5949Interleukin-6 and growth differentiation factor-15 in hypertensive heart failure

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Fernandez ◽  
J Rysa ◽  
J Nilsson ◽  
G Engstrom ◽  
M Orho-Melander ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transforming Growth Factor ◽  
Mechanical Stretch ◽  
Neonatal Rat ◽  
Chronic Hypertension ◽  
Mrna Levels ◽  
Growth Differentiation Factor 15 ◽  
Hypertrophic Growth ◽  
Differentiation Factor ◽  
Circulating Levels

Abstract Background Hypertension is the leading cause for the development of heart failure (HF). Increased hemodynamic load, including mechanical stretch and neurohumoral factors, is able to trigger hypertrophic growth of cardiac myocytes. Although hypertensive HF is prevalent, there is no useful biomarker to identify HF due to chronic hypertension. Aims To identify plasma markers associated with incidence of hypertensive HF. Methods Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4469 individuals from the Malmö Diet and Cancer study. Protein levels were compared to stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVM) in response to 1, 4, 12, 24 or 48 hours of cyclic mechanical stretch. Association between plasma proteins level and HF incidence and hypertension was studied using respectively Cox proportional hazards model and binary logistic regressions. Results After Bonferroni correction, 44 circulating proteins were significantly differentially expressed in individuals who developed HF during follow-up versus controls (P<3.4E-4). Out of these, 5 proteins (Interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF15), Interleukin-1 Receptor-Like-1 (ST2), Plasminogen Activator Urokinase Receptor (U-PAR), Transforming Growth Factor-α (TGF-α)), corresponding mRNA levels were upregulated by mechanical stretch in NRVM at all time points (P<0.05). Similar upregulation for the 5 proteins was shown in hypertensive versus normotensive individuals (P≤8.05E-4). In a model with all 5 proteins entered simultaneously, GDF15 and IL-6 were predictive of incident HF after adjustment for age, sex and NT-BNP levels (205 events; hazard ratio [HR] per SD increment of protein: HR=1.29, CI=1.05–1.58, P=0.013 and HR=1.16, CI=1.02–1.33, P=0.028). Using the same model, IL-6 but not GDF15 associated with hypertension (Odds ratio [OR] per SD increment of IL-6: OR=1.18, CI=1.09–1.27, P=3.3E-5). In hypertensive individuals GDF15 and IL-6 were individually predictive of future HF after adjustment for age, sex, NT-BNP levels, smoking, BMI and diabetes (183 events; HR=1.36, CI=1.16–1.60, P=1.64E-4 and HR=1.21, CI=1.05–1.40, P=0.008). Furthermore, in these hypertensive individuals, GDF15 and IL-6 were predictive of HF in a model with IL-6, GDF15, ST2 and TGF-α entered simultaneously after adjustment for age, sex and NT-BNP levels (176 events; HR=1.36, CI=1.13–1.64, P=0.001 and HR=1.16, CI=1.01–1.34, P=0.041). Conclusions Circulating levels of IL-6 and GDF15 might be used as NT-BNP independent biomarkers for HF development in hypertensive patients. Acknowledgement/Funding Påhlsson, Crafoord, Lundström, Åke Wiberg, Royal Physiographic Society and the Swedish Foundation for Strategic Research for IRC15-0067

scholarly journals Circulating Concentrations of Growth-Differentiation Factor 15 in Apparently Healthy Elderly Individuals and Patients with Chronic Heart Failure as Assessed by a New Immunoradiometric Sandwich Assay

2007 ◽  
Vol 53 (2) ◽  
pp. 284-291 ◽  
Author(s):  
Tibor Kempf ◽  
Rüdiger Horn-Wichmann ◽  
Georg Brabant ◽  
Timo Peter ◽  
Tim Allhoff ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Transforming Growth Factor ◽  
Size Exclusion ◽  
Igg Antibody ◽  
Elderly Individuals ◽  
Growth Differentiation Factor 15 ◽  
Healthy Elderly ◽  
Differentiation Factor ◽  
Apparently Healthy

Abstract Background: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor β (TGF-β) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. Methods: We developed an IRMA that uses a polyclonal, affinity chromatography–purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). Results: The assay had a detection limit of 20 ng/L, an intraassay imprecision of ≤10.6%, and an interassay imprecision of ≤12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-β. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th–75th percentiles, 600–959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity. Conclusion: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.

Growth Differential Factor 15 (GDF%15), Possible Biomarker in Heart Failure

2017 ◽  
Vol 68 (3) ◽  
pp. 631-634
Author(s):  
Valeriu Gabi Dinca ◽  
Gheorghe Manole ◽  
Daniel Cochior ◽  
Alexandra Ligia Dinca
Keyword(s):  
Heart Failure ◽  
Serum Concentration ◽  
The Other ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Other Hand ◽  
The One ◽  
Growth Differential

The present study aims at determining on the one hand the growth differentiation factor 15 significance as possible risk biomarker for this condition and, on the other hand, the degree of correlation between its serum concentration and the class of inotropism deficit.The value of the current research stems from the very selected theme, the activity of GDF-15, member of the superfamily of cytokines TGF-b recognized as having implication in atherosclerosis, but almost unexplored as role in the myocardiumremodeling processes, more precisely in fibrosis.

scholarly journals Dynamics of growth differentiation factor 15 in acute heart failure

2021 ◽  
Author(s):  
Patrícia Lourenço ◽  
Filipe M. Cunha ◽  
João Ferreira‐Coimbra ◽  
Isaac Barroso ◽  
João‐Tiago Guimarães ◽  
...  
Keyword(s):  
Heart Failure ◽  
Acute Heart Failure ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Growth differentiation factor‐15, treatment with liraglutide, and clinical outcomes among patients with heart failure

2021 ◽  
Author(s):  
Abhinav Sharma ◽  
Stephen Greene ◽  
Muthiah Vaduganathan ◽  
Marat Fudim ◽  
Andrew P. Ambrosy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Outcomes ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Patients With Heart Failure

Abstract P320: The Gut Microbial Metabolite Butyrate Suppresses Cardiac Hypertrophy Via An Epigenetic Mechanism

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Masahiko Umei ◽  
Hiroshi Akazawa ◽  
Akiko Saga-Kamo ◽  
Hiroki Yagi ◽  
Qing Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Epigenetic Mechanism ◽  
Neonatal Rat ◽  
Short Chain ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Growth

Introduction: Short-chain fatty acids (SCFA) are one of the gut microbial metabolites that can influence host health and disease. We previously reported that gut dysbiosis is associated with heart failure, and that the proportion of butyrate-producing bacteria is decreased in the gut of patients with heart failure. Purpose: We investigated the molecular mechanism of butyrate in the development of cardiac hypertrophy. Methods and Results: Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. On the other hand, treatment with butyrate inhibited ET1-induced and isoproterenol (ISO)-induced hypertrophic growth in cultured neonatal rat cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, suggesting the inhibitory effect of butyrate on HDAC. In addition, butyrate caused the degradation of HDAC2 and up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, leading to a significant decrease in the phosphorylation levels of Akt and glycogen synthase kinase 3β (GSK3β). Finally, intraperitoneal injection of butyrate inhibited ISO-induced cardiac hypertrophy in mice. These results suggest that butyrate protects against hypertrophic responses via suppression of the Akt-GSK3β pathway through HDAC inhibition. Conclusion: In the heart, there were no known short-chain fatty acid receptors in cardiomyocytes. However, butyrate was shown to have an epigenetic mechanism in suppressing effect on cardiomyocyte hypertrophy via suppression of HDAC2-Akt-GSK3β axis. Our results uncover a potential link between dysbiosis of intestinal microbiota and the development of cardiac hypertrophy.

Abstract 2423: B-type Natriuretic Peptide Upregulates Erythropoietin Receptor Gene Expression via Protein Kinase G in Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yoshiaki Ohyama ◽  
Toru Tanaka ◽  
Takehisa Shimizu ◽  
Hiroshi Doi ◽  
Norimichi Koitabashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Failing Heart ◽  
Epor Expression

Backgroud: Recent studies demonstrated non-hematopoietical effects of Erythropoietin (Epo) and its receptor (EpoR) in a variety of tissues including cardiovascular system. Epo treatment improves cardiac function in patients with heart failure and reduces infarct size after ischemia/reperfusion injury in the heart. However, little attention has been paid for the endogenous regulatory mechanisms regulating EpoR expression. In this study, we hypothesize that B-type natriuretic peptide upregulates EpoR gene expression in failing heart. Methods and Results: Wister rats underwent transverse aortic constriction surgery to induce hypertrophy. RT-PCR analyses of those rats showed that EpoR mRNA levels were increased in the left ventricle and positively correlated with the levels of BNP mRNA (n=10, r=0.67, p<0.05). Next we examined the expression of EpoR in human failing heart by using autopsy specimens and found that EpoR mRNA levels were significantly elevated in patients with dilated cardiomyopathy compared with those in normal heart. Immunohistochemistry of endomyocardial biopsy specimens of failing heart (n=54) showed that EpoR mRNA levels were correlated with severity of cardiac dysfunction estimated by diameter of cardiac chambers, pathomorphology, serum BNP concentration and functional class of New York Heart Association. Interestingly, stimulation of cultured neonatal rat cardiac myocytes with BNP, but not with hypertrophic reagents including endothelin I, angiotensin II and norepinephrine, significantly increased the EpoR mRNA levels in a time-dependent manner. Overexpression of cGMP-dependent protein kinase (PKG) increased EpoR transcript in cultured cardiac myocytes. BNP-induced EpoR expression was abrogated in the presence of KT5823, a specific inhibitor for PKG. Conclusion: These results suggest a role for BNP in mediating an induction of EpoR expression in failing myocardium and indicate that the cardiac EpoR gene is a target of cGMP/PKG signaling.

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Abstract P330: Growth Differentiation Factor 15 Causes Cardiac Cachexia In Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Da Young Lee ◽  
Zhe Jiao ◽  
Andrew Antolic ◽  
Daiana Weiss ◽  
M. Neale Weitzmann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Food Intake ◽  
Cardiac Fibrosis ◽  
Lean Tissue ◽  
Tissue Mass ◽  
Lean Tissue Mass ◽  
Growth Differentiation Factor 15 ◽  
Tissue Weight ◽  
Reduced Fat ◽  
Differentiation Factor

Background: Cachexia is wasting of normal body tissue and occurs in chronic medical diseases. It is a common complication of heart failure (HF) that is associated with very high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in humans, though its biologic function in HF is unknown. This study investigated the role of GDF15 in HF. Methods: We utilized a genetic mouse model of dilated cardiomyopathy (DCM) caused by a mutation in the phospholamban gene (PLN R9C ). PLN R9C mice have dysregulated cardiac calcium handling (a common feature of nearly all forms of HF) and develop progressive DCM that leads to HF and premature death. Q-PCR and ELISA were performed to assess expression, tissue distribution and circulating levels of GDF15 in PLN R9C and age-matched wild type (WT) mice. A double transgenic mouse was created by crossing our DCM model with a constitutive Gdf15 knock-out (KO). Using this novel model, we quantified food intake, and assessed fat and lean tissue mass by tissue weight at necropsy and by dual-energy X-ray absorptiometry (DXA). Cardiac function was assessed using echocardiography, and histochemistry performed to quantify cardiac fibrosis. Survival was assessed by Kaplan-Meier. Results: GDF15 mRNA (43-fold; p<0.01) and protein (54-fold; p<0.01) were increased in LV tissue, and circulating GDF15 was elevated (8.3-fold; p=0.03) in PLN R9C mice. Gdf15 was expressed at low levels and was not increased in other organs in PLN R9C mice. PLN R9C mice developed cachexia (reduced fat and lean mass by tissue weight, reduced fat mass by DXA vs. WT; p<0.01 for all) and consumed less food (p<0.01 vs. WT). Gdf15 KO in PLN R9C preserved fat and lean tissue mass and resulted in higher food intake (p≤0.01 for all). Gdf15 KO had no effect on cardiac structure or function by echocardiography and PLN R9C / Gdf15 KO mice displayed only a small reduction in cardiac fibrosis relative to PLN R9C mice (3%; p<0.01). Despite this, Gdf15 KO prolonged survival in PLN R9C (29±3 vs. 25±3 weeks; p<0.01). Conclusions: GDF15 is a novel cardiac hormone produced in HF that triggers anorexia and cachexia in HF by an extra-cardiac mechanism.

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