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Summary Background Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II–IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. Methods The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II–IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov , NCT03387813 . Findings Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74–1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66–1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80–1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70–1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61–0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. Interpretation Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. Funding Abbott.

OBJECTIVES This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF). BACKGROUND hs-TnT is a marker of myocardial injury in HF. METHODS The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT. RESULTS hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07). CONCLUSIONS Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan. (J Am Coll Cardiol HF 2021;9:627-635) (c) 2021 by the American College of Cardiology Foundation.

Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Aims The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result. Methods and results We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00). Conclusion Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

Background Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF). Objective Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies. Methods We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial. Results NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE. Conclusion We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death. Trial registration number PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658. Graphics abstract

The effect of loop diuretics on clinical outcomes in heart failure has not been evaluated in randomized controlled trials. In hospitalized patients with heart failure, a discharge loop diuretic prescription has been shown to be associated with improved 30-day outcomes, which appears to be more pronounced in subgroups with congestion. In the current study, we examined these associations and association modifications during longer follow-up.We assembled a propensity score-matched cohort of 2191 pairs of hospitalized heart failure patients discharged with, vs without, a prescription for loop diuretics, balanced on 74 baseline characteristics (mean age 78 years; 54% women; 11% African American).Hazard ratio (HR) and 95% confidence interval (CI) for 6-year combined endpoint of heart failure readmission or all-cause mortality was 1.02 (0.96-1.09). HRs and 95% CIs for this combined endpoint in patients with no, mild-to-moderate, and severe pulmonary rales were 1.19 (1.07-1.33), 0.95 (0.86-1.04), and 0.77 (0.63-0.94), respectively (P for interaction,.001). Respective HRs (95% CIs) for no, mild-to-moderate, and severe lower extremity edema were 1.16 (1.06-1.28), 0.94 (0.85-1.04), and 0.71 (0.56-0.89; interaction P.001).The association between a discharge loop diuretic prescription and long-term clinical outcomes in hospitalized patients with heart failure is modified by admission congestion with worse, neutral, and better outcomes in patients with no, mild-to-moderate, and severe congestion, respectively. If these findings can be replicated, congestion may be used to risk-stratify patients with heart failure for potential optimization of loop diuretic prescription and outcomes.

Aims Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non‐diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non‐DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature. Methods and results Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high‐sensitivity C‐reactive protein, pro‐collagen type III amino‐terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP‐1), and galectin‐3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high‐sensitivity troponin T (hs‐TnT), a marker of myocyte death, in DM patients. Elevated pro‐collagen type III amino‐terminal peptide and galectin‐3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs‐TnT and for TIMP‐1, with greater biomarker reductions among those with diabetes treated with spironolactone. Conclusions The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti‐fibrotic fashion in patients with diabetes, reflected by changes in hs‐TnT and TIMP‐1 levels over time.

BACKGROUND The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).OBJECTIVES This study aimed to examine the rate and impact of pneumonia in the 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) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.METHODS The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).RESULTS In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).CONCLUSIONS The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711) (J Am Coll Cardiol 2021;77:1961-73) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND: New hypertension and heart failure guidelines recommend that systolic blood pressure (SBP) in patients with heart failure with preserved ejection fraction (HFpEF) and hypertension be lowered to

International audience; Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.Methods and results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium 5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.

Aims Determine the feasibility of implementing a heart failure (HF) management strategy that (i) uses a device‐based, remote, dynamic, multimetric risk stratification model to predict the risk of HF events and (ii) uses a standardized, centrally administered, ambulatory medication intervention protocol to reproducibly and safely decrease elevated risk scores. Methods and results Prospective, non‐randomized, single‐arm, multicenter feasibility study (Intervene‐HF) was conducted in HF patients implanted with a cardiac resynchronization therapy with implantable cardio defibrillator (CRT‐D) with TriageHF risk score feature. Certified HF nurses (CHFN) in the Medtronic Care Management Services Program implemented an ambulatory medication intervention strategy by following a standardized guided action pathway triggered by risk‐based alert. When CHFN received notification of increased risk score (HF care alert), they implemented a 3 day course of diuretic up‐titration (PRN) previously prescribed by a physician. Safety was monitored daily. Recovery after PRN was defined as ≥70% recovery of impedance toward baseline levels. Sixty‐six patients followed for 8.2 ± 3.9 months had 49 HF care alerts. Twenty‐three of 49 alerts did not receive PRN due to protocol‐mandated criteria. Twenty‐six of 49 alerts received PRN, 22 were completed, and 19 led to impedance recovery. Four interventions were stopped for safety without leading to an adverse event (AE). One of 26 PRNs was followed by a HF event. Eighty‐five per cent (22/26) of PRNs were completed without an AE; 69% (18/26) met the recovery criteria. Conclusions The Intervene‐HF study supports the feasibility of testing, in a large randomized clinical trial, an ambulatory medication intervention strategy that is physician‐directed, CHFN‐implemented, and based on individualized device risk stratification.

Background Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. Methods Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. Results The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.71 (95% CI 0.68–0.75) and 0.78 (95% CI 0.75–0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. Conclusions The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. Clinical trial registration I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712. Graphic abstract

Objectives The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable ...

Aims This study aimed to examine the clinical utility of a multisensor, remote, ambulatory diagnostic risk score, TriageHF™, in a real‐world, unselected, large patient sample to predict heart failure events (HFEs) and all‐cause mortality. Methods and results TriageHF risk score was calculated in patients in the Optum® database who had Medtronic implantable cardiac defibrillator device from 2007 to 2016. Patients were categorized into three risk groups based on probability for having an HFE within 6 months (low risk

Background Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. Methods In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. Results Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. Conclusion Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

Background In heart failure (HF) patients, both natriuretic peptides (NP) and previous HF hospitalization (pHFH) have been used to predict prognosis. Hypothesis In a large real‐world population, both NP levels and pHFH have independent and interdependent predictive value for clinical outcomes of HFH and all‐cause mortality. Methods Linked electronic health records and insurance claims data from Decision Resource Group were used to identify HF patients that had a BNP or NT‐proBNP result between January 2012 and December 2016. NT‐proBNP was converted into BNP equivalents by dividing by 4. Index event was defined as most recent NP on or after 1 January 2012. Patients with incomplete records or age, In heart failure (HF) patients, both natriuretic peptides (NP) and previous HF hospitalization (pHFH) have been used to predict prognosis. However, this association has not been reported over a wide range of NP levels with and without pHFH for clinical outcomes of HFH and all‐cause mortality in a large real‐world population. The current study showed that in a large real‐world heart failure population, higher BNP levels were associated with increased risk for both HFH and mortality. At any given level of BNP, pHFH added greater prognostic value for prediction of future HFH than for mortality.

Aims OptiVol fluid index was developed as a transthoracic impedance‐based indicator of short‐term risk for heart failure hospitalization (HFH). OptiVol is calculated as the accumulating difference between daily impedance (measured impedance) and long‐term average impedance (reference impedance). Measured impedance alone was thought to have limited prognostic utility; however, measured impedance has the advantage of being simple, direct, and possibly additive to OptiVol fluid index in establishing long‐term HFH risk. We tested the hypothesis that directly measured impedance has independent prognostic value in predicting long‐term HFH risk and that changes in measured impedance result in a change in predicted long‐term HFH risk. Methods and results A retrospective analysis of 1719 patients studied in PARTNERS‐HF, FAST, and RAFT studies was performed. Baseline measured impedance was determined using daily values averaged over 1 month, from Month 6 to 7 post implant; change in measured impedance was determined from values averaged over 1 month, from Month 7 to 8 post implant compared with baseline. The predictive value of baseline measured impedance for HFHs was assessed beginning 7 months post implant. The predictive value of a change in measured impedance for a change in HFHs was assessed beginning 8 months post implant. Baseline measured impedance successfully predicted HFHs. For example, 3 year HFH rate for low baseline impedance 70 Ω (P = 0.004). In addition, when baseline measured impedance fell during follow‐up by >1%, 2%, or 3%, subsequent HFHs increased to 13%, 17%, or 18%, respectively. Finally, the prognostic value of measured impedance was additive to the prognostic value of the OptiVol fluid index. Conclusions Direct measurements of intrathoracic impedance using an implanted device can be used to stratify patients at varying risk of long‐term HFH. These direct measurements of impedance have practical clinical appeal because they are simple, continuous, and ambulatory.

Objectives The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). Background MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain. Methods The authors pooled data from 3 trials—CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)—and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization. Results At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p Conclusions Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)

Highlights •BNP and NT-proBNP are used as inclusion criteria in several HF clinical trials. •Despite widespread use, there is inconsistency in how BNP and NT-proBNP are utilized. •We call for standardization of natriuretic peptide inclusion criteria across HF trials.

OBJECTIVES: The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. BACKGROUND: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). METHODS: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. RESULTS: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. CONCLUSIONS: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). ispartof: JACC-HEART FAILURE vol:8 issue:5 pages:372-381 ispartof: location:United States status: published

Summary This study assessed the regional changes in myocardial geometry, microstructure, mechanical behavior, and properties that occur in response to progressive left ventricular pressure overload (LVPO) in a large animal model. Using an index of local biomechanical function at early onset of LVPO allowed for prediction of the magnitude of left ventricular chamber stiffness (Kc) and left atrial area at LVPO late timepoints. Our study found that LV myocardial collagen content alone was insufficient to identify mechanisms for LV myocardial stiffness with progression to heart failure with preserved ejection fraction (HFpEF). Serial assessment of regional biomechanical function might hold value in monitoring the natural history and progression of HFpEF, which would allow evaluation of novel therapeutic approaches.

Aims: \ud Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of ‘health deficits’ across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).\ud \ud Methods and results: \ud Using a cumulative deficits approach, we constructed a 42‐item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM‐HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non‐frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all‐cause death or all‐cause hospitalization: 40.7 (39.1–42.4) vs. 22.1 (21.2–23.0) per 100 person‐years in the non‐frail; adjusted hazard ratio 1.63 (1.53–1.75) (P

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro–B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59–0.90) in women and 1.03 (95% CI, 0.84–1.25) in men ( P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. Clinical Trial Registration: 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).

Symptoms of heart failure (HF) are due in large part to elevation of left and/or right ventricular filling pressures. Although abnormal diastolic function is difficult to define, it contributes to the elevation of filling pressures. Tests that characterize aspects of diastolic function or structural changes associated with diastolic dysfunction, may help in establishing a diagnosis of HF, assessing prognosis, and guiding treatments. Individual echocardiographic parameters correlate weakly with LV (LV) filling pressures measured directly. However, a combination of multiple parameters improves accuracy for detection of elevated filling pressures. Serum natriuretic peptide levels are related to ventricular filling pressures and, when elevated, are a key diagnostic criterion for HF. Currently available evidence is not adequate to recommend serial echocardiographic studies or natriuretic peptide level measurements to assess changes in filling pressures or to guide HF therapy. Measurements of inferior vena cava size and dynamics have potential for identifying inadequate decongestion during episodes of acute decompensated HF but have not yet demonstrated utility in improving HF outcomes. Direct measurement of LV filling pressures using implanted pressure sensors is the only "diastolic assessment" thus far that has proven efficacy in reducing HF hospitalization rates.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P P P Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711 .

Background Obesity is associated with heart failure with preserved ejection fraction (HFpEF). Weight loss can improve exercise capacity in HFpEF. However, previously reported methods of weight loss are impractical for widespread clinical implementation. We tested the hypothesis that an intensive lifestyle modification program would lead to relevant weight loss and improvement in functional status in patients with HFpEF and obesity. Methods and Results Patients with ejection fraction >45%, at least 1 objective criteria for HFpEF, and body mass index ≥30 kg/m 2 were offered enrollment in an established 15‐week weight management program that included weekly visits for counseling, weight checks, and provision of meal replacements. At baseline, 15 weeks, and 26 weeks, Minnesota Living With Heart Failure score, 6‐minute walk distance, echocardiography, and laboratory variables were assessed. A total of 41 patients completed the study (mean body mass index, 40.8 kg/m 2 ), 74% of whom lost >5% of their baseline body weight following the 15‐week program. At 15 weeks, mean 6‐minute walk distance increased from 223 to 281 m ( P =0.001) and then decreased to 267 m at 26 weeks. Minnesota Living With Heart Failure score improved from 59.9 to 37.3 at 15 weeks ( P r =0.452; P =0.000) and 6‐minute walk distance ( r =−0.388; P Conclusions In a diverse population of patients with obesity and HFpEF, clinically relevant weight loss can be achieved with a pragmatic 15‐week program. This is associated with significant improvements in quality of life and exercise capacity. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02911337.

Aims Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on ‘apparent resistant hypertension’ in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril–valsartan with valsartan. Methods and results In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). ‘Apparent resistant hypertension’ was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. ‘Apparent mineralocorticoid receptor antagonist (MRA)-resistant’ hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril–valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6–19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7–14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05–1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril–valsartan vs. valsartan in patients with apparent resistant hypertension [−4.8 (−7.0 to −2.5) and 3.9 (−6.6 to −1.3) mmHg] and apparent MRA-resistant hypertension [−8.8 (−14.0 to −3.5) and −6.3 (−12.5 to −0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril–valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30–2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18–5.89). Conclusion Sacubitril–valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA. Clinical trial registration PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711., Graphical Abstract Almost one in six patients with heart failure and preserved ejection fraction had apparent resistant hypertension in PARAGON-HF and this was associated with worse clinical outcomes; neprilysin inhibition reduced systolic blood pressure significantly in these patients.

Background: Antecedent conditions, like aortic stenosis, can induce left ventricular pressure overload (LVPO), that can lead to Heart Failure with Preserved Ejection Fraction (HFpEF). Myocardial fibrosis and stiffness are key characteristics of HFpEF. Cardiac fibroblasts are the primary cell type regulating ECM production and deposition. In previous studies, biopsies isolated at the time of SAVR surgery, to correct stenosis, and then at 1-year and 5-years post-SAVR showed reductions in hypertrophy and fibrosis demonstrating these processes can regress. However, cellular mechanisms, including fibroblast activity, are poorly defined. Objective: Define mechanisms that contribute to remodeling of ECM before and after LVPO. Methods: LVPO was induced using transverse aortic constriction (TAC). LVPO was relieved by removal of the band (unTAC) at 4 wks. Cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), and protein production was measured by histology and immunoblot for five time points: nonTAC, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, and 4wk TAC+4wk unTAC. Results: In response to LVPO, myocyte CSA increased by 23% at 2wk TAC and by 47% at 4wk. CVF increased by 64% and 204% at 2wk and 4wk TAC, respectively, versus nonTAC. In 2wk TAC hearts, SMA, a marker of fibroblast activation was increased as was production of two collagen cross-linking enzymes, lysyl oxidase (LOX) and LOXL2, in the absence of significant increases in markers of ECM degradation. After unloading, myocyte CSA decreased by 20% in 2wk unTAC versus 4wk TAC and CVF decreased by 38% in 4wk unTAC versus 4wk TAC. Coincident with decreases in CVF, levels of pro-MMP2 increased at 2wk unTAC as did levels of degraded collagen measured by collagen hybridizing peptide reactivity. Whereas markers of ECM deposition, LOX and LOXL2, were not increased in unTAC myocardium, a resurgence of SMA production occurred in 2wk unTAC. Conclusions: In LVPO hearts, hypertrophy was characterized by increases in myocyte CSA, greater CVF, and fibroblast activation with increased production of pro-fibrotic ECM. After unloading, hypertrophy and fibrosis significantly decreased accompanied by increases in ECM degrading activity and reductions in proteins that contribute to collagen assembly.

Visual Abstract, Highlights • The lean diabetic SKO mouse represents a novel and validated murine model of HFpEF. • The SKO HFpEF mouse model recapitulates the cardiac structure and function abnormalities in lean diabetic HFpEF patients in Asia. • Altered cellular titin phosphorylation and increased extracellular interstitial fibrosis associated with neutrophil extracellular traps contribute to the left ventricular stiffness. • Metabolic disturbances arising from insulin resistance and diabetes in the absence of hypertension or obesity may lead to HFpEF., Summary The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients.

Objectives This study sought to describe baseline health-related quality of life (HRQL) in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, the largest heart failure with preserved ejection fraction (HFpEF) trial to date. Background There are limited data characterizing HRQL in patients with HFpEF using validated metrics. Methods The PARAGON-HF trial randomized symptomatic patients with HFpEF (≥45%) ≥50 years of age to either sacubitril/valsartan or valsartan. The study reports comprehensive baseline HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period. The study then compares baseline HRQL with patients with heart failure with reduced ejection fraction (HFrEF) (≤40%) enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Forward multivariable stepwise regression modeling was performed separately in both trials to identify independent clinical correlates of KCCQ-Overall Summary (KCCQ-OS) score. PARADIGM-HF trial patients Results In the PARAGON-HF trial, 4,735 of 4,822 patients (mean age 73 ± 8 years; 48% men) completed baseline KCCQ at randomization. Mean KCCQ-OS score was 71. Women had worse mean KCCQ-OS score than men did. Patients in the PARAGON-HF trial reported lower KCCQ scores in nearly all domains when compared with the PARADIGM-HF trial (KCCQ-OS score 71 ± 19 vs. 73 ± 19; p Conclusions HRQL was largely worse in women and was similar in HFpEF and HFrEF after accounting for variation in demographics, functional status, and symptom burden. Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF [PARAGON-HF] NCT01920711; Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)

Background:\ud Although heart failure with preserved ejection fraction (HFpEF) is considered a disease of the elderly, younger patients are not spared from this syndrome.\ud \ud Objectives:\ud This study therefore investigated the associations among age, clinical characteristics, and outcomes in patients with HFpEF.\ud \ud Methods:\ud Using data on patients with left ventricular ejection fraction ≥45% from 3 large HFpEF trials (TOPCAT [Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function], I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], and CHARM Preserved [Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity]), patients were categorized according to age: ≤55 years (n = 522), 56 to 64 years (n = 1,679), 65 to 74 years (n = 3,405), 75 to 84 years (n = 2,464), and ≥85 years (n = 398). This study compared clinical and echocardiographic characteristics, as well as mortality and hospitalization rates, mode of death, and quality of life across age categories.\ud \ud Results:\ud Younger patients (age ≤55 years) with HFpEF were more often obese, nonwhite men, whereas older patients with HFpEF were more often white women with a higher prevalence of atrial fibrillation, hypertension, and chronic kidney disease (eGFR

Background Hemodynamic-guided heart failure (HF) management using pulmonary artery (PA) pressures reduces HF hospitalizations (HFHs) in previously hospitalized HF patients with New York Heart Association (NYHA) class III symptoms. It remains uncertain whether this approach reduces not only HFHs but all-cause mortality and if benefits extend to patients with NYHA class II and IV HF or to those symptomatic patients with elevated natriuretic peptides without recent HFH. Methods GUIDE-HF is a prospective trial with 2 arms enrolling patients with HF regardless of ejection fraction (EF). The randomized arm is a single-blind, randomized, controlled trial of PA pressure-guided therapy in NYHA class II-IV patients (n = 1,000) with either a previous HFH or elevated natriuretic peptides (B-type natriuretic peptide/NT-pro–B-type natriuretic peptide). All consenting subjects will receive an implantable PA pressure sensor (CardioMEMS HF System) followed by randomization to either a treatment group, managed with provider remote access to the hemodynamic data, or a control group, managed without provider access to these data. Subjects in the control group will receive scheduled, scripted, sham contacts from the study team to maintain blinding as to their study group assignment. The primary study end point is the composite of cumulative HF events and all-cause mortality at 12 months. Secondary end points include quality-of-life and functional assessments. The single arm of the trial is an observational arm in which NYHA class III patients (n = 2,600) with either a previous HFH or elevated natriuretic peptides (but no recent HFH) will be implanted with a PA pressure sensor and observed for occurrence of the primary composite end point of cumulative HF events and mortality at 12 months. This arm will test the hypothesis that hemodynamic-guided care is similarly effective in HF patients enrolled on the basis of elevated natriuretic peptide levels but no recent HFH and those with a recent HFH. Conclusions GUIDE-HF is the largest clinical trial of hemodynamic-guided HF management across a broad population of HF patients, with a study design and sample size adequate to examine survival, cumulative HF events, quality of life, and functional capacity.

Objectives The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. Background Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. Methods We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. Results Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum–related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). Conclusions Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255)

Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)

Background: Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years.\ud \ud Objectives: This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF.\ud \ud Methods: The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro–B-type natriuretic peptide.\ud \ud Results: Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life—median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)—despite similar left ventricular ejection fraction and N-terminal pro–B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001).\ud \ud Conclusions: Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.

Background Atrial fibrillation (AF) is less common in African Americans (AA) than Caucasians (C) despite a higher prevalence of risk factors such as hypertension (HTN). Objective Test the hypothesis that differences in extracellular matrix (ECM) between AA and C in response to HTN might attenuate atrial enlargement and alter myocardial fibrosis. Methods ECM-related plasma biomarkers and echo data were collected from 326 C and 129 AA subjects with no history of AF, stratified by the presence of HTN, HTN with left ventricular hypertrophy (LVH), or HTN with LVH and heart failure with preserved ejection fraction (HFpEF). Results Left atrial size was significantly smaller and the extent of enlargement in the presence of HTN was less in AA despite similar ventricular relative wall thickness, echocardiographic measures of diastolic function, and 6 minute-walk-test. AA had significantly lower levels of collagen I telopeptide and higher levels of collagen I propeptide among all strata, suggesting unique collagen homeostasis. Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP) showed a distinctive response to HTN in AA, with significantly lower levels of MMP-2, MMP-3, and MMP-8 in AA with HTN and significantly lower levels of TIMP-1 and TIMP-3 in AA with HTN and AA with LVH. AA had significantly lower levels of NT-pro-BNP in all strata. Conclusion This cross-sectional study demonstrates a racial disparity in ECM blood biomarkers and atrial remodeling in response to HTN and in the development of LVH and HFpEF that may partly help explain the decreased risk of AF in AA.

Background: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy (GDMT) for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and MRA use and dosing in a large randomized clinical trial. Methods: Patients with full data on medication/dose use were included. We examined β-blocker and MRA use/dose in patients randomized to sacubitril/valsartan versus enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Results: Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87.1% and 55%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-months and 12-months follow-up. New initiations through 12-months follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers (37 [9.0%] vs. 42 [10.2%], p = 0.56) and MRA (127 [7.6%] vs. 143 [9.2%], p = 0.10). Among patients on MRA therapy at baseline (n = 4634), there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12-months (125 [6.2%] vs. 187 [9.0%], p = 0.001). Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs 2.6%, p = 0.26). Conclusions: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose downtitrations of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.

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 The hemodynamic effects of cardiac resynchronization therapy in patients with left ventricular assist devices (LVADs) are uncharacterized. We aimed to quantify the hemodynamic effects of different ventricular pacing configurations in patients with LVADs, focusing on short‐term changes in load‐independent right ventricular (RV) contractility. Methods and Results Patients with LVADs underwent right heart catheterization during spontaneous respiration without sedation and with pressures recorded at end expiration. Right heart catheterization was performed at different pacemaker configurations (biventricular pacing, left ventricular pacing, RV pacing, and unpaced conduction) in a randomly generated sequence with >3 minutes between configuration change and hemodynamic assessment. The right heart catheterization operator was blinded to the sequence. RV maximal change in pressure over time normalized to instantaneous pressure was calculated from digitized hemodynamic waveforms, consistent with a previously validated protocol. Fifteen patients with LVADs who were in sinus rhythm were included. Load‐independent RV contractility, as assessed by RV maximal change in pressure over time normalized to instantaneous pressure, was higher in biventricular pacing compared with unpaced conduction (15.7±7.6 versus 11.0±4.0 s −1 ; P =0.003). Thermodilution cardiac output was higher in biventricular pacing compared with unpaced conduction (4.48±0.7 versus 4.38±0.8 L/min; P =0.05). There were no significant differences in heart rate, ventricular filling pressures, or atrioventricular valvular regurgitation across all pacing configurations. Conclusions Biventricular pacing acutely improves load‐independent RV contractility in patients with LVADs. Even in these patients with mechanical left ventricular unloading via LVAD who were relative pacing nonresponders (required LVAD support despite cardiac resynchronization therapy), biventricular pacing was acutely beneficial to RV contractility.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor Blocker–Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non‐COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P P P P P Conclusions In PARADIGM‐HF, COPD was associated with lower use of beta‐blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high‐risk subgroup. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01035255.

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 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.

Aims Sacubitril/valsartan combines renin–angiotensin–aldosterone system inhibition with amplification of natriuretic peptides. In addition to well‐described effects, natriuretic peptides exert direct effects on pulmonary vasculature. The effect of sacubitril/valsartan on pulmonary artery pressure (PAP) has not been fully defined. Methods and results This was a retrospective case‐series of PAP changes following transition from angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to sacubitril/valsartan in patients with heart failure reduced ejection fraction and a previously implanted CardioMEMS™ sensor. Pre‐sacubitril/valsartan and post‐sacubitril/valsartan PAPs were compared for each patient by examining averaged consecutive daily pressure readings from 1 to 5 days before and after sacubitril/valsartan exposure. PAP changes were also compared between patients based on elevated trans‐pulmonary gradients (trans‐pulmonary gradient ≥ 12 mmHg) at time of CardioMEMS™ sensor implantation. The cohort included 18 patients, 72% male, mean age 60.1 ± 13.6 years. There was a significant decrease in PAPs associated with transition from ACEI/ARB to sacubitril/valsartan. The median (interquartile range) pre‐treatment and post‐treatment change in mean, systolic and diastolic PAPs were −3.6 (−9.8, −0.7) mmHg (P

Introduction: Patients with heart failure and a preserved ejection fraction (HFpEF) present heart function abnormalities that remain poorly understood. Defining proteomic signature of HF that is independent of left ventricular hypertrophy (LVH) should allow for stratification of its subtypes and potential mechanism that contributes to the disease. Hypothesis: We hypothesized that HFpEF proteomic signature would be comprised of the hypertrophy and contractile protein phenotype. Methods: Intraoperative left ventricular (LV) myocardial biopsies were obtained from patients (n=21) recruited to undergo coronary artery bypass grafting (CABG). Patients were categorized to: control non-hypertensive (n=9), LVH (n=5), and HFpEF (n=7). Myocardial tissue was subfractionated: cytoplasmic- (neutral pH), myofilament- (acidic pH), and membrane-enriched extract (SDS-soluble). All fractions were assessed for protein quantity and Lys/Arg modifications using liquid chromatography mass spectrometry (LC-MS). Results: In HFpEF, 13% of the cardiac LV proteome changed compared to control heart, with a substantial proportion (77%) decreasing in quantity across all three cardiac fractions, while with LVH, 61% of the proteomic LV changes were increased. Although glycolysis and gluconeogenesis increased in both cardiopathies with respect to control, in HFpEF more subtly than in LVH. Modified proteome of the HFpEF was dominated by decreases in protein succinylation (e.g. ATP5L, THIM, IDHP, APOB, GSH1, KNTC1) and to a lesser degree in methylation (ROA3, HSP7C) or acetylation compared to control. This general trend of down-regulation of succinylation can be attributed to depletion in the levels of succinyl-CoA, the cofactor of enzymatic Lys succinylation. Importantly, there was a striking discordant activation/inhibition of cell death and proliferation pathways between the HFpEF and LVH. Two major upstream regulator clusters linked the proteome changes in cell growth and proliferation to RICTOR and Myc that showed completely opposite trends in LVH and HFpEF groups. Conclusions: HFpEF has a unique proteome signature compared to LV hypertrophy profile which does not arise from sub-proteome involved in contraction but rather is involved in overall cell death.

Introduction: In patients with heart failure (HF), worsening of HF signs and symptoms is associated with increased cardiovascular (CV) risk. Differences in burden of HF signs and symptoms and their prognostic value in HF with preserved (HFpEF) versus reduced ejection fraction (HFrEF) are poorly understood. Hypothesis: High burden of HF signs and symptoms is associated with adverse CV events, and is of greater prognostic value in patients with HFrEF. Methods: Using combined data from PARADIGM-HF (LVEF eligibility ≤40%) and PARAGON-HF (LVEF eligibility ≥45%), Cox models were fit to assess the relationship between burden of HF signs and symptoms (≤2 or ≥3) and first HHF or CV death in patients with HFrEF (n=8385) and HFpEF (n=4709) with available signs and symptoms at screening (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, third heart sound). Results: High burden of HF signs and symptoms (≥3) was more common among patients with HFpEF (48%) than HFrEF (42%, pinteraction = 0.03) (Figure). Conclusion: Patients with HFpEF have slightly higher burden of HF signs and symptoms than those with HFrEF. High burden of HF signs and symptoms identifies patients at high risk foradverse CV events, and may have greater prognostic importance in patients with HFrEF than HFpEF.