Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet ...activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.
...in 2006, a large prospective study utilizing a United Kingdom database identified elevated rates of both traditional CV risk factors and CVD in psoriasis and highlighted the independent ...association between psoriasis and CV risk 6–8. ...it is likely that an optimal CV risk prediction strategy in psoriasis would include both an emphasis on traditional CV risk factors and imaging or biomarker correlates of subclinical CVD burden. Data from randomized clinical trials treating skin disease in psoriasis yet failing to reduce vascular aortic inflammation support this notion 21.
Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after ...cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering.
Aortic arches containing plaques developed in
mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined.
Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus.
Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.
Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and ...represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (
<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of
(interleukin 8),
, and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of
, which correlated with psoriasis disease severity (
=0.83,
=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B
and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (
<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB
(
=0.48,
=0.02).
In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.
Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways ...in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10
) including upregulation of CASP5 and interleukin ( IL) -1β. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β ( Z score 3.7; P=1.02×10
) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.
Autoimmune diseases and cardiovascular risk Gelfand, Joel M.; Wang, Sonia; Garshick, Michael S.
Trends in molecular medicine,
December 2022, 2022-12-00, 20221201, Letnik:
28, Številka:
12
Journal Article
Recenzirano
Odprti dostop
There are more than 80 different autoimmune diseases which collectively affect 4–8% of the world’s population. In a recent study published in Lancet, Conrad et al. found that 19 autoimmune diseases ...are associated with a composite of cardiovascular disease (CVD). Inflammation promotes atherosclerotic CVD with psoriasis and rheumatoid arthritis recognized as CVD risk enhancers. New strategies are needed to identify and mitigate the impact of chronic inflammation on CVD-related morbidity and mortality.
Background Since solar activity and related geomagnetic disturbances modulate autonomic nervous system activity, we hypothesized that these events would be associated with blood pressure (BP). ...Methods and Results We studied 675 elderly men from the Normative Aging Study (Boston, MA) with 1949 BP measurements between 2000 and 2017. Mixed-effects regression models were used to investigate the association of average 1-day (ie, day of BP measurement) to 28-day interplanetary magnetic field intensity, sunspot number, and a dichotomized measure of global geomagnetic activity (K
index) in 4-day increments with diastolic and systolic BP. We adjusted for meteorological conditions and other covariates associated with BP, and in additional models adjusted for ambient air pollutants (particulate matter with an aerodynamic diameter ≤2.5 µm, black carbon, and particle number) and ambient particle radioactivity. There were positive associations between interplanetary magnetic field, sunspot number, and K
index and BP that were greatest with these exposures averaged over 16 through 28 days before BP measurement. An interquartile range increase of 16-day interplanetary magnetic field and sunspot number and higher K
index were associated with a 2.5 (95% CI, 1.7‒3.2), 2.8 (95% CI, 2.1‒3.4), and 1.7 (95% CI, 0.8‒2.5) mm Hg increase, respectively, for diastolic BP as well as a 2.1 (95% CI, 0.7‒3.6), 2.7 (95% CI, 1.5‒4.0), and 0.4 (95% CI, -1.2 to 2.1) mm Hg increase, respectively, for systolic BP. Associations remained after adjustment for ambient air pollutants and ambient particle radioactivity. Conclusions Solar activity and solar-driven geomagnetic disturbances were positively associated with BP, suggesting that these natural phenomena influence BP in elderly men.
Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires ...evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe
mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe
mice, Abx
WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx
WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx
mice. By 16S rRNA sequence analysis, the Abx
mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.
•In patients with psoriasis, atorvastatin reduces linoleic acid and increases arachidonic acid in vivo.•Atorvastatin upregulates circulating transcripts fatty acid desaturase 1 and 2 in vivo.•Our ...results suggest a possible interaction between statins and fatty acid synthesis in psoriasis.
Circulating fatty acids (FA) may be important in the psoriatic pro-inflammatory phenotype. FADS1 converts linoleic acid (LA) to arachidonic acid (AA), a precursor to potent signaling molecules. HMG-CoA reductase inhibitors (statins) increase FADS1/2 expression in vitro. Psoriasis patients (42 ± 14 years/age, 47% male) were randomized to 40 mg of atorvastatin (n = 20) or nothing (n = 10) for two weeks and plasma FA measured pre and post treatment. After treatment, LDL-C was 44% lower in the statin compared to the no-treatment group. Statins increased FADS1/2 expression, and lowered LA 12% (33% – > 29%, p<0.001) and raised AA 14% (7.7% – > 9.0%, p<0.01) with no change in the no-treatment group. In psoriasis, statins enhance AA and decrease LA, consistent with the action of enhanced FADS expression in vivo. Therapies intended to blunt the effects of AA on platelet aggregation, such as aspirin or omega-3 fatty acids, may require dose adjustment when co-administered with atorvastatin.
NCT: NCT03228017
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