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    Recombinant human brain natriuretic peptide ameliorates venous return function in congestive heart failure. ESC heart failure AIMS:Recombinant human brain natriuretic peptide (rh-BNP) is commonly used as a decongestive therapy. This study aimed to investigate the instant effects of rh-BNP on cardiac output and venous return function in post-cardiotomy patients with congestive heart failure (CHF). METHODS AND RESULTS:Twenty-four post-cardiotomy heart failure patients were enrolled and received a standard loading dose of rh-BNP. Haemodynamic monitoring was performed via a pulmonary artery catheter before and after the administration of rh-BNP. The cardiac output and venous return functions were estimated by depicting Frank-Starling and Guyton curves. After rh-BNP infusion, variables reflecting cardiac congestion and venous return function, such as pulmonary artery wedge pressure, mean systemic filling pressure (Pmsf) and venous return resistance index (VRRI), reduced from 15 ± 3 to 13 ± 3 mmHg, from 32 ± 7 to 28 ± 7 mmHg and from 6.7 ± 2.6 to 5.7 ± 1.8 mmHg min m /L, respectively. Meanwhile, cardiac index, stroke volume index, and the cardiac output function curve remained unchanged per se. The decline in Pmsf [-13% (-22% to -8%)] and VRRI [-12% (-25% to -5%)] was much greater than that in the systemic vascular resistance index [-7% (-14% to 0%)]. In the subgroup analysis of reduced ejection fraction (<40%) patients, the aforementioned changes were more significant. CONCLUSIONS:rh-BNP might ameliorate venous return rather than cardiac output function in post-cardiotomy CHF patients. 10.1002/ehf2.13987
    Electrical management of heart failure: from pathophysiology to treatment. European heart journal Electrical disturbances, such as atrial fibrillation (AF), dyssynchrony, tachycardia, and premature ventricular contractions (PVCs), are present in most patients with heart failure (HF). While these disturbances may be the consequence of HF, increasing evidence suggests that they may also cause or aggravate HF. Animal studies show that longer-lasting left bundle branch block, tachycardia, AF, and PVCs lead to functional derangements at the organ, cellular, and molecular level. Conversely, electrical treatment may reverse or mitigate HF. Clinical studies have shown the superiority of atrial and pulmonary vein ablation for rhythm control and AV nodal ablation for rate control in AF patients when compared with medical treatment. Ablation of PVCs can also improve left ventricular function. Cardiac resynchronization therapy (CRT) is an established adjunct therapy currently undergoing several interesting innovations. The current guideline recommendations reflect the safety and efficacy of these ablation therapies and CRT, but currently, these therapies are heavily underutilized. This review focuses on the electrical treatment of HF with reduced ejection fraction (HFrEF). We believe that the team of specialists treating an HF patient should incorporate an electrophysiologist in order to achieve a more widespread use of electrical therapies in the management of HFrEF and should also include individual conditions of the patient, such as body size and gender in therapy fine-tuning. 10.1093/eurheartj/ehac088
    Serum Chloride Is Inversely Associated With 3 Months Outcomes in Chinese Patients With Heart Failure, a Retrospective Cohort Study. Frontiers in cardiovascular medicine Background:Serum chloride was recently found to be associated with prognosis of heart failure in western countries. However, the evidence was scarce in Asia. We aimed to investigated the relationship between serum chloride and clinical outcomes in a Chinese cohort with hospitalized heart failure. Methods:We retrospectively analyzed the data from PhysioNet, involving 1996 patients who were admitted with heart failure between December 2016 and June 2019. Outcome was a composite endpoint of all-cause death or rehospitalization at 3 months. Results:The incidence of the composite endpoint was 26.8% (535/1,996); it was 32.2% (213/662), 25.0% (165/661), and 23.3% (157/673) by chloride tertiles (from the lowest to the highest), respectively. The serum chloride at admission was independently and inversely associated with the composite endpoint risk (hazard ratio: 0.967; 95% confidence interval: 0.939 to 0.996; = 0.026) in contrast to sodium, which was no longer significant ( > 0.05) after multivariable adjustment. Pearson correlation between serum chloride and sodium was 0.747 ( < 0.001). However, an increased AUC was not observed by adding sodium to model composed of age, sex, NYHA class, diabetes, log BNP and chloride (0.620 . 0.612, = 0.132). Subgroup analysis showed the presence or absence of hyponatremia did not affect the association between chloride and composite endpoint risk. Conclusions:Low serum chloride at admission was associated with poor outcomes in Chinese hospitalized patients with heart failure. These findings warrant future studies for tackling the potential pathophysiological mechanisms and correction methods of hypochloremia in heart failure. 10.3389/fcvm.2022.855053
    The Association of Nutritional Risk Screening 2002 With 1-Year Re-hospitalization and the Length of Initial Hospital Stay in Patients With Heart Failure. Frontiers in nutrition Backgrounds and Aims:Nutritional Risk Screening 2002 (NRS-2002) has been widely recommended for identifying the nutritional risk. However, the association between NRS-2002 and the prognosis of heart failure has not been fully addressed. This study aimed to explore the association of NRS-2002 with 1-year re-hospitalization and the length of initial hospital stay in heart failure patients. Methods:This retrospective study included 2,830 heart failure patients. The primary endpoint was 1-year re-hospitalization for heart failure. The secondary endpoint was the length of initial hospital stay. The Log-binomial regression analysis was performed to determine the association between NRS-2002 and re-hospitalization. The Cox regression model was fitted to estimate hazard of discharge. The cumulative incidence curves of discharge were plotted using Kaplan-Meier method and log-rank test was performed. Exploratory analysis was also conducted according to the classification of heart failure and the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) fold-elevation. Results:Among 2,830 heart failure patients, the mean age was 64.3 years and 66.4% were male. A total of 122 (4.3%) patients were considered at high nutritional risk. Log-binomial regression analysis demonstrated that higher NRS-2002 score was an independent risk factor of re-hospitalization ([1 vs. 0]: relative risks [] = 1.383, 95% = 1.152 to 1.660; [2 vs. 0]: = 1.425, 95% = 1.108 to 1.832; [3-7 vs. 0]: = 1.770, 95% = 1.310 to 2.393). Kaplan-Meier curve showed that the cumulative incidence of discharge was lower in high nutritional risk group (Log rank < 0.001). Cox regression analysis also found that higher NRS-2002 score (2 or ≥3) was strongly associated with longer length of initial hospital stay ([2 vs. 0]: Hazard ratios [] = 0.854, 95% = 0.748 to 0.976; [3-7 vs. 0]: = 0.609, 95% = 0.503 to 0.737). Exploratory analysis showed that such association still remained irrespective of NT-proBNP fold-elevation, but only existed in patients with heart failure with preserved ejection fraction (HFpEF). Conclusion:In patients with heart failure, high NRS-2002 score was strongly and independently associated with the incidence of 1-year re-hospitalization and the length of initial hospital stay. 10.3389/fnut.2022.849034
    Clinical Prediction Models for Heart Failure Hospitalization in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Journal of the American Heart Association Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models' performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts' clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta-analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point-of-care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta-analyzed c-statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta-analyzed c-statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps. 10.1161/JAHA.121.024833
    Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient. British journal of clinical pharmacology Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient. 10.1111/bcp.15085
    2022 American College of Cardiology/American Heart Association/Heart Failure Society of America Guideline for the Management of Heart Failure: Executive Summary. Journal of cardiac failure 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. 10.1016/j.cardfail.2022.02.009
    2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Journal of cardiac failure AIM:The "2022 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 on 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. STRUCTURE: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 with high-quality published economic analyses. 10.1016/j.cardfail.2022.02.010
    The cardiosplenic axis: the prognostic role of the spleen in heart failure. Heart failure reviews Despite the number of available methods to predict prognosis in patients with heart failure, prognosis remains poor, likely because of marked patient heterogeneity and varied heart failure etiologies. Thus, identification of novel prognostic indicators to stratify risk in patients with heart failure is of paramount importance. The spleen is emerging as a potential novel prognostic indicator for heart failure. In this article, we provide an overview of the current prognostic tools used for heart failure. We then introduce the spleen as a potential novel prognostic indicator, before outlining the structure and function of the spleen and introducing the concept of the cardiosplenic axis. This is followed by a focused discussion on the function of the spleen in the immune response and in hemodynamics, as well as a review of what is known about the usefulness of the spleen as an indicator of heart failure. Expert insight into the most effective spleen-related measurement indices for the prognostication of patients with heart failure is provided, and suggestions on how these could be measured in clinical practice are considered. In future, studies in humans will be required to draw definitive links between specific splenic measurements and different heart failure manifestations, as well as to determine whether splenic prognostic measurements differ between heart failure classes and etiologies. These contributions will provide a step forward in our understanding of the usefulness of the spleen as a prognostic predictor in heart failure. 10.1007/s10741-022-10248-4
    Association of Perceived Stress With Incident Heart Failure. Journal of cardiac failure BACKGROUND:The relationship between psychological stress and heart failure (HF) has not been well studied. We sought to assess the relationship between perceived stress and incident HF. METHODS:We used data from the national REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a large prospective biracial cohort study that enrolled community-dwellers aged 45 years and older between 2003 and 2007, with follow-up. We included participants free of suspected prevalent HF who completed the Cohen 4-item Perceived Stress Scale (PSS-4). Our outcome variables were incident HF event, HF with reduced ejection fraction events, and HF with preserved ejection fraction events. We estimated Cox proportional hazard models to determine if PSS-4 quartiles were independently associated with incident HF events, adjusting for sociodemographics, social support, unhealthy behaviors, comorbid conditions, and physiologic parameters. We also tested interactions by baseline statin use, given its anti-inflammatory properties. RESULTS:Among 25,785 participants with a mean age of 64 ± 9.3 years, 55% were female and 40% were Black. Over a median follow-up of 10.1 years, 1109 ± 4.3% experienced an incident HF event. In fully adjusted models, the PSS-4 was not associated with HF or HF with reduced ejection fraction. However, PSS-4 quartiles 2-4 (compared with the lowest quartile) were associated with incident HF with preserved ejection fraction (Q2 hazard ratio 1.37, 95% confidence interval 1.00-1.88; Q3 hazard ratio 1.42, 95% confidence interval 1.03-1.95; Q4 hazard ratio 1.41, 95% confidence interval 1.04-1.92). Notably, this association was attenuated among participants who took a statin at baseline (P for interaction = .07). CONCLUSIONS:Elevated perceived stress was associated with incident HF with preserved ejection fraction but not HF with reduced ejection fraction. 10.1016/j.cardfail.2022.04.013
    Combining chest X-rays and electronic health record (EHR) data using machine learning to diagnose acute respiratory failure. Journal of the American Medical Informatics Association : JAMIA OBJECTIVE:When patients develop acute respiratory failure (ARF), accurately identifying the underlying etiology is essential for determining the best treatment. However, differentiating between common medical diagnoses can be challenging in clinical practice. Machine learning models could improve medical diagnosis by aiding in the diagnostic evaluation of these patients. MATERIALS AND METHODS:Machine learning models were trained to predict the common causes of ARF (pneumonia, heart failure, and/or chronic obstructive pulmonary disease [COPD]). Models were trained using chest radiographs and clinical data from the electronic health record (EHR) and applied to an internal and external cohort. RESULTS:The internal cohort of 1618 patients included 508 (31%) with pneumonia, 363 (22%) with heart failure, and 137 (8%) with COPD based on physician chart review. A model combining chest radiographs and EHR data outperformed models based on each modality alone. Models had similar or better performance compared to a randomly selected physician reviewer. For pneumonia, the combined model area under the receiver operating characteristic curve (AUROC) was 0.79 (0.77-0.79), image model AUROC was 0.74 (0.72-0.75), and EHR model AUROC was 0.74 (0.70-0.76). For heart failure, combined: 0.83 (0.77-0.84), image: 0.80 (0.71-0.81), and EHR: 0.79 (0.75-0.82). For COPD, combined: AUROC = 0.88 (0.83-0.91), image: 0.83 (0.77-0.89), and EHR: 0.80 (0.76-0.84). In the external cohort, performance was consistent for heart failure and increased for COPD, but declined slightly for pneumonia. CONCLUSIONS:Machine learning models combining chest radiographs and EHR data can accurately differentiate between common causes of ARF. Further work is needed to determine how these models could act as a diagnostic aid to clinicians in clinical settings. 10.1093/jamia/ocac030
    Prognostic significance of serum potassium in patients hospitalized for acute heart failure. ESC heart failure AIM:We investigated the prognostic significance of serum potassium abnormalities at discharge in patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS:In a retrospective analysis, we included 926 patients hospitalized for AHF, stratified by serum potassium levels at discharge as hypokalaemia (<3.5 mEq/L), normokalaemia (3.5-5.0 mEq/L), and hyperkalaemia (>5.0 mEq/L). The primary endpoint was all-cause death at 1 year since hospital discharge. At discharge, 40 patients had hypokalaemia (4.3%), 840 normokalaemia (90.7%), and 46 hyperkalaemia (5.0%). Patients with hyperkalaemia at discharge were more frequently men, had more signs of congestion, and lower LVEF while patients with hypokalaemia were more likely to be women with HFpEF. Treatment with ACEi/ARBs and MRAs ≥50% of target dose at discharge was similar across groups. One year all-cause death occurred in 10% of the patients with hypokalaemia, 13.9% of those with normokalaemia, and 30.4% of those with hyperkalaemia (P = 0.006). After adjustment for covariates, including renal function, background treatment, and baseline potassium level, hyperkalaemia resulted an independent predictor of the primary endpoint (HR 1.96, 95% IC [1.01-3.82]; P = 0.048). CONCLUSIONS:In patients with AHF, the presence of hyperkalaemia at discharge is an independent predictor of 1 year all-cause death. 10.1002/ehf2.13925
    Inflammation and resolution signaling in cardiac repair and heart failure. EBioMedicine Unresolved inflammation is a key mediator of advanced heart failure. Especially, damage, pathogen, and lifestyle-associated molecular patterns are the major factors in initiating baseline inflammatory diseases, particularly in cardiac pathology. After a significant cardiac injury like a heart attack, splenic and circulating leukocytes begin a highly optimized sequence of immune cell recruitment (neutrophils and monocytes) to coordinate effective tissue repair. An injured cardiac tissue repair and homeostasis are dependent on clearance of cellular debris where the recruited leukocytes transition from a pro-inflammatory to a reparative program through resolution process. After a cardiac injury, macrophages play a decisive role in cardiac repair through the biosynthesis of endogenous lipid mediators that ensure a timely tissue repair while avoiding chronic inflammation and impaired cardiac repair. However, dysregulation of resolution of inflammation processes due to cardiometabolic defects (obesity, hypertension, and diabetes), aging, or co-medication(s) lead to impaired cardiac repair. Hence, the presented review demonstrates the fundamental role of leukocytes, in particular macrophages orchestrate the inflammation and resolution biology, focusing on the biosynthesis of specialized lipid mediators in cardiac repair and heart failure. This work was supported by research funds from National Institutes of Health (AT006704, HL132989, and HL144788) to G.V.H. The authors acknowledges the use of Servier Medical Art image bank and Biorender that is used to create schematic Figures 1-3. 10.1016/j.ebiom.2022.103992
    Noncardiac comorbidity clustering in heart failure: an overlooked aspect with potential therapeutic door. Heart failure reviews Heart failure is associated with a range of comorbidities that have the potential to impair both quality of life and clinical outcome. Unfortunately, noncardiac diseases are underrepresented in large randomized clinical trials, and their management remains poorly understood. In clinical practice, the prevalence of comorbidities in heart failure is high. Although the prognostic impact of comorbidities is well known, their prevalence and impact in specific heart failure settings have been overlooked. Many studies have described specific single noncardiac conditions, but few have examined their overall burden and grading in patients with multiple comorbidities. The risk of comorbidities in patients with heart failure rises with more advanced disease, older age, and increased frailty-three conditions that are poorly represented in clinical trials. The pathogenic links between comorbidities and heart failure involve many pathways and include neurohormonal overdrive, inflammatory activation, oxidative stress, and endothelial dysfunction. Such interactions may worsen prognoses, but details of these relationships are still under investigation. We propose a shift from cardiac-focused care to a more systemic approach that considers all noncardiac diseases and related medications. Some new drugs class such as ARNI or SGLT2 inhibitors could change prognosis by acting directly or indirectly on metabolic disorders and related vascular consequences. 10.1007/s10741-020-09972-6
    Reply to 'Exercise intolerance in heart failure: beyond mitochondrial dysfunction'. Letter regarding the article 'Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?' European journal of heart failure 10.1002/ejhf.2494
    Gabapentinoid-induced peripheral edema and acute heart failure: A translational study combining pharmacovigilance data and in vitro animal experiments. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie INTRODUCTION:Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure in connection with a potentially dual mechanism, vascular and cardiac. OBJECTIVES & METHODS:All cases of peripheral edema or heart failure involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were included to describe their onset patterns (e.g., time to onset). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries and on the electrophysiological properties of rat ventricular cardiomyocytes. RESULTS:A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57-85, range 32-95). The median time to onset were 23 days (IQR 10-54) and 17 days (IQR 3-30) for non-cardiogenic edema and acute heart failure, respectively. Cardiogenic and non-cardiogenic peripheral edema occurred frequently after a dose escalation (27/45, 60%), and the course was rapidly favorable after discontinuation of gabapentinoid (median 7 days, IQR 5-13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Acute application of gabapentinoids had no significant effect on Ca1.2 currents of ventricular cardiomyocytes. CONCLUSION:Gabapentinoids can cause concentration-dependent peripheral edema of early onset. The primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Ca1.2 blockade under the experimental conditions tested. 10.1016/j.biopha.2022.112807
    Incremental Value of Global Longitudinal Strain in the Long-Term Prediction of Heart Failure among Patients with Coronary Artery Disease. Haji Kawa,Marwick Thomas H,Stewart Simon,Carrington Melinda,Chan Yih-Kai,Chan William,Huynh Quan,Neil Christopher,Wong Chiew Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography BACKGROUND:Heart failure (HF) remains a common complication for patients with coronary artery disease (CAD), especially after acute myocardial infarction. Although left ventricular ejection fraction (LVEF) is conventionally used to assess cardiac function for risk stratification, it has been shown in other settings to underestimate the risk of HF compared with global longitudinal strain (GLS). Moreover, most evidence pertains to early-onset HF. We sought the clinical and myocardial predictors for late-onset HF in patients with CAD. METHODS:We analyzed echocardiograms (including GLS) in 334 patients with CAD (ages 65 ± 11 years, 77% male) who were enrolled in the Nurse-Led Intervention for Less Chronic Heart Failure trial, a prospective, randomized controlled trial that compared standard care with nurse-led intervention to prevent HF in individuals at risk of incident HF. Long-term (9 years) follow-up was obtained via data linkage. Analysis was performed using a competing-risk model. RESULTS:Baseline LVEF values were normal or mildly impaired (LVEF ≥ 40%) in all subjects. After a median of 9 years of follow-up, 50 (15%) of the 334 patients had new HF admissions, and 68 (20%) died. In a competing-risk model, HF was associated with GLS (hazard ratio = 1.15 [1.05-1.25], P = .001), independent of estimated glomerular filtration rate (hazard ratio = 0.98 [0.97-0.99], P = .045), Charlson comorbidity score (hazard ratio = 1.64 [1.25-2.15], P < .001), or E/e' (hazard ratio = 1.08 [1.02-1.14], P = .01). Global longitudinal strain-but not conventional echocardiographic measures-added incremental value to a clinical model based on age, gender, and Charlson score (area under the curve, 0.78-0.83, P = .01). Global longitudinal strain was still associated with HF development in patients taking baseline angiotensin convertase enzyme inhibitors (hazard ratio = 1.21 [1.11-1.31], P < .01) and baseline beta-blockers (1.17 [1.09, 1.26]; P < .01). Mortality was associated with older men, risk factors (hypertension or diabetes), and comorbidities (AF and chronic kidney disease). CONCLUSIONS:Global longitudinal strain is independently associated with risk of incident HF in patients admitted with CAD and provides incremental prognostic value to standard markers. Identifying an at-risk subgroup using GLS may be the focus of future randomized controlled trails to enable targeted therapeutic intervention. 10.1016/j.echo.2021.09.003
    Mid-wall striae fibrosis predicts heart failure admission, composite heart failure events, and life-threatening arrhythmias in dilated cardiomyopathy. Purmah Yanish,Cornhill Aidan,Lei Lucy Y,Dykstra Steven,Mikami Yoko,Satriano Alessandro,Labib Dina,Flewitt Jacqueline,Rivest Sandra,Sandonato Rosa,Seib Michelle,Howarth Andrew G,Lydell Carmen P,Heydari Bobak,Merchant Naeem,Bristow Michael,Kolman Louis,Fine Nowell M,White James A Scientific reports Heart failure (HF) admission is a dominant contributor to morbidity and healthcare costs in dilated cardiomyopathy (DCM). Mid-wall striae (MWS) fibrosis by late gadolinium enhancement (LGE) imaging has been associated with elevated arrhythmia risk. However, its capacity to predict HF-specific outcomes is poorly defined. We investigated its role to predict HF admission and relevant secondary outcomes in a large cohort of DCM patients. 719 patients referred for LGE MRI assessment of DCM were enrolled and followed for clinical events. Standardized image analyses and interpretations were conducted inclusive of coding the presence and patterns of fibrosis observed by LGE imaging. The primary clinical outcome was hospital admission for decompensated HF. Secondary heart failure and arrhythmic composite endpoints were also studied. Median age was 57 (IQR 47-65) years and median LVEF 40% (IQR 29-47%). Any fibrosis was observed in 228 patients (32%) with MWS fibrosis pattern present in 178 (25%). At a median follow up of 1044 days, 104 (15%) patients experienced the primary outcome, and 127 (18%) the secondary outcome. MWS was associated with a 2.14-fold risk of the primary outcome, 2.15-fold risk of the secondary HF outcome, and 2.23-fold risk of the secondary arrhythmic outcome. Multivariable analysis adjusting for all relevant covariates, inclusive of LVEF, showed patients with MWS fibrosis to experience a 1.65-fold increased risk (95% CI 1.11-2.47) of HF admission and 1-year event rate of 12% versus 7% without this phenotypic marker. Similar findings were observed for the secondary outcomes. Patients with LVEF > 35% plus MWS fibrosis experienced similar event rates to those with LVEF ≤ 35%. MWS fibrosis is a powerful and independent predictor of clinical outcomes in patients with DCM, identifying patients with LVEF > 35% who experience similar event rates to those with LVEF below this conventionally employed high-risk phenotype threshold. 10.1038/s41598-022-05790-y
    In vivo therapeutic genome editing via CRISPR/Cas9 magnetoplexes for myocardial infarction. Biomaterials CRISPR/Cas9-mediated gene-editing technology has gained attention as a new therapeutic method for intractable diseases. However, the use of CRISPR/Cas9 for cardiac conditions such as myocardial infarction remains challenging due to technical and biological barriers, particularly difficulties in delivering the system and targeting genes in the heart. In the present study, we demonstrated the in vivo efficacy of the CRISPR/Cas9 magnetoplexes system for therapeutic genome editing in myocardial infarction. First, we developed CRISPR/Cas9 magnetoplexes that magnetically guided CRISPR/Cas9 system to the heart for efficient in vivo therapeutic gene targeting during heart failures. We then demonstrated that the in vivo gene targeting of miR34a via these CRISPR/Cas9 magnetoplexes in a mouse model of myocardial infarction significantly improved cardiac repair and regeneration to facilitate improvements in cardiac function. These results indicated that CRISPR/Cas9 magnetoplexes represent an effective in vivo therapeutic gene-targeting platform in the myocardial infarction of heart, and that this strategy may be applicable for the treatment of a broad range of cardiac failures. 10.1016/j.biomaterials.2021.121327
    Acute Heart Failure in the 2021 ESC Heart Failure Guidelines: a scientific statement from the Association for Acute CardioVascular Care (ACVC) of the European Society of Cardiology. Masip Josep,Frank Peacok W,Arrigo Mattia,Rossello Xavier,Platz Elke,Cullen Louise,Mebazaa Alexandre,Price Susanna,Bueno Héctor,Di Somma Salvatore,Tavares Mucio,Cowie Martin R,Maisel Alan,Mueller Christian,Miró Òsar, European heart journal. Acute cardiovascular care The current European Society of Cardiology (ESC) Heart Failure Guidelines are the most comprehensive ESC document covering heart failure to date; however, the section focused on acute heart failure remains relatively too concise. Although several topics are more extensively covered than in previous versions, including some specific therapies, monitoring and disposition in the hospital, and the management of cardiogenic shock, the lack of high-quality evidence in acute, emergency, and critical care scenarios, poses a challenge for providing evidence-based recommendations, in particular when by comparison the data for chronic heart failure is so extensive. The paucity of evidence and specific recommendations for the general approach and management of acute heart failure in the emergency department is particularly relevant, because this is the setting where most acute heart failure patients are initially diagnosed and stabilized. The clinical phenotypes proposed are comprehensive, clinically relevant and with minimal overlap, whilst providing additional opportunity for discussion around respiratory failure and hypoperfusion. 10.1093/ehjacc/zuab122
    Anatomical and histological assessment of left bundle branch area pacing in human heart with refractory heart failure. Zhang Jiefang,Pan Yiwen,Sun Yaxun,Fu Guosheng ESC heart failure As an emerging pacing technique, left bundle branch area pacing (LBBAP) has served as a physiological pacing modality that overcomes the limitations of His bundle pacing (HBP) or right ventricular pacing. Three patients with terminal heart failure who were waiting for heart transplantation and met the indications of pacemaker implantations received LBBAP. Symptoms were relieved and stabilized and eventually received heart transplantation. Diseased hearts from the recipients were dissected post-transplantation, and the direct visual of pacing lead locations in the interventricular septum were evaluated, and the histopathological examination around the lead was conducted for the first time in human. As a result, we found that the locations of LBBAP leads were matched with fluoroscopic views during the procedure and Masson's staining showed extensive fibrosis occur around the lead but did not result in high thresholds. 10.1002/ehf2.13806
    Sex-related differences in the pharmacological treatment of heart failure. Tamargo Juan,Caballero Ricardo,Delpón Eva Pharmacology & therapeutics Heart failure (HF) represents a leading cause of morbidity and mortality. However, HF trials highlighted many differences between men and women with HF. Thus, women represent approximately a quarter of people with HF with reduced ejection fraction (HFrEF), while they account for over half of those with HF with preserved EF (HFpEF). There are also sex-related differences (SRDs) in the pharmacokinetics, pharmacodynamics and safety profile of some guideline-recommended drugs for the treatment of HF. As compared with men, women with HFrEF are less often treated with guideline-recommended HF drugs, experience more frequent and severe adverse reactions when these drugs are prescribed at the same doses in both sexes, and recent evidence suggests that women might need lower doses than men, bringing into question which are the optimal doses of HF drugs in women and men separately. However, information on SRDs in drug efficacy and safety in patients with HFrEF is very limited due to the underrepresentation of women and the lack of sex-specific evaluations of drug efficacy and safety in HF clinical trials. As a consequence, current clinical guidelines do not provide sex-specific recommendations, even when significant differences exist, at least, in drug safety. The aim of this article is to review the SRDs in the pharmacokinetics, efficacy and safety of guideline-recommended HF drugs and to identify emerging areas of research to improve our understanding of the SRDs, because a better understanding of these differences is the first step to achieve a personalized treatment of HF in women and men. 10.1016/j.pharmthera.2021.107891
    First-in-human experience of preload regulation with percutaneous transluminal caval flow regulation in heart failure with reduced ejection fraction patients. Herrera José E,Herrera José A,Finizola Bartolomé,García Eleazar,Velasco Luis E,Torres William R,D'empaire Gabriel,Octavio José A,Marqués Juan A,Levine Robert A,Palacios Igor F ESC heart failure AIMS:This study aims to investigate the acute haemodynamic effects of percutaneous transluminal flow regulation (PTCR®) with an inferior vena cava regulator balloon in heart failure patients. Preload reduction in heart failure has been achieved with high potency diuretics. However, no study has been conducted in humans to assess the effect of inferior vena cava intermittent occlusion for preload reduction. METHODS AND RESULTS:Six patients were included in the study: four men (55 ± 6 years old) and two women (63 ± 4 years old). Baseline evaluations included Doppler echocardiogram, coronary angiogram, and right heart catheterization. Caval balloon was kept inflated for 30 min, and right catheterization and control echocardiogram were performed while the balloon was still inflated. The balloon was then deflated and removed. Right haemodynamic variables were evaluated before balloon insertion and with the inflated balloon. The mean right atrial pressure decreased by 42.59% (P = 0.005); systolic right ventricular pressure decreased by 30.19% (P < 0.003); mean pulmonary arterial pressure decreased by 25.33% (P < 0.043); mean pulmonary capillary wedge pressure decreased by 31.37% (P > 0.016); and cardiac output increased by 9.92% (P < 0.175). CONCLUSIONS:The haemodynamic and echocardiographic changes obtained in our study using PTCR® suggest that this innovative approach can play a beneficial role in the heart failure treatment. 10.1002/ehf2.13780
    A comprehensive characterization of acute heart failure with preserved versus mildly reduced versus reduced ejection fraction - insights from the ESC-HFA EORP Heart Failure Long-Term Registry. Kapłon-Cieślicka Agnieszka,Benson Lina,Chioncel Ovidiu,Crespo-Leiro Maria G,Coats Andrew J S,Anker Stefan D,Filippatos Gerasimos,Ruschitzka Frank,Hage Camilla,Drożdż Jarosław,Seferovic Petar,Rosano Giuseppe M C,Piepoli Massimo,Mebazaa Alexandre,McDonagh Theresa,Lainscak Mitja,Savarese Gianluigi,Ferrari Roberto,Maggioni Aldo P,Lund Lars H, European journal of heart failure AIMS:To perform a comprehensive characterization of acute heart failure (AHF) with preserved (HFpEF), versus mildly reduced (HFmrEF) versus reduced ejection fraction (HFrEF). METHODS AND RESULTS:Of 5951 participants in the ESC HF Long-Term Registry hospitalized for AHF (acute coronary syndromes excluded), 29% had HFpEF, 18% HFmrEF, and 53% HFrEF. Hospitalization reasons were most commonly atrial fibrillation (more in HFmrEF and HFpEF), followed by ischaemia (HFmrEF), infection (HFmrEF and HFpEF), worsening renal function (HFrEF), and uncontrolled hypertension (HFmrEF and HFpEF). Hospitalization characteristics included lower blood pressure, more oedema and higher natriuretic peptides with lower ejection fraction, similar pulmonary congestion, more mitral regurgitation in HFrEF and HFmrEF and more tricuspid regurgitation in HFrEF. In-hospital mortality was 3.4% in HFrEF, 2.1% in HFmrEF and 2.2% in HFpEF. Intravenous diuretic (∼80%) and nitrate (∼15%) use was similar but inotrope use greater in HFrEF (16%, vs. HFmrEF 7.4% vs. HFpEF 5.3%). Weight loss and estimated glomerular filtration rate improvement were greater in HFrEF, whereas reduction in natriuretic peptides was similar. Over 1 year post-discharge, events per 100 patient-years (95% confidence interval) in HFrEF versus HFmrEF versus HFpEF were: all-cause death 22 (20-24) versus 17 (14-20) versus 17 (15-20); cardiovascular (CV) death 12 (10-13) versus 8.6 (6.6-11) versus 8.4 (6.9-10); non-CV death 2.4 (1.8-3.1) versus 3.3 (2.1-4.8) versus 4.5 (3.5-5.9); all-cause hospitalization 48 (45-51) versus 35 (31-40) versus 42 (39-46); HF hospitalization 29 (27-32) versus 19 (16-22) versus 17 (15-20); and non-CV hospitalization 7.7 (6.6-8.9) versus 9.6 (7.5-12) versus 15 (13-17). CONCLUSION:In AHF, HFrEF is more severe and has greater in-hospital mortality. Post-discharge, HFrEF has greater CV risk, HFpEF greater non-CV risk, and HFmrEF lower overall risk. 10.1002/ejhf.2408
    The Effects of the ManageHF4Life Mobile App on Patients With Chronic Heart Failure: Randomized Controlled Trial. Dorsch Michael P,Farris Karen B,Rowell Brigid E,Hummel Scott L,Koelling Todd M JMIR mHealth and uHealth BACKGROUND:The successful management of heart failure (HF) involves guideline-based medical therapy as well as self-management behavior. As a result, the management of HF is moving toward a proactive real-time technological model of assisting patients with monitoring and self-management. OBJECTIVE:The aim of this paper was to evaluate the efficacy of enhanced self-management via a mobile app intervention on health-related quality of life, self-management, and HF readmissions. METHODS:A single-center randomized controlled trial was performed. Participants older than 45 years and admitted for acute decompensated HF or recently discharged in the past 4 weeks were included. The intervention group ("app group") used a mobile app, and the intervention prompted daily self-monitoring and promoted self-management. The control group ("no-app group") received usual care. The primary outcome was the change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score from baseline to 6 and 12 weeks. Secondary outcomes were the Self-Care Heart Failure Index (SCHFI) questionnaire score and recurrent HF admissions. RESULTS:A total of 83 participants were enrolled and completed all baseline assessments. Baseline characteristics were similar between the groups except for the prevalence of ischemic HF. The app group had a reduced MLHFQ at 6 weeks (mean 37.5, SD 3.5 vs mean 48.2, SD 3.7; P=.04) but not at 12 weeks (mean 44.2, SD 4 vs mean 45.9, SD 4; P=.78), compared to the no-app group. There was no effect of the app on the SCHFI at 6 or 12 weeks. The time to first HF readmission was not statistically different between the app group and the no-app group (app group 11/42, 26% vs no-app group 12/41, 29%; hazard ratio 0.89, 95% CI 0.39-2.02; P=.78) over 12 weeks. CONCLUSIONS:The adaptive mobile app intervention, which focused on promoting self-monitoring and self-management, improved the MLHFQ at 6 weeks but did not sustain its effects at 12 weeks. No effect was seen on HF self-management measured by self-report. Further research is needed to enhance engagement in the app for a longer period and to determine if the app can reduce HF readmissions in a larger study. TRIAL REGISTRATION:ClinicalTrials.gov NCT03149510; https://clinicaltrials.gov/ct2/show/NCT03149510. 10.2196/26185
    An early relook identifies high-risk trajectories in ambulatory advanced heart failure. Kittleson Michelle M,Ambardekar Amrut V,Stevenson Lynne W,Gilotra Nisha A,Shah Palak,Ewald Gregory A,Thibodeau Jennifer T,Stehlik Josef,Palardy Maryse,Estep Jerry D,Cascino Thomas M,Baldwin J Timothy,Jeffries Neal,Khalatbari Shokoufeh,Yosef Matheos,Peters Wendy Taddei,Richards Blair,Mann Douglas L,Aaronson Keith D,Stewart Garrick C, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation INTRODUCTION:Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory. METHODS:REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook. RESULTS:Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p = .006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p = .006) during the year after Early Relook. CONCLUSIONS:Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies. 10.1016/j.healun.2021.09.003
    Prognostic Value of Insulin Resistance Assessed by HOMA-IR in Non-Diabetic Patients with Decompensated Heart Failure. Castillo Costa Yanina,Mauro Víctor,Fairman Enrique,Charask Adrián,Olguín Lisandro,Cáceres Leonardo,Barrero Carlos Current problems in cardiology The predictive value of insulin resistance in patients hospitalized with heart failure is unknown. To evaluate prognostic value of insulin resistance (defined by a HOMA IR ≥ 2.5) for the combined event of death and readmission at 90 and 365 days post discharge and to determine if there are differences according to ejection fraction. Prospective study of 156 p hospitalized for acute heart failure without diabetes. A total of 83 years, 48% female, EF ≤ 45% 48%. Of 28% presented HOMA ≥2.5. HOMA IR ≥2.5 was associated with combined event (OR 2.4; 95% CI 1.9-5.1; P: 0.02) at 90 days. A multivariate analysis demonstrated its independent predictive value (OR 2.5, 95% CI 1.1-5.8; P: 0.03). At 1 year follow-up HOMA IR did not predict events. The predictive value of HOMA-IR was not associated with ventricular function. HOMA IR index was a predictor of a combined event at 90 days in our population. It is a simple determination that could contribute to identify higher risk patients during this vulnerable post-discharge phase. These data must be validated in larger studies. 10.1016/j.cpcardiol.2022.101112
    Wave Intensity Analysis Combined With Machine Learning can Detect Impaired Stroke Volume in Simulations of Heart Failure. Reavette Ryan M,Sherwin Spencer J,Tang Meng-Xing,Weinberg Peter D Frontiers in bioengineering and biotechnology Heart failure is treatable, but in the United Kingdom, the 1-, 5- and 10-year mortality rates are 24.1, 54.5 and 75.5%, respectively. The poor prognosis reflects, in part, the lack of specific, simple and affordable diagnostic techniques; the disease is often advanced by the time a diagnosis is made. Previous studies have demonstrated that certain metrics derived from pressure-velocity-based wave intensity analysis are significantly altered in the presence of impaired heart performance when averaged over groups, but to date, no study has examined the diagnostic potential of wave intensity on an individual basis, and, additionally, the pressure waveform can only be obtained accurately using invasive methods, which has inhibited clinical adoption. Here, we investigate whether a new form of wave intensity based on noninvasive measurements of arterial diameter and velocity can detect impaired heart performance in an individual. To do so, we have generated a virtual population of two-thousand elderly subjects, modelling half as healthy controls and half with an impaired stroke volume. All metrics derived from the diameter-velocity-based wave intensity waveforms in the carotid, brachial and radial arteries showed significant crossover between groups-no one metric in any artery could reliably indicate whether a subject's stroke volume was normal or impaired. However, after applying machine learning to the metrics, we found that a support vector classifier could simultaneously achieve up to 99% recall and 95% precision. We conclude that noninvasive wave intensity analysis has significant potential to improve heart failure screening and diagnosis. 10.3389/fbioe.2021.737055
    Community-Level Economic Distress, Race, and Risk of Adverse Outcomes After Heart Failure Hospitalization Among Medicare Beneficiaries. Mentias Amgad,Desai Milind Y,Vaughan-Sarrazin Mary S,Rao Shreya,Morris Alanna A,Hall Jennifer L,Menon Venu,Hockenberry Jason,Sims Mario,Fonarow Gregg C,Girotra Saket,Pandey Ambarish Circulation BACKGROUND:Socioeconomic disadvantage is a strong determinant of adverse outcomes in patients with heart failure. However, the contribution of community-level economic distress to adverse outcomes in heart failure may differ across races and ethnicities. METHODS:Patients of self-reported Black, White, and Hispanic race and ethnicity hospitalized with heart failure between 2014 and 2019 were identified from the Medicare MedPAR Part A 100% Files. We used patient-level residential ZIP code to quantify community-level economic distress on the basis of the Distressed Community Index (quintile 5: economically distressed versus quintiles 1-4: nondistressed). The association of continuous and categorical measures (distressed versus nondistressed) of Distressed Community Index with 30-day, 6-month, and 1-year risk-adjusted mortality, readmission burden, and home time were assessed separately by race and ethnicity groups. RESULTS:The study included 1 611 586 White (13.2% economically distressed), 205 840 Black (50.6% economically distressed), and 89 199 Hispanic (27.3% economically distressed) patients. Among White patients, living in economically distressed (versus nondistressed) communities was significantly associated with a higher risk of adverse outcomes at 30-day and 1-year follow-up. Among Black and Hispanic patients, the risk of adverse outcomes associated with living in distressed versus nondistressed communities was not meaningfully different at 30 days and became more prominent by 1-year follow-up. Similarly, in the restricted cubic spline analysis, a stronger and more graded association was observed between Distressed Community Index score and risk of adverse outcomes in White patients (versus Black and Hispanic patients). Furthermore, the association between community-level economic distress and risk of adverse outcomes for Black patients differed in rural versus urban areas. Living in economically distressed communities was significantly associated with a higher risk of mortality and lower home time at 1-year follow-up in rural areas but not urban areas. CONCLUSIONS:The association between community-level economic distress and risk of adverse outcomes differs across race and ethnic groups, with a stronger association noted in White patients at short- and long-term follow-up. Among Black patients, the association of community-level economic distress with a higher risk of adverse outcomes is less evident in the short term and is more robust and significant in the long-term follow-up and rural areas. 10.1161/CIRCULATIONAHA.121.057756
    Intestinal barrier dysfunction is associated with elevated right atrial pressure in patients with advanced decompensated heart failure. Kitai Takeshi,Nemet Ina,Engelman Timothy,Morales Rommel,Chaikijurajai Thanat,Morales Kathryn,Hazen Stanley L,Tang W H Wilson American heart journal We prospectively performed serial differential sugar absorption test in 29 consecutively consented patients with advanced decompensated heart failure admitted to the heart failure intensive care unit for hemodynamically-guided therapy. We observed that intestinal barrier function was significantly impaired in our study cohort, and increased intestinal permeability was associated with elevated right atrial pressure and poorer prognosis yet without any association with systemic levels of the gut microbial metabolite, trimethylamine N-oxide (TMAO) or intestinal fatty acid binding protein that were thought to be indicative of intestinal abnormalities. 10.1016/j.ahj.2021.11.014
    Clinical and demographic factors associated with stimulant use disorder in a rural heart failure population. Hendricks Brian,Sokos George,Kimble Wes,Dai Zheng,Adeniran Olayemi,Osman Mohammed,Smith Gordon Stephen,Bianco Chris Drug and alcohol dependence BACKGROUND:Heart failure is becoming increasingly common among patients under 50 years of age, particularly in African Americans and patients with stimulant use disorder. Yet the sources of these disparities remain poorly understood. This study identified key demographic and clinical factors associated with stimulant use disorder in a largely rural heart failure patient registry. METHODS:Patient records reporting a diagnosis of heart failure between January 2008 and March 2020 were requested from West Virginia University Hospital Systems (n=37,872). Odds of stimulant use disorder were estimated by demographic group (age, race, sex), insurance carrier, and clinical comorbidities using logistic regression. RESULTS:Multivariable regression analysis identified higher odds of stimulant use disorder among Black/African Americans (1.95 [1.32, 2.77]) and patients who report drinking one or more alcoholic drinks per week (2.23 [1.72, 2.88]). Lower odds of stimulant use disorder were identified among patients with hypertension (0.59 [0.47, 0.73]), or diabetes (0.65 [0.52, 0.81]).. Likewise, lower odds of stimulant use disorder were noted among females, patients older than 30 years of age and those not enrolled in Medicaid. CONCLUSION:These results highlight the alarming extent to which Medicaid enrollees, Black/African Americans, people aged 18-24 and 25-44, or persons with a past alcohol use disorder diagnosis are associated with stimulant use disorder among heart failure populations living in largely rural areas. Additionally, they emphasize the need to develop policies and refine clinical care that affects this vulnerable population's prognoses. 10.1016/j.drugalcdep.2021.109060
    Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey. Cappetta Donato,De Angelis Antonella,Bellocchio Gabriella,Telesca Marialucia,Cianflone Eleonora,Torella Daniele,Rossi Francesco,Urbanek Konrad,Berrino Liberato Frontiers in cardiovascular medicine Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na levels with consequent positive effects on Ca handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs. 10.3389/fcvm.2021.810791
    Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice. Journal of molecular and cellular cardiology Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction (HFrEF). The prevalence of HFpEF continues to increase, while the pathogenic mechanisms underlying HFpEF remain largely elusive and evidence-based therapies are still lacking. This study was designed to investigate the metabolic signature of HFpEF and test the potential therapeutic intervention in a mouse model. By utilizing a "3-Hit" HFpEF mouse model, we observed a global protein hyperacetylation in the HFpEF hearts as compared to the pressure overload-induced HFrEF and adult/aged non-heart failure (NHF) hearts. Acetylome analysis identified that a large proportion of the hyperacetylated proteins (74%) specific to the HFpEF hearts are in mitochondria, and enriched in tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and fatty acid oxidation. Further study showed that the elevated protein acetylation in the HFpEF hearts was correlated with reduced NAD/NADH ratio, impaired mitochondrial function, and depleted TCA cycle metabolites. Normalization of NAD/NADH ratio by supplementation of nicotinamide riboside (NR) for 30 days downregulated the acetylation level, improved mitochondrial function and ameliorated HFpEF phenotypes. Therefore, our study identified a distinct protein acetylation pattern in the HFpEF hearts, and proposed NR as a promising agent in lowering acetylation and mitigating HFpEF phenotypes in mice. 10.1016/j.yjmcc.2021.12.015
    Hemodynamics for the Heart Failure Clinician: A State-of-the-Art Review. Hsu Steven,Fang James C,Borlaug Barry A Journal of cardiac failure Heart failure (HF) fundamentally reflects an inability of the heart to provide adequate blood flow to the body without incurring the cost of increased cardiac filling pressures. This failure occurs first during the stressed state, but progresses until hemodynamic derangements become apparent at rest. As such, the measurement and interpretation of both resting and stressed hemodynamics serve an integral role in the practice of the HF clinician. In this review, we discuss conceptual and technical best practices in the performance and interpretation of both resting and invasive exercise hemodynamic catheterization, relate important pathophysiologic concepts to clinical care, and discuss updated, evidence-based applications of hemodynamics as they pertain to the full spectrum of HF conditions. 10.1016/j.cardfail.2021.07.012
    Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients. Yu Yi,Jin Chunna,Zhao Chengchen,Zhu Shiyu,Meng Simin,Ma Hong,Wang Jian'an,Xiang Meixiang Frontiers in cardiovascular medicine Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF). This single-center, observational cohort study enrolled 183 AHF patients ( heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization. During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2-55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively. Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management. 10.3389/fcvm.2021.761537
    Dysglycemia and incident heart failure among blacks: The jackson heart study. Echouffo-Tcheugui Justin B,Mwasongwe Stanford E,Musani Solomon K,Hall Michael E,Correa Adolfo,Hernandez Adrian F,Golden Sherita H,Mentz Robert J,Bertoni Alain G American heart journal BACKGROUND:We aimed to investigate the associations of glycemic markers (hemoglobin A [HbA], fasting plasma glucose [FPG] and glycemic status [normoglycemia, prediabetes and diabetes]) with incident heart failure (HF) and its subtypes, among Blacks. METHODS:We included 2,290 community-dwelling Blacks (64% women, mean age 58 years) without prevalent HF from the Jackson Heart Study who attended the second exam (2005 - 2008). The associations between glycemic markers and incident HF (and subtypes including HF with preserved ejection fraction [HFpEF] and reduced ejection fraction [HFrEF]) were evaluated using Cox proportional hazards regression models, adjusting for risk factors and coronary heart disease. RESULTS:There were 119 incident HF events (48 HFpEF, 58 HFrEF, and 13 unclassified HF events) over a median follow-up of 10.5 years. Higher levels of HbA (HR per SD increment, 1.30; 95% CI 1.12, 1.51) and FPG (HR per SD increment FPG: 1.32; 95% CI: 1.17, 1.48) were associated with a higher risk of incident HF. Compared to normal glycemia, diabetes status was associated with a higher risk of incident HF (HR: 1.24; 95%CI: 1.02, 2.05). HbA was significantly associated with higher risks of HFpEF (HR per SD increment: 1.41, 95% CI: 1.18, 1.69) and HFrEF (HR per SD increment: 1.32; 95% CI: 1.12, 1.56). FPG was significantly associated with higher risk of HFpEF (HR per SD increment: 1.35, 95% CI: 1.14, 1.62) but not HFrEF (HR per SD increment: 1.12; 95% CI: 0.53, 2.35). CONCLUSIONS:Among community-dwelling Blacks, higher levels of glycemic markers were associated with higher risk of HF subtypes. 10.1016/j.ahj.2021.11.003
    Beta-blockers in patients without heart failure after myocardial infarction. Safi Sanam,Sethi Naqash J,Korang Steven Kwasi,Nielsen Emil Eik,Feinberg Joshua,Gluud Christian,Jakobsen Janus C The Cochrane database of systematic reviews BACKGROUND:Cardiovascular disease is the number one cause of death globally. According to the World Health Organization (WHO), 7.4 million people died from ischaemic heart disease in 2012, constituting 15% of all deaths. Beta-blockers are recommended and are often used in patients with heart failure after acute myocardial infarction. However, it is currently unclear whether beta-blockers should be used in patients without heart failure after acute myocardial infarction. Previous meta-analyses on the topic have shown conflicting results. No previous systematic review using Cochrane methods has assessed the effects of beta-blockers in patients without heart failure after acute myocardial infarction. OBJECTIVES:To assess the benefits and harms of beta-blockers compared with placebo or no treatment in patients without heart failure and with left ventricular ejection fraction (LVEF) greater than 40% in the non-acute phase after myocardial infarction. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index - Expanded, BIOSIS Citation Index, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, European Medicines Agency, Food and Drug Administration, Turning Research Into Practice, Google Scholar, and SciSearch from their inception to February 2021. SELECTION CRITERIA:We included all randomised clinical trials assessing effects of beta-blockers versus control (placebo or no treatment) in patients without heart failure after myocardial infarction, irrespective of publication type and status, date, and language. We excluded trials randomising participants with diagnosed heart failure at the time of randomisation. DATA COLLECTION AND ANALYSIS:We followed our published protocol, with a few changes made, and methodological recommendations provided by Cochrane and Jakobsen and colleagues. Two review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse events, and major cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial reinfarction). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow-up. We assessed all outcomes at maximum follow-up. We systematically assessed risks of bias using seven bias domains and we assessed the certainty of evidence using the GRADE approach. MAIN RESULTS:We included 25 trials randomising a total of 22,423 participants (mean age 56.9 years). All trials and outcomes were at high risk of bias. In all, 24 of 25 trials included a mixed group of participants with ST-elevation myocardial infarction and non-ST myocardial infarction, and no trials provided separate results for each type of infarction. One trial included participants with only ST-elevation myocardial infarction. All trials except one included participants younger than 75 years of age. Methods used to exclude heart failure were various and were likely insufficient. A total of 21 trials used placebo, and four trials used no intervention, as the comparator. All patients received usual care; 24 of 25 trials were from the pre-reperfusion era (published from 1974 to 1999), and only one trial was from the reperfusion era (published in 2018). The certainty of evidence was moderate to low for all outcomes. Our meta-analyses show that beta-blockers compared with placebo or no intervention probably reduce the risks of all-cause mortality (risk ratio (RR) 0.81, 97.5% confidence interval (CI) 0.73 to 0.90; I² = 15%; 22,085 participants, 21 trials; moderate-certainty evidence) and myocardial reinfarction (RR 0.76, 98% CI 0.69 to 0.88; I² = 0%; 19,606 participants, 19 trials; moderate-certainty evidence). Our meta-analyses show that beta-blockers compared with placebo or no intervention may reduce the risks of major cardiovascular events (RR 0.72, 97.5% CI 0.69 to 0.84; 14,994 participants, 15 trials; low-certainty evidence) and cardiovascular mortality (RR 0.73, 98% CI 0.68 to 0.85; I² = 47%; 21,763 participants, 19 trials; low-certainty evidence). Hence, evidence seems to suggest that beta-blockers versus placebo or no treatment may result in a minimum reduction of 10% in RR for risks of all-cause mortality, major cardiovascular events, cardiovascular mortality, and myocardial infarction. However, beta-blockers compared with placebo or no intervention may not affect the risk of angina (RR 1.04, 98% CI 0.93 to 1.13; I² = 0%; 7115 participants, 5 trials; low-certainty evidence). No trials provided data on serious adverse events according to good clinical practice from the International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP), nor on quality of life. AUTHORS' CONCLUSIONS:Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction in patients younger than 75 years of age without heart failure following acute myocardial infarction. Beta-blockers may further reduce the risks of major cardiovascular events and cardiovascular mortality compared with placebo or no intervention in patients younger than 75 years of age without heart failure following acute myocardial infarction. These effects could, however, be driven by patients with unrecognised heart failure. The effects of beta-blockers on serious adverse events, angina, and quality of life are unclear due to sparse data or no data at all. All trials and outcomes were at high risk of bias, and incomplete outcome data bias alone could account for the effect seen when major cardiovascular events, angina, and myocardial infarction are assessed. The evidence in this review is of moderate to low certainty, and the true result may depart substantially from the results presented here. Future trials should particularly focus on patients 75 years of age and older, and on assessment of serious adverse events according to ICH-GCP and quality of life. Newer randomised clinical trials at low risk of bias and at low risk of random errors are needed if the benefits and harms of beta-blockers in contemporary patients without heart failure following acute myocardial infarction are to be assessed properly. Such trials ought to be designed according to the SPIRIT statement and reported according to the CONSORT statement. 10.1002/14651858.CD012565.pub2
    Education and certification on heart failure of the Heart Failure Association of the European Society of Cardiology. Mullens Wilfried,Coats Andrew,Seferovic Petar,Metra Marco,Mebazaa Alexandre,Ruschitzka Frank,Filippatos Gerasimos,Volterrani Maurizio,Ponikowski Piotr,Jankowska Ewa A,Chioncel Ovidiu,McDonagh Theresa A,Piepoli Massimo F,Milicic Davor,Thum Thomas,Hill Loreena,Abdelhamid Magdy,Adamopoulos Stamatis,Belenkov Yuri,Gal Tuvia Ben,Böhm Michael,Cohen-Solal Alain,Gustafsson Finn,Jaarsma Tiny,Moura Brenda,Rakisheva Amina,Ristic Arsen,Bayes-Genis Antonio,Van Linthout Sophie,Anker Stefan D,Tocchetti Carlo Gabriele,Lopatin Yury,Lund Lars,Savarese Gianluigi,Čelutkienė Jelena,Cowie Martin,Lambrinou Ekaterini,Ray Robin,Lainscak Mitja,Skouri Hadi,Wallner Markus,Rosano Giuseppe M C European journal of heart failure 10.1002/ejhf.2430
    Tuning and external validation of an adult congenital heart disease risk prediction model. Geenen Laurie W,Opotowsky Alexander R,Lachtrupp Cara,Baggen Vivan J M,Brainard Sarah,Landzberg Michael J,van Klaveren David,Lingsma Hester F,Boersma Eric,Roos-Hesselink Jolien W European heart journal. Quality of care & clinical outcomes AIMS:Adequate risk prediction can optimize the clinical management in adult congenital heart disease (ACHD). We aimed to update and subsequently validate a previously developed ACHD risk prediction model. METHODS AND RESULTS:A prediction model was developed in a prospective cohort study including 602 moderately or severely complex ACHD patients, enrolled as outpatients at a tertiary centre in the Netherlands (2011-2013). Multivariable Cox regression was used to develop a model for predicting the 1-year risks of death, heart failure (HF), or arrhythmia (primary endpoint). The Boston ACHD Biobank study, a prospectively enrolled cohort (n = 749) of outpatients who visited a referral centre in Boston (2012-2017), was used for external validation. The primary endpoint occurred in 153 (26%) and 191 (28%) patients in the derivation and validation cohorts over median follow-up of 5.6 and 2.3 years, respectively. The final model included 5 out of 14 pre-specified predictors with the following hazard ratios; New York Heart Association class ≥II: 1.92 [95% confidence interval (CI) 1.28-2.90], cardiac medication 2.52 (95% CI 1.72-3.69), ≥1 reintervention after initial repair: 1.56 (95% CI 1.09-2.22), body mass index: 1.04 (95% CI 1.01-1.07), log2 N-terminal pro B-type natriuretic peptide (pmol/L): 1.48 (95% CI 1.32-1.65). At external validation, the model showed good discrimination (C-statistic 0.79, 95% CI 0.74-0.83) and excellent calibration (calibration-in-the-large = -0.002; calibration slope = 0.99). CONCLUSION:These data support the validity and applicability of a parsimonious ACHD risk model based on five readily available clinical variables to accurately predict the 1-year risk of death, HF, or arrhythmia. This risk tool may help guide appropriate care for moderately or severely complex ACHD. 10.1093/ehjqcco/qcaa090
    Percutaneous edge-to-edge mitral valve repair for mitral regurgitation improves heart failure symptoms in heart failure with preserved ejection fraction patients. Gröger Matthias,Scheffler Jinny Karin,Schösser Florian,Schneider Leonhard Moritz,Rottbauer Wolfgang,Markovic Sinisa,Keßler Mirjam ESC heart failure AIMS:Therapeutic options for patients with heart failure with preserved ejection fraction (HFpEF) are sparse. Mitral regurgitation (MR) is a common feature of HFpEF and worsens heart failure symptoms and prognosis. Our study examines the outcome of patients with preserved left ventricular ejection fraction (LVEF) and elevated left atrial (LAP) or left ventricular filling pressures (LVEDP), indicative of HFpEF, after undergoing percutaneous edge-to-edge mitral valve repair (pMVR) for moderate-severe MR. METHODS AND RESULTS:Two hundred eleven patients with preserved LVEF (>50%), who underwent pMVR, were dichotomized by LAP (< / ≥15 mmHg) and LVEDP (< / ≥16 mmHg). Forty-nine per cent of patients showed elevated LAP, and LVEDP was elevated in 55%, both indicating HFpEF. Patients with elevated filling pressures featured typical clinical characteristics of HFpEF, higher N-terminal pro-brain natriuretic peptide levels (5544.9 pg/mL in high LAP group vs. 3071.7 pg/mL in normal LAP group, P = 0.06; 5061.0 pg/mL in high LVEDP group vs. 3230.3 pg/mL in normal LVEDP group, P = 0.08), and higher prevalence of pulmonary hypertension (mean pulmonary artery pressure 36.4 mmHg in high LAP group vs. 26.3 mmHg in normal LAP group, P < 0.001; 35.2 mmHg in high LVEDP group vs. 29.7 mmHg in normal LVEDP group, P = 0.004) and atrial fibrillation (78.8% in normal LAP group vs. 61.0% in high LAP group, P = 0.04; 75.3% in high LVEDP group vs. 67.5% in normal LVEDP group, P = 0.25). Pre-treatment MR grade and New York Heart Association (NYHA) class were similar in both normal filling pressure and HFpEF groups. pMVR in HFpEF patients achieved effective heart failure symptom relief comparable with patients with normal filling pressures: significant decrease of MR grade and NYHA class, as well as significant reduction of heart failure hospitalizations 12 months after compared with 12 months before MitraClip. CONCLUSION:Percutaneous edge-to-edge mitral valve repair for moderate-severe MR is an effective treatment option for symptom relief in HFpEF patients. 10.1002/ehf2.13561
    MARK4 controls ischaemic heart failure through microtubule detyrosination. Nature Myocardial infarction is a major cause of premature death in adults. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate. Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure or have shown a very modest reduction of risk of heart failure. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility. Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction. 10.1038/s41586-021-03573-5
    Efficacy of Dapagliflozin in Black Versus White Patients With Heart Failure and Reduced Ejection Fraction. JACC. Heart failure OBJECTIVES:This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). BACKGROUND:Black patients may respond differently to certain treatments for HFrEF than White patients. METHODS:Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. RESULTS:Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. CONCLUSIONS:Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124). 10.1016/j.jchf.2021.08.006
    Mitochondrial dysfunction and mitochondrial therapies in heart failure. Wu Chennan,Zhang Zhen,Zhang Weidong,Liu Xia Pharmacological research Cardiovascular diseases remain the leading cause of death worldwide in the last decade, accompanied by immense health and economic burdens. Heart failure (HF), as the terminal stage of many cardiovascular diseases, is a common, intractable, and costly medical condition. Despite significant improvements in pharmacologic and device therapies over the years, life expectancy for this disease remains poor. Current therapies have not reversed the trends in morbidity and mortality as expected. Thus, there is an urgent need for novel potential therapeutic agents. Although the pathophysiology of the failing heart is extraordinarily complex, targeting mitochondrial dysfunction can be an effective approach for potential treatment. Increasing evidence has shown that mitochondrial abnormalities, including altered metabolic substrate utilization, impaired mitochondrial oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) formation, and aberrant mitochondrial dynamics, are closely related to HF. Here, we reviewed the findings on the role of mitochondrial dysfunction in HF, along with novel mitochondrial therapeutics and their pharmacological effects. 10.1016/j.phrs.2021.106038
    Current and future therapeutic perspective in chronic heart failure. Mascolo Annamaria,di Mauro Gabriella,Cappetta Donato,De Angelis Antonella,Torella Daniele,Urbanek Konrad,Berrino Liberato,Nicoletti Giovanni Francesco,Capuano Annalisa,Rossi Francesco Pharmacological research The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development. 10.1016/j.phrs.2021.106035
    Cost-utility analysis of add-on dapagliflozin in heart failure with reduced ejection fraction in the Philippines. ESC heart failure AIM:We aim to determine the cost-effectiveness of dapagliflozin in addition to standard therapy versus standard therapy alone among patients with heart failure with reduced ejection fraction (HFrEF) using the public healthcare provider's perspective in the Philippines. METHODS AND RESULTS:A thousand Filipino patients with HFrEF (with or without type 2 diabetes mellitus) were included in a simulation cohort using a lifetime Markov model. The model, which was developed based on the results of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial, was composed of three health states. These were 'alive without an event' (chronic heart failure state), 'alive but was hospitalized for heart failure' (worsening heart failure), and 'dead' (death from any cause). Data regarding costs and utilities were obtained from previous studies and local data. These were used to estimate the incremental cost per quality-adjusted life-year (ICER). A 3% annual discount rate was used for both costs and effects. One-way (deterministic) and probabilistic sensitivity analyses as well as scenario analyses were performed. The ICER for the addition of dapagliflozin to standard therapy among HFrEF patients was PHP177 868 (US$3434) and PHP160 983 (US$3108), respectively, if the present price (PHP44.00) and possible negotiated unit cost of dapagliflozin 10 mg tablet (PHP40.00) were used. These were deemed cost-effective because they were both below the threshold ICER which was equivalent to the gross domestic product per capita of the Philippines in 2019, PHP180 500 (US$3485). Using the unit costs of dapagliflozin previously mentioned, the ICERs among HFrEF patients with diabetes were PHP132 582 (US$2560) and PHP120 249 (US$2321), respectively. Doing PSA involving Monte Carlo simulation of 10 000 iterations and plotting the resulting ICERs against the threshold ICER in the cost-effectiveness acceptability curves, these ICERs for HFrEF among diabetics were determined to be 72% and 76% cost-effective. CONCLUSION:Dapagliflozin added to standard therapy for HFrEF patients is likely to be cost-effective using the perspective of the Philippine public healthcare provider. 10.1002/ehf2.13583
    Traditional Chinese medicine enhances myocardial metabolism during heart failure. Shao-Mei Wang,Li-Fang Ye,Li-Hong Wang Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The prognosis of various cardiovascular diseases eventually leads to heart failure (HF). An energy metabolism disorder of cardiomyocytes is important in explaining the molecular basis of HF; this will aid global research regarding treatment options for HF from the perspective of myocardial metabolism. There are many drugs to improve myocardial metabolism for the treatment of HF, including angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors. Although Western medicine has made considerable progress in HF therapy, the morbidity and mortality of the disease remain high. Therefore, HF has attracted attention from researchers worldwide. In recent years, the application of traditional Chinese medicine (TCM) in HF treatment has been gradually accepted, and many studies have investigated the mechanism whereby TCM improves myocardial metabolism; the TCMs studied include Danshen yin, Fufang Danshen dripping pill, and Shenmai injection. This enables the clinical application of TCM in the treatment of HF by improving myocardial metabolism. We systematically reviewed the efficacy of TCM for improving myocardial metabolism during HF as well as the pharmacological effects of active TCM ingredients on the cardiovascular system and the potential mechanisms underlying their ability to improve myocardial metabolism. The results indicate that TCM may serve as a complementary and alternative approach for the prevention of HF. However, further rigorously designed randomized controlled trials are warranted to assess the effect of TCM on long-term hard endpoints in patients with cardiovascular disease. 10.1016/j.biopha.2021.112538
    Characteristics and outcomes of heart failure with recovered left ventricular ejection fraction. Zhang Xinxin,Sun Yuxi,Zhang Yanli,Chen Feifei,Dai Mengyuan,Si Jinping,Yang Jing,Li Xiao,Li Jiaxin,Xia Yunlong,Tse Gary,Liu Ying ESC heart failure AIMS:There is an emerging interest in elucidating the natural history and prognosis for patients with heart failure with reduced ejection fraction (HFrEF) in whom left ventricular ejection fraction (LVEF) subsequently improves. The characteristics and outcomes were compared between heart failure with recovered ejection fraction (HFrecEF) and persistent HFrEF. METHODS AND RESULTS:This is a retrospective study of adults who underwent at least two echocardiograms 3 months apart between 1 November 2015 and 31 October 2019 with an initial diagnosis of HFrEF. The subjects were divided into HFrecEF group (second LVEF > 40%, ≥10% absolute improvement in LVEF) and persistent HFrEF group (<10% absolute improvement in LVEF) according to the second LVEF. To further study the characteristics of HFrecEF patients, the cohort was further divided into LVEF improvement of 10-20% and >20% subgroups. The primary outcomes were all-cause mortality and rehospitalization. A total of 1160 HFrEF patients were included [70.2% male, mean (standard deviation) age: 62 ± 13 years]. On the second echocardiogram, 284 patients (24.5%) showed HFrecEF and 876 patients (75.5%) showed persistent HFrEF. All-cause mortality was identified in 23 (8.10%) HFrecEF and 165 (18.84%) persistent HFrEF, whilst 76 (26.76%) and 426 (48.63%) showed rehospitalizations, respectively. Survival analysis showed that the persistent HFrEF subgroup experienced a significantly higher mortality at 12 and 24 months and a higher hospitalization at 12, 24, 48, and more than 48 months following discharge. Multivariate Cox regression showed that persistent HFrEF had a higher risk of all-cause mortality [hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.49-3.56, P = 0.000] and rehospitalization (HR 1.85, 95% CI 1.45-2.36, P = 0.000) than the HFrecEF group. Subgroup analysis showed that the LVEF ≥ 20% improvement subgroup had lower rates of adverse outcomes compared with those with less improvement of 10-20%. CONCLUSIONS:Heart failure with recovered ejection fraction is a distinct HF phenotype with better clinical outcomes compared with those with persistent HFrEF. HFrecEF patients have a relatively better short-term mortality at 24 months but not thereafter. 10.1002/ehf2.13630
    A year in heart failure: an update of recent findings. ESC heart failure Major changes have occurred in these last years in heart failure (HF) management. Landmark trials and the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of HF have established four classes of drugs for treatment of HF with reduced ejection fraction: angiotensin-converting enzyme inhibitors or an angiotensin receptor-neprilysin inhibitor, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, namely, dapagliflozin or empagliflozin. These drugs consistently showed benefits on mortality, HF hospitalizations, and quality of life. Correction of iron deficiency is indicated to improve symptoms and reduce HF hospitalizations. AFFIRM-AHF showed 26% reduction in total HF hospitalizations with ferric carboxymaltose vs. placebo in patients hospitalized for acute HF (P = 0.013). The guanylate cyclase activator vericiguat and the myosin activator omecamtiv mecarbil improved outcomes in randomized placebo-controlled trials, and vericiguat is now approved for clinical practice. Treatment of HF with preserved ejection fraction (HFpEF) was a major unmet clinical need until this year when the results of EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic HFpEF) were issued. Compared with placebo, empagliflozin reduced by 21% (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P < 0.001), the primary outcome of cardiovascular death or HF hospitalization. Advances in the treatment of specific phenotypes of HF, including atrial fibrillation, valvular heart disease, cardiomyopathies, cardiac amyloidosis, and cancer-related HF, also occurred. Coronavirus disease 2019 (COVID-19) pandemic still plays a major role in HF epidemiology and management. All these aspects are highlighted in this review. 10.1002/ehf2.13760
    Predictive value of plasma volume status for contrast-induced nephropathy in patients with heart failure undergoing PCI. He Chen,Zhang Sicheng,He Haoming,You Zhebin,Lin Xueqin,Zhang Liwei,Chen Jiankang,Lin Kaiyang ESC heart failure AIMS:Contrast-induced nephropathy remains a common complication of coronary procedure and increases poor outcomes, especially in patients with heart failure. Plasma volume expansion relates to worsening prognosis of heart failure. We hypothesized that calculated plasma volume status (PVS) might provide predictive utility for contrast-induced nephropathy in patients with heart failure undergoing elective percutaneous coronary intervention (PCI). METHODS AND RESULTS:We enrolled 441 patients with heart failure undergoing elective PCI from 2012 to 2018. Pre-procedural estimated PVS by the Duarte's formula (Duarte-ePVS) and Kaplan-Hakim formula (KH-ePVS) were calculated for all patients. CIN was defined as an absolute serum creatinine (SCr) increase ≥0.5 mg/dL or a relative increase ≥25% compared with the baseline value within 48 h of contrast medium exposure. We assessed the association between PVS and CIN in patients with heart failure undergoing elective PCI. In 441 patients, 28 (6.3%) patients developed CIN. The median Duarte-ePVS was 4.44 (3.87, 5.13) and the median KH-ePVS was -0.03 (-0.09, 0.05). The best cutoff values for Duarte-ePVS and KH-ePVS to predict CIN were 4.64 (with 78.6% sensitivity and 61.7% specificity) and 0.04 (with 64.5% sensitivity and 75.5% specificity), respectively. After adjusting for potential confounding variables, KH-ePVS > 0.04 [odds ratio (OR) 2.685, 95% confidence interval (CI) 1.012-7.123, P = 0.047] remained significantly associated with CIN whereas Duarte-ePVS was not. CONCLUSIONS:Pre-procedural KH-ePVS is an independent risk factor for CIN in patients with heart failure undergoing elective PCI. The best cutoff point of KH-ePVS for predicting CIN was 0.04. 10.1002/ehf2.13681
    Metabolite signatures of heart failure, sleep apnoea, their interaction, and outcomes in the community. Dutta Shashwati,Li Desmond,Wang Andy,Ishak Mark,Cook Kristina,Farnham Melissa,Dissanayake Hasthi,Cistulli Peter,Hunyor Imre,Liu Renping,Wilcox Ian,Koay Yen Chin,Yang Jean,Lal Sean,O'Sullivan John F ESC heart failure AIMS:Sleep apnoea and congestive heart failure (CHF) commonly co-exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome. METHODS AND RESULTS:We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively. We used linear and Cox regression to relate plasma concentrations of metabolites and lipids to echocardiographic parameters; CHF and its subtypes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF); and sleep indices. Adenine dinucleotide phosphate (ADP) associated with left ventricular (LV) fractional shortening; phosphocreatine with LV wall thickness; lysosomal storage molecule sphingomyelin 18:2 with LV mass; and nicotine metabolite cotinine with time spent with an oxygen saturation less than 90% (β = 2.3 min, P = 2.3 × 10 ). Pro-hypertrophic metabolite hydroxyglutarate partly mediated the association between LV wall thickness and HFpEF. Central sleep apnoea was significantly associated with HFpEF (P = 0.03) but not HFrEF (P = 0.5). There were three significant metabolite canonical variates, one of which conferred protection from cardiovascular death [hazard ratio = 0.3 (0.11, 0.81), P = 0.02]. CONCLUSIONS:Energetic metabolites were associated with cardiac function; energy- and lipid-storage metabolites with LV wall thickness and mass; plasma levels of nicotine metabolite cotinine were associated with increased time spent with a sleep oxygen saturation less than 90%, a clinically significant marker of outcome, indicating a significant hazard for smokers who have sleep apnoea. 10.1002/ehf2.13631
    A clinical score to predict mortality in patients after acute heart failure from Japanese registry. ESC heart failure AIMS:Clinical scores that consider physical and social factors to predict long-term observations in patients after acute heart failure are limited. This study aimed to develop and validate a prediction model for patients with acute heart failure at the time of discharge. METHODS AND RESULTS:This study was retrospective analysis of the Kitakawachi Clinical Background and Outcome of Heart Failure Registry database. The registry is a prospective, multicentre cohort of patients with acute heart failure between April 2015 and August 2017. The primary outcome to be predicted was the incidence of all-cause mortality during the 3 years of follow-up period. The development cohort derived from April 2015 to July 2016 was used to build the prediction model, and the test cohort from August 2016 to August 2017 was used to evaluate the prediction model. The following potential predictors were selected by the least absolute shrinkage and selection operator method: age, sex, body mass index, activities of daily living at discharge, social background, comorbidities, biomarkers, and echocardiographic findings; a risk scoring system was developed using a logistic model to predict the outcome using a simple integer based on each variable's β coefficient. Out of 1253 patients registered, 1117 were included in the analysis and divided into the development (n = 679) and test (n = 438) cohorts. The outcomes were 246 (36.2%) in the development cohort and 143 (32.6%) in the test cohort. Eleven variables including physical and social factors were set into the logistic regression model, and the risk scoring system was created. The patients were divided into three groups: low risk (score 0-5), moderate risk (score 6-11), and high risk (score ≥12). The observed and predicted mortality rates were described by the Kaplan-Meier curve divided by risk group and independently increased (P < 0.001). In the test cohort, the C statistic of the prediction model was 0.778 (95% confidence interval: 0.732-0.824), and the mean predicted probabilities in the groups were low, 6.9% (95% confidence interval: 3.8-10%); moderate, 30.1% (95% confidence interval: 25.4%-34.8%); and high, 79.2% (95% confidence interval: 72.6%-85.8%). The predicted probability was well calibrated to the observed outcomes in both cohorts. CONCLUSIONS:The Kitakawachi Clinical Background and Outcome of Heart Failure score was helpful in predicting adverse events in patients with acute heart failure over a long-term period. We should evaluate the physical and social functions of such patients before discharge to prevent adverse outcomes. 10.1002/ehf2.13664
    Phenomapping in patients experiencing worsening renal function during hospitalization for acute heart failure. Yagi Ryuichiro,Takei Makoto,Kohsaka Shun,Shiraishi Yasuyuki,Ikemura Nobuhiro,Shoji Satoshi,Niimi Nozomi,Higuchi Satoshi,Goda Ayumi,Kohno Takashi,Nagatomo Yuji,Nishihata Yosuke,Sujino Yasumori,Saji Mike,Ikegami Yukinori,Nakano Shintaro,Takahashi Toshiyuki,Fukuda Keiichi,Yoshikawa Tsutomu ESC heart failure AIMS:The impact of worsening renal function (WRF) on the prognosis of patients with acute heart failure (AHF) remains controversial. We aimed to identify phenotypically distinct subgroups among individuals with both AHF and WRF using cluster analysis. METHODS AND RESULTS:Overall, the data of 483 patients with both AHF and WRF enrolled in the West Tokyo Heart Failure Registry were analysed. Using cluster analysis, we identified three phenotypically distinct subgroups (phenogroups 1, 2, and 3). We assessed the impact of WRF on the prognosis of each phenogroup by comparing the incidence of composite endpoints, including all-cause death and re-hospitalization due to heart failure, with those of a propensity score-matched, non-WRF control group. Participants in phenogroup 1 (N = 122) were the youngest (69.3 ± 13.7 years), had relatively preserved estimated glomerular filtration rate (eGFR, 70.0 ± 27.7 mL/min/1.73 m ), and reduced left ventricular ejection fraction (LVEF) (41.8 ± 13.7%). Conversely, participants in phenogroup 3 (N = 122) were the oldest (81.7 ± 8.5 years), had the worst eGFR (33.0 ± 20.9 mL/min/1.73 m ), and had preserved LVEF (51.7 ± 14.8%). The characteristics of the participants in phenogroup 2 (N = 239) were between those of phenogroups 1 and 3. The propensity score matching analysis showed that WRF was associated with a higher incidence of composite endpoints in phenogroup 1, whereas this association was not observed in phenogroups 2 and 3. CONCLUSIONS:Using cluster analysis, we revealed three phenotypically distinct subgroups of patients with both AHF and WRF. WRF was associated with worse clinical outcomes in the subgroup of younger patients with reduced LVEF and preserved renal function. 10.1002/ehf2.13598
    Cardiac remodelling predicts outcome in patients with chronic heart failure. Xu Lingyu,Pagano Joseph,Chow Kelvin,Oudit Gavin Y,Haykowsky Mark J,Mikami Yoko,Howarth Andrew G,White James A,Howlett Jonathan G,Dyck Jason R B,Anderson Todd J,Ezekowitz Justin A,Thompson Richard B,Paterson D Ian ESC heart failure AIMS:Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome. METHODS AND RESULTS:A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow-up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan-Meier analyses compared to those with no remodelling, log-rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction. CONCLUSIONS:Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long-term outcomes whereas change in left ventricular ejection fraction did not. 10.1002/ehf2.13626
    Pulmonary Hypertension in the Context of Heart Failure With Preserved Ejection Fraction. Inampudi Chakradhari,Silverman Daniel,Simon Marc A,Leary Peter J,Sharma Kavita,Houston Brian A,Vachiéry Jean-Luc,Haddad Francois,Tedford Ryan J Chest Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and frequently is associated with pulmonary hypertension (PH). HFpEF associated with PH may be difficult to distinguish from precapillary forms of PH, although this distinction is crucial because therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach using history, clinical examination, and noninvasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. After diagnosis, HFpEF associated with PH can be subdivided into isolated postcapillary pulmonary hypertension (IpcPH) and combined postcapillary and precapillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance. CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on PH for HFpEF associated with PH remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiologic features, therapeutic strategies, and ongoing challenges in this patient population. 10.1016/j.chest.2021.08.039