Pathophysiological pathways related to high plasma growth differentiation factor 15 concentrations in patients with heart failure

Ceelen, Daan; Voors, Adriaan A.; Tromp, Jasper; Veldhuisen, Dirk J. van; Dickstein, Kenneth; Boer, Rudolf A. de; Lang, Chim C.; Anker, Stefan D.; Ng, Leong L.; Metra, Marco; Ponikowski, Piotr; Figarska, Sylwia M.

doi:10.1002/ejhf.2424

Cited by 12 publications

(11 citation statements)

References 84 publications

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“…GDF signaling was specifically involved in FB subsets with DM ( Figure 6 D and Figure S6 ). GDF15 , the only ligand detected in our study, was associated with systematic inflammation, DM and obesity [ 45 , 46 , 47 , 48 ]. Our results showed that ANGPTL7 + FBs and SFRP1 + FBs expressed GDF15 and acted on a variety of cells ( Figure 6 D).…”

Section: Resultsmentioning

confidence: 99%

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Sun

Zhang

et al. 2022

Cells

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Background: The great saphenous vein (GSV) is the most commonly used conduit for coronary arterial bypass graft. However, the status of the GSV, including metabolic dysfunction such as diabetes mellitus (DM) complication, is strongly associated with vein graft failure (VGF). To date, the molecular mechanism underlying VGF remains elusive. Detailed characterization of the cellular components and corresponding expression regulation in GSVs would be of great importance for clinical decision making to reduce VGF. Methods: To this end, we performed single-cell RNA sequencing to delineate cellular heterogeneity in three human GSV samples. Results: Scrutinization of cellular composition and expression revealed cell diversity in human GSVs, particularly endothelial cells (ECs). Our results unraveled that functional adaptation drove great expression differences between venous ECs and valvular ECs. For instance, cell surface receptor ACKR1 demarcated venous Ecs, whereas ACRK3/ACKR4 were exclusively expressed by valvular ECs. Differential gene expression analysis suggested that genes highly expressed in venous ECs were mainly involved in vasculature development and regulation of leukocyte adhesion, whereas valvular ECs have more pronounced expression of genes participating in extracellular matrix organization, ossification and platelet degranulation. Of note, pseudo-time trajectory analysis provided in silico evidence indicating that venous ECs, valvular ECs and lymphatic vessels were developmentally connected. Further, valvular ECs might be an importance source for lymphatic vessel differentiation in adults. Additionally, we found a venous EC subset highly expressing IL6, which might be associated with undesirable prognosis. Meanwhile, we identified a population of ANGPTL7+ fibroblasts (FBs), which may be profibrotic and involved in insulin resistance in human GSVs. Additionally, our data suggest that immune cells only accounted for a small fraction, most of which were macrophages. By assessing the intertwined remodeling in metabolic dysfunction that potentially increases the gene expression regulatory network in mural cells and leukocytes, we found that transcription factor KLF9 likely operated a proinflammatory program, inducing the transcription of metallothionein proteins in two mural cell subsets and proinflammatory immune cells. Lastly, cellular communication analysis revealed that proinflammatory signaling, including TRAIL, PVR, CSF and GDF, were uniquely activated in patients with metabolic dysfunction. Conclusions: Our results identified critical cell-specific responses and cellular interactions in GSVs. Beyond serving as a repertoire, this work illustrates multifactorial likelihood of VGF.

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Section: Resultsmentioning

confidence: 99%

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Sun

Zhang

et al. 2022

Cells

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“… 29 As for the relationship between GDF‐15 and haemoglobin, a recently published study showed that the elevated GDF‐15 levels correlated with up‐regulation of the interleukin‐6 (IL‐6) pathway, leading to the reduction of the plasma iron levels, which then contributed to the observed decrease in the levels of haemoglobin. 30 Therefore, a high level of GDF‐15 may serve as an indicator of the risk of anaemia in patients with HF. In view of the aforementioned, GDF‐15 appears to integrate information on cardiac and extracardiac disease pathways that are related to the occurrence, progression, and prognosis of HF.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of Growth differentiation factors 15 in Acute heart failure patients with preserved ejection fraction

et al. 2022

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Aims There is an increasing proportion of hospitalized heart failure (HF) patients classified as HF with preserved ejection fraction (HFpEF) around the world. Growth differentiation factor 15 (GDF‐15) is a promising biomarker in HFpEF prognostication; however, the majority of the existing data has been derived from the research on undifferentiated HF, whereas the studies focusing on HFpEF are still limited. This study aimed to determine the prognostic power of GDF‐15 in the hospitalized patients with HFpEF in a Chinese cohort. Methods and results We analysed the levels of serum GDF‐15 in 380 patients hospitalized for acute onset of HFpEF measured by heart ultrasound at admission in a prospective cohort. The associations of GDF‐15 with 1 year risk of all‐cause death and 1 year HF readmission were assessed by the Cox proportional hazards model. Area under the receiver operating characteristic curves was used to compare predictive accuracy. GDF‐15 was strongly correlated with 1 year HF readmission and 1 year all‐cause death, with event rates of 24.8%, 40.0%, and 50.0% for 1 year HF readmission ( P < 0.001), respectively, and with 11.2%, 13.6%, and 24.6% for 1 year all‐cause death ( P = 0.004) in the corresponding tertile, respectively. In the multivariate linear regression model, GDF‐15 had a significantly negative correlation with haemoglobin ( P = 0.01) and a positive correlation with creatinine ( P = 0.01), alanine transaminase ( P = 0.001), and therapy of aldosterone antagonist ( P = 0.018). The univariate Cox regression model of GDF‐15 showed that c‐statistic was 0.632 for 1 year HF readmission and 0.644 for 1 year all‐cause death, which were superior to the N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) model with c‐statistics of 0.595 and 0.610, respectively. In the multivariable Cox regression model, GDF‐15 tertiles independently predicted 1 year HF readmission (hazard ratio 2.25, 95% confidence interval: 1.43–3.54, P < 0.001) after adjusting for baseline Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND‐HF) risk score, history of HF, NT‐proBNP, and high‐sensitivity cardiac troponin T. Compared with the model including all the adjusted variables, the model with the addition of GDF‐15 improved predictive power, with c‐statistic increasing from 0.643 to 0.657 for 1 year HF readmission and from 0.638 to 0.660 for 1 year all‐cause death. Conclusions In hospitalized patients with HFpEF, GDF‐15 measured within 48 h of admission is a strong independent biomarker for 1 year HF readmission and even better than NT‐proBNP. GDF‐15 combined with the traditional indicators provided incremental prognostic value in this population.

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“…High levels of growth differentiation factor 15 (GDF‐15) have been associated with a worse outcome. Ceelen et al 13 . measured the levels of over 300 biomarkers and analysed key biological pathways in patients divided based on GDF‐15 levels.…”

Section: Pathophysiologymentioning

confidence: 99%

“…[10][11][12] High levels of growth differentiation factor 15 (GDF-15) have been associated with a worse outcome. Ceelen et al 13 measured the levels of over 300 biomarkers and analysed key biological pathways in patients divided based on GDF-15 levels. They found that patients with higher levels of GDF-15 had an increased activation of inflammation, as well as of pathways related to the regulation of insulin-like growth factor (IGF-1) and bone/tissue remodelling.…”

Section: Biomarkersmentioning

confidence: 99%

February 2022 at a glance: focus on pathophysiology and acute heart failure

Tomasoni

Adamo

Metra

2022

European J of Heart Fail

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This issue includes a two-part position statement from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) about the pathophysiology of Takotsubo syndrome. It provides an overview on the role of catecholamines and sympathetic nervous system and a throughout discussion on vascular pathophysiology and gender differences. 1,2 Physical exercise and nutritionExercise capacity is impaired in patients with heart failure (HF) with a major impact on their poorer quality of life and frequent hospitalizations. [3][4][5] Nijholt et al. 6 reviewed the most recent findings in the field, focusing on newly discovered pathways associated with muscular growth, mechanisms of exercise intolerance and potential therapeutic options.The role of nutritional status in HF patients is well-established. 7,8 Malnutrition refers also to specific micronutrient deficiencies (i.e. selenium). The levels of selenium were measured in a cohort of 5973 Dutch subjects. Higher levels of selenium were independently associated with a lower risk of death and new-onset HF. A significant interaction was found between smoking status and the impact of selenium levels on clinical events. 9

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Pathophysiological pathways related to high plasma growth differentiation factor 15 concentrations in patients with heart failure

Cited by 12 publications

References 84 publications

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins

Prognostic value of Growth differentiation factors 15 in Acute heart failure patients with preserved ejection fraction

February 2022 at a glance: focus on pathophysiology and acute heart failure

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