Circulating TNF receptors predict cardiovascular disease in patients with chronic kidney disease

Bae, Eunjin; Hui, Ran; Kim, Yong C.; An, Jung Nam; Yoo, Kyung Don; Lee, Su M.; Kim, Myoung Hee; Park, Jung T.; Kang, Shin Wook; Park, Jae Young; Lim, Chun Soo; Kim, Yon Su; Yang, Seung Hee; Lee, Jung Pyo

doi:10.1097/md.0000000000006666

Cited by 37 publications

(27 citation statements)

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“…Higher levels of TNFR1 and TNFR2 have previously been associated with an increased risk of cardiovascular events and mortality in specific patient groups, such as in people with diabetes mellitus, chronic kidney disease, rheumatoid arthritis, or heart failure after myocardial infarction, as well as in the general population . No association with mortality risk was found in patients undergoing hemodialysis .…”

Section: Discussionmentioning

confidence: 98%

10‐Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

Carlsson

Ruge

Kjøller

et al. 2018

JAHA

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BackgroundWe aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)‐α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.Methods and ResultsCLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all‐cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C‐reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05–1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08–1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).ConclusionsIncreased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

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Section: Discussionmentioning

confidence: 98%

10‐Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

Carlsson

Ruge

Kjøller

et al. 2018

JAHA

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“…Tumor necrosis factor-α has been reported to be increased in intracellular aging studies in elderly people, in centenarians and octogenarians with atherosclerosis, and associated with mortality ( 197 – 202 ). In post-MI patients, a rise in TNF-α increased risk of recurrent cardiac events and in renal patients TNF-α receptors predicted cardiovascular disease ( 203 – 205 ). In genetic studies, the A allele of TNF-α 308 G/A gene associated with risk for MI, whereas TNF-α polymorphisms and TNF-α itself, have been variably associated with increased Alzheimer’s disease risk ( 206 – 210 ).…”

Section: Pro-inflammatory and Anti-inflammatory Cytokine Dysregulatiomentioning

confidence: 99%

Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines

et al. 2018

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Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called “inflamm-aging.” Despite research there is no clear understanding about the causes of “inflamm-aging” that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer’s disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with “inflammageing” or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.

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“…Chitotriosidase-1 implicated in the development of atherosclerosis (Boot et al, 1999;Kitamoto et al, 2013) P-selectin, IL-8 reported to be significantly higher in unstable coronary heart disease patients in comparison to stable coronary heart disease patients or controls (Romuk et al, 2002) JAM-A, P-selectin, and MMP-1 reported in different studies to induce platelet activation and to enhance aggregation and thrombus formation (Babinska et al, 2002;Galt et al, 2002;Thé orêt et al, 2011) CDCP1 genetic copy number variants in the CDCP1 gene locus were found to be significantly associated with myocardial infarction (Shia et al, 2011) CD40 ligand reported to be mainly derived from activated platelets and to contribute to the pathophysiology of atherosclerosis (Lievens et al, 2010;Pamukcu et al, 2011) Caspase-3 expressed in atherosclerotic plaques and its levels are correlated with measures of atherosclerosis (Matulevicius et al, 2008) TNF receptors reported to be negatively correlated with kidney function and to predict cardiovascular disease in patients with chronic kidney disease (Bae et al, 2017) TNF, tumor necrosis factor.…”

Section: Proteins Previous Findingsmentioning

confidence: 99%

A Multi-omic Association Study of Trimethylamine N-Oxide

Manor¹,

Zubair²,

Conomos³

et al. 2018

Cell Reports

136

100

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Trimethylamine N-oxide (TMAO) is a circulating metabolite that has been implicated in the development of atherosclerosis and cardiovascular disease (CVD). In this paper, we identify blood markers, metabolites, proteins, gut microbiota patterns, and diets that are significantly associated with levels of plasma TMAO. We find that kidney markers are strongly associated with TMAO and identify CVD-related proteins that are positively correlated with TMAO. We show that metabolites derived by the gut microbiota are strongly correlated with TMAO and that the magnitude of this correlation varies with kidney function. Moreover, we identify diet-associated patterns in the microbiome that are correlated with TMAO. These findings suggest that both the process of TMAO accumulation and the mechanism by which TMAO promotes atherosclerosis are a complex interplay between diet and the microbiome on one hand and other system-level factors such as circulating proteins, metabolites, and kidney function.

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Circulating TNF receptors predict cardiovascular disease in patients with chronic kidney disease

Abstract: Supplemental Digital Content is available in the text

Cited by 37 publications

References 50 publications

10‐Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

10‐Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines

A Multi-omic Association Study of Trimethylamine N-Oxide

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