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Background: Higher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation., Methods: We prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of 6 lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality., Results: Among 1382 patients with heart failure (median follow-up 13.9 years), a one-standard-deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.97-0.99). Among LP-IR parameters, mean high-density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83; 95% CI, 0.78-0.89), suggesting that the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size., Conclusions: LP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size., (Published by Elsevier Inc.)

Background: Heart failure (HF) risk is greater in rural versus urban regions in the United States (US), potentially due to differences in healthcare coverage and access. Whether this excess risk applies to countries with universal healthcare is unclear and the underlying biological mechanisms are unknown. In the prospective United Kingdom (UK) Biobank, we investigated urban-rural regional differences in HF risk and the mechanistic role of biological aging., Methods: Multivariable Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to residential urban-rural region and a Biological Health Score (BHS) that reflects biological aging from environmental, social, or dietary stressors. We estimated the proportion of the total effect of urban-rural region on HF mediated through BHS., Results: Among 417,441 European participants, 10,332 incident HF cases were diagnosed during the follow-up. Compared to participants in large urban regions of Scotland, those in England/Wales had significantly increased HF risk (smaller urban: HR = 1.83, 95%CI: 1.64-2.03; suburban: HR = 1.77, 95%CI: 1.56-2.01; very rural: HR = 1.61, 95%CI: 1.39-1.85). Additionally, we found a dose-response relationship between increased biological aging and HF risk (HR per 1 SD increase  = 1.14 (95%CI: 1.12-1.17). Increased biological aging mediated a notable 6.6% ( p  < 0.001) of the total effect of urban-rural region on HF., Conclusion: Despite universal healthcare in the UK, disparities in HF risk by region were observed and may be partly explained by environmental, social, or dietary factors related to biological aging. Our study contributes to precision public health by informing potential biological targets for intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wong, Blechter, Rodriquez, Shearer, Breeze, Pérez-Stable and Roger.)

Background: Heart failure (HF) and kidney disease frequently co-occur, increasing mortality risk. The cardiorenal syndrome results from damage to either the heart or kidney impacting the other organ. The epidemiology of cardiorenal syndrome among the general population is incompletely characterized and despite shared risk factors with HF, differences in mortality risk across key demographics have not been well described. Thus, the primary goal of this study was to analyze annual trends in cardiorenal-related mortality, evaluate if these trends differed by age, sex, and race or ethnicity, and describe these trends against a backdrop of HF mortality., Methods and Findings: The Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research database was used to examine cardiorenal- and HF-related mortality in the US between 2011and 2020. International Classification of Diseases, 10 Revision codes were used to classify cardiorenal-related deaths (I13.x) and HF-related deaths (I11.0, I13.0, I13.2, and I50.x), among decedents aged 15 years or older. Decedents were further stratified by age group, sex, race, or ethnicity. Crude and age-adjusted mortality rates (AAMR) per 100,000 persons were calculated. A total of 97,135 cardiorenal-related deaths and 3,453,655 HF-related deaths occurred. Cardiorenal-related mortality (AAMR, 3.26; 95% CI: 3.23-3.28) was significantly lower than HF-related mortality (AAMR, 115.7; 95% CI: 115.6-115.8). The annual percent change (APC) was greater and increased over time for cardiorenal-related mortality (2011-2015: APC, 7.1%; 95% CI: 0.7-13.9%; 2015-2020: APC, 19.7%, 95% CI: 16.3-23.2%), whereas HF-related mortality also increased over that time period, but at a consistently lower rate (2011-2020: APC, 2.4%; 95% CI: 1.7-3.1%). Mortality was highest among older and male decedents for both causes. Cardiorenal-related deaths were more common in non-Hispanic or Latino Blacks compared to Whites, but similar rates were observed for HF-related mortality. A larger proportion of cardiorenal-related deaths, compared to HF-related deaths, listed cardiorenal syndrome as the underlying cause of death (67.0% vs. 1.2%)., Conclusions: HF-related deaths substantially outnumber cardiorenal-related deaths; however, cardiorenal-related deaths are increasing at an alarming rate with the highest burden among non-Hispanic or Latino Blacks. Continued surveillance of cardiorenal-related mortality trends is critical and future studies that contain detailed biomarker and social determinants of health information are needed to identify mechanisms underlying differences in mortality trends., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Frailty is common in heart failure (HF) and is associated with death but not routinely captured clinically. Frailty is linked with inflammation and malnutrition, which can be assessed by a novel plasma multimarker score: the metabolic vulnerability index (MVX). We sought to evaluate the associations between frailty and MVX and their prognostic impact., Methods and Results: In an HF community cohort (2003-2012), we measured frailty as a proportion of deficits present out of 32 physical limitations and comorbidities, MVX by nuclear magnetic resonance spectroscopy, and collected extensive longitudinal clinical data. Patients were categorized by frailty score (≤0.14, >0.14 and ≤0.27, >0.27) and MVX score (≤50, >50 and ≤60, >60 and ≤70, >70). Cox models estimated associations of frailty and MVX with death, adjusted for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Uno's C-statistic measured the incremental value of MVX beyond frailty and clinical factors. Weibull's accelerated failure time regression assessed whether MVX mediated the association between frailty and death. We studied 985 patients (median age, 77; 48% women). Frailty and MVX were weakly correlated (Spearman's ρ=0.21). The highest frailty group experienced an increased rate of death, independent of MVX, MAGGIC score, and NT-proBNP (hazard ratio, 3.3 [95% CI, 2.5-4.2]). Frailty improved Uno's c-statistic beyond MAGGIC score and NT-proBNP (0.69-0.73). MVX only mediated 3.3% and 4.5% of the association between high and medium frailty groups and death, respectively., Conclusions: In this HF cohort, frailty and MVX are weakly correlated. Both independently contribute to stratifying the risk of death, suggesting that they capture distinct domains of vulnerability in HF.

Background: Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure., Methods: Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed., Results: The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP., Conclusions: This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers., Competing Interests: Disclosures Dr Connelly is an employee of and holds stock in Labcorp. Dr Otvos is a consultant, stockholder, and former employee of Labcorp. The other authors report no conflicts.

Background: Inflammation and protein energy malnutrition are associated with heart failure (HF) mortality. The metabolic vulnerability index (MVX) is derived from markers of inflammation and malnutrition and measured by nuclear magnetic resonance spectroscopy. MVX has not been examined in HF., Objectives: The authors sought to examine the prognostic value of MVX in patients with HF., Methods: The authors prospectively assembled a population-based cohort of patients with HF from 2003 to 2012 and measured MVX scores with a nuclear magnetic resonance scan from plasma collected at enrollment. Patients were divided into 4 MVX score groups and followed until March 31, 2021., Results: The authors studied 1,382 patients (median age: 78 years; 48% women). The median MVX score was 64.6. Patients with higher MVX were older, more likely to be male, have atrial fibrillation, have higher NYHA functional class, and have HF duration of >18 months. Higher MVX was associated with mortality independent of Meta-analysis Global Group in Chronic Heart Failure score, ejection fraction, and other prognostic biomarkers. Compared to those with the lowest MVX, the HRs for MVX groups 2, 3, and 4 were 1.2 (95% CI: 0.9-1.4), 1.6 (95% CI: 1.3-2.0), and 1.8 (95% CI: 1.4-2.2), respectively (P trend  < 0.001). Measures of model improvement document the added value of MVX in HF for classifying the risk of death beyond the Meta-analysis Global Group in Chronic Heart Failure score and other biomarkers., Conclusions: In this HF community cohort, MVX was strongly associated with mortality independently of established clinical factors and improved mortality risk classification beyond clinically validated markers. These data underscore the potential of MVX to stratify risk in HF., Competing Interests: Funding Support and Author Disclosures The investigators were supported by the Intramural Research program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. This study also used in part the resources from the Rochester Epidemiology Project medical records linkage system, which is supported by the National Institute on Aging (AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by Rochester Epidemiology Project users. The funding institution did not play a role in the design, conduct, analysis, or reporting or in the decision to submit this manuscript for publication. The study was approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards. Dr Connelly is an employee of and holds stock in LabCorp. Dr Otvos is a consultant, stockholder, and former employee of LabCorp. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Background: Heart failure (HF) is a complex clinical syndrome with persistently high mortality. High-throughput proteomic technologies offer new opportunities to improve HF risk stratification, but their contribution remains to be clearly defined. We aimed to systematically review prognostic studies using high-throughput proteomics to identify protein signatures associated with HF mortality., Methods: We searched four databases and two clinical trial registries for articles published from 2012 to 2023. HF proteomics studies measuring high numbers of proteins using aptamer or antibody-based affinity platforms on human plasma or serum with outcomes of all-cause or cardiovascular death were included. Two reviewers independently screened articles, extracted data, and assessed the risk of bias. A third reviewer resolved conflicts. We assessed the risk of bias using the Risk Of Bias In Non-randomized Studies-of Exposure tool., Results: Out of 5131 unique articles identified, nine articles were included in the review. The nine studies were observational; three used the aptamer platform, and six used the antibody platform. We found considerable heterogeneity across studies in measurement panels, HF definitions, ejection fraction categorization, follow-up duration, and outcome definitions, and a lack of risk estimates for most protein associations. Hence, we proceeded with a systematic review rather than a meta-analysis. In two comparable aptamer studies in patients with HF with reduced ejection fraction, 21 proteins were identified in common for the association with all-cause death. Among these, one protein, WAP four-disulfide core domain protein 2 was also reported in an antibody study on HFrEF and for the association with CV death. We proposed standardized reporting criteria to facilitate the interpretation of future studies., Conclusions: In this systematic review of nine studies evaluating the association of proteomics with mortality in HF, we identified a limited number of proteins common across several studies. Heterogeneity across studies compromised drawing broad inferences, underscoring the importance of standardized approaches to reporting., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Heart failure (HF) is increasing in the United States, and awareness is needed for prevention. Hypertension is the leading cause of HF, and adherence to antihypertensive medication is critical for reducing HF risk. Self-efficacy positively influences health-promoting behaviors., Objectives: Assess HF awareness, test associations with antihypertensive medication adherence, and self-efficacy for managing chronic conditions., Design: We conducted a cross-sectional, observational survey research study., Methods: We leveraged data from participants enrolled in the American Heart Association's Research Goes Red™ registry, an online platform powered by Verily. Three surveys ascertained HF awareness, blood pressure management, and self-efficacy. Chi-squared and Wilcoxon rank sum determined associations between survey domains and participant characteristics., Results: Two thousand three hundred twenty women took the HF awareness survey, 678 the blood pressure management survey, and 755 the self-efficacy survey (response rates: 12%, 78%, and 76%, respectively). Participants were predominantly non-Hispanic White (78%), with a median age of 51 (interquartile range (IQR): 39, 62). Median HF awareness score was 4/5 (IQR: 4, 5). Participants with high HF awareness versus low were more likely to be older ( p  < 0.001), non-Hispanic White ( p  < 0.001), and less likely to smoke ( p  < 0.001) or have depression ( p  = 0.004). Nearly 90% of hypertensive participants reported medication adherence, which was not associated with HF awareness or self-efficacy. Participants with greater self-efficacy versus less were more likely to have higher HF awareness ( p  = 0.01), be older ( p  = 0.01), and less likely to have depression ( p  < 0.001)., Conclusion: Women's awareness of HF and adherence to antihypertensive medication in this cohort was high. Depression and younger age may be important factors affecting women's HF awareness and confidence in managing chronic disease medication plans.

Background: Heart failure (HF) is a complex clinical syndrome with high mortality. Current risk stratification approaches lack precision. High-throughput proteomics could improve risk prediction. Its use in clinical practice to guide the management of patients with HF depends on validation and evidence of clinical benefit., Objective: To develop and validate a protein risk score for mortality in patients with HF., Design: Community-based cohort., Setting: Southeast Minnesota., Participants: Patients with HF enrolled between 2003 and 2012 and followed through 2021., Measurements: A total of 7289 plasma proteins in 1351 patients with HF were measured using the SomaScan Assay (SomaLogic). A protein risk score was derived using least absolute shrinkage and selection operator regression and temporal validation in patients enrolled between 2003 and 2007 (development cohort) and 2008 and 2012 (validation cohort). Multivariable Cox regression was used to examine the association between the protein risk score and mortality. The performance of the protein risk score to predict 5-year mortality risk was assessed using calibration plots, decision curves, and relative utility analyses and compared with a clinical model, including the Meta-Analysis Global Group in Chronic Heart Failure mortality risk score and N -terminal pro-B-type natriuretic peptide., Results: The development ( n = 855; median age, 78 years; 50% women; 29% with ejection fraction <40%) and validation cohorts ( n = 496; median age, 76 years; 45% women; 33% with ejection fraction <40%) were mostly similar. In the development cohort, 38 unique proteins were selected for the protein risk score. Independent of ejection fraction, the protein risk score demonstrated good calibration, reclassified mortality risk particularly at the extremes of the risk distribution, and showed greater clinical utility compared with the clinical model., Limitation: Participants were predominantly of European ancestry, potentially limiting the generalizability of the findings to different patient populations., Conclusion: Validation of the protein risk score demonstrated good calibration and evidence of predicted benefits to stratify the risk for death in HF superior to that of clinical methods. Further studies are needed to prospectively evaluate the score's performance in diverse populations and determine risk thresholds for interventions., Primary Funding Source: Division of Intramural Research at the National Heart, Lung, and Blood Institute of the National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2328.