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Background: Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK)., Methods and Results: This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous 24 months, or estimated glomerular filtration rate < 45 mL/min/1.73 m 2 ). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥ 6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1000 patients are presented., Conclusions: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure replaces the 2013 ACCF/AHA Guideline for the Management of Heart Failure and the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose and manage patients with heart failure., Methods: A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews and other evidence conducted in human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies published through September 2021 were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021., Results and Conclusions: Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments that have high-quality published economic analyses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heart failure (HF) continues to be a major contributor of morbidity and mortality for men and women alike, yet how the predisposition for, course and management of HF differ between men and women remains underexplored. Sex differences in traditional risk factors as well as sex-specific risk factors influence the prevalence and manifestation of HF in unique ways. The pathophysiology of HF differs between men and women and may explain sex-specific differences in clinical presentation and diagnosis. This in turn, contributes to variation in response to both pharmacologic and device/surgical therapy. This review examines sex-specific differences in HF spanning prevalence, risk factors, pathophysiology, presentation, and therapies with a specific focus on highlighting gaps in knowledge with calls to action for future research efforts., (Copyright © 2021. Published by Elsevier Inc.)

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB., (Copyright © 2021. Published by Elsevier Inc.)

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%., (Published by Elsevier Inc.)

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as: At-risk for HF (Stage A) , for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-heart failure (Stage B) for patients without current or prior symptoms or signs of HF but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C) for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D) for patients with severe symptoms and/ or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT) , refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF) . The classification includes HF with reduced EF (HFrEF) : HF with LVEF ≤ 40%; HF with mid-range EF (HFmrEF) : HF with LVEF 41-49%; HF with preserved EF (HFpEF) : HF with LVEF ≥ 50%; and HF with improved EF (HFimpEF) : HF with a baseline LVEF ≤ 40%, a ≥ 10 point increase from baseline LVEF, and a second measurement of LVEF > 40., (Published by Elsevier Inc.)

Objective: The aim of this work was to evaluate the hypothesis that the distribution of circulating immune cell subsets, or their activation state, is significantly different between peripartum cardiomyopathy (PPCM) and healthy postpartum (HP) women., Background: PPCM is a major cause of maternal morbidity and mortality, and an immune-mediated etiology has been hypothesized. Cellular immunity, altered in pregnancy and the peripartum period, has been proposed to play a role in PPCM pathogenesis., Methods: The Investigation of Pregnancy-Associated Cardiomyopathy (IPAC) study enrolled 100 women presenting with a left ventricular ejection fraction of <0.45 within 2 months of delivery. Peripheral T-cell subsets, natural killer (NK) cells, and cellular activation markers were assessed by flow cytometry in PPCM women early (<6 wk), 2 months, and 6 months postpartum and compared with those of HP women and women with non-pregnancy-associated recent-onset cardiomyopathy (ROCM)., Results: Entry NK cell levels (CD3-CD56+CD16+; reported as % of CD3- cells) were significantly (P < .0003) reduced in PPCM (6.6 ± 4.9% of CD3- cells) compared to HP (11.9 ± 5%). Of T-cell subtypes, CD3+CD4-CD8-CD38+ cells differed significantly (P < .004) between PPCM (24.5 ± 12.5% of CD3+CD4-CD8- cells) and HP (12.5 ± 6.4%). PPCM patients demonstrated a rapid recovery of NK and CD3+CD4-CD8-CD38+ cell levels. However, black women had a delayed recovery of NK cells. A similar reduction of NK cells was observed in women with ROCM., Conclusions: Compared with HP control women, early postpartum PPCM women show significantly reduced NK cells, and higher CD3+CD4-CD8-CD38+ cells, which both normalize over time postpartum. The mechanistic role of NK cells and "double negative" (CD4-CD8-) T regulatory cells in PPCM requires further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD., Methods: Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model., Results: A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77)., Conclusions: CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention., (Published by Elsevier Inc.)

Background: Long-term heart failure (HF) treatment has been shown to result in reverse chamber remodeling. However, it is unknown whether sizes of cardiac chambers acutely change during HF therapy and whether these changes are associated with favorable clinical outcomes., Methods and Results: Using the Evaluation Study of Congestive Heart Failure and Pulsmonary Artery Catheterization Effectiveness (ESCAPE) trial database, echocardiographic parameters at baseline and discharge, changes from baseline to discharge, and their association with the combined endpoint of death or HF rehospitalization (HFH) at 6 months were evaluated in patients admitted with acute decompensated HF (ADHF). Also, the correlation between changes in invasive hemodynamic parameters compared with changes in echocardiographic parameters was analyzed. During the treatment of ADHF, right atrium, right ventricle, and inferior vena cava (IVC) sizes decreased acutely. Mitral regurgitation severity and mitral inflow parameters also improved significantly. However, the majority of acute changes in echocardiographic parameters did not have an impact on clinical outcome, except for the reduction in left ventricular (LV) end-diastolic and end-systolic volumes, which was associated with a reduction in the combined outcome of HFH or death. The change in invasive hemodynamics that best correlated with change in echocardiographic parameters was change in pulmonary capillary wedge pressure with change in IVC diameter and IVC collapsibility., Conclusions: This is the first study to identify the echocardiographic parameters that change during the treatment of ADHF and the echocardiographic parameters that most reliably correlate with invasive hemodynamic changes. Most changes in echocardiographic parameters were not associated with clinical outcomes, except for the reduction in LV volume, which was associated with a reduction in HFH or death., (Published by Elsevier Inc.)

Background: Few data exist on prevalence, morbidity, and mortality of pediatric heart failure hospitalizations. We tested the hypotheses that pediatric heart failure-related hospitalizations increased over time but that mortality decreased. Factors associated with mortality and length of stay were also assessed., Methods and Results: A retrospective analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database was performed for pediatric (age ≤18 years) heart failure-related hospitalizations for the years 1997, 2000, 2003, and 2006. Hospitalizations did not significantly increase over time, ranging from 11,153 (95% confidence interval [CI] 8,898-13,409) in 2003 to 13,892 (95% CI 11,528-16,256) in 2006. Hospital length of stay increased from 1997 (mean 13.8 days, 95% CI 12.5-15.2) to 2006 (mean 19.4 days, 95% CI 18.2 to 20.6). Hospital mortality was 7.3% (95% CI 6.9-8.0) and did not vary significantly between years; however, risk-adjusted mortality was less in 2006 (odds ratio 0.70, 95% CI 0.61 to 0.80). The greatest risk of mortality occurred with extracorporeal membrane oxygenation, acute renal failure, and sepsis., Conclusions: Heart failure-related hospitalizations occur in 11,000-14,000 children annually in the United States, with an overall mortality of 7%. Many comorbid conditions influenced hospital mortality., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: It is unclear whether improvement in left ventricular (LV) ejection fraction (LVEF) following treatment with a combined α(1),β(1),β(2)-blockade can be attributed to improvement in LV contractility, to a reduction in afterload, and/or to improvements in LV remodeling and chamber size. We aimed to examine whether the observed improvement in LVEF following carvedilol treatment is due to changes in intrinsic myocardial contractility beyond changes in LV chamber size or loading conditions., Methods and Results: In 49 consecutive patients with chronic heart failure (HF), LVEF ≤35%, NYHA functional class II-IV, on angiotensin-converting enzyme inhibitors but not on ß-blockers, LV contractile performance and remodeling were assessed by comprehensive echocardiography at baseline and after 3 and 6 months of treatment with carvedilol. Carvedilol treatment resulted in significant improvements in LVEF, shortening fraction, and velocity of circumferential shortening (VCF(c)). There were no significant changes in the mean arterial blood pressure or systemic vascular resistance index; but LV end-systolic wall stress (LVESS), effective arterial elastance, ventriculoarterial coupling, and LV end-diastolic and end-systolic dimensions and volumes were significantly reduced. Estimated end-systolic elastance, VCF(c)-to-LVESS ratio, and pulsatile arterial compliance significantly improved after 6 months of treatment with carvedilol. The slope of the VCF(c) relationship to LVESS worsened from 0 to 3 months, but significantly improved from 3 to 6 months., Conclusions: Despite an initial transient negative inotropic effect from 0 to 3 months, carvedilol treatment was associated with a positive inotropic effect with significant improvement in load-independent indexes of myocardial contractility beyond what can be attributed to changes in LV chamber size and load after 3 months. There were no changes in systemic vascular resistance with carvedilol treatment; however, improvement in pulsatile arterial compliance and ventriculoarterial coupling suggested enhanced cardiac mechanoenergetic performance along with improved systemic arterial compliance., (Published by Elsevier Inc.)

Background: Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF)., Methods and Results: In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E', P = .01)., Conclusions: Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined., (Published by Elsevier Inc.)

Background: Brain natriuretic peptide (BNP) levels correlate with outcomes in patients with heart failure (HF). We sought to compare the relationship between absolute and relative changes in BNP with future clinical events, and whether serial BNP measurements add prognostic information in patients treated for decompensated HF., Methods and Results: In 203 patients treated for HF, increasing tertiles of BNP levels after treatment had a hazard ratio of 1.4 (1.1-1.7, P < .01) and increasing tertiles of percent reduction in BNP, had a hazard ratio of 0.7 (0.6-0.9, P = .005), respectively, for the combined end point of total mortality or readmission for HF. Higher baseline BNP levels did not decrease to lower BNP levels as often as lower BNP levels (P < .001). Follow-up BNP performed better in a model, incorporating age, ejection fraction, prior HF hospitalization, New York Heart Association Class, race, use of beta-blockers and renin-angiotensin axis inhibitors and renal insufficiency, than did baseline BNP or percent reduction in BNP. More BNP measurements other than the follow-up BNP did not improve the fit of the model further., Conclusions: These results suggest that both lower absolute BNP levels and greater percentage reduction in BNP with treatment of decompensated HF are associated with better event-free survival. Advocating a threshold BNP to which patients should be treated may not be possible given that high BNP levels tend not to decrease to levels associated with better outcomes during the short period of treatment. More BNP measurements do not add prognostic information beyond that provided by a single BNP level after treatment.

Background: In the general population, 27% of adults have the metabolic syndrome (MetS) and is associated with increased mortality. Similar data are not available for a heart failure (HF) population. This study sought to determine the prevalence of the MetS and its effect on mortality in a HF population., Methods and Results: Patients (n = 886) discharged from the hospital with a primary diagnosis of HF were retrospectively identified. Demographic, clinical, and laboratory data were extracted by chart review. The MetS was defined according to National Cholesterol Education Program Expert Panel criteria with a body mass index >or=30 kg/m(2) substituted for increased waist circumference. Mortality data were acquired by query of the National Death Index, with a median follow-up of 856 days. Data were available to evaluate for the presence or absence of MetS in 71% (n = 625). The prevalence of MetS in this cohort was 68%. MetS was most common in Hispanics (79%) compared with whites (70%) and blacks (61%, P = .003). Mortality was lower in those with MetS (44%) compared with those without (58%, unadjusted HR 0.67 [95% CI, 0.53-0.85]). In a fully adjusted model, there was still a significantly lower risk of mortality in those with MetS (adjusted HR 0.73 [95% CI, 0.56-0.94])., Conclusions: In a cohort hospitalized with HF, the prevalence of MetS exceeds that of the general population, and unlike the general population, MetS is associated with a lower mortality.

Background: Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles., Methods and Results: Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels., Conclusions: The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.

Background: Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure., Methods: Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure., Results: Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide., Conclusions: Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.

Although the development and progression of heart failure have traditionally been viewed as hemodynamic disorders, there is now an increasing awareness that the syndrome of heart failure cannot be simply and/or precisely defined solely in hemodynamic terms. The inability of the so-called hemodynamic hypothesis to explain the progression of heart failure has given rise to the notion that heart failure may progress as a result of the overexpression of an ensemble of biologically active molecules referred to generically as neurohormones. More recently, it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.