To determine the spectrum of phenotypes linked to the ABO blood group system, using genetic determinants of the ABO blood group system. Approach and Results: We assessed the risk of 41 health and ...disease outcomes, and 36 linear traits associated with the ABO blood group system in the UK Biobank cohort. A total of 406 755 unrelated individuals were included in this study. Blood groups A, B, and O were determined based on allele combinations of previously established single-nucleotide polymorphisms rs8176746, rs8176719 in the ABO gene. Group AB was excluded because of its relative small sample size. Overall, 187 387 (46%) were male with a mean (SD) age of 57±8.1 years and a median total exposure of 64 person-years (interquartile range, 57-70). Of 406 755 individuals, 182 621 (44.9%) participants had blood group O, 182 786 (44.9%) had blood group A, and 41 348 (10.2%) had blood group B. ABO blood groups were associated with 11 health and disease outcomes (
<2.19×10
). ABO blood groups were primarily associated with cardiovascular outcomes. Compared with individuals with blood group O, blood groups A and B were associated with increased odds of up to 1.56 (95% CI, 1.43-1.69) for thromboembolic events and decreased odds for hypertension (0.94 95% CI, 0.92-0.97).
The ABO blood group system is associated with several parameters of healthy aging and disease development. Knowledge of ABO blood groups might be of interest for more personalized approaches towards health maintenance and the prevention of diseases.
Genetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)-mediated ...inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia.
PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals.
These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.
The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; ...EDA) is upregulated after tissue injury and may act as a "danger signal" for leukocytes to cause adverse cardiac remodeling after infarction.
In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction.
Wild-type and EDA(-/-) mice underwent permanent ligation of the left anterior coronary artery. Despite equal infarct size between groups (38.2±4.6% versus 38.2±2.9% of left ventricle; P=0.985), EDA(-/-) mice exhibited less left ventricular dilatation and enhanced systolic performance compared with wild-type mice as assessed by serial cardiac MRI measurements. In addition, EDA(-/-) mice exhibited reduced fibrosis of the remote area without affecting collagen production, cross-linking, and deposition in the infarct area. Subsequently, ventricular contractility and relaxation was preserved in EDA(-/-). At tissue level, EDA(-/-) mice showed reduced inflammation, metalloproteinase 2 and 9 activity, and myofibroblast transdifferentiation. Bone marrow transplantation experiments revealed that myocardium-induced EDA and not EDA from circulating cells regulates postinfarct remodeling. Finally, the absence of EDA reduced monocyte recruitment as well as monocytic Toll-like receptor 2 and CD49d expression after infarction.
Our study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. Absence of fn-EDA enhances survival and cardiac performance by modulating matrix turnover and inflammation via leukocytes and fibroblasts after infarction.
Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we ...aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-α (TNF-α) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1β inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n < 100) generally reported favorable results of anticytokine therapy on cardiac function, but only one of the larger studies (n > 100) evaluating IL-1β inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans.
Inflammation plays a pivotal role across all stadia of the cardiovascular disease (CVD) continuum, i.e. non-obstructive coronary artery disease (CAD), myocardial infarction (MI), and ischemic heart ...failure (iHF). However, inflammation across CVD continuum has not been studied yet within one population. Therefore, we mapped leukocyte profiles across the continuum within the UK Biobank.
The UK Biobank cohort study includes >500,000 participants aged 40 to 70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. A total of 333,218 individuals with available laboratory measurements at baseline were included in this study. These consisted of controls and individuals who had progression of CVD during follow-up (i.e. who developed CAD, MI, or iHF during follow-up). We investigated whether leukocytes and subtypes of leukocytes at baseline differed among the CVD continuum. Furthermore, we studied the possible interactions between sex and CVD on leukocytes.
Of 333,218 individuals, 325,054 (97.5%) individuals were categorized as controls, and 8164 (2.5%) individuals had progression of CVD during follow-up. Of those 8164 individuals, 4552 (1.4%) developed CAD during follow-up, 2839 (0.9%) MI, and 773 (0.2%) in iHF. Compared to controls, mean leukocyte levels at baseline increased across the CVD continuum from 6.8·109 cells/L (SD 1.7·109 cells/L) to 7.7·109 cells/L (SD 1.9·109 cells/L) (Ptrend = 2.19·10−132) in individuals who developed iHF. This increase mainly depended on an increase in neutrophils. Furthermore, controls with leukocyte levels in the highest quartile at baseline had a 1.44 higher chance of being diagnosed with CAD during follow-up compared with individuals with leukocyte levels in lower quartiles (OR 1.44, 95% CI 1.34–1.56 P = 9.63·10−21). A similar increased change was observed for neutrophils, lymphocytes, monocytes, and eosinophils. There was a significant interaction between sex and CVD continuum on lymphocytes (P = 8.49·10−5).
Overall leukocyte count increased across the CVD continuum, which mainly depended on the increase in neutrophil count. High leukocytes in individuals not having CAD at baseline were predictive for the development of CAD during follow-up. Women had a greater increase of lymphocytes across the CVD continuum compared to men. Understanding which cells are key players in which stadium, could serve as a starting point for the identification of new potential therapeutic targets in CVD.
•Overall leukocyte count increase across the cardiovascular disease (CVD) continuum.•This increase mainly depends on the increase in neutrophil count.•High leukocyte levels are predictive for the development of coronary artery disease.•Women have a greater lymphocyte increase across the CVD continuum compared to men.
Small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of ...disease and healthy aging remains unknown. We aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition. 180 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to assess the association with health and disease outcomes in 422,417 UK Biobank participants. Potential causal estimates were obtained using a Mendelian randomization (MR) approach. From the total sample analysed (mean age was 57 ± 8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59-72). Eleven SNPs were significantly associated with 28 outcomes (Bonferroni corrected P value < 4.63·10
) including food intake, hypertension, atopy, COPD, BMI, and lipids. Multiple SNP MR pointed to a possible causal link between Ruminococcus flavefaciens and hypertension, and Clostridium and platelet count. Microbiota and their metabolites might be of importance in the interplay between overlapping pathophysiological processes, although challenges remain in establishing causal relationships.
Background and aims
Myocardial infarction triggers an inflammatory response involved in cardiac repair. We studied the association of the interleukin 6 (IL-6) cascade with infarct size and cardiac ...function after ST-elevation myocardial infarction (STEMI).
Methods
In 369 STEMI patients IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein (sgp) 130 were measured at baseline (hospital admission), 24 h, 2 weeks, 7 weeks, 4 months, and 1 year post-PCI and sIL-6R/IL-6 ratio was calculated. At 4 months, infarct size and left ventricular ejection fraction (LVEF) were assessed by magnetic resonance imaging. Diastolic function (
E
/
e
′) was determined by echocardiography.
Results
Hospital admission levels for IL-6, sIL-6R, sgp 130 were 3.7 pg/ml (IQR 2.1–6.7 pg/ml), 51.6 ng/ml (IQR 37.3–69.0 ng/ml), and 332 ng/ml (IQR 280–399 ng/ml), respectively. 24 h after admission, IL-6 had increased threefold compared to baseline (
p
< 0.001) and returned below baseline (
p
< 0.001) 2 weeks after STEMI. sIL-6R and sgp130 levels at 24 h remained similar to baseline but were increased at 2 weeks (
p
< 0.001;
p
< 0.001, respectively). IL-6 and sIL-6R/IL-6 ratio at 24 h were independently associated with infarct size
β
5.4 (95% CI 3.3–7.5);
p
< 0.001,
β
− 4.0 (95% CI − 6.1 to − 1.9);
p
< 0.001, respectively. Higher levels of IL-6 at 24 h were associated with lower LVEF
β
− 4.2 (95% CI -6.7 to − 1.8);
p
= 0.001.
Conclusions
Higher IL-6 and lower sIL-6R/IL-6 ratio early after presentation with STEMI are indicative for larger infarct size and decreased cardiac function at 4 months.
We investigated the role of the TLR4-accessory molecule RP105 (CD180) in post-ischemic neovascularization, i.e. arteriogenesis and angiogenesis. TLR4-mediated activation of pro-inflammatory Ly6Chi ...monocytes is crucial for effective neovascularization. Immunohistochemical analyses revealed that RP105+ monocytes are present in the perivascular space of remodeling collateral arterioles. As RP105 inhibits TLR4 signaling, we hypothesized that RP105 deficiency would lead to an unrestrained TLR4-mediated inflammatory response and hence to enhanced blood flow recovery after ischemia.
RP105-/- and wild type (WT) mice were subjected to hind limb ischemia and blood flow recovery was followed by Laser Doppler Perfusion Imaging. Surprisingly, we found that blood flow recovery was severely impaired in RP105-/- mice. Immunohistochemistry showed that arteriogenesis was reduced in these mice compared to the WT. However, both in vivo and ex vivo analyses showed that circulatory pro-arteriogenic Ly6Chi monocytes were more readily activated in RP105-/- mice. FACS analyses showed that Ly6Chi monocytes became activated and migrated to the affected muscle tissues in WT mice following induction of hind limb ischemia. Although Ly6Chi monocytes were readily activated in RP105-/- mice, migration into the ischemic tissues was hampered and instead, Ly6Chi monocytes accumulated in their storage compartments, bone marrow and spleen, in RP105-/- mice.
RP105 deficiency results in an unrestrained inflammatory response and monocyte over-activation, most likely due to the lack of TLR4 regulation. Inappropriate, premature systemic activation of pro-inflammatory Ly6Chi monocytes results in reduced infiltration of Ly6Chi monocytes in ischemic tissues and in impaired blood flow recovery.
RP105 (CD180) is TLR4 homologue lacking the intracellular TLR4 signaling domain and acts a TLR accessory molecule and physiological inhibitor of TLR4-signaling. The role of RP105 in vascular ...remodeling, in particular post-interventional remodeling is unknown.
TLR4 and RP105 are expressed on vascular smooth muscle cells (VSMC) as well as in the media of murine femoral artery segments as detected by qPCR and immunohistochemistry. Furthermore, the response to the TLR4 ligand LPS was stronger in VSMC from RP105(-/-) mice resulting in a higher proliferation rate. In RP105(-/-) mice femoral artery cuff placement resulted in an increase in neointima formation as compared to WT mice (4982 ± 974 µm(2) vs.1947 ± 278 µm(2),p = 0.0014). Local LPS application augmented neointima formation in both groups, but in RP105(-/-) mice this effect was more pronounced (10316±1243 µm(2) vs.4208 ± 555 µm(2),p = 0.0002), suggesting a functional role for RP105. For additional functional studies, the extracellular domain of murine RP105 was expressed with or without its adaptor protein MD1 and purified. SEC-MALSanalysis showed a functional 2∶2 homodimer formation of the RP105-MD1 complex. This protein complex was able to block the TLR4 response in whole blood ex-vivo. In vivo gene transfer of plasmid vectors encoding the extracellular part of RP105 and its adaptor protein MD1 were performed to initiate a stable endogenous soluble protein production. Expression of soluble RP105-MD1 resulted in a significant reduction in neointima formation in hypercholesterolemic mice (2500 ± 573 vs.6581 ± 1894 µm(2),p<0.05), whereas expression of the single factors RP105 or MD1 had no effect.
RP105 is a potent inhibitor of post-interventional neointima formation.
PDF
