Journal: JACC Heart Fail

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Abstract

The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation.

Witte KK, Lipiecki J, Siminiak T, Meredith IT, ... Kaye DM, Sievert H
Objectives
This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling.
Background
Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis.
Methods
In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis.
Results
Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: -11.7 to -2.5] vs. an increase of 3.3 ml/beat [95% CI: -6.0 to 12.6], respectively; p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: -18.5 to -2.4] vs. an increase of 6.5 ml [95% CI: -5.1 to 18.2]; p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: -12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: -1.42 to 13.6]; p = 0.04).
Conclusions
The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR]; NCT02325830).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:945-955
Witte KK, Lipiecki J, Siminiak T, Meredith IT, ... Kaye DM, Sievert H
JACC Heart Fail: 30 Oct 2019; 7:945-955 | PMID: 31521683
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Abstract

Design of a \"Lean\" Case Report Form for Heart Failure Therapeutic Development.

Psotka MA, Fiuzat M, Carson PE, Kao DP, ... O\'Connor CM, Abraham WT

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:913-921
Psotka MA, Fiuzat M, Carson PE, Kao DP, ... O'Connor CM, Abraham WT
JACC Heart Fail: 30 Oct 2019; 7:913-921 | PMID: 31401097
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Abstract

Pregnant women with Uncorrected Congenital Heart Disease: Heart failure and mortality.

Sliwa K, Baris L, Sinning C, Zengin-Sahm E, ... Hall R, Roos-Hesselink J
Background
Globally, congenital heart disease (CHD) is an important cause of maternal morbidity and mortality in women reaching reproductive stage. There is lack of data from larger cohorts of women with uncorrected CHD.
Objectives
To study maternal and fetal outcome of women with uncorrected CHD.
Methods
An analysis of 10-year data from the ESC EORP ROPAC Registry of women with uncorrected CHD.
Results
Of a total of 5739 pregnancies in 53 countries, 3295 women had CHD, with 1059 uncorrected. Of these, 41.4 % were from emerging countries. There were marked differences in cardiac defects in uncorrected versus corrected CHD with primary shunt lesions (44.7% vs 32.4%), valvular abnormalities (33.5% vs 12.6%) and Tetralogy of Fallot/Pulmonary atresia (0.8% vs 20.3%), p<0.001. In uncorrected CHD 6.8% were in mWHO risk class IV, about 10 % had pulmonary hypertension (PH) and 3% were cyanotic prior to pregnancy. Maternal mortality and heart failure (HF) in the women with uncorrected CHD was 0.7% and 8.7%. Eisenmenger syndrome was associated with a very high risk of cardiac events (65.5%), maternal mortality (10.3%) and HF (48.3%). Coming from an emerging country was associated with higher pre-pregnancy signs of HF, PH and cyanosis (p<0.001) and worse maternal and fetal outcomes, with a threefold higher rate of hospital admissions for cardiac events and intrauterine growth retardation (p<0.001).
Conclusions
We found marked differences in cardiac conditions in pregnant women with uncorrected CHD versus corrected CHD, with a markedly worse outcome, particularly in women with Eisenmenger syndrome and from emerging countries.

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 06 Sep 2019; epub ahead of print
Sliwa K, Baris L, Sinning C, Zengin-Sahm E, ... Hall R, Roos-Hesselink J
JACC Heart Fail: 06 Sep 2019; epub ahead of print | PMID: 31511192
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Abstract

Hyperkalemia and Treatment With RAAS Inhibitors During Acute Heart Failure Hospitalizations and Their Association With Mortality.

Beusekamp JC, Tromp J, Cleland JGF, Givertz MM, ... Voors AA, van der Meer P
Objectives
This study investigated associations between incident hyperkalemia during acute heart failure (HF) hospitalizations and changes in renin-angiotensin-aldosterone system (RAAS) inhibitors.
Background
Hyperkalemia is a potential complication of RAAS inhibitors. For patients with HF, fear of hyperkalemia may lead to failure to deliver guideline-recommended doses of RAAS inhibitors.
Methods
Serum potassium concentrations were measured daily from baseline (<24 h after admission) until discharge or day 7 in 1,589 patients enrolled in the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) trial. Incident hyperkalemia was defined as at least 1 episode of potassium >5.0 mEq/l. The primary outcome was all-cause mortality at 180 days.
Results
Overall, serum potassium concentrations increased from 4.3 ± 0.6 mEq/l at baseline to 4.5 ± 0.6 mEq/l at discharge or day 7 (p < 0.001). Patients developing incident hyperkalemia (n = 564; 35%) were more often taking mineralocorticoid antagonists (MRAs) therapy prior to hospitalization and were more likely to have them down-titrated during hospitalization, independent of confounders. Incident hyperkalemia was not associated with adverse outcomes. Yet, down-titration of MRAs during hospitalization was independently associated with 180-day mortality (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.15 to 2.60), regardless of incident hyperkalemia (p >0.10). Patients with incident hyperkalemia who were discharged with the same or increased dose of MRAs (HR: 0.52; 95% CI: 0.32 to 0.85) or angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (HR: 0.47; 95% CI: 0.29 to 0.77) had a lower 180-day mortality.
Conclusions
Incident hyperkalemia is common in patients hospitalized for acute HF and is not associated with adverse outcomes. Incident hyperkalemia is associated with down-titration of MRAs, but patients who maintained or increased their dose of MRAs and/or ACE inhibitors/ARB during acute HF hospitalization had better 180-day survival.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:970-979
Beusekamp JC, Tromp J, Cleland JGF, Givertz MM, ... Voors AA, van der Meer P
JACC Heart Fail: 30 Oct 2019; 7:970-979 | PMID: 31606364
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Abstract

The Future of Wearables in Heart Failure Patients.

DeVore AD, Wosik J, Hernandez AF

The adoption of mobile health (mHealth) devices is creating a unique opportunity to improve heart failure (HF) care. The rise of mHealth is driven by multiple factors including consumerism, policy changes in health care, and innovations in technology. Wearable health devices are one aspect of mHealth that may improve the delivery of HF care by allowing for medical data collection outside of a clinician\'s office or hospital. Wearable devices are externally applied and capture functional or physiological data in order to monitor and improve patients\' health. Most wearable sensors capture data continuously and may be incorporated into accessories (e.g., a watch or clothing) or may be applied as a cutaneous patch. Wearable devices are often paired with another device, such as a smartphone, to collect, interpret, or transmit data. This study assessed the potential applications of wearable devices in HF care, summarizes available data for wearables, and discusses the future of wearables for improving the health of patients with HF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:922-932
DeVore AD, Wosik J, Hernandez AF
JACC Heart Fail: 30 Oct 2019; 7:922-932 | PMID: 31672308
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Abstract

Association Between Sacubitril/Valsartan Initiation and Health Status Outcomes in Heart Failure With Reduced Ejection Fraction.

Khariton Y, Fonarow GC, Arnold SV, Hellkamp A, ... McCague K, Spertus JA
Objectives
This study sought to describe the short-term health status benefits of angiotensin-neprilysin inhibitor (ARNI) therapy in patients with heart failure and reduced ejection fraction (HFrEF).
Background
Although therapy with sacubitril/valsartan, a neprilysin inhibitor, improved patients\' health status (compared with enalapril) at 8 months in the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study, the early impact of ARNI on patients\' symptoms, functions, and quality of life is unknown.
Methods
Health status was assessed by using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ) in 3,918 outpatients with HFrEF and left ventricular ejection fraction ≤40% across 140 U.S. centers in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry. ARNI therapy was initiated in 508 patients who were matched 1:2 to 1,016 patients who were not initiated on ARNI (no-ARNI), using a nonparsimonious time-dependent propensity score (6 sociodemographic factors, 23 clinical characteristics), prior KCCQ overall summary (KCCQ-OS) score, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker status.
Results
Multivariate linear regression demonstrated a greater mean improvement in KCCQ-OS in patients initiated on ARNI therapy (5.3 ± 19 vs. 2.5 ± 17.4, respectively; p < 0.001) over a median (interquartile range [IQR]) of 57 (32 to 104) days. The proportions of ARNI versus no-ARNI groups with ≥10-point (large) and ≥20-point (very large) improvements in KCCQ-OS were 32.7% versus 26.9%, respectively, and 20.5% versus 12.1%, respectively, consistent with numbers needed to treat of 18 and 12, respectively.
Conclusions
In routine clinical care, ARNI therapy was associated with early improvements in health status, with 20% experiencing a very large health status benefit compared with 12% who were not started on ARNI therapy. These findings support the use of ARNI to improve patients\' symptoms, functions, and quality of life.

Published by Elsevier Inc.

JACC Heart Fail: 30 Oct 2019; 7:933-941
Khariton Y, Fonarow GC, Arnold SV, Hellkamp A, ... McCague K, Spertus JA
JACC Heart Fail: 30 Oct 2019; 7:933-941 | PMID: 31521679
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Abstract

Representativeness of a Heart Failure Trial by Race and Sex: Results From ASCEND-HF and GWTG-HF.

Greene SJ, DeVore AD, Sheng S, Fonarow GC, ... O\'Connor CM, Mentz RJ
Objectives
This study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex.
Background
Black patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear.
Methods
The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines-Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria.
Results
Among 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p < 0.02), with consistent mortality findings by race and sex. After propensity score matching, mortality rates were similar; however, trial-eligible patients continued to have higher rates of 30-day readmission (23.1% vs. 17.3%; p < 0.01), driven by differences among black patients and women (all p for interaction ≤0.02).
Conclusions
Patients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:980-992
Greene SJ, DeVore AD, Sheng S, Fonarow GC, ... O'Connor CM, Mentz RJ
JACC Heart Fail: 30 Oct 2019; 7:980-992 | PMID: 31606362
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Abstract

Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes.

Li J, Woodward M, Perkovic V, Figtree GA, ... Matthews DR, Neal B
Objectives
The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754).
Background
Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain.
Methods
The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses.
Results
Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%).
Conclusions
A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 22 Oct 2019; epub ahead of print
Li J, Woodward M, Perkovic V, Figtree GA, ... Matthews DR, Neal B
JACC Heart Fail: 22 Oct 2019; epub ahead of print | PMID: 31676303
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Abstract

A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis.

Barrett CD, Dobos K, Liedtke M, Tuzovic M, ... Schrier S, Witteles RM
Objectives
The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.
Background
Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.
Methods
We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients\' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.
Results
At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.
Conclusions
Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2019; 7:958-966
Barrett CD, Dobos K, Liedtke M, Tuzovic M, ... Schrier S, Witteles RM
JACC Heart Fail: 30 Oct 2019; 7:958-966 | PMID: 31606365
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Abstract

HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation.

Packer M

Both obesity and type 2 diabetes are important risk factors for the development of heart failure with a preserved ejection fraction (HFpEF), and both disorders increase the risk of systemic thromboembolic events. Traditionally, the risk of stroke has been explained by the strong association of these disorders with atrial fibrillation (AF). However, adiposity and diabetes are risk factors for systemic thromboembolism, even in the absence of AF, because both can lead to the development of an inflammatory and fibrotic atrial and ventricular myopathy, the 2 major elements of HFpEF. Atrial myopathy: 1) exacerbates pulmonary venous hypertension and exertional dyspnea; 2) leads to decreased flow, thrombogenesis, and systemic thromboembolization; and 3) often clinically manifests as AF; however, the relationship between AF and thromboembolism is unclear. Atrial fibrosis predisposes to thrombus formation, even in the absence of AF, and most thromboembolic events bear a poor temporal relationship to the occurrence of AF, whereas HFpEF (and the accompanying atrial disease) predicts stroke in patients with or without AF. Furthermore, rhythm control does not reduce the risk of stroke, although it reduces the burden of AF. These observations support the primacy of atrial myopathy as a critical component of HFpEF, rather than AF, as the mediator of systemic thromboembolism in obesity or diabetes. The well-established association between AF and stroke is likely explained by the fact that AF is a biomarker of more advanced inflammatory atrial disease but not necessarily a direct causal mechanism.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2019; epub ahead of print
Packer M
JACC Heart Fail: 03 Nov 2019; epub ahead of print | PMID: 31706838
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Abstract

Differential Regulation of ANP and BNP in Acute Decompensated Heart Failure: Deficiency of ANP.

Reginauld SH, Cannone V, Iyer S, Scott C, ... Sangaralingham SJ, Burnett JC
Objectives
This study investigated the differential regulation of circulating atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in patients with acute decompensated heart failure (ADHF) and tested the hypothesis that a relative deficiency of ANP exists in a subgroup of patients with ADHF.
Background
The endocrine heart releases the cardiac hormones ANP and BNP, which play a key role in cardiovascular (CV), renal, and metabolic homeostasis. In heart failure (HF), both plasma ANP and BNP are increased as a compensatory homeostatic response to myocardial overload.
Methods
ANP and BNP concentrations were measured in a small group of patients with ADHF (n = 112). To support this study\'s goal, a total of 129 healthy subjects were prospectively recruited to establish contemporary normal values for ANP and BNP. Plasma 3\',5\'cyclic guanosine monophosphate (cGMP), ejection fraction (EF), and body mass index (BMI) were measured in these subjects.
Results
In cases of ADHF, 74% of patients showed elevated ANP and BNP. Importantly, 26% of patients were characterized as having normal ANP (21% of this subgroup had normal ANP and elevated BNP). Cyclic GMP was lowest in the ADHF group with normal levels of ANP (p < 0.001), whereas BMI and EF were inversely related to ANP levels (p = 0.003).
Conclusions
Among a subgroup of patients hospitalized with ADHF, the presence of an ANP deficiency is consistent with a differential regulation of ANP and BNP and suggests the existence of a potentially compromised compensatory cardiac endocrine response. These findings have implications for the pathophysiology, diagnostics, and therapeutics of human HF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Sep 2019; 7:891-898
Reginauld SH, Cannone V, Iyer S, Scott C, ... Sangaralingham SJ, Burnett JC
JACC Heart Fail: 29 Sep 2019; 7:891-898 | PMID: 31521687
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Abstract

Exercise-Based Rehabilitation for Heart Failure: Cochrane Systematic Review, Meta-Analysis, and Trial Sequential Analysis.

Taylor RS, Long L, Mordi IR, Madsen MT, ... Gluud C, Zwisler AD
Objectives
This study performed a contemporary systematic review and meta-analysis of exercise-based cardiac rehabilitation (ExCR) for heart failure (HF).
Background
There is an increasing call for trials of models of ExCR for patients with HF that provide alternatives to conventional center-based provision and recruitment of patients that reflect a broader HF population.
Methods
The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and PsycINFO databases were searched between January 2013 and January 2018. Randomized trials comparing patients undergoing ExCR to control patients not undergoing exercise were included. Study outcomes were pooled using meta-analysis. Metaregression examined potential effect modification according to ExCR program characteristics, and risk of bias, trial sequential analysis (TSA), and Grading of Recommendations Assessment Development and Evaluation (GRADE) were applied.
Results
Across 44 trials (n = 5,783; median follow-up of 6 months), compared with control subjects, ExCR did not reduce the risk of all-cause mortality (relative risk [RR]: 0.89; 95% confidence interval [CI]: 0.66 to 1.21; TSA-adjusted CI: 0.26 to 3.10) but did reduce all-cause hospitalization (RR: 0.70; 95% CI: 0.60 to 0.83; TSA-adjusted CI: 0.54 to 0.92) and HF-specific hospitalization (RR: 0.59; 95% CI: 0.42 to 0.84; TSA-adjusted CI: 0.14 for 2.46), and patients reported improved Minnesota Living with Heart Failure questionnaire overall scores (mean difference: -7.1; 95% CI: -10.5 to -3.7; TSA-adjusted CI: -13.2 to -1.0). No evidence of differential effects across different models of delivery, including center- versus home-based programs, were found.
Conclusions
This review supports the beneficial effects of ExCR on patient outcomes. These benefits appear to be consistent across ExCR program characteristics. GRADE and TSA assessments indicated that further high-quality randomized trials are needed.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:691-705
Taylor RS, Long L, Mordi IR, Madsen MT, ... Gluud C, Zwisler AD
JACC Heart Fail: 30 Jul 2019; 7:691-705 | PMID: 31302050
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Abstract

Hemodynamic Effects of Weight Loss in Obesity: A Systematic Review and Meta-Analysis.

Reddy YNV, Anantha-Narayanan M, Obokata M, Koepp KE, ... Carter RE, Borlaug BA
Objectives
The authors aimed to explore whether weight loss may improve central hemodynamics in obesity.
Background
Hemodynamic abnormalities in obese heart failure with preserved ejection fraction patients are correlated with the amount of excess body mass, suggesting a possible causal relationship.
Methods
Relevant databases were systematically searched from inception to May 2018, without language restriction. Studies reporting invasive hemodynamic measures before and following therapeutic weight loss interventions in patients with obesity but no clinically overt heart failure were extracted.
Results
A total of 9 studies were identified, providing data for 110 patients. Six studies tested dietary intervention and 3 studies tested bariatric surgery. Over a median duration of 9.7 months (range 0.75 to 23.0 months), a median weight loss of 43 kg (range 10 to 58 kg) was associated with significant reductions in heart rate (-9 beats/min, 95% confidence interval [CI]: -12 to -6; p < 0.001), mean arterial pressure (-7 mm Hg, 95% CI: -11 to -3; p < 0.001), and resting oxygen consumption (-85 ml/min, 95% CI: -111 to -60; p < 0.001). Central cardiac hemodynamics improved, manifested by reductions in pulmonary capillary wedge pressure (-3 mm Hg, 95% CI: -5 to -1; p < 0.001) and mean pulmonary artery pressure (-5 mm Hg, 95% CI: -8 to -2; p = 0.001). Exercise hemodynamics were assessed in a subset of patients (n = 49) in which there was significant reduction in exercise pulmonary artery pressure (p = 0.02).
Conclusions
Therapeutic weight loss in obese patients without HF is associated with favorable hemodynamic effects. Randomized controlled trials evaluating strategies for weight loss in obese patients with heart failure such as the obese phenotype of heart failure with preserved ejection fraction are needed.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:678-687
Reddy YNV, Anantha-Narayanan M, Obokata M, Koepp KE, ... Carter RE, Borlaug BA
JACC Heart Fail: 30 Jul 2019; 7:678-687 | PMID: 31302042
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Abstract

Burden and Causes of Hospital Admissions in Heart Failure During the Last Year of Life.

Madelaire C, Gustafsson F, Kristensen SL, D\'Souza M, ... Gislason G, Schou M
Objectives
This study aimed to evaluate the incidence and causes of hospitalization in the year preceding death of patients with heart failure (HF).
Background
Hospitalizations in HF are common, especially in the last period of the lives of patients with HF, but little is known about hospitalization burden and causes during this phase of the disease.
Methods
From Danish nationwide registries, we identified patients who died in the period 2001-2016 after having experienced HF for at least 1 year, and examined hospitalizations during the last year of life in age- and sex-stratified analyses.
Results
We included 32,157 patients. Median age at time of death was 81 years; 39% were women. A total of 26,561 (84%) patients were hospitalized at least once during the last year of life. The patients experienced a median of 2 (1 to 3) hospitalizations and spent 14 (3 to 31) days in the hospital. Of all hospitalizations (n = 80,362), 9,644 (12%) were due to HF, 14,738 (18%) due to other cardiovascular (CV) causes, and 51,696 (64%) due to non-CV causes (p < 0.001). The frequency of hospitalizations increased toward death, but the domination of non-CV causes remained consistent throughout the year, regardless of age and sex. If we included diagnoses covering renal insufficiency in the definition of HF hospitalizations, non-CV hospitalizations remained dominant (58%).
Conclusions
During the last year alive, patients with HF were more often hospitalized due to non-CV causes rather than HF. These findings warrant more focus on a multidisciplinary approach toward end-of-life care in patients with HF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:561-570
Madelaire C, Gustafsson F, Kristensen SL, D'Souza M, ... Gislason G, Schou M
JACC Heart Fail: 29 Jun 2019; 7:561-570 | PMID: 31248567
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Impact:
Abstract

Ambulatory Advanced Heart Failure in Women: A Report From the REVIVAL Registry.

Stewart GC, Cascino T, Richards B, Khalatbari S, ... Aaronson KD,
Objectives
This study sought to explore clinical characteristics and outcomes in women and men with ambulatory advanced heart failure (HF).
Background
Women have been underrepresented in studies of advanced HF and have an increased mortality on the transplant waiting list and early after mechanical circulatory support (MCS). An increased understanding of the differential burden of HF between women and men is required to inform the use of mechanical circulatory support in ambulatory advanced HF patients.
Methods
REVIVAL (Registry Evaluation for Vital Information on Ventricular Assist Devices in Ambulatory Life) is a prospective, observational study of 400 outpatients with chronic systolic HF, New York Heart Association functional class II to IV, and 1 additional high-risk feature. Clinical characteristics, quality of life, and functional capacity were compared between women and men, as was a primary composite endpoint of death, durable MCS, or urgent heart transplantation at 1 year.
Results
REVIVAL enrolled 99 women (25% of the cohort) who had similar age, ejection fraction, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles, medication use, and willingness to consider MCS as the men enrolled; however, women reported significantly greater limitations in quality of life with respect to physical limitation, reduced 6-min walk distance, and more frequent symptoms of depression. Nevertheless, 1-year combined risk of death, durable MCS, or urgent transplantation did not differ between women and men (24% vs. 22%; p = 0.94).
Conclusions
This study represents the largest report to date of women with ambulatory advanced HF receiving contemporary therapies. Systematic elicitation of patient-reported outcome measures uncovered an added burden of HF in women and may be an appropriate target of augmented support and intervention.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:602-611
Stewart GC, Cascino T, Richards B, Khalatbari S, ... Aaronson KD,
JACC Heart Fail: 29 Jun 2019; 7:602-611 | PMID: 31078480
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Impact:
Abstract

Financial Incentives to Increase Cardiac Rehabilitation Participation Among Low-Socioeconomic Status Patients: A Randomized Clinical Trial.

Gaalema DE, Elliott RJ, Savage PD, Rengo JL, ... Higgins ST, Ades PA
Objectives
This study sought to examine the efficacy of financial incentives to increase Medicaid patient participation in and completion of cardiac rehabilitation (CR).
Background
Participation in CR reduces morbidity, mortality, and hospitalizations while improving quality of life. Lower-socioeconomic status (SES) patients are much less likely to attend and complete CR, despite being at increased risk for recurrent cardiovascular events.
Methods
A total of 130 individuals enrolled in Medicaid with a CR-qualifying cardiac event were randomized 1:1 to receive financial incentives on an escalating schedule ($4 to $50) for completing CR sessions or to receive usual care. Primary outcomes were CR participation (number of sessions completed) and completion (≥30 sessions completed). Secondary outcomes included changes in sociocognitive measurements (depressive/anxious symptoms, executive function), body composition (waist circumference, body mass index), fitness (peak VO) over 4 months, and combined number of hospitalizations and emergency department (ED) contacts over 1 year.
Results
Patients randomized to the incentive condition completed more sessions (22.4 vs. 14.7, respectively; p = 0.013) and were almost twice as likely to complete CR (55.4% vs. 29.2%, respectively; p = 0.002) as controls. Incentivized patients were also more likely to experience improvements in executive function (p < 0.001), although there were no significant effects on other secondary outcomes. Patients who completed ≥30 sessions had 47% fewer combined hospitalizations and ED visits (p = 0.014), as reflected by a nonsignificant trend by study condition with 39% fewer hospital contacts in the incentive condition group (p = 0.079).
Conclusions
Financial incentives improve CR participation among lower-SES patients following a cardiac event. Increasing participation among lower-SES patients in CR is critical for positive longer-term health outcomes. (Increasing Cardiac Rehabilitation Participation Among Medicaid Enrollees; NCT02172820).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:537-546
Gaalema DE, Elliott RJ, Savage PD, Rengo JL, ... Higgins ST, Ades PA
JACC Heart Fail: 29 Jun 2019; 7:537-546 | PMID: 31078475
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Impact:
Abstract

Factors Associated With Live Discharge of Heart Failure Patients From Hospice: A Multimethod Study.

Russell D, Baik D, Jordan L, Dooley F, ... Bowles KH, Creber RM
Objectives
This study identified sociodemographic and clinical factors that predicted live discharge among home hospice patients with heart failure, and related these findings to perspectives among health care providers about challenges to caring for these patients.
Background
Hospice patients with heart failure are frequently discharged from hospice before death (\"live discharge\"). However, little is known about the factors and circumstances associated with live discharge among patients with heart failure.
Methods
Quantitative analyses of patient medical records (N = 1,498) and qualitative interviews were performed with health care providers (n = 19) at a not-for-profit hospice agency in New York City.
Results
Thirty percent of home hospice patients with heart failure experienced a live discharge, most frequently due to 911 calls that led to acute hospitalization. The odds of acute hospitalization were higher for younger patients (age 18 to 74 years: adjusted odds ratio [AOR]: 2.10; 95% confidence interval [CI]: 1.34 to 3.28), African American (AOR: 2.06; 95% CI: 1.31 to 3.24) or Hispanic (AOR: 2.99; 95% CI: 1.99 to 4.50) patients, and higher functioning patients (Palliative Performance Scores of 50% to 70%; AOR: 5.68; 95% CI: 3.66 to 8.79). Qualitative interviews with health care providers highlighted the unique characteristics of heart failure (e.g., sudden changes in patients\' condition), the importance of patients\' understanding of hospice and their own prognosis, and the role of sociocultural and family context in precipitating and potentially preventing live discharge (e.g., absence of social supports in the home).
Conclusions
Live discharge from hospice, especially due to acute hospitalization, is common with heart failure. Greater attention is needed for patients\' knowledge of and readiness for hospice care, especially among younger and diverse populations, and for factors related to the social and family context in which hospice care is provided.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:550-557
Russell D, Baik D, Jordan L, Dooley F, ... Bowles KH, Creber RM
JACC Heart Fail: 29 Jun 2019; 7:550-557 | PMID: 31078473
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Impact:
Abstract

Natriuretic Response Is Highly Variable and Associated With 6-Month Survival: Insights From the ROSE-AHF Trial.

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

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:383-391
Hodson DZ, Griffin M, Mahoney D, Raghavendra P, ... Mullens W, Testani JM
JACC Heart Fail: 29 Apr 2019; 7:383-391 | PMID: 31047017
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Abstract

Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization.

Bhagat AA, Greene SJ, Vaduganathan M, Fonarow GC, Butler J

Patients with worsening heart failure with reduced ejection fraction (HFrEF) spend a large proportion of time in the hospital and other health care facilities. The benefits of guideline-directed medical therapy (GDMT) in the outpatient setting have been shown in large randomized controlled trials. However, the decision to initiate, continue, switch, or withdraw HFrEF medications in the inpatient setting is often based on multiple factors and subject to significant variability across providers. Based on available data, in well-selected, treatment-naïve patients who are hemodynamically stable and clinically euvolemic after stabilization during hospitalization for HF, elements of GDMT can be safely initiated. Inpatient continuation of GDMT for HFrEF appears safe and well-tolerated in most hemodynamically stable patients. Hospitalization is also a potential time for switching from an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker to sacubitril/valsartan therapy in eligible patients, and is the subject of ongoing study. Therapy withdrawal or need for dose reduction is rarely required, but if needed identifies a particularly at-risk group of patients with progressive HF. If recurrent intolerance to neurohormonal blockers is observed, these patients should be evaluated for advanced HF therapies. There is an enduring need for using the teachable moment of HFrEF hospitalization for optimal initiation, continuation, and switching of GDMT to improve post-discharge patient outcomes and the quality of chronic HFrEF care.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:1-12
Bhagat AA, Greene SJ, Vaduganathan M, Fonarow GC, Butler J
JACC Heart Fail: 30 Dec 2018; 7:1-12 | PMID: 30414818
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Impact:
Abstract

Machine Learning Prediction of Mortality and Hospitalization in Heart Failure with Preserved Ejection Fraction.

Angraal S, Mortazavi BJ, Gupta A, Khera R, ... Spertus JA, Krumholz HM
Objectives
This study sought to develop models for predicting mortality and heart failure (HF) hospitalization for outpatients with HF with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial.
Background
Although risk assessment models are available for patients with HF with reduced ejection fraction, few have assessed the risks of death and hospitalization in patients with HFpEF.
Methods
The following 5 methods: logistic regression with a forward selection of variables; logistic regression with a lasso regularization for variable selection; random forest (RF); gradient descent boosting; and support vector machine, were used to train models for assessing risks of mortality and HF hospitalization through 3 years of follow-up and were validated using 5-fold cross-validation. Model discrimination and calibration were estimated using receiver-operating characteristic curves and Brier scores, respectively. The top prediction variables were assessed by using the best performing models, using the incremental improvement of each variable in 5-fold cross-validation.
Results
The RF was the best performing model with a mean C-statistic of 0.72 (95% confidence interval [CI]: 0.69 to 0.75) for predicting mortality (Brier score: 0.17), and 0.76 (95% CI: 0.71 to 0.81) for HF hospitalization (Brier score: 0.19). Blood urea nitrogen levels, body mass index, and Kansas City Cardiomyopathy Questionnaire (KCCQ) subscale scores were strongly associated with mortality, whereas hemoglobin level, blood urea nitrogen, time since previous HF hospitalization, and KCCQ scores were the most significant predictors of HF hospitalization.
Conclusions
These models predict the risks of mortality and HF hospitalization in patients with HFpEF and emphasize the importance of health status data in determining prognosis. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 04 Oct 2019; epub ahead of print
Angraal S, Mortazavi BJ, Gupta A, Khera R, ... Spertus JA, Krumholz HM
JACC Heart Fail: 04 Oct 2019; epub ahead of print | PMID: 31606361
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Impact:
Abstract

The Hospital Readmissions Reduction Program: Nationwide Perspectives and Recommendations.

Psotka MA, Fonarow GC, Allen LA, Joynt Maddox KE, ... Yancy CW, O\'Connor CM

The mandatory federal pay-for-performance Hospital Readmissions Reduction Program (HRRP) was created to decrease 30-day hospital readmissions by instituting accountability and stimulating quality care and coordination, particularly during care transitions. The HRRP has changed the landscape of hospital readmissions and reimbursement within the United States by imposing substantial Medicare payment penalties on hospitals with higher-than-expected readmission rates. However, the HRRP has been controversial since its inception, particularly in the field of heart failure. Proponents argue that it has reduced national readmission rates, in part by raising awareness and investment in mechanisms to better assist patients during discharge and transitions; opponents contend that it unfairly penalizes hospitals for issues beyond their control, has unintended negative consequences due to incentivizing readmission over survival, that it encourages \"gaming\" the system, was not tested before implementation, and that it does not specify how hospitals can improve their performance. This paper incorporates the diverse, nuanced, and sometimes divergent interpretations presented during a multifaceted expert clinician discussion regarding the HRRP and heart failure; in cases in which consensus opinions were achieved, they are presented, including regarding potential new iterations of the HRRP for the future. Potential improvements include more comprehensive incorporation of outcomes into the HRRP measure and better risk adjustment to improve equality and fairness.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 04 Oct 2019; epub ahead of print
Psotka MA, Fonarow GC, Allen LA, Joynt Maddox KE, ... Yancy CW, O'Connor CM
JACC Heart Fail: 04 Oct 2019; epub ahead of print | PMID: 31606360
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Impact:
Abstract

Lung Ultrasound in Acute Heart Failure: Prevalence of Pulmonary Congestion and Short- and Long-Term Outcomes.

Platz E, Campbell RT, Claggett B, Lewis EF, ... Solomon SD, McMurray JJV
Objectives
This study sought to assess the prevalence, changes in, and prognostic importance of B-lines, a pulmonary congestion measure by using a simplified lung ultrasonography (LUS) method in acute heart failure (AHF).
Background
Pulmonary congestion is an important finding in AHF, but conventional methods for its detection are insensitive.
Methods
In a 2-site, prospective, observational study, 4-zone LUS was performed early during hospitalization for AHF (LUS1) and at discharge (LUS2). B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory.
Results
Among 349 patients (median, 75 years of age; 59% men; mean ejection fraction 39%), the sum of B-lines in 4 zones ranged from 0 to 18 (LUS1). The risk of an adverse in-hospital event increased with rising number of B-lines on LUS1: the odds ratio for each B-line tertile was 1.82 (95% confidence interval [CI]: 1.14 to 2.88; p = 0.011). B-line count decreased from a median of 6 (LUS1) to 4 (LUS2; p < 0.001) over 6 days (median). In 132 patients with LUS2 images, the risk of HF hospitalization or all-cause death was greater in patients with a higher number of B-lines at discharge. This relationship was stronger closer to discharge: unadjusted hazard ratio (HR) at 60 days was 3.30 (95% CI: 1.52 to 7.17; p = 0.002); 2.94 at 90 days (95% CI: 1.46 to 5.93; p = 0.003); and 2.01 at 180 days (95% CI: 1.11 to 3.64; p = 0.021). The association between number of B-lines and short- and long-term outcomes persisted after adjusting for important clinical variables, including N-terminal pro-B-type natriuretic peptide.
Conclusions
Pulmonary congestion using a simplified 4-zone LUS method was common in patients with AHF and improved with therapy. A higher number of B-lines at baseline and discharge identified patients at increased risk for adverse events.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Sep 2019; 7:849-858
Platz E, Campbell RT, Claggett B, Lewis EF, ... Solomon SD, McMurray JJV
JACC Heart Fail: 29 Sep 2019; 7:849-858 | PMID: 31582107
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Impact:
Abstract

CABG Improves Outcomes in Patients With Ischemic Cardiomyopathy: 10-Year Follow-Up of the STICH Trial.

Howlett JG, Stebbins A, Petrie MC, Jhund PS, ... Al-Khalidi HR,
Objectives
The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population.
Background
In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction <35%.
Methods
A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis.
Results
Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p < 0.001). This was driven by fewer total cardiovascular (CV) hospitalizations (744 vs. 968; p < 0.001, adjusted HR: 0.66, 95% CI: 0.55 to 0.81; p = 0.001), the majority of which were due to HF (395 vs. 512; p < 0.001, adjusted HR: 0.68, 95% CI: 0.52-0.89; p = 0.005). We did not observe a difference in non-CV events.
Conclusions
CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595).

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 29 Sep 2019; 7:878-887
Howlett JG, Stebbins A, Petrie MC, Jhund PS, ... Al-Khalidi HR,
JACC Heart Fail: 29 Sep 2019; 7:878-887 | PMID: 31521682
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Abstract

Diagnostic and Therapeutic Gaps in Patients With Heart Failure and Chronic Obstructive Pulmonary Disease.

Canepa M, Franssen FME, Olschewski H, Lainscak M, ... Tavazzi L, Rosenkranz S

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coincide in a significant number of patients. Recent population-based registries suggest that spirometry is largely underused in patients with HF to diagnose comorbid COPD and that patients with COPD frequently do not receive the recommended beta-blocker (BB) treatment. This state-of-the-art review summarizes: 1) current challenges in the implementation of recommended spirometry for COPD diagnosis in patients with HF; and 2) current underuse and underdosing of BBs in patients with HF and COPD despite guideline recommendations. Open issues in the therapeutic management of patients with HF and COPD are discussed in the third section, including the use of the nonselective BB carvedilol, target BB doses in patients with HF and COPD, BB and bronchodilator management during HF hospitalization with and without COPD exacerbation, and the use of BBs in patients with COPD with right HF or free from cardiovascular disease. The whole scenario described herein advocates for a bipartisan initiative to drive immediate attention to the translation of guideline recommendations into clinical practice for patients with HF with co-occurring COPD.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Sep 2019; 7:823-833
Canepa M, Franssen FME, Olschewski H, Lainscak M, ... Tavazzi L, Rosenkranz S
JACC Heart Fail: 29 Sep 2019; 7:823-833 | PMID: 31521680
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Impact:
Abstract

CORT-AHF Study: Effect on Outcomes of Systemic Corticosteroid Therapy During Early Management Acute Heart Failure.

Miró Ò, Takagi K, Gayat E, Llorens P, ... Mueller C, Mebazaa A
Objectives
This study investigated whether systemic corticosteroids (new onset) administered to patients with acute heart failure (AHF) have any association with outcomes, with differentiated analyses for patients with and without chronic obstructive pulmonary disease (COPD) as a comorbidity.
Background
Patients with undiagnosed dyspnea frequently receive corticosteroids in emergency departments while determining a final diagnosis, but their effect on the outcomes of patients with AHF without overt COPD exacerbation is unknown.
Methods
We selected patients with AHF from the EAHFE (Epidemiology of Acute Heart Failure in the Emergency Departments) registry, recording key data (new-onset corticosteroid therapy, COPD condition). Patients with and without COPD were analyzed separately. We calculated unadjusted and adjusted ratios for corticosteroid-treated compared with corticosteroid-untreated patients for 2 coprimary endpoints: 90-day all-cause mortality (from index episode) and 90-day post-discharge combined endpoint (all-cause mortality or readmission for AHF), with intermediate time-point estimations. Other secondary endpoints were calculated, and some sensitive and stratified analyses were performed.
Results
We analyzed 11,356 patients: 8,635 without COPD (841 corticosteroid-treated, 9.7%) and 2,721 with COPD (753 corticosteroid-treated, 27.7%). There were several differences between treated and untreated patients, essentially because corticosteroid-treated patients were sicker. Although unadjusted outcomes were worse in corticosteroid-treated patients, especially in patients without COPD, these differences disappeared after adjustment: hazard ratios for 90-day mortality (without/with COPD) were 0.91 (95% confidence interval (CI): 0.76 to 1.10)/0.99 (95% CI: 0.78 to 1.26), and 1.09 (95% CI: 0.93 to 1.28)/1.02 (95% CI: 0.86 to 1.21) for the post-discharge combined endpoint. Analyses of intermediate time-point coprimary endpoints and secondary outcomes rendered similar estimations. Sensitivity and stratified analysis did not significantly modify these results.
Conclusions
There is no evidence of harm related to the new onset of systemic corticosteroid therapy during an episode of AHF, either in patients with or without concomitant COPD.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Sep 2019; 7:834-845
Miró Ò, Takagi K, Gayat E, Llorens P, ... Mueller C, Mebazaa A
JACC Heart Fail: 29 Sep 2019; 7:834-845 | PMID: 31521676
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Impact:
Abstract

Carvedilol Among Patients With Heart Failure With a Cocaine-Use Disorder.

Banerji D, Alvi RM, Afshar M, Tariq N, ... Groarke JD, Neilan TG
Objectives
This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD).
Background
Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown.
Methods
This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission.
Results
From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro-B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863).
Conclusions
Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:771-778
Banerji D, Alvi RM, Afshar M, Tariq N, ... Groarke JD, Neilan TG
JACC Heart Fail: 30 Aug 2019; 7:771-778 | PMID: 31466673
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Impact:
Abstract

Socioeconomic Factors and Clinical Outcomes Among Patients With Heart Failure in a Universal Health Care System.

Schjødt I, Johnsen SP, Strömberg A, Kristensen NR, Løgstrup BB
Objectives
This study examined the associations between socioeconomic factors (SEF), readmission, and mortality in patients with incident heart failure (HF) with reduced ejection fraction (HFrEF) in a tax-financed universal health care system.
Background
Lack of health insurance is considered a key factor in health inequality, leading to poor clinical outcomes. However, data are sparse for the association between SEF and clinical outcomes among patients with HF in countries with tax-financed health care systems.
Methods
A nationwide population-based cohort study of 17,122 patients with incident HFrEF was carried out. Associations were assessed between individual-level SEF (cohabitation status, education, and income) and all-cause, HF, and non-HF readmission and mortality within 1 to 30, 31 to 90, and 91 to 365 days, as well as hospital bed days within 1 year after HF diagnosis.
Results
Low income was associated with a higher risk of all-cause readmission (adjusted hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.08 to 1.43) and non-HF readmission (HR: 1.36; 95% CI: 1.17 to 1.58) within days 31 to 90 as well as with a higher risk of all-cause (HR: 1.27; 95% CI: 1.14 to 1.41), HF (HR: 1.26; 95% CI: 1.02 to 1.55) and non-HF readmission (HR: 1.25; 95% CI: 1.12 to 1.39) within days 91 to 365. Low-income patients also had a higher use of hospital bed days and risk of mortality during follow-up.
Conclusions
In a tax-financed universal health care system, low income was associated with a higher risk of all-cause and non-HF readmission within 1 to 12 months after HF diagnosis and with HF readmission within 3 to 12 months among patients with incident HFrEF. Low-income patients also had a higher number of hospital bed days and a higher rate of mortality during follow-up.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:746-755
Schjødt I, Johnsen SP, Strömberg A, Kristensen NR, Løgstrup BB
JACC Heart Fail: 30 Aug 2019; 7:746-755 | PMID: 31466671
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Impact:
Abstract

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity.

Goel S, Liu J, Guo H, Barry W, ... Kohonen-Corish M, Beith J
Objectives
The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC).
Background
Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results.
Methods
A total of 222 patients with early-stage human epidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%.
Results
TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a \"low-risk TRC score\" to identify patients with low TRC incidence.
Conclusions
Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:795-804
Goel S, Liu J, Guo H, Barry W, ... Kohonen-Corish M, Beith J
JACC Heart Fail: 30 Aug 2019; 7:795-804 | PMID: 31401102
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Impact:
Abstract

Imaging, Biomarker, and Clinical Predictors of Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction.

Aimo A, Gaggin HK, Barison A, Emdin M, Januzzi JL

In response to injury, hemodynamic changes, or neurohormonal activation, the heart undergoes a series of structural and functional changes that have been termed cardiac remodeling. Remodeling is defined as changes in cardiac geometry and/or function over time and can be measured in terms of changes in cardiac chamber dimensions, wall thickness, volumes, mass, and ejection fraction at serial imaging examinations. As to cardiac chambers, left ventricular (LV) remodeling has been best studied in patients with heart failure with reduced ejection fraction. Although LV remodeling may compensate for abnormal hemodynamic parameters and function in the short term, left unchecked, it is associated with worsening cardiac function and poor prognosis. On the other hand, reversing LV geometry and/or function closer to that of a normal heart (also known as reverse remodeling) is associated with improved cardiac function and better prognosis. Because of its close relationship with clinical outcomes, remodeling may potentially be targeted in clinical management and used in trials as a surrogate endpoint. Standardized definition of remodeling and reliable tools to predict and monitor the presence, direction, and magnitude of cardiac remodeling are needed. Together with clinical and imaging findings, circulating biomarkers (most notably N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin, and soluble suppression of tumorigenesis-2) may be helpful in this respect.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:782-794
Aimo A, Gaggin HK, Barison A, Emdin M, Januzzi JL
JACC Heart Fail: 30 Aug 2019; 7:782-794 | PMID: 31401101
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Impact:
Abstract

Diastolic Determinants of Excess Mortality in Heart Failure With Reduced Ejection Fraction.

Benfari G, Miller WL, Antoine C, Rossi A, ... Thapa P, Enriquez-Sarano M
Objectives
The objective of this study was to determine short- and long-term excess mortality associated with diastolic echocardiographic measures (primarily E/e\' ratio) in patients with HF with reduced ejection fraction.
Background
In patients with heart failure (HF), Doppler echocardiography diastolic alterations are frequently but not convincingly linked to survival. Consequently, they are not included in risk-score algorithms or substantially mentioned in HF guidelines.
Methods
Consecutive patients with HF Stage B to C, diagnosed between 2003 and 2011, with ejection fraction <50%, Doppler diastolic characterization, complete clinical evaluation, and estimated pulmonary pressure, were analyzed. Outcome measure was mortality under medical management.
Results
The 12,421 eligible patients were 69 ± 14 years of age, 32% were women, 72% had Stage C HF, with ejection fraction 36 ± 10% and E/e\' ratio of 17 ± 9. During median follow-up 4.0 (1.1 to 7.0) years, 1-year and 5-year mortality were 17 ± 0.4% and 42 ± 0.5%. E/e\' ratio >20 was linked to elevated 1-year mortality (adjusted odds ratio: 1.45 [95% confidence interval (CI): 1.16 to 1.83]; p = 0.001). Long-term E/e\' ratios >20 and >14 to 20 were associated with reduced survival (adjusted hazard ratio: 1.21 [95% CI: 1.07 to 1.37]; p = 0.003, and adjusted hazard ratio: 1.15 [95% CI: 1.02 to 1.29]; p = 0.02), independent of all HF characteristics and in all patients\' subsets, including HF Stage B and Stage C. Guideline-based diastolic-grade algorithm also independently predicted mortality (p < 0.0001) but was definable less frequently (70%).
Conclusions
In reduced ejection fraction HF, diastolic Doppler alterations entail considerable mortality independent of all presentation characteristics. Elevated E/e\' ratio, associated with worse HF at diagnosis, is also, independent of presentation, linked to substantial short-term reduced survival and long-term sustained excess mortality and should be incorporated into HF risk assessment.

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 30 Aug 2019; 7:808-817
Benfari G, Miller WL, Antoine C, Rossi A, ... Thapa P, Enriquez-Sarano M
JACC Heart Fail: 30 Aug 2019; 7:808-817 | PMID: 31401099
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Impact:
Abstract

The Risk for Sudden Cardiac Death Among Patients Living With Heart Failure and Human Immunodeficiency Virus.

Alvi RM, Neilan AM, Tariq N, Hassan MO, ... Zanni MV, Neilan TG
Objectives
The aim of this study was to determine the incidence of sudden cardiac death (SCD) among persons living with human immunodeficiency virus infection (PHIV) with heart failure (HF), who were hospitalized for HF, and the risk factors associated with it.
Background
HF is associated with an increased risk for SCD. PHIV are at heightened risk for HF.
Methods
This was a retrospective study of 2,578 patients hospitalized with HF from a single academic center, of whom 344 were PHIV. The outcome of interest was SCD. Subgroup analyses were performed by strata of viral load (VL) and left ventricular ejection fraction (LVEF) <35%, 35% to 49%, and ≥50%.
Results
Of 2,578 patients with HF, 2,149 (86%) did not have implantable cardioverter-defibrillators; of these, there were 344 PHIV and 1,805 uninfected control subjects. Among PHIV with HF, 313 (91%) were prescribed antiretroviral therapy and 64% were virally suppressed. There were 191 SCDs over a median follow-up period of 19 months. Compared with control subjects, PHIV had a 3-fold increase in SCD (21.0% vs. 6.4%; adjusted odds ratio: 3.0; 95% confidence interval: 1.78 to 4.24). Among PHIV, cocaine use, lower LVEF, absence of beta-blocker prescription, and VL were predictors of SCD. The SCD rate among PHIV with undetectable VL was similar to the rate among uninfected subjects. Similar findings were observed by LVEF strata. Among PHIV with HF without conventional indications for an implantable cardioverter-defibrillator, the rate of SCD was 10% per year.
Conclusions
PHIV hospitalized with HF are at a markedly increased risk for SCD. SCD risk was increased in patients with lower LVEFs, lower CD4 counts, and higher VL.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:759-767
Alvi RM, Neilan AM, Tariq N, Hassan MO, ... Zanni MV, Neilan TG
JACC Heart Fail: 30 Aug 2019; 7:759-767 | PMID: 31401096
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Impact:
Abstract

Heart Failure and the Affordable Care Act: Past, Present, and Future.

Wolfe JD, Joynt Maddox KE

The Affordable Care Act (ACA) and other major health care legislative acts have had an important impact on the care of heart failure patients in the United States. The main effects of the ACA include regulation of the health insurance industry, expansion of access to health care, and health care delivery system reform, which included the creation of several alternative payment models. Particular components of the ACA, such as the elimination of annual and lifetime caps on spending, Medicaid expansion, and the individual and employer mandate, could have positive effects for heart failure patients. However, the benefits of value-based and alternative payment models such as the Hospital Readmissions Reduction Program and bundled payment programs for heart failure outcomes are less clear, and controversy exists regarding whether some of these programs may even worsen outcomes. As the population ages and the prevalence of heart failure continues to rise, this syndrome will likely remain a key clinical focus for policymakers. Therefore, heart failure clinicians should be aware of how legislation affects clinical practice and be prepared to adapt to continued changes in health policy.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Aug 2019; 7:737-745
Wolfe JD, Joynt Maddox KE
JACC Heart Fail: 30 Aug 2019; 7:737-745 | PMID: 31401094
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Impact:
Abstract

Health-Related Quality of Life in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Chandra A, Vaduganathan M, Lewis EF, Claggett BL, ... Solomon SD,
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 <50 years of age were excluded to enable comparison.
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 < 0.001). The strongest independent clinical correlates of adverse HRQL in both the PARAGON-HF and PARADIGM-HF trials were New York Heart Association functional class, female gender, lower extremity edema, body mass index, angina, dyspnea, and paroxysmal nocturnal dyspnea. After accounting for these clinical correlates of adverse HRQL that were common to both HFpEF and HFrEF patients, KCCQ-OS score did not differ significantly.
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).

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 29 Sep 2019; 7:862-874
Chandra A, Vaduganathan M, Lewis EF, Claggett BL, ... Solomon SD,
JACC Heart Fail: 29 Sep 2019; 7:862-874 | PMID: 31302043
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Impact:
Abstract

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

Lyle MA, Iyer SR, Redfield MM, Reddy YNV, ... Burnett JC, Pereira NL
Background
In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival.
Objectives
This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in HFpEF patients with normal controls.
Methods
A case-control study was performed in 242 symptomatic HFpEF patients previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates\'s Effect on Activity Tolerance in Heart Failure With Preserved Ejection (NEAT-HFpEF) clinical trials and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography) who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects.
Results
Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 9.7]; p = 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history, and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02).
Conclusions
Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 06 Aug 2019; epub ahead of print
Lyle MA, Iyer SR, Redfield MM, Reddy YNV, ... Burnett JC, Pereira NL
JACC Heart Fail: 06 Aug 2019; epub ahead of print | PMID: 31392960
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Impact:
Abstract

Risk Models for Prediction of Implantable Cardioverter-Defibrillator Benefit: Insights From the DANISH Trial.

Kristensen SL, Levy WC, Shadman R, Nielsen JC, ... Køber L, Thune JJ
Objectives
This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models.
Background
It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure.
Methods
The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial.
Results
Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction <0.001).
Conclusions
Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:717-724
Kristensen SL, Levy WC, Shadman R, Nielsen JC, ... Køber L, Thune JJ
JACC Heart Fail: 30 Jul 2019; 7:717-724 | PMID: 31302052
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Impact:
Abstract

Impact of Malnutrition Using Geriatric Nutritional Risk Index in Heart Failure With Preserved Ejection Fraction.

Minamisawa M, Seidelmann SB, Claggett B, Hegde SM, ... Pitt B, Solomon SD
Objectives
This study sought to investigate the relationship between malnutrition and adverse cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF).
Background
Malnutrition is associated with poor prognosis in a wide range of illnesses, however, the prognostic impact of malnutrition in HFpEF patients is not well known.
Methods
Baseline malnutrition risk was determined in 1,677 patients with HFpEF enrolled in the Americas regions of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial, according to 3 categories of the geriatric nutritional risk index (GNRI) as previously validated: moderate to severe, GNRI of <92; low, GNRI of 92 to <98; and absence of risk, GNRI of ≥98. The relationships between malnutrition risk and the primary composite outcome of CV events (CV death, heart failure hospitalization, or resuscitated sudden death) and all-cause death were examined.
Results
Approximately one-third of patients were at risk for malnutrition (moderate to severe: 11%; low: 25%; and absence of risk: 64%). Over a median of 2.9-years\' follow-up, compared to those with absent risk for malnutrition, moderate to severe risk was associated with significantly increased risk for the primary outcome, CV death and all-cause death (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.02 to 1.76; HR: 2.06; 95% CI: 1.40 to 3.03; and HR: 1.79; 95% CI: 1.33 to 2.42, respectively) after multivariate adjustment for age, sex, history of CV diseases, and laboratory biomarkers.
Conclusions
Patients with HFpEF are at an elevated risk for malnutrition, which was associated with an increased risk for CV events in this population.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:664-675
Minamisawa M, Seidelmann SB, Claggett B, Hegde SM, ... Pitt B, Solomon SD
JACC Heart Fail: 30 Jul 2019; 7:664-675 | PMID: 31302049
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Impact:
Abstract

Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice.

Witteles RM, Bokhari S, Damy T, Elliott PM, ... Rapezzi C, Garcia-Pavia P

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic \"red flags\" that can assist in its diagnosis among the wider population of patients with heart failure.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:709-716
Witteles RM, Bokhari S, Damy T, Elliott PM, ... Rapezzi C, Garcia-Pavia P
JACC Heart Fail: 30 Jul 2019; 7:709-716 | PMID: 31302046
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Impact:
Abstract

Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA.

Block RC, Liu L, Herrington DM, Huang S, ... O\'Connell TD, Shearer GC
Objectives
The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study of Atherosclerosis) trial.
Background
Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear.
Methods
In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling.
Results
A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 [95% confidence interval: 0.60 to 0.91] per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type.
Conclusions
Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:651-661
Block RC, Liu L, Herrington DM, Huang S, ... O'Connell TD, Shearer GC
JACC Heart Fail: 30 Jul 2019; 7:651-661 | PMID: 31302044
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Impact:
Abstract

Risk for Heart Failure: The Opportunity for Prevention With the American Heart Association\'s Life\'s Simple 7.

Uijl A, Koudstaal S, Vaartjes I, Boer JMA, ... Hoes AW, Sluijs I
Objectives
The aim of this study is to determine whether combinations of specific Life\'s Simple 7 (LS7) components are associated with reduced risk for heart failure (HF).
Background
The American Heart Association recommends the concept of LS7: healthy behaviors that have been shown to reduce cardiovascular disease.
Methods
A total of 37,803 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition-Netherlands) cohort were included (mean age: 49.4 ± 11.9 years, 74.7% women). The LS7 score ranged from 0 to 14 and was calculated by assigning 0, 1, or 2 points for smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose. An overall ideal score (11 to 14 points) was present in 23.2% of participants, an intermediate score (9 or 10 points) in 35.3%, and an inadequate score (0 to 8 points) in 41.5%.
Results
Over a median follow-up period of 15.2 years (interquartile range: 14.1 to 16.5 years), 690 participants (1.8%) developed HF. In Cox proportional hazards models, ideal and intermediate LS7 scores were associated with reduced risk for HF compared with the inadequate category (hazard ratio: 0.45 [95% confidence interval (CI): 0.34 to 0.60] and hazard ratio: 0.53 [95% CI: 0.44 to 0.64], respectively). Our analyses show that combinations with specific LS7 components, notably glucose, body mass index, smoking, and blood pressure, are associated with a lower incidence of HF.
Conclusions
A healthy lifestyle, as reflected in an ideal LS7 score, was associated with a 55% lower risk for HF compared with an inadequate LS7 score. Preventive strategies that target combinations of specific LS7 components could have a significant impact on decreasing incident HF in the population at large.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jul 2019; 7:637-647
Uijl A, Koudstaal S, Vaartjes I, Boer JMA, ... Hoes AW, Sluijs I
JACC Heart Fail: 30 Jul 2019; 7:637-647 | PMID: 31302040
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Impact:
Abstract

The Role of the Pericardium in Heart Failure: Implications for Pathophysiology and Treatment.

Borlaug BA, Reddy YNV

The elastic pericardium exerts a compressive contact force on the surface of the myocardium that becomes more substantial when heart volume increases, as in patients with various forms of heart failure (HF). Pericardial restraint plays an important role in determining hemodynamics and ventricular function in both health and disease. This review discusses the physiology of pericardial restraint in HF and explores the question of whether it can be targeted indirectly through medical interventions or directly through a number of existing and future therapies.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:574-585
Borlaug BA, Reddy YNV
JACC Heart Fail: 29 Jun 2019; 7:574-585 | PMID: 31248569
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Impact:
Abstract

Association of Changes in Heart Failure Treatment With Patients\' Health Status: Real-World Evidence From CHAMP-HF.

Thomas M, Khariton Y, Fonarow GC, Arnold SV, ... McCague K, Spertus JA
Objectives
The aim of this study was to use a multicenter, observational outpatient registry of patients with heart failure with reduced ejection fraction (HFrEF) to describe the association between changes in patients\' medications with changes in health status.
Background
Alleviating symptoms and improving function and quality of life for patients with HFrEF are primary treatment goals and potential indicators of quality. Whether titrating medications in routine clinical care improves patients\' health status is unknown.
Methods
The association of any change in HFrEF medications with 3-month change in health status, as measured using the 12-item Kansas City Cardiomyopathy Questionnaire Overall Summary Scale, was determined in unadjusted and multivariate-adjusted (25 clinical characteristics, baseline health status) models using hierarchical linear regression.
Results
Among 3,313 outpatients with HFrEF from 140 centers, 21.9% had medication changes. Three months later, 23.7% and 46.4% had clinically meaningfully worse (≥5-point decrease) and improved (≥5-point increase) Kansas City Cardiomyopathy Questionnaire Overall Summary Scale scores. The 3-month median change in Kansas City Cardiomyopathy Questionnaire Overall Summary Scale score for patients whose HFrEF medications were changed was significantly larger (7.3 points; interquartile range: -3.1 to 20.8 points) than in patients whose medications were not changed (3.1 points; interquartile range: -4.7 to 12.5 points) (adjusted difference 3.0 points; 95% confidence interval: 1.4 to 4.6 points; p < 0.001). Among patients whose medications were adjusted, 26% had very large clinical improvement (≥20 points) compared with 14% whose regimens were not changed.
Conclusions
In routine care of patients with HFrEF, changes in HFrEF medications were associated with significant improvements in patients\' health status, suggesting that health status-based performance measures can quantify the benefits of titrating medicines in patients with HFrEF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Jun 2019; 7:615-625
Thomas M, Khariton Y, Fonarow GC, Arnold SV, ... McCague K, Spertus JA
JACC Heart Fail: 29 Jun 2019; 7:615-625 | PMID: 31176672
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Impact:
Abstract

Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications.

Stolfo D, Uijl A, Vedin O, Strömberg A, ... Dahlström U, Savarese G
Objectives
This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum.
Background
Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials.
Methods
In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females.
Results
Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF.
Conclusions
Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:505-515
Stolfo D, Uijl A, Vedin O, Strömberg A, ... Dahlström U, Savarese G
JACC Heart Fail: 30 May 2019; 7:505-515 | PMID: 31146874
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Impact:
Abstract

Sex-Based Differences in Outcomes After Mitral Valve Surgery for Severe Ischemic Mitral Regurgitation: From the Cardiothoracic Surgical Trials Network.

Giustino G, Overbey J, Taylor D, Ailawadi G, ... Lala A, Hung J
Objectives
This study investigated sex-based differences in outcomes after mitral valve (MV) surgery for severe ischemic mitral regurgitation (SIMR).
Background
Whether differences in outcomes exist between men and women after surgery for SIMR remains unknown.
Methods
Patients enrolled in a randomized trial comparing MV replacement versus MV repair for SIMR were included and followed for 2 years. Endpoints for this analysis included all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE) (defined as the composite of death, stroke, hospitalization for heart failure, worsening New York Heart Association functional class or MV re-operation), quality of life (QOL), functional status, and percentage of change in left ventricular end-systolic volume index (LVESVI) from baseline through 2 years.
Results
Of 251 patients enrolled in the trial, 96 (38.2%) were women. Compared with men, women had smaller LV volumes and effective regurgitant orifice areas (EROA) but greater EROA/left ventricular (LV) end-diastolic volume ratios. At 2 years, women had higher rates of all-cause mortality (27.1% vs. 17.4%, respectively; adjusted hazard ratio [adjHR]: 1.85; 95% confidence interval [CI]: 1.05 to 3.26; p = 0.03) and of MACCE (49.0% vs. 38.1%, respectively; adjHR: 1.58; 95% CI: 1.06 to 2.37; p = 0.02). Women also reported worse QOL and functional status at 2 years. There were no significant differences in the percentage of change over 2 years in LVESVI between women and men (adjβ: -10.4; 95% CI: -23.4 to 2.6; p = 0.12).
Conclusions
Women with SIMR displayed different echocardiographic features and experienced higher mortality and worse QOL after MV surgery than men. There were no significant differences in the degree of reverse LV remodeling between sexes. (Comparing the Effectiveness of Repairing Versus Replacing the Heart\'s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation [Severe Ischemic Mitral Regurgitation]; NCT00807040).

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:481-490
Giustino G, Overbey J, Taylor D, Ailawadi G, ... Lala A, Hung J
JACC Heart Fail: 30 May 2019; 7:481-490 | PMID: 31146872
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Abstract

Heart Failure and Atrial Fibrillation, Like Fire and Fury.

Carlisle MA, Fudim M, DeVore AD, Piccini JP

Heart failure and atrial fibrillation are 2 common cardiovascular disorders that frequently complicate one another and exert a significant detrimental effect on cardiovascular health and well-being. Both heart failure and atrial fibrillation continue to increase in prevalence as the risk factors underlying each condition become more common. This review encompasses what is currently known about the epidemiology and pathophysiology of these comorbidities along with incorporation of landmark trials that have contributed to current guidelines. The focus is on clinically relevant considerations, including the contribution of inflammation in the pathophysiology of atrial fibrillation and heart failure. We explore the emerging role of catheter ablation relative to medical therapy in the management of heart failure with reduced ejection fraction, along with indications for biventricular pacing modalities in cardiac resynchronization therapy. We discuss current guideline-directed therapies and how practice models and national recommendations will likely change based on the most recent randomized controlled trials.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:447-456
Carlisle MA, Fudim M, DeVore AD, Piccini JP
JACC Heart Fail: 30 May 2019; 7:447-456 | PMID: 31146871
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Abstract

Outcomes and Effect of Treatment According to Etiology in HFrEF: An Analysis of PARADIGM-HF.

Balmforth C, Simpson J, Shen L, Jhund PS, ... Packer M, McMurray JJV
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).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:457-465
Balmforth C, Simpson J, Shen L, Jhund PS, ... Packer M, McMurray JJV
JACC Heart Fail: 30 May 2019; 7:457-465 | PMID: 31078482
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Abstract

Cardiogenic Shock in Takotsubo Cardiomyopathy Versus Acute Myocardial Infarction: An 8-Year National Perspective on Clinical Characteristics, Management, and Outcomes.

Vallabhajosyula S, Dunlay SM, Murphree DH, Barsness GW, ... Lerman A, Prasad A
Objectives
This study sought to evaluate the clinical characteristics and outcomes of Takotusbo cardiomyopathy cardiogenic shock (TC-CS) in comparison to those of acute myocardial infarction cardiogenic shock (AMI-CS) among patients hospitalized in the United States. We additionally sought to compare the incidence of multiorgan failure and use of supportive therapies as well as the trends over time, given the increasing awareness and diagnosis of TC.
Background
CS is a major complication of TC; however, there are limited data, especially as to how TC-CS compares to AMI-CS.
Methods
The National Inpatient Sample Database was used to identify adults hospitalized with CS in the setting of TC and AMI from 2007 to 2014. We required patients admitted with TC to have undergone coronary angiography without intervention. Clinical characteristics and in-hospital outcomes in TC-CS patients were compared with those in AMI-CS patients. Multivariate regression and propensity matching were used to adjust for potential confounding factors.
Results
Between 2007 and 2014, there were 374,152 admissions for CS due to either TC or AMI, of which 4,614 patients (1.2%) had TC-CS. TC-CS admission patients were more likely to be younger, white females with fewer comorbidities. Rates of respiratory failure and mechanical ventilation were higher in TC-CS, but cardiac arrest and acute kidney injury were lower. There were no differences between cohorts in use of intra-aortic balloon pumps. TC-CS admissions had lower in-hospital mortality (15% vs. 37%, respectively) and hospital costs (U.S. dollars: $135,397 ± $127,617 vs. $154,827 ± $186,035, respectively) and were discharged home more often (45% vs. 36%, respectively) compared to AMI-CS admissions (all: p < 0.001). After adjustments for potential confounders, TC-CS was associated with lower in-hospital mortality (odds ratio [OR]: 0.35; 95% confidence interval [CI]: 0.32 to 0.38; p < 0.001). Similar findings were observed in the propensity-matched cohort (OR: 0.32; 95% CI: 0.25 to 0.39; p < 0.001).
Conclusions
There are key differences between the clinical characteristics and multiorgan failure patterns in TC-CS compared to those in AMI-CS. In-hospital mortality (15%) is lower in TC-CS.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:469-476
Vallabhajosyula S, Dunlay SM, Murphree DH, Barsness GW, ... Lerman A, Prasad A
JACC Heart Fail: 30 May 2019; 7:469-476 | PMID: 31078481
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Abstract

Urinary Sodium Profiling in Chronic Heart Failure to Detect Development of Acute Decompensated Heart Failure.

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

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:404-414
Martens P, Dupont M, Verbrugge FH, Damman K, ... Testani J, Mullens W
JACC Heart Fail: 29 Apr 2019; 7:404-414 | PMID: 31047021
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Impact:
Abstract

Association of Urine Albumin Excretion With Incident Heart Failure Hospitalization in Community-Dwelling Adults.

Bailey LN, Levitan EB, Judd SE, Sterling MR, ... Safford MM, Gutiérrez OM
Objectives
This study examined the association between urinary albumin excretion and incident heart failure (HF) hospitalization.
Background
Excess urinary albumin excretion is more strongly associated with incident stroke and coronary heart disease risk in black than in white individuals. Whether similar associations extend to HF is unclear.
Methods
This study examined the associations between the urinary albumin-to-creatinine ratio (ACR) and incident hospitalization for HF overall in 24,433 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants free of suspected HF at baseline; findings were stratified by race and HF subtype (preserved vs. reduced ejection fraction). Models were adjusted for sociodemographic, clinical, and laboratory variables including estimated glomerular filtration rate, and multiple imputation was used to account for missing covariate data.
Results
After a median follow-up of 9.2 years, 881 incident HF events (332 preserved ejection fraction, 447 reduced ejection fraction, 102 unspecified) were observed. Compared to the lowest ACR category (<10 mg/g), the risk of incident HF increased with increasing ACR categories (10 to 29 mg/g hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.26 to 1.78; 30 to 300 mg/g HR: 2.32; 95% CI: 1.93 to 2.78; >300 mg/g HR: 4.42; 95% CI: 3.36 to 5.83) in the fully adjusted model. Results did not differ by race. The magnitude of the association between ACR and HF with preserved ejection fraction was greater than with HF with reduced ejection fraction (HR comparing highest vs. lowest ACR category: 6.20; 95% CI: 4.15 to 9.26 vs. HR: 4.37; 95% CI: 3.00 to 6.25, respectively; p = 0.05).
Conclusions
Higher ACR was associated with greater risk of incident HF hospitalization in community-dwelling black and white adults.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:394-401
Bailey LN, Levitan EB, Judd SE, Sterling MR, ... Safford MM, Gutiérrez OM
JACC Heart Fail: 29 Apr 2019; 7:394-401 | PMID: 31047019
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Impact:
Abstract

Medical Management of Heart Failure With Reduced Ejection Fraction in Patients With Advanced Renal Disease.

Hein AM, Scialla JJ, Edmonston D, Cooper LB, DeVore AD, Mentz RJ

Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT). This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research directions.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:371-382
Hein AM, Scialla JJ, Edmonston D, Cooper LB, DeVore AD, Mentz RJ
JACC Heart Fail: 29 Apr 2019; 7:371-382 | PMID: 31047016
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Abstract

Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial.

Piccini JP, Abraham WT, Dufton C, Carroll IA, ... Connolly SJ,
Objectives
The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF).
Background
Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta-adrenergic receptor (ADRB1) Arg389Arg genotype.
Methods
A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period.
Results
The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were <12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (n = 196), the HR was 0.54 (95% CI: 0.33 to 0.87; p = 0.011).
Conclusions
Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 29 Jun 2019; 7:586-598
Piccini JP, Abraham WT, Dufton C, Carroll IA, ... Connolly SJ,
JACC Heart Fail: 29 Jun 2019; 7:586-598 | PMID: 31042551
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Impact:
Abstract

Prior Pacemaker Implantation and Clinical Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

Shen L, Jhund PS, Docherty KF, Petrie MC, ... Zile MR, McMurray JJV
Objectives
This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).
Background
Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown.
Methods
Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses.
Results
Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro-B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses.
Conclusions
These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:418-427
Shen L, Jhund PS, Docherty KF, Petrie MC, ... Zile MR, McMurray JJV
JACC Heart Fail: 29 Apr 2019; 7:418-427 | PMID: 30981744
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Impact:
Abstract

Heart Failure Site-Based Research in the United States: Results of the Heart Failure Society of America Research Network Survey.

Psotka MA, Ammon SE, Fiuzat M, Bozkurt B, ... Jessup M, O\'Connor CM
Objectives
This study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States.
Background
Improvements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact.
Methods
The Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research.
Results
Overall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators.
Conclusions
Many U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 29 Apr 2019; 7:431-438
Psotka MA, Ammon SE, Fiuzat M, Bozkurt B, ... Jessup M, O'Connor CM
JACC Heart Fail: 29 Apr 2019; 7:431-438 | PMID: 30981742
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Impact:
Abstract

Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure.

Savarese G, Vedin O, D\'Amario D, Uijl A, ... Lam CSP, Lund LH
Objectives
This study sought to evaluate the incidence, the predictors, and the associations with outcomes of changes in ejection fraction (EF) in heart failure (HF) patients.
Background
EF determines therapy in HF, but information is scarce about incidence, determinants, and prognostic implications of EF change over time.
Methods
Patients with ≥2 EF measurements were made in the Swedish Heart Failure Registry were categorized as heart failure with preserved ejection fraction (HFpEF) (EF ≥50%), heart failure with midrange ejection fraction (HFmrEF) (EF 40% to 49%), or heart failure with reduced ejection fraction (HFrEF) (EF <40%). Changes among categories were recorded, and associations among EF changes, predictors, and all-cause mortality and/or HF hospitalizations were analyzed using logistic and Cox regressions.
Results
Of 4,942 patients at baseline, 18% had HFpEF, 19% had HFmrEF, and 63% had HFrEF. During follow-up, 21% and 18% of HFpEF patients transitioned to HFmrEF and HFrEF, respectively; 37% and 25% of HFmrEF patients transitioned to HFrEF and HFpEF, respectively; and 16% and 10% of HFrEF patients transitioned to HFmrEF and HFpEF, respectively. Predictors of increased EF included use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, female sex, cases of less severe HF, and comorbidities. Predictors of decreased EF included diabetes, ischemic heart disease, and cases of more severe HF. Increased EF was associated with a lower risk (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.55 to 0.69) and decreased EF with a higher risk (HR: 1.15; 95% CI: 1.01 to 1.30) of mortality and/or HF hospitalizations. Prognostic implications were most evident for transitions to and from HFrEF.
Conclusions
Increases in EF occurred in one-fourth of HFrEF and HFmrEF patients, and decreases occurred in more than one-third of patients with HFpEF and HFmrEF. EF change was associated with a wide range of important clinical, treatment, and organizational factors as well as with outcomes, particularly transitions to and from HFrEF.

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 30 Mar 2019; 7:306-317
Savarese G, Vedin O, D'Amario D, Uijl A, ... Lam CSP, Lund LH
JACC Heart Fail: 30 Mar 2019; 7:306-317 | PMID: 30852236
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Impact:
Abstract

Central and Peripheral Determinants of Exercise Capacity in Heart Failure Patients With Preserved Ejection Fraction.

Wolsk E, Kaye D, Komtebedde J, Shah SJ, ... Møller JE, Gustafsson F
Objectives
This study sought to discern which central (e.g., heart rate, stroke volume [SV], filling pressure) and peripheral factors (e.g., oxygen use by skeletal muscle, body mass index [BMI]) during exercise were most strongly associated with the presence of heart failure and preserved ejection fraction (HFpEF) as compared with healthy control subjects exercising at the same workload.
Background
The underlying mechanisms limiting exercise capacity in patients with HFpEF are not fully understood.
Methods
In patients with HFpEF (n = 108), the hemodynamic response at peak exercise was measured using right-sided heart catheterization and was compared with that in healthy control subjects (n = 42) at matched workloads to reveal hemodynamic differences that were not attributable to the workload performed. The patients studied were prospectively included in the REDUCE-LAP HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trials and HemReX (Effect of Age on the Hemodynamic Response During Rest and Exercise in Healthy Humans) study. Univariable and multivariable logistic regression models were used to analyze variables associated with HFpEF versus control subjects.
Results
Compared with healthy control subjects, pulmonary capillary wedge pressure (PCWP) and SV were the only independent hemodynamic variables that were associated with HFpEF, a finding explaining 66% (p < 0.0001) of the difference between the groups. When relevant baseline characteristics were added to the base model, only BMI emerged as an additional independent variable, in total explaining of 90% of the differences between groups (p < 0.0001): PCWP (47%), BMI (31%), and SV (12%).
Conclusions
The study identified 3 key variables (PCWP, BMI, and SV) that independently correlate with the presence of patients with HFpEF compared with healthy control subjects exercising at the same workload. Therapies that decrease left-sided heart filling pressures could improve exercise capacity and possibly prognosis.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Mar 2019; 7:321-332
Wolsk E, Kaye D, Komtebedde J, Shah SJ, ... Møller JE, Gustafsson F
JACC Heart Fail: 30 Mar 2019; 7:321-332 | PMID: 30852235
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Impact:
Abstract

Adverse Drug Reactions to Guideline-Recommended Heart Failure Drugs in Women: A Systematic Review of the Literature.

Bots SH, Groepenhoff F, Eikendal ALM, Tannenbaum C, ... Asselbergs FW, den Ruijter HM
Objectives
This study sought to summarize all available evidence on sex differences in adverse drug reactions (ADRs) to heart failure (HF) medication.
Background
Women are more likely to experience ADRs than men, and these reactions may negatively affect women\'s immediate and long-term health. HF in particular is associated with increased ADR risk because of the high number of comorbidities and older age. However, little is known about ADRs in women with HF who are treated with guideline-recommended drugs.
Methods
A systematic search of PubMed and EMBASE was performed to collect all available information on ADRs to angiotensin-converting enzyme inhibitors, β-blockers, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, ivabradine, and digoxin in both women and men with HF.
Results
The search identified 155 eligible records, of which only 11 (7%) reported ADR data for women and men separately. Sex-stratified reporting of ADRs did not increase over the last decades. Six of the 11 studies did not report sex differences. Three studies reported a higher risk of angiotensin-converting enzyme inhibitor-related ADRs in women, 1 study showed higher digoxin-related mortality risk for women, and 1 study reported a higher risk of mineralocorticoid receptor antagonist-related ADRs in men. No sex differences in ADRs were reported for angiotensin II receptor blockers and β-blockers. Sex-stratified data were not available for ivabradine.
Conclusions
These results underline the scarcity of ADR data stratified by sex. The study investigators call for a change in standard scientific practice toward reporting of ADR data for women and men separately.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:258-266
Bots SH, Groepenhoff F, Eikendal ALM, Tannenbaum C, ... Asselbergs FW, den Ruijter HM
JACC Heart Fail: 27 Feb 2019; 7:258-266 | PMID: 30819382
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Impact:
Abstract

Sex-Related Differences in Use and Outcomes of Left Ventricular Assist Devices as Bridge to Transplantation.

DeFilippis EM, Truby LK, Garan AR, Givens RC, ... Farr MA, Topkara VK
Objectives
This study examined sex-related differences in use and outcomes of continuous-flow left ventricular assist devices (CF-LVADs) among individuals awaiting heart transplantation using the United Network for Organ Sharing registry.
Background
Advanced therapies for heart failure including CF-LVADs remain underused in women. There have been contradictory results regarding sex-specific outcomes. Many studies have been limited by small sample sizes or included pulsatile-flow devices.
Methods
De-identified patient-level data were obtained from the United Network for Organ Sharing database. The database was queried to identify adult patients (≥18 years of age) who required mechanical circulatory support with HeartWare HVAD (Medtronic, Minneapolis, Minnesota), HeartMate II (Abbott, Lake Bluff, Illinois), or HeartMate 3 (Abbott) as bridge to heart transplantation between 2008 and 2018. Each patient was assigned a propensity score. The primary outcomes of interest were rates of transplantation and death.
Results
A total of 13,305 patients (2,771 women, 20.8%) received support with CF-LVAD in the study period. There were significant sex disparities in CF-LVAD use in listed patients (29.9% men vs. 18.9% women in 2017). Female patients receiving CF-LVAD support had lower chances of heart transplantation (55.1% vs. 67.5%), increased risk of waitlist mortality (7.0% vs. 4.2%), and delisting for worsening clinical status (8.5% vs. 4.7%) at 2 years post-implantation (all p < 0.001). After adjusting for device type, sex was still a significant predictor of waitlist mortality (hazard ratio: 1.51; p < 0.001).
Conclusions
Durable mechanical circulatory support with CF-LVADs remains underused in women. When matched with similar male control subjects, women experienced higher mortality and lower rates of heart transplantation.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:250-257
DeFilippis EM, Truby LK, Garan AR, Givens RC, ... Farr MA, Topkara VK
JACC Heart Fail: 27 Feb 2019; 7:250-257 | PMID: 30819381
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Impact:
Abstract

Sex Differences in Heart Failure With Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis.

Beale AL, Nanayakkara S, Segan L, Mariani JA, ... Lam CSP, Kaye DM
Objectives
This study sought to identify sex differences in central and peripheral factors that contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) by using complementary invasive hemodynamic and echocardiographic approaches.
Background
Women are overrepresented among patients with HFpEF, and there are established sex differences in myocardial structure and function. Exercise intolerance is a fundamental feature of HFpEF; however, sex differences in the physiological determinants of exercise capacity in HFpEF are yet to be established.
Methods
Patients with exertional intolerance with confirmed HFpEF were included in this study. Evaluation of the subjects included resting and exercise hemodynamics, echocardiography, and mixed venous blood gas sampling.
Results
A total of 161 subjects included 114 females (71%). Compared to males, females had a higher pulmonary capillary wedge pressure (PCWP) indexed to peak exercise workload (0.8 [0.5 to 1.2] mm Hg/W vs. 0.6 [0.4 to 1] mm Hg/W, respectively; p = 0.001) and lower systemic (1.1 [0.9 to 1.5] ml/mm Hg vs. 1 [0.7 to 1.2] ml/mm Hg, respectively; p = 0.019) and pulmonary (2.9 [2.2 to 4.2] ml/mm Hg vs. 2.4 [1.9 to 3] ml/mm Hg, respectively; p = 0.032) arterial compliance at exercise. Mixed venous blood gas analysis demonstrated a greater rise in lactate indexed to peak workload (0.05 [0.04 to 0.09] mmol/l/W vs. 0.04 [0.03 to 0.06] mmol/l/W, respectively; p = 0.007) in women compared to men. Women had higher mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e\') ratios at rest and peak exercise, along with a higher ejection fraction and smaller ventricular dimensions.
Conclusions
Women with HFpEF demonstrate poorer diastolic reserve with higher echocardiographic and invasive measurements of left ventricular filling pressures at exercise, accompanied by lower systemic and pulmonary arterial compliance and poorer peripheral oxygen kinetics.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:239-249
Beale AL, Nanayakkara S, Segan L, Mariani JA, ... Lam CSP, Kaye DM
JACC Heart Fail: 27 Feb 2019; 7:239-249 | PMID: 30819380
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Impact:
Abstract

Sex Differences in Outcomes and Responses to Spironolactone in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of TOPCAT Trial.

Merrill M, Sweitzer NK, Lindenfeld J, Kao DP
Objectives
This study sought to investigate sex differences in outcomes and responses to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF).
Background
HFpEF affects women more frequently than men. Sex differences in responses to effects of mineralocorticoid antagonists have not been reported.
Methods
This was an exploratory, post hoc, non-pre-specified analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. Subjects with symptomatic HF and a left ventricular ejection fraction ≥45% were randomized to spironolactone or placebo therapy. Subjects enrolled from the Americas were analyzed. The primary outcome was a composite of cardiovascular (CV) death, cardiac arrest, or HF hospitalization. Secondary outcomes included all-cause mortality, CV, and non-CV mortality and CV, HF, and non-CV hospitalization. Sex differences in outcomes and treatment effects were determined using time-to-event analysis.
Results
In total, 882 of 1,767 subjects (49.9%) were women. Women were older with fewer comorbidities but worse patient-reported outcomes. There were no sex differences in outcomes in the placebo arm or in response to spironolactone for the primary outcome or its components. Spironolactone therapy was associated with reduced all-cause mortality in women (hazard ratio: 0.66; p = 0.01) but not in men (p = 0.02).
Conclusions
In TOPCAT, women and men presented with different clinical profiles and similar clinical outcomes. The interaction between spironolactone and sex in TOPCAT overall and in the present analysis was nonsignificant for the primary outcome, but there was a reduction in all-cause mortality associated with spironolactone therapy in women, with a significant interaction between sex and treatment arm. Prospective evaluation is needed to determine whether spironolactone therapy may be effective for treatment of HFpEF in women. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:228-238
Merrill M, Sweitzer NK, Lindenfeld J, Kao DP
JACC Heart Fail: 27 Feb 2019; 7:228-238 | PMID: 30819379
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Impact:
Abstract

Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab.

Banke A, Fosbøl EL, Ewertz M, Videbæk L, ... Schou M, Møller JE
Objectives
This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy.
Background
Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described.
Methods
In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks.
Results
Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment.
Conclusions
Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:217-224
Banke A, Fosbøl EL, Ewertz M, Videbæk L, ... Schou M, Møller JE
JACC Heart Fail: 27 Feb 2019; 7:217-224 | PMID: 30819377
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Impact:
Abstract

Sex-Specific Epidemiology of Heart Failure Risk and Mortality in Europe: Results From the BiomarCaRE Consortium.

Magnussen C, Niiranen TJ, Ojeda FM, Gianfagna F, ... Schnabel RB,
Objectives
This study investigates differences between women and men in heart failure (HF) risk and mortality.
Background
Sex differences in HF epidemiology are insufficiently understood.
Methods
In 78,657 individuals (median 49.5 years of age; age range 24.1 to 98.7 years; 51.7% women) from community-based European studies (FINRISK, DanMONICA, Moli-sani, Northern Sweden) of the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium, the association between incident HF and mortality, the relationship of cardiovascular risk factors, prevalent cardiovascular diseases, biomarkers (C-reactive protein [CRP]; N-terminal pro-B-type natriuretic peptide [NT-proBNP]) with incident HF, and their attributable risks were tested in women vs. men.
Results
Over a median follow-up of 12.7 years, fewer HF cases were observed in women (n = 2,399 [5.9%]) than in men (n = 2,771 [7.3%]). HF incidence increased markedly after 60 years of age, initially with a more rapid increase in men, whereas incidence in women exceeded that of men after 85 years of age. HF onset substantially increased mortality risk in both sexes. Multivariable-adjusted Cox models showed the following sex differences for the association with incident HF: systolic blood pressure hazard ratio (HR) according to SD in women of 1.09 (95% confidence interval [CI]: 1.05 to 1.14) versus HR of 1.19 (95% CI: 1.14 to 1.24) in men; heart rate HR of 0.98 (95% CI: 0.93 to 1.03) in women versus HR of 1.09 (95% CI: 1.04 to 1.13) in men; CRP HR of 1.10 (95% CI: 1.00 to 1.20) in women versus HR of 1.32 (95% CI: 1.24 to 1.41) in men; and NT-proBNP HR of 1.54 (95% CI: 1.37 to 1.74) in women versus HR of 1.89 (95% CI: 1.75 to 2.05) in men. Population-attributable risk of all risk factors combined was 59.0% in women and 62.9% in men.
Conclusions
Women had a lower risk for HF than men. Sex differences were seen for systolic blood pressure, heart rate, CRP, and NT-proBNP, with a lower HF risk in women.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:204-213
Magnussen C, Niiranen TJ, Ojeda FM, Gianfagna F, ... Schnabel RB,
JACC Heart Fail: 27 Feb 2019; 7:204-213 | PMID: 30819375
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Impact:
Abstract

Is Cardiac Diastolic Dysfunction a Part of Post-Menopausal Syndrome?

Maslov PZ, Kim JK, Argulian E, Ahmadi A, ... Bax J, Narula J

Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.

Copyright © 2019. Published by Elsevier Inc.

JACC Heart Fail: 27 Feb 2019; 7:192-203
Maslov PZ, Kim JK, Argulian E, Ahmadi A, ... Bax J, Narula J
JACC Heart Fail: 27 Feb 2019; 7:192-203 | PMID: 30819374
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Impact:
Abstract

Primary Prevention of Heart Failure in Women.

Daubert MA, Douglas PS

The incidence of heart failure (HF) is increasing, particularly among women, and constitutes a rapidly growing public health problem. The primary prevention of HF in women should involve targeted, sex-specific strategies to increase awareness, promote a heart healthy lifestyle, and improve treatments that optimally control the risk factors for HF with reduced ejection fraction and HF with preserved ejection fraction. Epidemiological and pathophysiological differences in both HF subtypes strongly suggest that sex-specific preventive strategies and risk factor reduction may be particularly beneficial. However, significant gaps in sex-specific knowledge exist and are impeding preventive efforts. To overcome these limitations, women need to be adequately represented in HF research, sex differences must be prospectively investigated, and effective sex-specific interventions should be incorporated into clinical practice guidelines. This review summarizes the existing evidence that supports the primary prevention of HF in women and identifies potential strategies that are most likely to be effective in reducing the burden of HF among women.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2019; 7:181-191
Daubert MA, Douglas PS
JACC Heart Fail: 27 Feb 2019; 7:181-191 | PMID: 30819373
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Impact:
Abstract

Income Inequality and Outcomes in Heart Failure: A Global Between-Country Analysis.

Dewan P, Rørth R, Jhund PS, Ferreira JP, ... McMurray JJV,
Objectives
This study examined the relationship between income inequality and heart failure outcomes.
Background
The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes.
Methods
This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density.
Results
Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively.
Conclusions
Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Mar 2019; 7:336-346
Dewan P, Rørth R, Jhund PS, Ferreira JP, ... McMurray JJV,
JACC Heart Fail: 30 Mar 2019; 7:336-346 | PMID: 30738981
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Impact:
Abstract

Impact of Degree of Left Ventricular Remodeling on Clinical Outcomes From Cardiac Resynchronization Therapy.

Shamoun F, De Marco T, DeMets D, Mei C, ... Feldman AM, Bristow MR
Objectives
This study tested the hypothesis that the extent of left ventricular (LV) eccentric structural remodeling in heart failure with reduced ejection fraction (HFrEF) is directly associated with clinical event responses to cardiac resynchronization therapy (CRT).
Background
Whether the severity of LV structural remodeling influences CRT treatment effects is unknown.
Methods
COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure) trial data were analyzed retrospectively. Left ventricular internal dimensions at end diastole indexed by body surface area (LVEDDI) were measured pre-randomization by 2-dimensional echocardiography. LVEDDI values were stratified around the median value of 35 mm/m, and CRT (including CRT-P [CRT with only pacing capability] and/or CRT-D [CRT with an implantable defibrillator]) treatment effects were assessed and compared by LVEDDI group. Patients assigned to these treatments were compared to those undergoing optimal pharmacologic therapy (OPT) for the outcomes of all-cause mortality (ACM) or ACM and heart-failure hospitalization (ACM/HFH).
Results
In the LVEDDI ≥35 mm/m group (n = 614), CRT vs. OPT was associated with a lower ACM/HFH hazard ratio (HR) (HR: 0.53; 95% confidence interval [CI]: 0.40 to 0.70; p <0.001), whereas in the LVEDDI <35 mm/m group, the CRT vs. OPT ACM/HFH hazard ratio was not statistically significant (HR: 0.80; 95% CI: 0.59 to 1.08; p = 0.15). For ACM alone, in the LVEDDI ≥35 mm/m group, the hazard ratio for CRT-P was 0.59 (95% CI: 0.39 to 0.90; p = 0.012) and for CRT-D 0.50 (95% CI: 0.32 to 0.77; p = 0.002). Neither of the CRT groups showed a statistically significant reduction in ACM in the LVEDDI <35 mm/m group.
Conclusions
Larger versus smaller LVEDDIs are associated with a reduction in ACM with CRT-P or CRT-D treatment, and with a more effective reduction in ACM/HFH for the combined CRT treatment groups.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Mar 2019; 7:281-290
Shamoun F, De Marco T, DeMets D, Mei C, ... Feldman AM, Bristow MR
JACC Heart Fail: 30 Mar 2019; 7:281-290 | PMID: 30738980
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Impact:
Abstract

Target Doses of Heart Failure Medical Therapy and Blood Pressure: Insights From the CHAMP-HF Registry.

Peri-Okonny PA, Mi X, Khariton Y, Patel KK, ... Patterson JH, Spertus JA
Objectives
This study sought to determine the rate of use of target doses of foundational guideline-directed medical therapy (GDMT) in a contemporary cohort of patients with heart failure with reduced ejection fraction (HFrEF) across systolic blood pressure (SBP) categories.
Background
Patients with HFrEF are infrequently titrated to recommended doses of GDMT. The relationship between SBP and achieving GDMT target doses is not well studied.
Methods
Patients enrolled in the CHAMP-HF (Change the Management of Patients With Heart Failure) registry without documented intolerance to angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and beta blockers (BBs) were assessed at enrollment. We estimated the proportion receiving target doses (% of target dose [95% confidence interval (CI)]) based on the most recent American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure guidelines at baseline in all patients, and by SBP category (≥110 vs. <110 mm Hg).
Results
Of the 3,095 patients eligible for analysis, 2,421 (78.2%) had SBP ≥110 mm Hg. The proportion of patients receiving target doses were 18.7% (95% CI: 17.3% to 20.0%; BB), 10.8% (95% CI: 9.7% to 11.9%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.5%; ARNI). Among those with SBP <110 mm Hg (n = 674), 17.5% (95% CI: 14.6% to 20.4%; BB), 6.2% (95% CI: 4.4% to 8.1%; ACEI/ARB), and 1.8% (95% CI: 0.8% to 2.8%; ARNI) were receiving target doses. Among those with SBP ≥110 mm Hg (n = 2,421), 19.0% (95% CI: 17.4% to 20.6%; BB), 12.1% (95% CI: 10.8% to 13.4%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.6%; ARNI) were receiving target doses.
Conclusions
In a large, contemporary registry of outpatients with chronic HFrEF eligible for treatment with BBs and ACEI/ARB/ARNI, <20% of patients were receiving target doses, even among those with SBP ≥110 mm Hg.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Mar 2019; 7:350-358
Peri-Okonny PA, Mi X, Khariton Y, Patel KK, ... Patterson JH, Spertus JA
JACC Heart Fail: 30 Mar 2019; 7:350-358 | PMID: 30738978
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Impact:
Abstract

Identification of Frailty in Chronic Heart Failure.

Sze S, Pellicori P, Zhang J, Weston J, Clark AL
Objectives
This study sought to report the prevalence of frailty, classification performance, and agreement among 3 frailty assessment tools and 3 screening tools in chronic heart failure (CHF) patients.
Background
Frailty is common in patients with CHF. There are many available frailty tools, but no standard method for evaluating frailty.
Methods
We used the following frailty screening tools: the clinical frailty scale (CFS); the Derby frailty index; and the acute frailty network frailty criteria. We used the following frailty assessment tools: the Fried criteria; the Edmonton frailty score; and the Deficit Index.
Results
A total of 467 consecutive ambulatory CHF patients (67% male; median age: 76 years; interquartile range [IQR]: 69 to 82 years; median N-terminal pro-B-type natriuretic peptide: 1,156 ng/l [IQR: 469 to 2,463 ng/l]) and 87 control patients (79% male; median age: 73 years; IQR: 69 to 77 years) were studied. The prevalence of frailty using the different tools was higher in CHF patients than in control patients (30% to 52% vs. 2% to 15%, respectively). Frail patients tended to be older, have worse symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and more comorbidities. Of the screening tools, CFS had the strongest correlation and agreement with the assessment tools (correlation coefficient: 0.86 to 0.89, kappa coefficient: 0.65 to 0.72, depending on the frailty assessment tools, all p < 0.001). CFS had the highest sensitivity (87%) and specificity (89%) among screening tools and the lowest misclassification rate (12%) among all 6 frailty tools in identifying frailty according to the standard combined frailty index.
Conclusions
Frailty is common in CHF patients and is associated with increasing age, comorbidities, and severity of heart failure. CFS is a simple screening tool that identifies a similar group using more lengthy assessment tools.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Mar 2019; 7:291-302
Sze S, Pellicori P, Zhang J, Weston J, Clark AL
JACC Heart Fail: 30 Mar 2019; 7:291-302 | PMID: 30738977
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Impact:
Abstract

Cardiac Dysfunction Among People Living With HIV: A Systematic Review and Meta-Analysis.

Erqou S, Lodebo BT, Masri A, Altibi AM, ... Wu WC, Kengne AP
Objective
To synthesize existing epidemiological data on cardiac dysfunction in HIV.
Background
Data on the burden and risk of human immunodeficiency virus (HIV) infection-associated cardiac dysfunction have not been adequately synthesized. We performed meta-analyses of extant literature on the frequency of several subtypes of cardiac dysfunction among people living with HIV.
Methods
We searched electronic databases and reference lists of review articles and combined the study-specific estimates using random-effects model meta-analyses. Heterogeneity was explored using subgroup analyses and meta-regressions.
Results
We included 63 reports from 54 studies comprising up to 125,382 adults with HIV infection and 12,655 cases of various cardiac dysfunctions. The pooled prevalence (95% confidence interval) was 12.3% (6.4% to 19.7%; 26 studies) for left ventricular systolic dysfunction (LVSD); 12.0% (7.6% to 17.2%; 17 studies) for dilated cardiomyopathy; 29.3% (22.6% to 36.5%; 20 studies) for grades I to III diastolic dysfunction; and 11.7% (8.5% to 15.3%; 11 studies) for grades II to III diastolic dysfunction. The pooled incidence and prevalence of clinical heart failure were 0.9 per 100 person-years (0.4 to 2.1 per 100 person-years; 4 studies) and 6.5% (4.4% to 9.6%; 8 studies), respectively. The combined prevalence of pulmonary hypertension and right ventricular dysfunction were 11.5% (5.5% to 19.2%; 14 studies) and 8.0% (5.2% to 11.2%; 10 studies), respectively. Significant heterogeneity was observed across studies for all the outcomes analyzed (I > 70%, p < 0.01), only partly explained by available study level characteristics. There was a trend for lower prevalence of LVSD in studies reporting higher antiretroviral therapy use or lower proportion of acquired immune deficiency syndrome. The prevalence of LVSD was higher in the African region. After taking into account the effect of regional variation, there was evidence of lower prevalence of LVSD in studies published more recently.
Conclusions
Cardiac dysfunction is frequent in people living with HIV. Additional prospective studies are needed to better understand the burden and risk of various forms of cardiac dysfunction related to HIV and the associated mechanisms. (Cardiac dysfunction in people living with HIV-a systematic review and meta-analysis; CRD42018095374).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:98-108
Erqou S, Lodebo BT, Masri A, Altibi AM, ... Wu WC, Kengne AP
JACC Heart Fail: 30 Jan 2019; 7:98-108 | PMID: 30704613
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Impact:
Abstract

Practical Guide to Prescribing Sodium-Glucose Cotransporter 2 Inhibitors for Cardiologists.

Vardeny O, Vaduganathan M

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering therapies that have been shown to reduce risks of heart failure (HF) events in patients with type 2 diabetes mellitus (T2DM) at high-risk for or with cardiovascular disease. The United States Food and Drug Administration has expanded the regulatory label for empagliflozin and canagliflozin for use to lower cardiovascular risk in patients with T2DM and cardiovascular disease. SGLT2 inhibitors are being actively studied in the treatment of patients with HF, including in those without diabetes mellitus. Despite the accumulating data supporting this class of therapies in HF prevention, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to lack of familiarity with their use. We provide an up-to-date practical guide highlighting important elements for treatment initiation, dosing, anticipated adverse effects, and barriers to uptake.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:169-172
Vardeny O, Vaduganathan M
JACC Heart Fail: 30 Jan 2019; 7:169-172 | PMID: 30704605
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Impact:
Abstract

Cardiac Abnormalities in Alzheimer Disease: Clinical Relevance Beyond Pathophysiological Rationale and Instrumental Findings?

Sanna GD, Nusdeo G, Piras MR, Forteleoni A, ... Parodi G, Ganau A
Objectives
This case control study sought to assess the presence and characteristics of cardiac abnormalities in patients with Alzheimer disease (AD).
Background
Protein misfolding is involved in the pathophysiology of neurodegenerative disorders such as AD. Recently, amyloid-beta (Aβ) aggregates were identified within the cardiomyocytes and interstitium of patients with AD, suggesting that Aβ oligomers may reach and damage the heart.
Methods
The authors studied 32 patients with AD and 34 controls matched by age and sex, all of whom were free from cardiac or systemic diseases. A clinical evaluation, an electrocardiogram, and an echocardiogram were performed in all subjects. Furthermore, patients with AD underwent genetic analyses (of the PSEN1, PSEN2, APP, and APOE genes).
Results
Compared to the control group, patients with AD had a higher prevalence of low-voltage electrocardiographic QRS complexes (28% vs. 3%, respectively; p = 0.004), a lower voltage/mass ratio (p = 0.05), a greater echocardiographic interventricular septum (10.1 ± 1.3 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.01), a greater maximum wall thickness (10.8 ± 1.7 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.0001), and a 2-fold higher prevalence of diastolic dysfunction (70% vs. 35%, respectively; p = 0.007). Symptoms and signs of heart failure were absent in all patients with AD.
Conclusions
This study shows that electrocardiographic and echocardiographic abnormalities, including diastolic dysfunction, are present in patients with AD and that these studies reproduce the pattern of cardiac amyloidosis. These findings suggest that, in AD, there may be subclinical cardiac involvement likely associated with Aβ amyloid deposition. The clinical relevance of these cardiac abnormalities should be evaluated in larger prospective studies.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:121-128
Sanna GD, Nusdeo G, Piras MR, Forteleoni A, ... Parodi G, Ganau A
JACC Heart Fail: 30 Jan 2019; 7:121-128 | PMID: 30704603
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Impact:
Abstract

NT-proBNP Goal Achievement Is Associated With Significant Reverse Remodeling and Improved Clinical Outcomes in HFrEF.

Daubert MA, Adams K, Yow E, Barnhart HX, ... Januzzi J, Felker GM
Objectives
This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.
Background
In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.
Methods
The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) Echo Substudy was a multicenter study that randomized 268 patients with HFrEF (EF ≤40%) to either pro-B-type natriuretic peptide (NT-proBNP)-guided treatment or usual care. Echocardiograms were performed at baseline and 12 months in 124 patients. Remodeling indices and clinical outcomes were compared between treatment arms and by achievement of the NT-proBNP goal of <1,000 pg/ml at 12 months.
Results
At 12 months, the changes in EF and LV volumes were similar between the biomarker-guided and usual care arms with no difference in clinical outcomes; however, lowering NT-proBNP to <1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF compared with those not reaching goal (9.9 ± 8.8% vs. 2.9 ± 7.9%; p < 0.001) and lower LV volumes. The extent of reverse remodeling correlated with the change in NT-proBNP: a decrease of 1,000 pg/ml was associated with an increase in EF of 6.7% and a reduction in systolic and diastolic volumes of 17.3 ml/m and 15.7 ml/m, respectively. Adverse events were significantly lower among patients achieving the NT-proBNP goal (p < 0.001).
Conclusions
Among patients with HFrEF, lowering NT-proBNP to <1,000 pg/ml by 12 months was associated with significant reverse remodeling and improved outcomes. A greater reduction in NT-proBNP was associated with more extensive reverse remodeling. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:158-168
Daubert MA, Adams K, Yow E, Barnhart HX, ... Januzzi J, Felker GM
JACC Heart Fail: 30 Jan 2019; 7:158-168 | PMID: 30611722
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Impact:
Abstract

Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome: A Systematic Review and Meta-Regression Study.

Pelliccia F, Pasceri V, Patti G, Tanzilli G, ... Gaudio C, Camici PG
Objectives
This study assessed the incidence of long-term adverse outcomes in patients with Takotsubo syndrome (TTS).
Background
The long-term prognosis of TTS is controversial. It is also unclear whether presenting characteristics are associated with the subsequent long-term prognosis.
Methods
We searched the PubMed, Embase, and Cochrane databases and reviewed cited references up to March 31, 2018, to identify studies with >6 months of follow-up data.
Results
Overall, we selected 54 studies that included a total of 4,679 patients (4,077 women and 602 men). Death during admission occurred in 112 patients (2.4%), yielding a frequency of 1.8% (95% confidence interval [CI]: 1.2% to 2.5%), with significant heterogeneity (I = 78%; p < 0.001). During a median follow-up of 28 months (interquartile range: 23 to 34 months), 464 of 4,567 patients who the survived index admission died (103 because of cardiac causes and 351 because of noncardiac issues). The annual rate of total mortality was 3.5% (95% CI: 2.6% to 4.5%), with significant heterogeneity (I = 74%; p < 0.001). Overall, 104 cases of recurrence of TTS were detected during follow-up, yielding a 1.0% annual rate of recurrence (95% CI: 0.7% to 1.3%), without significant heterogeneity (I = 39%; p = 0.898). Meta-regression analysis showed that long-term total mortality in each study was significantly associated with older age (p = 0.05), physical stressor (p = 0.0001), and the atypical ballooning form of TTS (p = 0.009).
Conclusions
Our update analysis of patients discharged alive after TTS showed that long-term rates of overall mortality and recurrence were not trivial, and that some presenting features (older age, physical stressor, and atypical ballooning) were significantly associated with an unfavorable long-term prognosis.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:143-154
Pelliccia F, Pasceri V, Patti G, Tanzilli G, ... Gaudio C, Camici PG
JACC Heart Fail: 30 Jan 2019; 7:143-154 | PMID: 30611720
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Impact:
Abstract

Effect of Influenza on Outcomes in Patients With Heart Failure.

Panhwar MS, Kalra A, Gupta T, Kolte D, ... Bhatt DL, Ginwalla M
Objectives
This study sought to determine whether influenza infection increases morbidity and mortality in patients hospitalized with heart failure (HF).
Background
Patients with HF may be at increased risk of morbidity and mortality from influenza infection. However, there are limited data for the associated hazards of influenza infection in patients with HF.
Methods
We queried the 2013 to 2014 National Inpatient Sample database for all adult patients (18 years of age or older) admitted with HF with and without concomitant influenza infection. Propensity score matching was used to match patients across age, race, sex, and comorbidities. Outcomes included in-hospital mortality, in-hospital complications, length of stay, and average hospital costs.
Results
Of 8,189,119 all-cause hospitalizations in patients with HF, 54,590 (0.67%) had concomitant influenza infection. Patients with concomitant influenza had higher incidence of in-hospital mortality (6.2% vs. 5.4%, respectively; odds ratio [OR]: 1.15 [95% confidence interval [CI]: 1.03 to 1.30]; p = 0.02), acute respiratory failure (36.9% vs. 23.1%, respectively; OR: 1.95 [95% CI: 1.83 to 2.07]; p < 0.001), acute respiratory failure requiring mechanical ventilation (18.2% vs. 11.3%, respectively; OR: 1.75 [95% CI: 1.62 to 1.89]; p < 0.001), acute kidney injury (AKI) (30.3% vs. 28.7%, respectively; OR: 1.08 [95% CI: 1.02 to 1.15]; p = 0.01), and AKI requiring dialysis (2.4% vs. 1.8%, respectively; OR: 1.37 [95% CI: 1.14 to 1.65]; p = 0.001). Patients with influenza had longer mean lengths of stay (5.9 days vs. 5.2 days, respectively; p <0.001) but similar average hospital costs ($12,137 vs. $12,003, respectively; p = 0.40).
Conclusions
Influenza infection is associated with increased in-hospital morbidity and mortality in patients with HF. Our results emphasize the need for efforts to mitigate the incidence of influenza, specifically in this high-risk patient cohort.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:112-117
Panhwar MS, Kalra A, Gupta T, Kolte D, ... Bhatt DL, Ginwalla M
JACC Heart Fail: 30 Jan 2019; 7:112-117 | PMID: 30611718
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Impact:
Abstract

Efficacy and Safety of Spironolactone in Patients With HFpEF and Chronic Kidney Disease.

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

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:25-32
Beldhuis IE, Myhre PL, Claggett B, Damman K, ... Solomon SD, Desai AS
JACC Heart Fail: 30 Dec 2018; 7:25-32 | PMID: 30606484
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Impact:
Abstract

Contemporary Drug Treatment of Chronic Heart Failure With Reduced Ejection Fraction: The CHECK-HF Registry.

Brunner-La Rocca HP, Linssen GC, Smeele FJ, van Drimmelen AA, ... Brugts JJ,
Objectives
This study investigated adherence to drug therapy guidelines in heart failure (HF) with reduced left-ventricular ejection fraction (LVEF) of <40% (heart failure with reduced ejection fraction [HFrEF]), in which evidence-based treatment has been established.
Background
Despite previous surveys of HF, important uncertainties remain regarding guideline adherence in a representative real-world population.
Methods
A cross-sectional registry in 34 Dutch HF outpatient clinics that included 10,910 patients with the diagnosis of HF was examined. Of that number, 8,360 patients had LVEF <50% (72 ± 12 years of age; 64% male) and were divided into HFrEF (n = 5,701), HF with mid-range LVEF (HFmrEF) with LVEF 40% to 49% (n = 1,574), and those with semiquantitatively measured LVEF but <50% (n = 1,085).
Results
In the HFrEF group, 81% of the patients were treated with loop diuretics, 84% with renin-angiotensin-system (RAS) inhibitors, 86% with β-blockers, 56% with mineralocorticoid-receptor antagonists (MRA), and 5% with I-channel inhibition. Differences in medication use were minor among the 3 groups but were significant among centers. Inability to tolerate the medications was recorded in 9.4% patients taking RAS inhibitors, 3.3% taking β-blockers, and 5.4% taking MRAs. Median loop diuretic dose was 40 mg of furosemide equivalent, RAS inhibitor dose 50% of target, β-blocker dose 25% of target, and MRA dose 12.5 mg of spironolactone equivalent. Elderly patients were treated predominantly with diuretics and less often with RAS inhibitors, β-blockers, and MRAs.
Conclusions
This large contemporary HF registry showed a relatively high use of evidence-based treatment, particularly in younger patients. However, the average dose of evidence-based medication was still lower than recommended by guidelines. Furthermore, the more recently introduced I-channel inhibition has hardly been adopted. There is ample room for improvement of HFrEF therapy, even more than 25 years after convincing evidence that HFrEF treatment leads to better outcome.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:13-21
Brunner-La Rocca HP, Linssen GC, Smeele FJ, van Drimmelen AA, ... Brugts JJ,
JACC Heart Fail: 30 Dec 2018; 7:13-21 | PMID: 30606482
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Impact:
Abstract

Emerging Trends in Financing of Adult Heart Transplantation in the United States.

DeFilippis EM, Vaduganathan M, Machado S, Stehlik J, Mehra MR
Objectives
This study examined longitudinal trends in types of payers for adult heart transplantations in the United States.
Background
In the last decade, volume of heart transplantations in the United States has substantially increased, a trend that has coincided with Medicaid expansion and greater insurance coverage in the general U.S.
Population
Limited data are available characterizing the changes in payer mix supporting these recent increases in heart transplantation activity.
Methods
De-identified data were obtained from the Organ Procurement and Transplantation Network for heart transplantation recipients 18 to 64 years of age in the United States between 1997 and 2017. Primary sources of insurance payment were determined at the time of transplantation in aggregate and stratified by sex and race. Changes in volume and payer mix of patients added to the candidate waitlist between 1997 and 2017 were also examined.
Results
A total of 36,340 adults from 18 to 64 years of age underwent heart transplantations between 1997 and 2017. Support by public payer insurance increased from 28.2% (in 1997) to a peak of 48.8% (in 2016). Medicaid coverage increased from 9.4% in 1997 to 15.5% in 2007 and remained stable to 2017 (14.7%; β-coefficient: +0.23% [0.04]; p < 0.001 for trend). Medicare beneficiaries accounted for 18.2% of recipients in 1997, 22% in 2007, and 30.3% in 2016 (β-coefficient: +0.60% [0.06]; p < 0.001 for trend). The proportion of transplantation candidates receiving Medicare coverage increased over time across all races and both sexes. Similar aggregate patterns were observed in waitlist trends for adult heart transplantation candidates.
Conclusions
Public payer insurance has emerged as an increasingly dominant source of funding for adult heart transplantations in the United States, supporting nearly half of all transplants in 2017.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:56-62
DeFilippis EM, Vaduganathan M, Machado S, Stehlik J, Mehra MR
JACC Heart Fail: 30 Dec 2018; 7:56-62 | PMID: 30553907
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Impact:
Abstract

Incidence, Predictors, and Outcome Associations of Dyskalemia in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction.

Savarese G, Xu H, Trevisan M, Dahlström U, ... Lund LH, Carrero JJ
Objectives
This study investigated 1-year incidence and predictors of dyskalemia (dysK) and its outcome associations in heart failure with preserved ejection fraction (HFpEF), HF with mid-range EF (HFmrEF), and HF with reduced EF (HFrEF).
Background
DysK in real-world HF is insufficiently characterized. Fear of dyskalemia may lead to underuse or underdosing of renin-angiotensin-aldosterone system inhibitors.
Methods
Patients enrolled in the SwedeHF (Swedish Heart Failure) Registry from 2006 to 2011 in Stockholm, Sweden were included in the analyses. Multivariate Cox regression analysis identified independent predictors of dysK within 1 year. Time-dependent Cox models assessed outcomes associated with incident dysK (all-cause death, HF, and other cardiovascular disease [CVD] hospitalizations) within 1 year from baseline.
Results
Of 5,848 patients, 24.4% experienced hyperkalemia (hyperK [K >5.0 mmol/l]) at least once, and 10.2% had moderate or severe hyperK (K >5.5 mmol/l). Adjusted risk of moderate or severe hyperK was highest in HFpEF and HFmrEF. Similarly, 20.3% of patients had at least one episode of hypokalemia (hypoK [<3.5 mmol/l]), and 3.7% had severe hypoK (<3.0 mmol/l). Adjusted risk of any hypoK was highest in HFpEF. Independent predictors of both hyperK and hypoK were sex, baseline potassium and estimated glomerular filtration rate, low hemoglobin, chronic obstructive pulmonary disease (COPD), inpatient status, and higher New York Heart Association functional class. Incident dysK was associated with increased risk of mortality. Furthermore, hypoK was associated with increased CVD hospitalizations (HF-related excluded). There was no association between dysK and HF hospitalization risk, regardless of EF.
Conclusions
DysK is common in HF and is associated with increased mortality. Risk of moderate or severe hyperK was highest in HFpEF and HFmrEF, whereas risk of hypoK was highest in HFpEF. HF severity, low hemoglobin, COPD, baseline high and low potassium, and low eGFR were relevant predictors of dysK occurrence.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:65-76
Savarese G, Xu H, Trevisan M, Dahlström U, ... Lund LH, Carrero JJ
JACC Heart Fail: 30 Dec 2018; 7:65-76 | PMID: 30553905
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Impact:
Abstract

Heart Failure and Liver Disease: Cardiohepatic Interactions.

Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F

Heart failure (HF) and liver disease often co-exist. This is because systemic disorders and diseases affect both organs (alcohol abuse, drugs, inflammation, autoimmunity, infections) and because of complex cardiohepatic interactions. The latter, which are the focus of this review, include the development of acute cardiogenic liver injury and congestive hepatopathy in HF as well as cardiac dysfunction and failure in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and sequelae following liver transplantation. The emerging role of altered liver X receptor signaling in the pathogenesis of HF comorbidities as well as of the intestinal microbiome and its metabolites in HF and liver disease are fruitful areas for future research.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:87-97
Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F
JACC Heart Fail: 30 Jan 2019; 7:87-97 | PMID: 30553904
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Impact:
Abstract

Iron Deficiency in Heart Failure: An Overview.

von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD

Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:36-46
von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD
JACC Heart Fail: 30 Dec 2018; 7:36-46 | PMID: 30553903
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Impact:
Abstract

3D Printing and Heart Failure: The Present and the Future.

Farooqi KM, Cooper C, Chelliah A, Saeed O, ... Einstein AJ, Jorde UP

Advanced imaging modalities provide essential anatomic and spatial information in patients with complex heart disease. Two-dimensional imaging can be limited in the extent to which true 3-dimensional (3D) relationships are represented. The application of 3D printing technology has increased the creation of physical models that overcomes the limitations of a 2D screen. Many groups have reported the use of 3D printing for preprocedural planning in patients with different causes of heart failure. This paper reviews the innovative applications of this technique to provide patient-specific models to improve patient care.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2019; 7:132-142
Farooqi KM, Cooper C, Chelliah A, Saeed O, ... Einstein AJ, Jorde UP
JACC Heart Fail: 30 Jan 2019; 7:132-142 | PMID: 30553901
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Impact:
Abstract

History of Atrial Fibrillation and Trajectory of Decongestion in Acute Heart Failure.

Patel RB, Vaduganathan M, Rikhi A, Chakraborty H, ... Butler J, Shah SJ
Objectives
This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL).
Background
AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding the impact of AF/AFL on relief of congestion among patients who develop AHF.
Methods
We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models.
Results
Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17).
Conclusions
More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2018; 7:47-55
Patel RB, Vaduganathan M, Rikhi A, Chakraborty H, ... Butler J, Shah SJ
JACC Heart Fail: 30 Dec 2018; 7:47-55 | PMID: 30409707
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Impact:
Abstract

Physical Activity, Fitness, and Obesity in Heart Failure With Preserved Ejection Fraction.

Pandey A, Patel KV, Vaduganathan M, Sarma S, ... Berry JD, Lavie CJ

Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and refractory to available pharmacotherapies. Our understanding of HFpEF has evolved from a disorder of diastolic dysfunction to a constellation of physiologic impairments that lead to elevated left ventricular filling pressures and exercise intolerance. Accordingly, the therapeutic and preventive focus has shifted to identifying lifestyle factors that may have more pleotropic effects on the pathophysiologic mechanisms that define HFpEF. Recent studies have demonstrated that physical inactivity, low fitness, and obesity are potential modifiable targets for prevention as well as management of HFpEF. In this review, we have discussed the emerging epidemiological, mechanistic, and clinical evidence that support the role of these lifestyle factors as key determinants of development and progression of HFpEF. We also summarize the available evidence and major knowledge gaps with regard to developing exercise training and weight loss as unique and effective therapeutic strategies for management of HFpEF.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:975-982
Pandey A, Patel KV, Vaduganathan M, Sarma S, ... Berry JD, Lavie CJ
JACC Heart Fail: 30 Dec 2017; 6:975-982 | PMID: 30497652
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Impact:
Abstract

Unloading of the Left Ventricle During Venoarterial Extracorporeal Membrane Oxygenation Therapy in Cardiogenic Shock.

Schrage B, Burkhoff D, Rübsamen N, Becher PM, ... Blankenberg S, Westermann D
Objectives
This report relates the authors\' ongoing experience with percutaneous left ventricular (LV) unloading by using a transaortic LV assist device in combination with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and provides an in-depth analysis of the hemodynamic benefit of this approach.
Background
VA-ECMO is increasingly used in cases of severe cardiogenic shock. However, increase in afterload with subsequent LV overload is a major drawback of VA-ECMO.
Methods
Consecutive patients were treated with a transaortic LV assist device in addition to VA-ECMO for cardiogenic shock. The primary endpoint was 30-day all-cause mortality. Additional endpoints included weaning from VA-ECMO and safety endpoints.
Results
Between September 2013 and January 2018, 106 patients were treated with percutaneous LV unloading, using a transaortic LV assist device in combination with VA-ECMO. Successful weaning from VA-ECMO support was achieved in 51.9% of all patients. In the overall cohort, survival at day 30 was 35.8%, which was higher than predicted by the SAVE score (20%) or by the SAPS-II score (6.9%). Right heart catheterization indicated a marked decrease of PCWP after addition of the device to VA-ECMO.
Conclusions
The strategy of percutaneous LV unloading using a transaortic LV assist device in combination with VA-ECMO improved outcome in an all-comers cohort compared to established risk scores. A prospective, randomized study is needed to further investigate this approach.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:1035-1043
Schrage B, Burkhoff D, Rübsamen N, Becher PM, ... Blankenberg S, Westermann D
JACC Heart Fail: 30 Dec 2017; 6:1035-1043 | PMID: 30497643
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Impact:
Abstract

Influence of Baseline Physical Activity Level on Exercise Training Response and Clinical Outcomes in Heart Failure: The HF-ACTION Trial.

Mediano MFF, Leifer ES, Cooper LS, Keteyian SJ, ... Mentz RJ, Fleg JL
Objectives
This study sought to evaluate the influence of baseline physical activity (PA) on responses to aerobic exercise training and clinical events in outpatients with chronic systolic heart failure (HF) from the multicenter HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial.
Background
The influence of baseline PA on exercise capacity, responses to exercise training and clinical outcomes in patients with chronic HF is unclear.
Methods
Of 2,130 participants who provided consent for this analysis, 1,494 patients (64%) had complete baseline PA data, using a modified version of the International Physical Activity Questionnaire-Short Form questionnaire and were included in the analysis; 742 received usual care and 752 were allocated to the exercise training group. Changes in exercise capacity, all-cause mortality and hospitalization, cardiovascular (CV) mortality and hospitalization, and CV mortality and HF hospitalization were evaluated as a function of baseline PA tertile.
Results
At baseline, the highest PA tertile showed greater peak oxygen uptake, cardiopulmonary exercise test duration, and 6-min walk test distance than the other 2 PA tertiles, as well as lower New York Heart Association functional class, lower Beck depression score, and lower atrial fibrillation prevalence than the lowest PA tertile. Compared to the lowest PA tertile, the middle tertile had 18% lower risk of CV death/CV hospitalizations, and the upper tertile showed 23% lower risk of CV death/HF hospitalizations. Exercise capacity and clinical outcome responses to training were similar and largely nonsignificant across baseline PA tertiles with significant benefit of training on exercise test duration for all tertiles.
Conclusions
In patients with chronic systolic HF, aerobic exercise training significantly improves exercise test duration to a similar extent across baseline PA tertiles. Although higher baseline PA was associated with lower risk of clinical events, no significant differences in event rates within each PA tertile were seen between subgroups randomized to exercise training versus usual care. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure [HF-ACTION]; NCT00047437).

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:1011-1019
Mediano MFF, Leifer ES, Cooper LS, Keteyian SJ, ... Mentz RJ, Fleg JL
JACC Heart Fail: 30 Dec 2017; 6:1011-1019 | PMID: 30497641
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Impact:
Abstract

Frequency of Transition From Stage A to Stage B Heart Failure After Initiating Potentially Cardiotoxic Chemotherapy.

Jones DN, Jordan JH, Meléndez GC, Lamar Z, ... D\'Agostino RB, Hundley WG
Objectives
This study sought to determine the prevalence of American Heart Association/American College of Cardiology Foundation (AHA/ACCF) heart failure (HF) stages after potentially cardiotoxic chemotherapy was initiated.
Background
For individuals receiving potentially cardiotoxic chemotherapy, the frequency of transitioning from Stage A to more advanced HF stages is not well described.
Methods
In 143 Stage A HF patients with breast cancer, lymphoma and leukemia, renal cell carcinoma, or sarcoma prior to and then at 3, 6, and 12 to 24 months after potentially cardiotoxic chemotherapy was initiated, we obtained blinded cardiac magnetic resonance measurements of left ventricular ejection fraction (LVEF).
Results
Three months after potentially cardiotoxic chemotherapy was initiated, 18.9% of patients transitioned from Stage A to Stage B HF. A total of 83% and 80% of patients with Stage A HF at 3 months, respectively, exhibited Stage A HF at 6 and 12 to 24 months; 68% and 56% of those with Stage B HF at 3 months, respectively, exhibited Stage B HF at 6 and 12 to 24 months (p < 0.0001 and p = 0.026, respectively).
Conclusions
Transitioning from Stage A to Stage B or remaining in Stage A HF 3 months after potentially cardiotoxic chemotherapy was initiated relates to longer-term (6 to 24 months post-treatment) assessments of HF stage.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:1023-1032
Jones DN, Jordan JH, Meléndez GC, Lamar Z, ... D'Agostino RB, Hundley WG
JACC Heart Fail: 30 Dec 2017; 6:1023-1032 | PMID: 30414819
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Impact:
Abstract

Aortic Insufficiency During Contemporary Left Ventricular Assist Device Support: Analysis of the INTERMACS Registry.

Truby LK, Garan AR, Givens RC, Wayda B, ... Takayama H, Topkara VK
Objectives
This study sought to evaluate the impact of moderate to severe aortic insufficiency (AI) on outcomes in patients with continuous flow left ventricular assist devices (CF-LVADs).
Background
Development of worsening AI is a common complication of prolonged CF-LVAD support and portends poor prognosis in single-center studies. Predictors of worsening AI and its impact on clinical outcomes have not been examined in a large cohort.
Methods
We conducted a retrospective analysis of patients with CF-LVAD in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) study. Development of significant AI was defined as the first instance of at least moderate AI. Primary outcomes of interest were survival after development of significant AI and time to adverse events, including device complications and rehospitalizations.
Results
Among 10,603 eligible patients, 1,399 patients on CF-LVAD support developed moderate to severe AI. Prevalence of significant AI progressively increased over time. Predictors of worsening AI included older age, female sex, smaller body mass index, mild pre-implantation AI, and destination therapy strategy. Moderate to severe AI was associated with significantly higher left ventricular end-diastolic diameter, reduced cardiac output, and higher levels of brain natriuretic peptide. Significant AI was associated with higher rates of rehospitalization (32.1% vs. 26.6%, respectively, at 2 years; p = 0.015) and mortality (77.2% vs. 71.4%, respectively, at 2 years; p = 0.005), conditional upon survival to 1 year.
Conclusions
Development of moderate to severe AI has a negative impact on hemodynamics, hospitalizations, and survival on CF-LVAD support. Pre- and post-implantation management strategies should be developed to prevent and treat this complication.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:951-960
Truby LK, Garan AR, Givens RC, Wayda B, ... Takayama H, Topkara VK
JACC Heart Fail: 30 Dec 2017; 6:951-960 | PMID: 30384913
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Abstract

Heart Failure Outcomes With Volume-Guided Management.

Strobeck JE, Feldschuh J, Miller WL
Objectives
This study performed a retrospective outcome analyses of a large cohort of mixed ejection fraction patients admitted for acute heart failure (HF), whose inpatient care was guided by individual quantitative blood volume analysis (BVA) results.
Background
Decongestion strategies in patients hospitalized for HF are based on clinical assessment of volume and have not integrated a quantitative intravascular volume metric.
Methods
Propensity score control matching analysis was performed in 245 consecutive HF admissions to a community hospital (September 2007 to April 2014; 78 ± 10 years of age; 50% with HF with reduced ejection fraction [HFrEF]; and 30% with Stage 4 chronic kidney disease). Total blood volume (TBV), red blood cell volume (RBCV), and plasma volume (PV) were measured at admission by using iodine-131-labeled albumin indicator-dilution technique. Decongestion strategy targeted a TBV threshold of 6% to 8% above patient-specific normative values. Anemia was treated based on cause. Hematocrit (Hct) measurements were monitored to assess effectiveness of interventions. Control subjects derived from Centers for Medicare and Medicaid Services data were matched 10:1 for demographics, comorbidity, and year of treatment.
Results
Although 66% of subjects had PV expansion, only 37% were hypervolemic (TBV >10% excess). True anemia (RBCV ≥10% deficit) was present in 62% of subjects. Treatment of true anemia without hypervolemia resulted in a rise in peripheral Hct of 2.7 ± 2.9% (p < 0.001), and diuretic treatment of hypervolemia in cases without anemia caused a 4.5 ± 3.9% (p < 0.001) increase in peripheral Hct at 11.3 ± 7.5 days after admission. Subjects had lower 30-day rates of readmission (12.2% vs. 27.7%, respectively; p < 0.001), of 30-day mortality (2.0% vs. 11.1%, respectively; p < 0.001), and of 365-day mortality (4.9% vs. 35.5%, respectively; p < 0.001) but longer lengths of stay (7.3 vs. 5.6 days, respectively; p < 0.001) than control subjects.
Conclusions
Retrospective outcomes using volume-guided HF therapy versus propensity-matched controls support the benefit of BVA in guiding volume management and reducing death and rehospitalization due to HF.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:940-948
Strobeck JE, Feldschuh J, Miller WL
JACC Heart Fail: 30 Dec 2017; 6:940-948 | PMID: 30316941
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Abstract

Forgotten No More: A Focused Update on the Right Ventricle in Cardiovascular Disease.

Amsallem M, Mercier O, Kobayashi Y, Moneghetti K, Haddad F

In the last decade, there has been renewed interest in the study of the right ventricle. It is now well established that right ventricular function is a strong predictor of mortality, not only in heart failure but also in pulmonary hypertension, congenital heart disease, and cardiothoracic surgery. The right ventricle is part of a cardiopulmonary unit with connections to the pulmonary circulation, venous return, atria, and left ventricle. In this context, ventriculoarterial coupling, interventricular interactions, and pericardial constraint become important to understand right ventricular adaptation to injury or abnormal loading conditions. This state-of-the-art review summarizes major advances that occurred in the field of right ventricular research over the last decade. The first section focuses on right ventricular physiology and pulmonary circulation. The second section discusses the emerging data on right ventricular phenotyping, highlighting the importance of myocardial deformation (strain) imaging and assessment of end-systolic dimensions. The third section reviews recent clinical trials involving patients at risk for or with established right ventricular failure, focusing on beta blockade, phosphodiesterase inhibition, and mechanical support of the failing right heart. The final section presents a perspective on active areas of research that are most likely to translate in clinical practice in the next decade.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2017; 6:891-903
Amsallem M, Mercier O, Kobayashi Y, Moneghetti K, Haddad F
JACC Heart Fail: 30 Dec 2017; 6:891-903 | PMID: 30316939
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Abstract

Importance of Nonobstructive Coronary Artery Disease in the Prognosis of Patients With Heart Failure.

Braga JR, Austin PC, Ross HJ, Tu JV, Lee DS
Objectives
This study sought to examine the prognostic significance of nonobstructive coronary artery disease (CAD) in patients with heart failure (HF), as a distinct category apart from those with normal coronary arteries.
Background
Individuals with HF are often dichotomized into ischemic versus nonischemic categories according to the underlying etiology. This binary classification creates a heterogeneous group, combining individuals with nonobstructive CAD with those with normal coronary arteries under the nonischemic label.
Methods
A cohort of individuals with HF and reduced ejection fraction undergoing invasive coronary angiography was examined and linked to administrative databases for outcomes evaluation. Patients were divided into those with normal coronary arteries, nonobstructive disease, and obstructive disease. The primary outcome was the composite of cardiovascular death, nonfatal acute myocardial infarction, nonfatal stroke, or HF hospitalization.
Results
Of 12,814 individuals, 2,656 (20.7%) had normal coronary arteries, 2,254 (17.6%) had nonobstructive CAD, and 7,904 (61.7%) had obstructive CAD. The risk of the primary outcome was increased in the nonobstructive group (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.04 to 1.32; p = 0.01) relative to those with normal coronary arteries. Nonobstructive CAD was associated with an increased hazard of cardiovascular death (HR: 1.82; 95% CI: 1.27 to 2.62; p = 0.001) and death of any cause (HR: 1.18; 95% CI: 1.05 to 1.33; p = 0.005). There were no significant differences in the rate of acute myocardial infarction, stroke, or HF hospitalization.
Conclusions
Among HF patients with reduced ejection fraction, the presence of nonobstructive CAD was independently associated with an increased hazard of the primary composite outcome and death of any cause.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 May 2019; 7:493-501
Braga JR, Austin PC, Ross HJ, Tu JV, Lee DS
JACC Heart Fail: 30 May 2019; 7:493-501 | PMID: 31078476
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Abstract

Healthy Aging and Cardiovascular Function: Invasive Hemodynamics During Rest and Exercise in 104 Healthy Volunteers.

Pandey A, Kraus WE, Brubaker PH, Kitzman DW
Objectives
The aim of this study was to evaluate the association between age and invasive cardiovascular hemodynamics during upright exercise among healthy adults.
Background
The marked age-related decline in maximal exercise oxygen uptake (peak VO) may contribute to the high burden of heart failure among older individuals and their greater severity of exertional symptoms. However, the mechanisms underlying this decline are not well understood.
Methods
A total of 104 healthy community-dwelling volunteers age 20 to 76 years well screened for cardiovascular disease underwent exhaustive upright exercise with brachial and pulmonary artery catheters; radionuclide ventriculography; and expired gas analysis for the measurement of peak VO, cardiac output, left ventricular stroke volume, end-diastolic volume, end-systolic volume, ejection fraction, pulmonary capillary wedge pressure, and arteriovenous oxygen difference.
Results
Over a 5.5-decade age range, there was a 40% decline in peak VO due primarily to reduced peak exercise cardiac output; peak arteriovenous oxygen difference was unaffected by age. The lower age-related exercise cardiac output was related to lower peak exercise heart rate and stroke volume. Aging was also associated with lower peak exercise ejection fraction, indicating reduced inotropic reserve. Peak exercise end-diastolic volume was lower with aging despite similar left ventricular filling pressure, suggesting age-related reduced diastolic compliance limiting the use of the Frank-Starling mechanism to compensate for reduced chronotropic and inotropic reserves. These age relationships were unaffected by sex.
Conclusions
The age-related decline in exercise capacity among healthy persons is due predominantly to cardiac mechanisms, including reduced chronotropic and inotropic reserve and possibly reduced Frank-Starling reserve. Peak exercise left ventricular filling pressure and arteriovenous oxygen difference are unchanged with healthy aging.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2019; epub ahead of print
Pandey A, Kraus WE, Brubaker PH, Kitzman DW
JACC Heart Fail: 03 Nov 2019; epub ahead of print | PMID: 31706837
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Abstract

Prescribing Patterns of Heart Failure-Exacerbating Medications Following a Heart Failure Hospitalization.

Goyal P, Kneifati-Hayek J, Archambault A, Mehta K, ... Maurer MS, Safford MM
Objectives
This study sought to describe the patterns of heart failure (HF)-exacerbating medications used among older adults hospitalized for HF and to examine determinants of HF-exacerbating medication use.
Background
HF-exacerbating medications can potentially contribute to adverse outcomes and could represent an important target for future strategies to improve post-hospitalization outcomes.
Methods
Medicare beneficiaries ≥65 years of age with an adjudicated HF hospitalization between 2003 and 2014 were derived from the geographically diverse REGARDS (Reasons for Geographic and Racial Difference in Stroke) cohort study. Major HF-exacerbating medications, defined as those listed on the 2016 American Heart Association Scientific Statement listing medications that can precipitate or induce HF, were examined. Patterns of prescribing medications at hospital admission and at discharge were examined, as well as changes that occurred between admission and discharge; and a multivariable logistic regression analysis was conducted to identify determinants of harmful prescribing practices following HF hospitalization (defined as either the continuation of an HF-exacerbating medications or an increase in the number of HF-exacerbating medications between hospital admission and discharge).
Results
Among 558 unique individuals, 18% experienced a decrease in the number of HF-exacerbating medications between admission and discharge, 19% remained at the same number, and 12% experienced an increase. Multivariable logistic regression analysis revealed that diabetes (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.18 to 2.75]) and small hospital size (OR: 1.93; 95% CI: 1.18 to 3.16) were the strongest, independently associated determinants of harmful prescribing practices.
Conclusions
HF-exacerbating medication regimens are often continued or started following an HF hospitalization. These findings highlight an ongoing need to develop strategies to improve safe prescribing practices in this vulnerable population.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2019; epub ahead of print
Goyal P, Kneifati-Hayek J, Archambault A, Mehta K, ... Maurer MS, Safford MM
JACC Heart Fail: 03 Nov 2019; epub ahead of print | PMID: 31706836
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This program is still in alpha version.