome was increased in patients with BMI <23.5 (hazard ratio, 1.27; 95% confidence interval, 1.04 to 1.56; P=0.019) and in those with BMI ≥35 kg/m(2) (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52; P=0.011) compared with the referent group. A similar relationship was found for all-cause mortality and for HF hospitalization., Conclusions: Obesity is common in HFPEF patients and is accompanied by multiple differences in clinical characteristics. Independent of other key prognostic variables, there was a U-shaped relationship, with the greatest rate of adverse outcomes in the lowest and highest BMI categories., Clinical Trial Registration- Url: http://www.clinicaltrials.gov. Unique identifier: NCT000095238.

Background: Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix may contribute to the development of pressure-overload-induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiological mechanisms would have diagnostic application to identify (1) patients who have development of LV hypertrophy (LVH) and (2) patients with LVH who have development of diastolic heart failure., Methods and Results: Plasma concentration of 17 biomarkers (matrix metalloproteinase [MMP]-1, -2, -3, -7, -8, and -9; tissue inhibitors -1, -2, -3, and -4; N-terminal propeptide of brain natriuretic peptide (NT-proBNP); cardiotrophin; osteopontin; soluble receptor for advanced glycation end products; collagen I teleopeptide; collagen I NT-proBNP; and collagen III N-terminal propetide [PIIINP]), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LVH but no evidence of heart failure, and 61 patients with LVH and diastolic heart failure (DHF). A plasma multibiomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an area under the curve of 0.80. A plasma multibiomarker panel consisting of increased MMP-2, TIMP-4, PIIINP, and decreased MMP-8 predicted the presence of DHF with an area under the curve of 0.79. These multibiomarker panels performed better than any single biomarker including NT-proBNP and better than using clinical covariates alone (area under the curve, 0.73 for LVH and 0.68 for DHF)., Conclusions: Plasma biomarkers reflecting changes in extracellular matrix fibrillar collagen homeostasis, combined into a multibiomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

Background: The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented., Methods and Results: We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro-B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro-B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks., Conclusions: In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events.