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Background: This study aimed to identify heart failure (HF) subphenotypes using 92 repeatedly measured circulating proteins in 250 patients with heart failure with reduced ejection fraction, and to investigate their clinical characteristics and prognosis., Methods: Clinical data and blood samples were collected tri-monthly until the primary endpoint (PEP) or censoring occurred, with a maximum of 11 visits. The Olink Cardiovascular III panel was measured in baseline samples and the last two samples before the PEP (in 66 PEP cases), or the last sample before censoring (in 184 PEP-free patients). The PEP comprised cardiovascular death, heart transplantation, Left Ventricular Assist Device implantation, and hospitalization for HF. Cluster analysis was performed on individual biomarker trajectories to identify subphenotypes. Then biomarker profiles and clinical characteristics were investigated, and survival analysis was conducted., Results: Clustering revealed three clinically diverse subphenotypes. Cluster 3 was older, with a longer duration of, and more advanced HF, and most comorbidities. Cluster 2 showed increasing levels over time of most biomarkers. In cluster 3, there were elevated baseline levels and increasing levels over time of 16 remaining biomarkers. Median follow-up was 2.2 (1.4-2.5) years. Cluster 3 had a significantly poorer prognosis compared to cluster 1 (adjusted event-free survival time ratio 0.25 (95%CI:0.12-0.50), p < 0.001). Repeated measurements clusters showed incremental prognostic value compared to clusters using single measurements, or clinical characteristics only., Conclusions: Clustering based on repeated biomarker measurements revealed three clinically diverse subphenotypes, of which one has a significantly worse prognosis, therefore contributing to improved (individualized) prognostication., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective:  This article investigates whether longitudinally measured fibrinolysis factors are associated with cardiac events in patients with chronic heart failure (CHF)., Methods:  A median of 9 (interquartile range [IQR] 5-10) serial, tri-monthly blood samples per patient were prospectively collected in 263 CHF patients during a median follow-up of 2.2 (IQR 1.4-2.5) years. Seventy patients (cases) reached the composite endpoint of cardiac death, heart failure hospitalization, left ventricular assist device, or heart transplantation. From all longitudinal samples, we selected baseline samples in all patients and the last two samples before the event in cases or the last sample available in event-free patients. Herein, we measured plasminogen activator inhibitor 1 (PAI-1), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and soluble urokinase plasminogen activator surface receptor (suPAR). Associations between temporal biomarker patterns during follow-up and the cardiac event were investigated using a joint model., Results:  Cases were on average older and showed higher New York Heart Association class than those who remained event-free. They also had lower blood pressures, and were more likely to have diabetes, renal failure, and atrial fibrillation. Longitudinally measured PAI-1, uPA, and suPAR were independently associated with adverse cardiac events after correction for clinical characteristics (hazard ratio [95% confidence interval]) per standard deviation increase of 2.09 (1.28-3.45) for PAI-1, 1.91 (1.18-3.24) for uPA, and 3.96 (2.48-6.63) for suPAR. Serial measurements of tPA were not significantly associated with the event after correction for multiple testing., Conclusion:  Longitudinally measured PAI-1, uPA, and suPAR are strongly associated with adverse cardiac events during the course of CHF. If future research confirms our results, these fibrinolytic factors may carry potential for improved, and personalized, heart failure surveillance and treatment monitoring., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: We aimed to compare the prognostic value of a single "baseline" echocardiogram with repeated echocardiography in stable chronic heart failure (CHF) patients. We hypothesized that repeated echocardiograms would contain incremental prognostic information., Methods: In the prospective Bio-SHiFT study, we performed 332 echocardiograms in 106 patients during a median follow-up of 2.3 years. The endpoint comprised HF hospitalization, left ventricular (LV) assist device implantation, heart transplantation, and cardiovascular death. We compared hazard ratios (HRs; adjusted for N-terminal pro-brain natriuretic peptide) from Cox models for the first available measurement with HRs from joint models, which model individual trajectories based on the repeated measurements and link these to the time-to-event data., Results: The mean age of the patients was 58.1 years; 78.3% were male, 12.6% had New York Heart Association class >II, all had reduced ejection fraction, and the most common HF etiologies were cardiomyopathies (51%) and ischemia (40%). The endpoint occurred in 25 patients. Both the single measurements and the temporal trajectories were significantly associated with the endpoint (adjusted HR Cox model [95% CI] vs adjusted HR joint model [95% CI]): LV ejection fraction, 1.47 (0.93-2.31) vs 1.77 (1.13-2.93); diastolic LV diameter, 1.64 (1.09-2.47) vs 1.68 (1.12-2.57); systolic LV diameter, 1.72 (1.10-2.69) vs 1.68 (1.13-2.63); systolic left atrial diameter, 1.88 (1.18-3.00) vs 2.60 (1.48-4.97); E/A ratio, 2.73 (1.42-5.26) vs 3.87 (1.75-10.13); and E/e' ratio, 2.30 (1.38-3.84) vs 2.99 (1.68-6.19). None of the trajectories from the investigated parameters showed worsening prior to events., Conclusions: Although single baseline or repeatedly measured echocardiographic parameters were associated with the endpoint, all parameters remained on average stable during the 2.3 years of follow-up in this largely minimally symptomatic CHF cohort. Thus, regular echocardiographic monitoring of systolic or diastolic LV function within this time frame does not carry incremental prognostic information over a single baseline measurement., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4–2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59–76) years, with 72% men and 74% New York Heart Association class I–II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66–3.16) per SD difference in level, followed by JAM-A (2.10, 1.42–3.23) and C1qR (1.90, 1.36–2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients. [ABSTRACT FROM AUTHOR]