Risk Factor For Heart Failure Research Articles

Abstract 4137726: A Deep Learning Digital Biomarker for Mitral Valve Prolapse using Echocardiogram Videos

Background: Mitral valve prolapse (MVP) has a prevalence of 2–3% and is a risk factor for heart failure and sudden death, but MVP diagnosis by transthoracic echocardiography (TTE) requires time and clinical expertise. We trained a deep learning model to classify MVP from TTE videos. Methods: DROID-MVP is a convolutional neural network trained to classify MVP using echocardiographer labels using 973,531 digital videos (parasternal long axis and apical views) from 45,657 studies performed in 15,728 cardiology patients at Massachusetts General Hospital. We validated DROID-MVP in 1,726 cardiology patients (4,869 studies) and 8,903 primary care patients (8,903 studies), and tested associations between predicted MVP score (range 0-1) and mitral regurgitation (MR) severity and left atrial (LA) anterior-posterior diameter in primary care patients with available measurements. Results: Of 15,728 patients (6,029 [38%] women; mean age at first TTE 61 ± 17 years) in the training set, 729 (4.6%) had at least 1 study with MVP. DROID-MVP identified MVP in both the cardiology (area under the receiver operating characteristic curve [AUC] 0.955 [95% confidence interval: 0.939-0.970]; average precision [AP] 0.716 [0.649-0.776]; prevalence 0.035) and primary care (AUC 0.966 [0.955-0.978]; AP 0.668 [0.601-0.730]; prevalence 0.022) test sets ( Figure 1 ). Discrimination persisted across strata of MR severity (AUC range 0.877-0.987). High (>0.67) vs low (<0.33) MVP score was associated with higher odds of moderate/severe MR (odds ratio 20.1 [12.2-33.4], p<0.001) and higher LA diameter (2.7 [0.9-4.4] mm, p<0.001; Figure 2 ), after adjusting for age, sex, height, and weight. Conclusions: A deep learning model identifies MVP from TTE videos with excellent discrimination and higher model predictions are associated with greater MR severity and LA size. Our work demonstrates how deep learning can automate MVP diagnosis and may serve as a digital biomarker of MVP-associated structural abnormalities.

Abstract 4126304: A Cardiac Targeting Peptide Linked to miRNA106a Targets and Suppresses Genes Known to Cause Heart Failure: Reversing Heart Failure at the Source

Background: About one in five adults at age 40 will develop heart failure (HF) during their lifetime. Risk factors for HF (e.g., hypertension, etc.) alter cardiomyocytes structure and function resulting in HF. At the cellular level, these changes consist of mis/over-expression of genes that regulate cardiac identity (e.g., CamK2d, PKC, etc). The current paradigm for treating HF is pharmacological intervention or surgery; however, with few exceptions, the condition worsens with time. We are proposing a paradigm-shift for treating HF from a drug-centric system to a molecular approach that would reverse hypertrophy and adverse remodeling. Methods: A cardiac targeting peptide (CTP) was generated and linked by disulfide bond to miRNA106a, which was then introduced into a HF mouse model to measure its ability to reverse multiple heart failure parameters. CTP-miRNA106a was also introduced into a human cardiac cell line, followed by multiple analyses including Western Blot, qPCR, FACS, immunofluorescence all used to identify mechanism(s) utilized by CTP-miRNA106a to reverse HF characteristics. Results: Bio-distribution studies showed CTP delivered its miRNA106a cargo specifically to the heart within 30 mins, followed by clearance of CTP from the heart to the kidneys and liver by 3-5hrs post systemic drug injection. MiRNA106a persisted in cardiomyocytes until day 7 (latest tested time-point). CTP-miRNA106a reversed Ang2/Iso induced hypertrophy in 90% of the experimental mice ( Fig1 ). We also identified two potential HF intracellular signaling mechanisms (PLCb1/PKC/IP3 and NfkB) targeted by CTP-miRNA106a that could benefit both types of HF, HFrEF and HFpEF. PLCβ1 is a direct target for miRNA106a while the Nfkb pathway is indirectly targeted by decreased Camk2d (an miRNA106a target) signaling to IκBα. NfkB activity is quelled by miRNA106a. Conclusions: Our approach utilizes the function of miRNA106a to downregulate genes involved in cardiac hypertrophy and inflammation through the PLCb1 and CamKIId/Nfkb pathways. Most importantly, using a CTP-miRNA106a, we show delivery of miRNA106a cargo is specific to cardiomyocytes both in vitro and in vivo and that once delivered, many HF parameters including hypertrophy are reversed.

Abstract 4118380: In-Hospital Outcome of Acute Heart Failure in Patients with Active Chronic Lymphocytic Leukemia

Introduction: Chronic lymphocytic leukemia (CLL) is prevalent among adults in Western countries, posing a significant health challenge due to its incurable nature and associated complications. Among these, cardiovascular disease, particularly heart failure (HF), has emerged as a major concern. Despite growing recognition, understanding of acute HF's epidemiology, outcomes, and risk factors in CLL patients remains limited. To address these gaps, we conducted a large-scale study using the National Inpatient Sample (NIS) database, aiming to examine acute HF prevalence, trends, outcomes, and predictors among CLL hospitalizations. Methods: We employed a retrospective cohort design utilizing NIS data from 2016 to 2021. CLL hospitalizations with and without acute HF were identified using ICD-10 codes. Our analysis included demographic characteristics, in-hospital outcomes, and multivariable logistic regression to identify predictors of outcomes. Propensity score matching was performed to mitigate confounding factors. Results: Among 423,829 CLL hospitalizations, 27.8% presented with acute HF. Patients with acute HF were older and had higher rates of comorbidities. While acute HF prevalence remained stable, in-hospital mortality increased over time, contrasting with stable rates among patients without acute HF. Acute HF was associated with higher mortality, cardiogenic shock, cardiac arrest, and major adverse cardiovascular events. Propensity score-matched analysis confirmed these associations. Discussion: Our study highlights acute HF as a common complication in CLL hospitalizations, linked with worse outcomes. The multifactorial nature of HF in CLL involves disease-related factors, treatment toxicities, and traditional cardiovascular risk factors. Prompt recognition and multidisciplinary management are essential for improving outcomes. Future research should focus on developing risk stratification tools and interventions targeting acute HF in CLL patients. Conclusion: Acute HF poses a significant burden on CLL hospitalizations, emphasizing the need for heightened awareness and tailored management strategies. Our findings underscore the importance of early recognition and intervention to improve outcomes in this vulnerable population.

Abstract 4116714: Macrophage Colony Stimulating Factor as a Causal Metabolic Mediator of Cardiovascular Disease: An Observational and Mendelian Randomization Analysis

Background: Macrophage biology plays a key role in the pathogenesis of atherosclerosis and circulating macrophage colony-stimulating factor (M-CSF) is a marker of macrophage activity. However, there is conflicting evidence regarding its role as a mediator of cardiovascular disease. Methods: We evaluated the association between plasma M-CSF concentration with myocardial infarction, stroke, heart failure and mortality in a large substudy involving 9992 participants drawn from 14 countries and followed for a median period of 9.8 years (Interquartile Range 8.9 years - 11.4 years) utilizing a nested case-cohort design in the Prospective Urban Rural Epidemiology (PURE) study. We then conducted a two-sample Mendelian randomization (MR) analysis to evaluate the upstream determinants (using genome wide association data from the PURE biobank and publicly available consortia) and downstream effects on clinical events.. Results: The strongest causal upstream determinant of M-CSF concentration was body mass index (BMI), which showed a positive association with plasma M-CSF concentration (Beta: 0.17 SD increase; 95% CI: 0.08 - 0.27). In a survival analysis, M-CSF was independently associated with increased incident myocardial infarction (HR: 1.25 per 1 SD M-CSF increase; 95% CI: 1.13-1.38), stroke (HR: 1.17; 95% CI:1.04-1.32), and heart failure (HR: 1.34; 95% CI: 1.15-1.56) and other cardiovascular disease risk factors. Circulating M-CSF concentration also showed a strong association with long-term risk of overall mortality (HR: 1.44; 95% CI: 1.39-1.60). Mendelian randomization analyses confirmed that increased M-CSF was associated with increased risk of MI, heart failure, and ischemic stroke (specifically large artery atherosclerotic and cardioembolic stroke). Conclusions: M-CSF is a strong causal driver of cardiovascular disease morbidity whose concentration is causally influenced by body mass index. Our analysis suggests a role for macrophage activity in mediating the relationship between body mass index and cardiovascular disease outcomes.

Healthy longevity-associated protein improves cardiac function in murine models of cardiomyopathy with preserved ejection fraction

AimsAging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.Materials and MethodsIn two controlled, randomized studies, 18-month-old male C57BL/6 J mice and 9-week-old C57BLKS/J-Leprdb/Leprdb/Dock7 + [db/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3 µg/animal, every three days) or vehicle by gavage. After 30 days, the animals underwent echocardiography, and the hearts were collected post-termination for histology.ResultsAll the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.ConclusionsThis study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy.

USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.

Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To define whether the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild-type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4 wk of TAC compared with WT cohorts. Both USP20-KO TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume overload states and decompensated heart failure. In contrast, WT-TAC mice displayed an increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis, and mouse mortality were augmented in USP20-KO-TAC compared with WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling, was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts, indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure.NEW & NOTEWORTHY We identify ubiquitin-specific peptidase 20 (USP20) as an important enzyme that is required for cardiac homeostasis and function, particularly during myocardial pressure overload. USP20 regulates protein stability of cardiac MYH7, an essential molecular motor protein expressed in sarcomeres; loss-of-function mutations of MYH7 are associated with human hypertrophic cardiomyopathy, cardiac failure, and sudden death. Enhancing USP20 activity could be a potential therapeutic approach to prevent the development of maladaptive state of eccentric hypertrophy and heart failure.

Metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: risk of heart failure

Background and aimsThe association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) is unclear. This study aimed to investigate the impact of spectrum of SLD on the risk of heart failure and cardiovascular (CV) mortality in patients with T2DM.MethodsIn a nationwide cohort study, 2,745,689 adults with T2DM were followed from 2009 to 2012 until 2018. Participants were categorized into no steatotic liver disease (no SLD) and SLD groups. The SLD group was stratified based on metabolic risk factors, alcohol consumption and viral hepatitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for heart failure (HF) and CV mortality risk.ResultsThe prevalence of MASLD, metabolic alcohol-associated liver disease (MetALD), alcohol-associated liver disease with metabolic dysfunction (ALD with MD) and MASLD with viral hepatitis (VH) was 49.6%, 7.2%, 2.3%, and 2.0%. Individuals with MASLD (adjusted HR [aHR], 1.11), MetALD (aHR, 1.14), ALD with MD (aHR, 1.32) and MASLD with VH (aHR, 1.12) had a higher risk of developing HF compared with the no SLD group. The risk of CV mortality was also increased in those with SLD groups compared to those with no SLD. The risk of new-onset HF and CV mortality showed a J-shaped association with alcohol consumption regardless of SLD status.ConclusionSLD is independent risk factor of new-onset HF and CV mortality in persons with T2DM, and alcohol consumption has a J-shaped association with risk of HF and CV mortality, regardless of SLD status.

Prevalence and Risk Factors of Heart Failure in Patients Diagnosed with Hyperthyroidism: A Systematic Review and Meta-analysis

Prevalence and Risk Factors of Heart Failure in Patients Diagnosed with Hyperthyroidism: A Systematic Review and Meta-analysis

MiR-421-mediated suppression of FGF13 as a novel mechanism ameliorates cardiac hypertrophy by inhibiting endoplasmic reticulum stress

Pathological cardiac hypertrophy is an independent risk factor for heart failure. Currently, clinical treatments offer limited effectiveness, and both mortality and morbidity from cardiac hypertrophy and heart failure continue to be significant. Therefore, it is extremely urgent to find new intervention targets to prevent and alleviate pathological cardiac hypertrophy. In this study, we explored FGF13 expression and its upstream regulators in hypertrophic hearts. Firstly, we observed an increase in FGF13 expression levels in human hypertrophic myocardium tissues, as well as in mouse models of TAC-induced hypertrophy and in neonatal rat cardiomyocyte (NRCM) models induced by isoproterenol (ISO). Moreover, these elevated levels of FGF13 were shown to positively correlate with hypertrophic markers, including ANP and BNP. By using both gain-of-function and loss-of-function approaches in an in vitro hypertrophy model, we demonstrated that FGF13 knockdown could inhibit endoplasmic reticulum stress (ERS), thereby ameliorating cardiomyocyte hypertrophy. Meanwhile, we investigated the upstream regulators of FGF13 in hypertrophic hearts, and a dual-luciferase reporter assay confirmed that FGF13 is a direct target of miR-421. Overexpression of miR-421 decreased the protein level of FGF13 and ameliorated ISO-induced cardiomyocyte hypertrophy via modulating ER stress. In contrast, overexpression of FGF13 attenuated the ameliorative effect of miR-421 on ISO-induced cardiomyocyte hypertrophy. Taken together, the present results suggested that miR-421 ameliorated ISO-induced cardiomyocyte hypertrophy by negatively regulating FGF13 expression. This finding may offer a novel approach for the treatment of cardiac hypertrophy.

Prevalence of stage B heart failure in healthy adults and people with type 2 diabetes

Abstract Introduction People with Type 2 Diabetes (T2D) are at increased risk of heart failure, and as such are classified as having Stage A Heart Failure (SAHF). Those with additional evidence of raised filling pressures, biochemical or structural cardiac changes, without heart failure symptoms, are deemed to have Stage B heart failure (SBHF). Identifying patients with SBHF may help determine those at highest risk of disease progression. Purpose The aim of this work was to assess the prevalence of SBHF in a cohort of asymptomatic healthy volunteers and people with T2D characterised according to current American Heart Association/American College Cardiology/Heart Failure Society of America. Methods A single-centre, prospectively recruited cohort of middle-aged asymptomatic adults with T2D and healthy volunteers, with no history or signs of cardiovascular disease, underwent comprehensive cardiac phenotyping with transthoracic echocardiography and circulating brain natriuretic peptide. Healthy volunteers with risk factors for heart failure, including hypertension and obesity, were excluded from analysis. Prevalence of SBHF was determined by comparing cardiovascular data to proposed standards, left ventricular ejection fraction and global longitudinal strain parameters were omitted from analysis due to data availability. Results We included 383 T2Ds (diabetes duration 9(5,15) years) and 65 healthy volunteers (Table 1); 91% of those with T2D and 65% of healthy volunteers met ≥1 criteria for SBHF (Table 2). Median number of SBHF criteria met in the T2D cohort was 3 (2,4); in particular, a large proportion of the cohort met defined cut offs for relative wall thickness (70.6%), lateral e’ (62.2%), septal e’ (54.1%) and LV wall thickness (47.4%). Of the 65 healthy volunteers, median number of SBHF criteria met was 1 (0,2.5). In healthy volunteers, SBHF was most commonly defined by lateral e’ (40.0%), septal e’ (38.3%), relative wall thickness (32.2%), left atrial volume indexed (22.4%) and serum brain natriuretic peptide (23.3%). Of note, brain natriuretic peptide levels met current SBHF parameters in 18.8% of healthy volunteers and 9.9% people with T2D, which may be attributable to the exclusion of obesity in the healthy volunteer group. Conclusion Using currently proposed standards, a high proportion of middle-aged asymptomatic people with T2D, and healthy volunteers without any risk factors for heart failure, would be categorised as having SBHF. These data strongly suggest that the majority of the proposed parameters for the definition of SBHF are not specific for a UK population and if applied will incorrectly classify many asymptomatic people at high risk of developing heart failure.

Association between impaired left ventricular global longitudinal strain and B-type natriuretic peptide in obstructive hypertrophic cardiomyopathy

Abstract Background Left ventricular global longitudinal strain (LV-GLS) is considered valuable in explaining impaired left ventricular contractility in hypertrophic cardiomyopathy (HCM) with preserved ejection fraction and is associated with worse outcome. Elevated B-type natriuretic peptide (BNP) is a biomarker of increased LV wall stretch and a risk factor of heart failure, mortality, and other adverse cardiovascular events. However, relationship between GLS and BNP has not received sufficient attention in the obstructive variant of HCM. Purpose This study aimed to determine the association between echocardiographic LV-GLS and plasma BNP in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods A total of 145 consecutive patients (32% females) with symptomatic HOCM were enrolled in the retrospective study. HOCM was defined with a maximum end-diastolic wall thickness ≥15mm without other etiologies for LV hypertrophy, and peak LV outflow tract (LVOT) gradient ≥30mmHg. The echocardiographic parameters regarding LV geometry, loading conditions, and GLS were evaluated according to guidelines. Patients were divided into two groups according to absolute GLS values (greater or lower than median LV-GLS). Patient baseline clinical data, echocardiographic parameters, and BNP were compared. Univariate and multivariable regression analysis were applied to identify the independent determinator of LV-GLS. Results The median value of LV-GLS of this study cohort was -13.4%. Eighty-one patients (47.6±13.4 years-old) had a |GLS|≥13.4% and 64 individuals (48.7±12.6 years-old) had a |GLS|<13.4%. No differences were found in age, gender, physical examinations, LVEF, cardiovascular comorbidities, or active medications between the two groups, except for body mass index (BMI). Patients with |GLS|≥13.4% had statistically lower BMI (24.58±2.42 vs. 26.00±3.12kg/m², p=0.030). BNP was found significantly elevated in patients with |GLS|<13.4% when compared with individuals with |GLS|≥13.4% {median (IQR); 550.05 (214.50, 899.35) vs. 182.40 (78.90, 479.90)pg/mL, p=0.004}. In univariate regression analysis, decreased |GLS| was associated with male gender, maximum and mean LV wall thickness, peak LVOT gradient, reduced mitral annular e’ velocity, elevated BNP and cardiac troponin I. In multivariable regression analysis, GLS was found independently associated with mean LV wall thickness and BNP. Conclusions In patients with symptomatic HOCM with preserved ejection fraction, impaired LV-GLS was found to be associated with plasma BNP and mean LV wall thickness, independent of gender, age, loading conditions, LVEF, or LVOT gradient. Reduced GLS may be a more sensitive surrogate in assessing increased myocardial wall tension or stretch, rather than LV contractility in these patients. Therefore, the interpretation of GLS in HOCM should shift away from systolic interest toward emphasizing its potential value in risk stratification of diastolic heart failure with preserved LVEF.Figure 1

Trajectories of weight and their impact on cardiac remodeling and function 16 years after bariatric surgery

Abstract Introduction Obesity is a major risk factor for heart failure, particularly heart failure with preserved left ventricular (LV) ejection fraction. Surgical treatment of obesity have significant beneficial short-term effects on weight loss and on cardiac function; its long-term impact on cardiac remodeling and function remains largely unknown. Purpose We examine the long-term effect of bariatric surgery on cardiac remodeling and function in adults with preserved LV ejection fraction. Methods Forty-four individuals with severe obesity [body mass index (BMI) ≥35kg/m2] and preserved LV ejection fraction (≥50%) who underwent bariatric surgery (biliopancreatic diversion with duodenal switch [BPD-DS]) were included. Anthropometric measurements and echocardiography were obtained at baseline, 12 months and 16 years follow-up. Results Mean age of participants (71% female) was 44 ± 8 years and body mass index (BMI) 49.6 ± 6.1 kg/m2. Bariatric surgery led to marked weight reduction and significant improvements in obesity-related metabolic conditions/comorbidities (hypertension, dyslipidemia, type 2 diabetes). Mean percentage of weight loss at 12 months was 37.1 ± 7.0 %. Percentage of weight regain at 16 years averaged 8.9 ± 35.0 %. Bariatric surgery was associated with a significant reduction in indexed LV mass and LV hypertrophy (p <0.01), and improvement in LV diastolic function parameters (p <0.01) at 12 months. In many participants, cardiac remodeling parameters deteriorated at 16 years follow-up compared to the echocardiographic measurements taken at 12 months post-surgery. Prevalence of LV diastolic dysfunction increased at 16 years (81 vs. 38%; p<0.001), even after adjusting for age. Weight regain at 16 years (regaining >10% of weight lost; n=25; 57%) was not found to be associated with a worsening in cardiac remodeling compared to those who maintained weight loss, except for indexed LV mass (-9.3 ± 10.6 vs. -5.5 ± 7.8 g/m2.7; p=0.04) and LV end-diastolic diameter (-5.4 ± 4.0 vs. -3.5 ± 3.3 cm; p=0.01). Conclusion Bariatric surgery (BPD-DS) leads to durable long-term weight loss. Weight regain following bariatric surgery does not appear to have adverse effect on cardiac remodeling and function. Surgical treatment of obesity may be an effective and safe way to prevent clinical cardiac dysfunction and heart failure related to obesity.

Sex-biased proteomic regulation in obesity

Abstract Background Obesity is a major risk factor for heart failure with preserved ejection fraction, particularly in women. Obesity-associated inflammation is thought to contribute to this relationship. However, the role of biological sex in the regulation of circulating inflammatory proteins in obesity is not well understood. Purpose We aimed to explore sex differences in the plasma inflammatory protein profile in obese subjects. Methods Clinical data and samples were collected from 450 women and men with a body mass index (BMI) >27 kg/m² without known cardiovascular disease participating in the FAT associated CardiOvasculaR dysfunction study. Obesity was defined as BMI≥30 kg/m². Olink’s Target 96 inflammation panel, which profiles 92 proteins using proximity extension assay technology, was analysed in biobank samples. A comprehensive correlation analysis was performed to describe relationships between protein biomarkers and clinical variables. Gene enrichment analysis was performed to shed light on biological pathways associated with differentially expressed proteins (DEPs). To determine the functional significance of the DEPs, we used the repositories Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Pearson correlation coefficients were calculated to assess linear associations between the DEPs and relevant clinical variables. Results Women and men did not differ by age (49±9 vs 48±9 years), BMI (32.3±4.6 vs 31.6±3.7 kg/m²) or in prevalences of diabetes (both 11%) or obesity (65% vs 62%) (all p>0.05). However, hypertension was more common in men than women (74% vs 52%, p<0.001). In men (n=188), obesity was associated with downregulation of monocyte chemotactic protein 3, tumor necrosis factor (ligand) superfamily member 12, interleukin 10 and protein S100-A12 and with upregulation of neurotrophin-3 (all p<0.05), thereby suggesting a mechanism for the observed impaired inflammatory response and insulin resistance. In women (n=262), obesity was associated with the downregulation of interleukin 7, interleukin 12 subunit beta, interleukin 6, and C-X-C motif chemokine 11, suggesting a state of persistent low-grade inflammation. In addition, the upregulated sulfotransferase 1A1 and SIR2-like protein 2 proteins indicate a physiologic adaptation to oxidative stress and the metabolic excess endemic to obesity. Conclusion We found that the abundance of several circulating inflammatory proteins was altered in presence of obesity, and that the plasma proteomic profile differed by sex. Interestingly, there was no overlap in the DEPs between women and men in the presence of obesity. These findings support the hypothesis that the pathophysiological mechanisms driving obesity-associated inflammation and immune dysregulation differ by sex. In turn, this may aid in the pursuit of discovering sex-specific biomarkers to identify obese individuals at particular risk of heart failure.

Prevalence and outcomes of American Heart Association stages of heart failure in an adult brazilian population of the ELSA-Brasil study

Abstract Aims Heart failure (HF) has a major impact on public health, affecting up to 2% of adult population. HF staging is helpful in capturing pre-clinical disease and its progression to advanced stages. We aimed to determine the prevalence and mortality of HF stages in the participants of a Brazilian adult cohort. Methods The ELSA-Brasil cohort comprises 15,105 adult public servants from 6 Brazilian capitals. In the initial evaluation of the study (2008-2010), ELSA carried out interviews and clinical, laboratory, and cardiovascular ancillary tests. In this analysis, we included participants who had electrocardiogram and echocardiogram performed at baseline visit, and additional information regarding risk factors and functional capacity. The HF stages were defined based on AHA guidelines criteria as follow: Stage 0 was defined as a healthy individual with no risk factors for heart failure. Stage A (at risk for HF) included those without cardiac structural or functional abnormality but with any of the following conditions: systemic hypertension; diabetes mellitus, obesity, history of myocardial revascularization, history of rheumatic fever, and seropositivity for Chagas’ disease. Stage B (pre-HF) was defined as asymptomatic participants with history of myocardial infarction or any major abnormalities on ECG or echocardiogram. Stage C (symptomatic HF) included participants with a clinical history of HF, or HF symptoms in the presence of structural heart disease (defined as in Pre-HF stage). Considering the community-dwelling profile of the sample, we did not expect to have advanced heart failure patients in our sample. Results We included the 3,267 participants (61±9 years; 53% women) with baseline data. Prevalences of HF stages were stage 0: 938 (29%) A: 1,385 (42%), B: 651 (28%) and C: 293 (9%), with different distribution between sexes (p<0.001). Older participants had higher prevalences of stages B and C (p<0.001), with the prevalence of stage C increasing from 1.8% at 35-44 years to 12.2% at 65-74 years. After 12 years of follow-up, total mortality rates of HF stages were Stage 0: 4%; A:10%. B: 16%, and C: 26%, and respective Cox proportional hazard ratios [95% CI] adjusted for age and sex were A: 1.94 [1.3-2.8], B:2.78 [1.9-4.1], and C: 5.39 [3.6-8.1] compared to stage 0. Conclusions The prevalence of HF in Brazilians reflects what is described in international literature, with a large proportion of individuals in pre-symptomatic stages. A notable shift in the sample toward pre-symptomatic and symptomatic HF occurred gradually and persistently across the age span studied. Mortality rates increase incrementally across the HF stages. This information is important for understanding and planning health policies for this syndrome.

Is the female sex a risk factor for heart failure after myocardial infarction?

Abstract Background In previous observations, female sex was associated with heart failure after myocardial infarction (MI). However, women were older and had more risk factors and were not treated the same as men. Purpose Our aim was to investigate the differential impact of sex on heart failure (including cardiogenic shock) and outcome in a propensity score matched population with MI who had undergone percutaneous coronary intervention (PCI) and the association between sex, heart failure and long-term mortality. Methods Data from 3624 (30.6% women) MI patients who underwent PCI at our institution were analyzed. Propensity-score matching analysis was performed to adjust for differences in baseline characteristics between men and women. After propensity matching, the sample comprised 2170 patients (1085 women and 1085 men). Heart failure was defined by clinical criteria (bilateral pulmonary rales, S3 gallop, edema or cardiogenic shock) and/or pulmonary edema on chest X-ray and/or ejection fraction <30%. The data were analyzed using descriptive statistics. The median follow-up time was 27 months (25th, 75th percentile: 9,48). Results In hospital, 329 (16.4%) patients developed heart failure, with a similar incidence in men and women (156(15.5%) vs. 173(17.2%);p=0.33) (Figure 1). Furthermore, female sex was not associated with heart failure either univariately (OR 1.13;95%CI 0.89-1.43;p=0.31) or after adjustment for confounding factors (aOR 1.27;95% CI 0.96-1.66;p=0.093). Age, hypertension, hyperlipidemia, ST- elevation MI, and P2Y12 receptor inhibitors were associated with heart failure. We followed the patients for up to six years. At the end of the observation period, 330(16.4%) patients had died. The mortality rate was similar in both sexes (159(15.8%) men died compared to 171(17.0%) women; p=0.51) (Figure 2). In addition, sex was not associated with long-term mortality (aHR 1.11;95%CI 0.88-1.40;p=0.38) after adjusting for confounders. In-hospital heart failure was independently associated with long-term mortality (aHR 2.64;95%CI 2.04-3.41;p<0.0001). Hyperlipidemia, age, ST- elevation MI, radial access, P2Y12 receptor inhibitor and GFR were also associated with long-term mortality. Conclusions Our results suggest that sex itself is not associated with heart failure after MI when women are treated similarly to men, have similar risk factors, and are of similar age. It is more likely that women are more frequently affected by heart failure because they are older, have more risk factors, are less likely to be revascularized, and are less likely than men to be treated with guideline-recommended therapy,Heart failure in men and womenLong-term all-cause mortality

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical diabetic cardiomyopathy

Abstract Background Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with so-called diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. Purpose This study aimed to evaluate associations between NT-proBNP concentrations, clinical characteristics, echocardiographic findings, health status and activity, and outcomes from cardiopulmonary exercise testing Methods The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) trial is evaluating the effects of AT-001, a novel aldose-reductase inhibitor in participants with DbCM without a prior history of heart failure (1). Participants were included if they had a known diagnosis of type 2 diabetes and age ≥60 (or ≥45 with a duration of diabetes of ≥10 years or estimated glomerular filtration rate ≤60 mL/min/1.73m2). Participants were required to have evidence of one of: structural cardiac abnormality, elevated cardiac biomarkers, or impaired exercise tolerance, defined as a peak oxygen uptake (VO2) ≤75% of predicted. In this prespecified subgroup analysis of the ARISE-HF trial, 685 participants with baseline echocardiography data, laboratory investigations, and functional assessment were included. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. Results The mean age of participants was 67.4 years and 50% were female. The mean duration of type 2 diabetes was 14.5 years with a mean hemoglobin A1c of 6.98. The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/e’, or right ventricular systolic pressure (Figure 1). In contrast, NT-proBNP was significantly correlated with components of the Kansas City Cardiomyopathy Questionnaire (P<0.001), the Physical Activity Scale in the Elderly (P=0.004), duration of cardiopulmonary exercise testing (P<0.001), peak VO 2 (P<0.001), and ratio of minute ventilation/carbon dioxide production (P=0.002; Figure 2). Conclusion Among highly selected patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals.

Estimation of salt intake from urinalysis as a prognostic indicator in patients with heart failure

Abstract Background Restricting sodium consumption by reducing salt intake is crucial in heart failure management. The average salt intake in Japan is approximately 10 g/day, which is significantly higher than that in other countries. Therefore, the Japanese guidelines for heart failure recommend a target salt intake of less than 6 g/day. Purpose Excessive salt intake is a well-known risk factor for heart failure, but it has also been reported that excessive salt restriction does not affect clinical outcomes in patients with heart failure. Moreover, although previous reports have mainly focused on clinically stable patients with chronic heart failure, appropriate salt intake management in patients with unstable heart failure immediately after hospital discharge remains unexplored. Therefore, this study aimed to investigate the effect of salt intake management on patients with heart failure in the early post-discharge period. Methods The study was conducted between April 2015 and March 2023, and included 395 of 4,292 patients (mean age: 72 y; sex: 63% male) who were hospitalized owing to heart failure and whose salt intake was measured at early post-discharge. Salt intake was estimated via the Tanaka Method, using spot urine samples. The patients were divided into four groups based on the estimated salt intake: very low (< 4 g/day) (n = 24), low (≥ 4 and < 7 g/day) (n = 109), high (≥ 7 and < 10 g/day) (n = 149), and very high (≥ 10 g/day) (n = 113). The primary endpoint was all-cause rehospitalization within 1 year of discharge. Results During a median follow-up period of 303 days, 153 rehospitalization occurred. 96 were heart failure rehospitalization; others included infection, arrhythmia, dehydration etc. Spline curve analysis for estimated salt intake and rehospitalization (Fig. 1) showed a significant nonlinear curve (P = 0.017). Cox regression analysis (Fig. 2) revealed a significantly higher number of rehospitalization in the very low group (hazard ratio [HR]: 2.29; 95% confidence interval [CI]: 1.24–4.25; P = 0.009), compared with the low group, and a similar trend was also observed in the very high group (HR: 1.51; 95% CI: 0.99–2.31; P = 0.056). Subgroup analysis (Fig. 3) showed that the impact of estimated salt intake on rehospitalization, as represented by a U-shaped curve, was more pronounced in patients who were not treated with loop or thiazide diuretics. Conclusion The results of this study suggest that both excessive salt intake and excessive restriction may increase the risk of rehospitalization in patients with heart failure during the early post-discharge period. Additionally, the results indicate that estimation of salt intake using the Tanaka method may be particularly useful for patients not undergoing diuretic treatment. Conversely, patients with very low salt intake, potentially indicative of inadequate oral intake due to an impaired general condition, may require careful follow-up.

Obesity paradox exists in super elderly patients with heart failure

Abstract Background Aging and obesity are two global concerns in public health. As obesity is associated with several metabolic disorders, it is a well-known risk factor of heart failure (HF). However, several studies have suggested that obesity may have paradoxical survival benefits in patients with HF. Therefore, the aim of this study was to investigate whether the obesity paradox exists in super elderly patients with HF in Japan. Methods A total of 4,292 patients from our hospital HF registry were divided into four age subgroups: (A) less than 65, (B) elderly 65-74, (C) high elderly 75-84, (D) super elderly ≥85. The primary endpoint was the all-cause death within 1-year after discharge. Results At baseline, the proportion of men in each group was 42-76%, the mean left ventricular ejection fraction was 49-61%, the average of N-terminal pro-B-type natriuretic peptide was 1972-2944 pg/ml, and the mean body mass index (BMI) ranged 21-25 kg/m2. Patients with higher BMI were more common in the younger age group, while those with lower BMI were more common in the older age group. Cubic spline curves of Cox proportional hazard regression models demonstrated an inverse relationship between BMI and mortality (Fig. 1). Lower BMI was associated with higher all-cause mortality in all ages, although this association was attenuated at the young age, and pre-obesity (25–29.9 kg/m2) was associated with the greatest survival benefit. Meanwhile, the impact of underweight (<18.5 kg/m2) was stronger super elderly subjects, a one-unit increase in BMI was associated with a 10.3% decrease in the hazard ratio of death (P=0.021). Kaplan-Meier curves for all-cause mortality also showed that lower BMI was associated with higher all-cause mortality in all groups, and the differences were statistically significant in Groups B, C, and D (Fig. 2). Conclusion Our study suggested the existence of the obesity paradox among HF patients in super elderly. Mildly overweight may be beneficial at old age with HF.

Exploring heart failure prevalence and overlooked dimensions: a comprehensive NT Pro-BNP study in high-risk primary care patients

Abstract Background Heart failure (HF) is a prevalent syndrome linked to significant morbidity and mortality, especially in those with comorbid conditions like diabetes, hypertension, and atherosclerotic cardiovascular disease. Early detection and intervention are crucial. Natriuretic peptides, particularly NT-proBNP, are promising biomarkers for identifying at-risk individuals, but their use in primary care settings is not fully understood. Methods This prospective cohort study enrolled 874 participants aged 40 and above with documented risk factors for HF, such as diabetes mellitus, hypertension, metabolic syndrome, obesity, atherosclerotic cardiovascular disease, genetic variants for cardiomyopathy, or exposure to cardiotoxic agents. NT-proBNP levels were measured in blood samples collected at primary care clinics, and participants underwent comprehensive cardiac evaluations at a referral hospital. Clinical characteristics, laboratory findings, electrocardiography, and echocardiography results were recorded. Results The study included 874 patients with at least one risk factor for HF, with a mean age of 62.5 ± 9.1 years and 51.9% female. According to the 2022 AHA/ACC/HFSA HF Guideline, 69.1% were Stage A HF, 21.9% Stage B HF, and 9% Stage C HF. Clinical characteristics, laboratory and echocardiographic findings are shown in Picture 1. The majority had hypertension (71.1%), while other prevalent comorbidities included diabetes mellitus (43.4%), dyslipidemia (35.2%), obesity (27.1%), and atherosclerotic cardiovascular disease (26.2%). Laboratory findings showed a significant decrease in HbA1C, eGFR, LDL, triglycerides, and hemoglobin from Stage A to C HF. Median NT-proBNP levels rose from Stage A to C HF (46.4 pg/mL in Stage A, 219 pg/mL in Stage B, and 268.5 pg/mL in stage C), with 84.8% of Stage B HF patients exhibiting elevated levels. NT-proBNP levels were correlated positively with left atrial volume index, left ventricular mass index, age, E/e’, and estimated systolic pulmonary artery pressure levels. Conversely, NT-proBNP levels showed a negative correlation with estimated glomerular filtration rate and left ventricular ejection fraction. Among Stage C patients, 92.4% had HFpEF. The Picture 2 depicted the study's design and outcomes, providing a comprehensive visual representation. Conclusion NT-proBNP screening in primary care settings identified a substantial proportion of individuals with undiagnosed HF, particularly those in Stage B and Stage C. The high prevalence of HFpEF underscores the need for comprehensive evaluation and management strategies targeting this population. Early detection facilitated by NT-proBNP screening may lead to timely interventions and improved outcomes in individuals at risk for HF.

Unveiling the clinical profiles of heart failure across diverse stages and phenotypes: insights from the national echocardiographic society registry

Abstract Background The modern comprehension of heart failure (HF), based on a staging paradigm, demands systematic screening to promptly identify individuals at risk, those in the pre-HF stage, and symptomatic HF patients across various phenotypes (HFpEF, HFmrEF, and HFrEF). The discernment of clinical profiles within these categories holds significant potential for improving screening and ensuring timely therapeutic interventions. Material and Methods Our national echocardiographic society executed a multicenter HF screening program. General practitioners in 13 primary care centers utilized the original mobile app to determine referrals for transthoracic echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing in patients without a prior HF diagnosis. The 2021 ESC guidelines' algorithms were employed for HF diagnosis (HFpEF, HFmrEF, HFrEF). This study identifies two pre-heart failure (pre-HF) stages: "heart stress" (elevated NT-proBNP in asymptomatic individuals with risk factors, regardless of structural heart disease or cardiac dysfunction) and individuals "at risk for HF" (normal NTproBNP and at least one HF risk factor). Ultimately, all patients were categorized into six groups: (I) no HF, no risk; (II) at risk for HF; (III) heart stress; (IV) HFpEF; (V) HFmrEF; and (VI) HFrEF. Subsequently, the eleven clinical variables were compared among groups (II) to (VI) using chi-square test. Results Among 930 screened outpatients (mean age 66±11 years, 61% female), diagnosis of HF was established in 34.2% (Figure, pie). Heart stress was found in 22.3% patients, and 38.1% were at risk for HF, while 5.5 % had neither HF nor risk factors. Group comparison revealed that older individuals were more frequent in the HFpEF group, females predominated in the heart-stress and HFpEF groups, and males in the HFrEF group (Figure, table). Obesity was the most frequent among those at risk and HFmrEF. Atrial fibrillation and pathological ECG increased gradually from those at risk to HFrEF. Previous MI was the most common in heart stress and HFmrEF groups, while arterial hypertension >10 years prevailed in HFpEF and HFmrEF patients. Diabetes mellitus > 5 years was present in 24-28% across groups. CKD or eGFR≤60 ml/min/1.73m² increased gradually towards HFmrEF. The family history of CMP or SCD was positive in 17-24%, with no significant differences observed across groups. Additionally, a small number of patients had a history of previous cardiotoxic cancer treatment, and no significant differences were found between groups. Conclusions The mobile phone application used in primary care successfully identified a significant number of pre-heart failure patients requiring further evaluation. Different HF stages and phenotypes exhibit distinct clinical profiles, aiding in the screening process and contributing to a deeper understanding of the heart's pathophysiological adaptation to diverse risk factors during HF development.