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Objective: Heart failure (HF) pathophysiology in patients with obesity may be distinct. To study these features, we identified obesity‐related biomarkers from 4210 circulating proteins in patients with HF with reduced ejection fraction (HFrEF) and examined associations of these proteins with HF prognosis and biological mechanisms. Methods: In 373 patients with trimonthly blood sampling during a median follow‐up of 2.1 (25th–75th percentile: 1.1–2.6) years, we applied an aptamer‐based multiplex approach measuring 4210 proteins in baseline samples and the last two samples before study end. Associations between obesity (BMI > 30 kg/m2) and baseline protein levels were analyzed. Subsequently, associations of serially measured obesity‐related proteins with biological mechanisms and the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, left ventricular assist device implantation, and heart transplantation) were examined. Results: Obesity was identified in 26% (96/373) of patients. A total of 30% (112/373) experienced a PEP (with obesity: 26% [25/96] vs. without obesity: 31% [87/277]). A total of 141/4210 proteins were linked to obesity, reflecting mechanisms of neuron projection development, cell adhesion, and muscle cell migration. A total of 50/141 proteins were associated with the PEP, of which 12 proteins related to atherosclerosis or hypertrophy provided prognostic information beyond clinical characteristics, N‐terminal pro‐B‐type natriuretic peptide, and high‐sensitivity troponin T. Conclusions: Patients with HFrEF and obesity show distinct proteomic profiles compared to patients with HFrEF without obesity. Obesity‐related proteins are independently associated with HF outcome. These proteins carry potential to improve management of obesity‐related HF and could be leads for future research. [ABSTRACT FROM AUTHOR]

Circulating proteins may provide insights into the varying biological mechanisms involved in heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). We aimed to identify specific proteomic patterns for HF, by comparing proteomic profiles across the ejection fraction spectrum. We investigated 4210 circulating proteins in 739 patients with normal (Stage A/Healthy) or elevated (Stage B) filling pressures, HFpEF, or ischemic HFrEF (iHFrEF). We found 2122 differentially expressed proteins between iHFrEF-Stage A/Healthy, 1462 between iHFrEF–HFpEF and 52 between HFpEF-Stage A/Healthy. Of these 52 proteins, 50 were also found in iHFrEF vs. Stage A/Healthy, leaving SLITRK6 and NELL2 expressed in lower levels only in HFpEF. Moreover, 108 proteins, linked to regulation of cell fate commitment, differed only between iHFrEF–HFpEF. Proteomics across the HF spectrum reveals overlap in differentially expressed proteins compared to stage A/Healthy. Multiple proteins are unique for distinguishing iHFrEF from HFpEF, supporting the capacity of proteomics to discern between these conditions. [ABSTRACT FROM AUTHOR]

Aims: This study aims to provide insight into sex‐specific cardiovascular protein profiles and their associations with adverse outcomes, which may contribute to a better understanding of heart failure (HF) pathophysiology and the optimal use of circulating proteins for prognostication in women and men. Methods and results: In 250 stable patients with HF with reduced ejection fraction (HFrEF), we performed trimonthly blood sampling (median follow‐up: 26 [17–30] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or one sample closest to censoring and applied the Olink Cardiovascular III panel. We used linear regression to study sex‐based differences in baseline levels and joint models to study differences in the prognostic value of serially measured proteins. In 66 women and 184 men (mean age of 66 and 67 years, respectively), 21% and 28% reached the PEP, respectively. Mean baseline levels of fatty acid‐binding protein 4, secretoglobin family 3A member 2, paraoxonase 3, and trefoil factor 3 were higher in women (Pinteraction: 0.001, 0.007, 0.018, and 0.049, respectively), while matrix metalloproteinase‐3, interleukin 1 receptor‐like 1, and myoglobin were higher in men (Pinteraction: <0.001, 0.001, and 0.049, respectively), independent of clinical characteristics. No significant differences between sexes were observed in the longitudinal associations of proteins with the PEP. Only peptidoglycan recognition protein 1 showed a suggestive interaction with sex for the primary outcome (Pinteraction = 0.028), without multiple testing correction, and was more strongly associated with adverse outcome in women {hazard ratio [HR] 3.03 [95% confidence interval (CI), 1.42 to 6.68], P = 0.008} compared with men [HR 1.18 (95% CI, 0.84 to 1.66), P = 0.347]. Conclusions: Although multiple cardiovascular‐related proteins show sex differences at baseline, temporal associations with the adverse outcome do not differ between women and men with HFrEF. [ABSTRACT FROM AUTHOR]

Aims The relation between non-cardiac comorbidities and health-related quality of life (HRQoL) in patients with heart failure (HF) has been studied to a limited extent. To investigate the HRQoL and their determinants among HF patients with and without comorbidities. Methods and results TRIUMPH (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure) is a Dutch prospective, multicentre study enrolling 496 acute HF patients between 2009 and 2014. We included 334 patients who had completed the HRQoL questionnaires at baseline. The HRQoL was measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) en EuroQuality-of-life five Dimensions (EQ-5D). Comorbidity was defined as having a history of at least one of the following comorbidities: chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and/or cerebrovascular accident. Patients with comorbidity (n  = 205, 61%) had lower scores on the physical limitation scale and clinical summary score of the KCCQ (P  = 0.03 and P  = 0.01, respectively). Female sex, COPD, previous HF, increasing body mass index (BMI), elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), high systolic blood pressure, and the presence of anxiety and/or depression negatively influenced the HRQoL among HF patients with comorbidity. Besides anxiety and depression, we hardly found any other determinant of HRQoL in patients without comorbidity. Conclusion Heart failure patients without comorbidity had better HRQoL than patients with comorbidity. Sex, previous HF, BMI, COPD, systolic blood pressure, NT-proBNP levels, and also anxiety and depression were determinants of HRQoL in patients with comorbidity. In those without comorbidity, apart from anxiety and depression, no further determinants of HRQoL were found. [ABSTRACT FROM AUTHOR]

Background: We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long-term mortality risk., Methods and Results: BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high-frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker-based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all-cause death were evaluated using accelerated failure time models (median follow-up, 9.1 years; 141 deaths). Three biomarker-based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long-term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44-0.93; P =0.018) compared with cluster 1, and 0.71 (95% CI, 0.39-1.32; P =0.281) compared with patients with a repeat ACS., Conclusions: Patients with subphenotypes of post-ACS with different all-cause mortality risks during long-term follow-up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Aims: Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF., Methods and Results: In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c -index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c -index of 0.85 upon internal validation and c -indices up to 0.80 upon external validation. The c -index was higher than that of a model containing established risk factors ( P = 0.021)., Conclusion: Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24., Competing Interests: Conflict of interest: R.O. is employed by Somalogic Inc. D.L. reports non-financial support from Somalogic Inc., during the conduct of the study; grants and personal fees from Janssen, personal fees from Ortho Diagnostics, personal fees from DCRI (Novartis), grants from Bayer, grants from Astra Zeneca, grants from Critical Diagnostics, non-financial support from Somalogic, grants from Lilly, personal fees from ACI (Abbott Laboratories), personal fees from Martin Pharmaceuticals, personal fees from Illumina, personal fees from Vicardia, other from Hridaya, grants and personal fees from Amgen, personal fees from Cytokinetics, outside the submitted work. In addition, D.L. has a patent genomic predictors of BB response issued. The other authors have no disclosures to report., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Higher soluble ST2 (sST2) levels at admission are associated with adverse outcome in acute coronary syndrome (ACS) patients. We studied the dynamics of sST2 over time in post-ACS patients prior to a recurrent ACS or cardiac death., Methods: We used the BIOMArCS case cohort, consisting of 187 patients who underwent serial blood sampling during one-year follow-up post-ACS. sST2 was batch-wise quantified after completion of follow-up in a median of 8 (IQR: 5-11) samples per patient. Joint modelling was used to investigate the association between longitudinally measured sST2 and the endpoint, adjusted for gender, GRACE risk score and history of cardiovascular diseases., Results: Median age was 64 years and 79% were men. The 36 endpoint patients had systematically higher sST2 levels than those that remained endpoint free (mean value 29.6 ng/ml versus 33.7 ng/ml, p-value 0.052). The adjusted hazard ratio for the endpoint per standard deviation increase of sST2 was 1.64 (95% confidence interval: 1.09-2.34; p  = 0.019) at any time point. We could not identify a steady or sudden increase of sST2 in the run-up to the combined endpoint., Conclusion: Asymptomatic post-ACS patients with persistently higher sST2 levels are at higher risk of recurrent ACS or cardiac death during one-year follow-up.

Aims: The relation between non-cardiac comorbidities and health-related quality of life (HRQoL) in patients with heart failure (HF) has been studied to a limited extent. To investigate the HRQoL and their determinants among HF patients with and without comorbidities., Methods and Results: TRIUMPH (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure) is a Dutch prospective, multicentre study enrolling 496 acute HF patients between 2009 and 2014. We included 334 patients who had completed the HRQoL questionnaires at baseline. The HRQoL was measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) en EuroQuality-of-life five Dimensions (EQ-5D). Comorbidity was defined as having a history of at least one of the following comorbidities: chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and/or cerebrovascular accident. Patients with comorbidity (n = 205, 61%) had lower scores on the physical limitation scale and clinical summary score of the KCCQ (P = 0.03 and P = 0.01, respectively). Female sex, COPD, previous HF, increasing body mass index (BMI), elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), high systolic blood pressure, and the presence of anxiety and/or depression negatively influenced the HRQoL among HF patients with comorbidity. Besides anxiety and depression, we hardly found any other determinant of HRQoL in patients without comorbidity., Conclusion: Heart failure patients without comorbidity had better HRQoL than patients with comorbidity. Sex, previous HF, BMI, COPD, systolic blood pressure, NT-proBNP levels, and also anxiety and depression were determinants of HRQoL in patients with comorbidity. In those without comorbidity, apart from anxiety and depression, no further determinants of HRQoL were found., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)