Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

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Abstract 6133: Microvascular Dysfunction and Chronic Inflammation in Patients without Cardiovascular Risk Factors

Circulation ◽

10.1161/circ.118.suppl_18.s_1068-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Alejandro Recio-Mayoral ◽

Justin C Mason ◽

Juan C Kaski ◽

Michael B Rubens ◽

Olivier A Harari ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Cardiovascular Risk ◽

Coronary Artery ◽

Cardiovascular Risk Factors ◽

Chronic Inflammation ◽

Coronary Atherosclerosis ◽

Microvascular Dysfunction ◽

Early Marker ◽

Artery Disease

Premature coronary atherosclerosis, which is actually seen as an active inflammatory process, is an established complication of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We hypothesized that exposure to chronic inflammation, even in the absence of classical cardiovascular risk factors (CVRF), could result in coronary microvascular dysfunction (CMD), an early marker of coronary atherosclerosis. By means of positron emission tomography in combination with oxygen-15 labeled water, myocardial blood flow (MBF) was measured at rest and during iv adenosine infusion (140 μg/kg/min) in 13 SLE and 12 RA patients (mean [±SD] age 44±10 years) without CVRF. All patients underwent coronary angiography using multi-slice (64 slices) computed tomography and only those with none or trivial coronary artery disease (<30% luminal stenosis) were included. A group of 25 age- and gender-matched controls were also studied. There were no differences between patients and controls regarding body-mass index, blood pressure and lipid parameters. RA and SLE patients showed similar mean disease duration (16±11 and 11±7 years, respectively; p=0.12). Resting MBF was similar in patients and controls (1.25±0.27 vs 1.15±0.24 ml/min/g, p=0.15). However, during adenosine stress patients had lower MBF compared with controls (2.94±0.83 vs 4.11±0.84 ml/min/g, p<0.001). As result, coronary flow reserve (CFR; adenosine/resting MBF) was significantly reduced in patients (2.44±0.78) compared with controls (3.81±1.07; p<0.001). Seven patients showed ischemic electrocardiographic changes during adenosine and had a more severe reduction in CFR (1.76±0.81) and more years of disease (21±7 years) compared with those patients without ischemic changes (CFR 2.49±0.54; p=0.006; duration of disease 14±5 years; p=0.03). CFR was inversely correlated with years of disease (r=−0.65, p<0.001), but not with corticosteroid cumulative dose (r=0.20, p=0.39). Chronic inflammation in the absence of traditional CVRF is characterized by severe CMD. This may represent an early marker of disease which precedes and contributes to premature coronary artery disease in patients with RA and SLE.

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HIV indirectly accelerates coronary artery disease by promoting the effects of risk factors: longitudinal observational study

Scientific Reports ◽

10.1038/s41598-021-02556-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Márton Kolossváry ◽

David Celentano ◽

Gary Gerstenblith ◽

David A. Bluemke ◽

Raul N. Mandler ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Hiv Infection ◽

Risk Scores ◽

Atherosclerotic Cardiovascular Disease ◽

Cocaine Use ◽

Significant Difference ◽

Ascvd Risk ◽

Artery Disease

AbstractOur objective was to assess whether human immunodeficiency virus (HIV)-infection directly or indirectly promotes the progression of clinical characteristics of coronary artery disease (CAD). 300 African Americans with asymptomatic CAD (210 male; age: 48.0 ± 7.2 years; 226 HIV-infected) who underwent coronary CT angiography at two time points (mean follow-up: 4.0 ± 2.3 years) were randomly selected from 1429 participants of a prospective epidemiological study between May 2004 and August 2015. We calculated Agatston-scores, number of coronary plaques and segment stenosis score (SSS). Linear mixed models were used to assess the effects of HIV-infection, atherosclerotic cardiovascular disease (ASCVD) risk, years of cocaine use on CAD. There was no significant difference in annual progression rates between HIV-infected and—uninfected regarding Agatston-scores (10.8 ± 25.1/year vs. 7.2 ± 17.8/year, p = 0.17), the number of plaques (0.2 ± 0.3/year vs. 0.3 ± 0.5/year, p = 0.11) or SSS (0.5 ± 0.8/year vs. 0.5 ± 1.3/year, p = 0.96). Multivariately, HIV-infection was not associated with Agatston-scores (8.3, CI: [− 37.2–53.7], p = 0.72), the number of coronary plaques (− 0.1, CI: [− 0.5–0.4], p = 0.73) or SSS (− 0.1, CI: [− 1.0–0.8], p = 0.84). ASCVD risk scores and years of cocaine-use significantly increased all CAD outcomes among HIV-infected individuals, but not among HIV-uninfected. Importantly, none of the HIV-medications were associated with any of the CAD outcomes. HIV-infection is not directly associated with CAD and therefore HIV-infected are not destined to have worse CAD profiles. However, HIV-infection may indirectly promote CAD progression as risk factors may have a more prominent role in the acceleration of CAD in these patients.

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A large-scale multi-ethnic genome-wide association study of coronary artery disease

10.21203/rs.3.rs-275591/v1 ◽

2021 ◽

Author(s):

Themistocles Assimes ◽

Catherine Tcheandjieu ◽

Xiang Zhu ◽

Austin Hilliard ◽

Shoa Clarke ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Association Study ◽

Genome Wide Association Study ◽

Critical Role ◽

Genome Wide Association ◽

Human Populations ◽

Genome Wide ◽

Artery Disease

Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

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Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease

European Heart Journal ◽

10.1093/eurheartj/ehp205 ◽

2009 ◽

Vol 30 (15) ◽

pp. 1837-1843 ◽

Cited By ~ 115

Author(s):

A. Recio-Mayoral ◽

J. C. Mason ◽

J. C. Kaski ◽

M. B. Rubens ◽

O. A. Harari ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Chronic Inflammation ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Artery Disease

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Separating the direct effects of risk factors for atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

10.1101/2021.08.05.21261658 ◽

2021 ◽

Author(s):

Venexia Walker ◽

Marijana Vujkovic ◽

Alice R Carter ◽

Neil M Davies ◽

Miriam Udler ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Mendelian Randomization ◽

Atherosclerotic Cardiovascular Disease ◽

Peripheral Artery ◽

Artery Disease

Background: Type 2 diabetes and atherosclerotic cardiovascular disease share several risk factors. However, it is unclear whether the effect of these risk factors on liability to atherosclerotic cardiovascular disease is independent of their effect on liability to type 2 diabetes. Methods: We performed univariate Mendelian randomization to quantify the effects of continuous risk factors from the IEU OpenGWAS database on liability to three outcomes: type 2 diabetes, coronary artery disease, and peripheral artery disease, as well as the effects of liability to type 2 diabetes on the risk factors. We also performed two-step Mendelian randomization for mediation to estimate the mediating pathways between the risk factors, liability to type 2 diabetes, and liability to the atherosclerotic cardiovascular disease outcomes where possible. Results: We found evidence for 53 risk factors as causes of liability to coronary artery disease, including eight which were causes of liability to type 2 diabetes only and four which were consequences only. Except for fasting insulin and hip circumference, the direct and total effects from the two-step Mendelian randomization were similar. This suggests that the combination of these risk factors with liability to type 2 diabetes was unlikely to alter liability to coronary artery disease beyond their individual effects. We also found 13 risk factors that were causes of liability peripheral artery disease, including six which were causes of liability to type 2 diabetes only and four which were consequences only. Again, the direct and total effects were similar for these ten risk factors apart from fasting insulin. Conclusions: Most risk factors were likely to affect liability to atherosclerotic cardiovascular disease independently of their relationship with liability to type 2 diabetes. Control of modifiable risk factors therefore remains important for reducing atherosclerotic cardiovascular disease risk regardless of patient liability to type 2 diabetes.

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