Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC)1 and carotid intimal medial thickness (C-IMT)2 provide information about the burden of disease. However, despite multiple validation studies of CAC3–5, and C-IMT2,6, these modalities do not accurately assess plaque characteristics7,8, and the composition and inflammatory state of the plaque determine its stability and, therefore, the risk of clinical events9–13.
[18F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) has been extensively studied in oncologic metabolism14,15. Studies using animal models and immunohistochemistry in humans show that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity16, an important source of cellular inflammation in vessel walls. More recently, we17,18 and others have shown that FDG-PET/CT enables highly precise, novel measurements of inflammatory activity of activity of atherosclerotic plaques in large and medium-sized arteries9,16,19,20. FDG-PET/CT studies have many advantages over other imaging modalities: 1) high contrast resolution; 2) quantification of plaque volume and metabolic activity allowing for multi-modal atherosclerotic plaque quantification; 3) dynamic, real-time, in vivo imaging; 4) minimal operator dependence. Finally, vascular inflammation detected by FDG-PET/CT has been shown to predict cardiovascular (CV) events independent of traditional risk factors21,22 and is also highly associated with overall burden of atherosclerosis23. Plaque activity by FDG-PET/CT is modulated by known beneficial CV interventions such as short term (12 week) statin therapy24 as well as longer term therapeutic lifestyle changes (16 months)25.
The current methodology for quantification of FDG uptake in atherosclerotic plaque involves measurement of the standardized uptake value (SUV) of an artery of interest and of the venous blood pool in order to calculate a target to background ratio (TBR), which is calculated by dividing the arterial SUV by the venous blood pool SUV. This method has shown to represent a stable, reproducible phenotype over time, has a high sensitivity for detection of vascular inflammation, and also has high inter-and intra-reader reliability26. Here we present our methodology for patient preparation, image acquisition, and quantification of atherosclerotic plaque activity and vascular inflammation using SUV, TBR, and a global parameter called the metabolic volumetric product (MVP). These approaches may be applied to assess vascular inflammation in various study samples of interest in a consistent fashion as we have shown in several prior publications9,20,27,28
FDG-PET/CT; atherosclerosis; vascular inflammation; quantitative radiology
Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes.
Methods and Results
Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V, CD3, CD31, CD41a, CD64, CD105, and CD144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet‐free plasma was separated from whole blood by one‐step centrifugation for microparticle analysis. Microparticles were fluorescently labeled and characterized by flow cytometry. Higher concentrations of CD105 (5.5/μL versus 2.5/μL, P<0.001), CD31 (31/μL versus 18/μL, P=0.002), CD41a (50/μL versus 22/μL, P<0.001), and CD64 (5.0/μL versus 4.1/μL, P=0.02) singly positive microparticles corresponding to endothelial cell‐, platelet‐, and monocyte/macrophage‐derived microparticles, respectively, were found in psoriasis patients compared with controls. These differences persisted after adjustment for traditional cardiometabolic risk factors including body mass index.
Increased microparticle concentrations, independent of cardiometabolic risk factors, in patients with psoriasis suggest that the presence of increased endothelial cell, platelet, and monocyte/macrophage activation with cell turnover may contribute to the heightened atherogenesis associated with psoriasis.
atherosclerosis; inflammation; microparticles endothelium; platelets; psoriasis; risk factor
Objective: Psoriasis (PSO) and rheumatoid arthritis (RA) increase cardiovascular diseases (CVD) beyond traditional risk factors. Vascular inflammation has previously been demonstrated to be present in PSO and RA using [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging. However, vascular inflammation has not been compared in these two disorders relative to a healthy reference population. Thus, vascular inflammation was quantitatively assessed in patients with PSO (n=10), RA (n=5), and healthy subjects (n=10) using FDG-PET/CT. Methods: FDG-PET/CT mean standardized uptake value (SUVmean) was determined slice by slice within the ascending, aortic arch, descending thoracic, suprarenal abdominal, and infrarenal abdominal aorta, and the mean metabolic volumetric product (MVPmean) was then calculated for each aortic subsegment. Plasma lipids and metabolic and inflammatory markers were also assessed. Results: CVD risk profiles were largely similar across groups. After adjustment for CV risk factors, regional aortic vascular inflammation based on MVPmean was elevated for both PSO (beta coefficients 0.31-1.47, p<0.001) and RA (beta coefficients 0.15-0.69, p<0.05) compared to healthy subjects. Conclusions: These observations using FDG-PET/CT to estimate vascular inflammation support epidemiological findings of premature atherosclerosis in PSO and RA. The use of FDG-PET/CT to investigate vascular inflammation across systemic inflammatory diseases warrants further examination in larger study populations.
Psoriasis; rheumatoid arthritis; atherosclerosis; vascular inflammation; FDG-PET/CT
Psoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis.
Methods and Results
We prospectively enrolled a consecutive sample of patients with psoriasis (n=122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n=134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n=100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dL (36–58) vs 50 (42–62), p<0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002–1498) vs 1115 (935–1291), p=0.03] with decrease in LDL size [20.6 (20.3–21.1) vs 21.3 (20.6–21.1), p<0.001] beyond CV risk factors and HOMA-IR (p=0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta −0.14, p=0.001).
These data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.
inflammation; atherosclerosis; HDL efflux; cholesterol; lipoprotein particles
editorial; monocytes; cardiovascular outcomes; inflammation
genomics; genetics; coronary artery disease; genome wide association; meta-analysis
The field of vascular molecular imaging is searching for the `holy grail' of an imaging technique that will quantitatively and reliably assess vulnerable coronary plaques. Fluorescence imaging with indocyanine green specifically identifies lipid-rich plaques in rabbits and in human plaques and represents a promising, though invasive, approach.
genomics; genetics; coronary artery disease; genome wide association; metaanalysis
Metabolic syndrome (MS) definitions predict cardiovascular events beyond traditional risk factors in type 2 diabetic (DM) as well as non-diabetics subjects. We and other have shown that apolipoprotein B (apoB) and non-HDL cholesterol (non-HDL-C) are associated with coronary artery calcification (CAC) in DM. However, the relative value of MS, apoB lipoproteins and estimates of insulin resistance is unknown in predicting atherosclerosis in DM. We performed cross sectional analyses of white subjects in 2 community based studies (N= 611 type 2 diabetic subjects, N= 803 non-diabetic subjects) using multivariate analysis of traditional risk factors and then adding MS, apoB and homeostatic model assessment for insulin resistance (HOMA-IR). Incremental value was tested with likelihood ratio testing. Beyond traditional risk, HOMA-IR [Tobit regression ratio 1.86 (p=0.002)], apoB [1.55 (p=0.001)] and MS [2.37 (p=0.007)] were independently associated with CAC. In nested models, HOMA-IR added value to apoB [1.72 (p=0.008)], MS [1.72 (p=0.011)] and both apoB and MS [1.64 (p=0.021)]. ApoB showed a similar pattern when added to HOMA-IR [1.51 (p=0.004)], MS [1.46 (p=0.005)] and both HOMA-IR and MS [1.48 (p=0.006)]. MS added to apoB [1.99 (p=0.032)], but not HOMA-IR [1.54 (p=0.221)] or both apoB and HOMA-IR [1.32 (p=0.434)]. In conclusion, insulin resistance estimates add value to MS and apoB in predicting CAC scores in DM and warrant further evaluation in clinic for identification of DM patients at higher risk for atherosclerotic cardiovascular disease.
insulin resistance; apolipoprotein B; coronary artery calcification; type 2 diabetes
Genome-wide association studies (GWAS) in over 100,000 people have revealed novel loci associated with coronary artery disease (CAD) and myocardial infarction (MI) which present exciting opportunities to discover novel disease pathways. One such recently identified locus is on chromosome 10q11, near the gene for the chemokine CXCL12 which has been implicated in cardiovascular disease (CVD) in both mouse and human studies. These GWAS demonstrate that CXCL12 may emerge as a potential therapeutic target for atherosclerosis and thrombosis.
CXCL12; atherosclerosis; GWAS; cardiovascular disease; inflammation
To evaluate the feasibility of utilizing [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) to detect and quantify systemic inflammation in psoriasis patients.
Case series with a nested case-control study.
Referral dermatology and preventive cardiology practices.
Six patients with psoriasis affecting >10% body surface area and 4 controls age and sex matched to 4 psoriasis patients for a nested case-control study.
Main Outcome Measures
FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean Standardized Uptake Value (SUV), a measure of FDG tracer uptake by macrophages and other inflammatory cells.
FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints was observed in a patient with psoriatic arthritis as well as in 1 patient with no history of joint disease or joint symptoms. In a nested case-control study, FDG-PET/CT imaging demonstrated increased vascular inflammation in multiple segments of the aorta compared to controls. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate analysis (mean beta 0.33, p<0.001). Patients with psoriasis further demonstrated increased hepatic inflammation after adjusting for cardiovascular risk factors (beta 0.18, p<0.001), but the association was no longer significant when adjusted for alcohol intake (beta −0.25, p=0.07).
FDG-PET/CT is a sensitive tool for identifying inflammation and can be used to identify clinically observed inflammation in the skin and subclinical inflammation in the blood vessels, joints, and liver of patients with psoriasis.
Recent studies suggest that psoriasis, particularly if severe, may be a risk factor for major adverse cardiac events such as myocardial infarction, stroke, and mortality from cardiovascular disease. We compared the risk of major adverse cardiac events between patients with psoriasis and the general population and estimated the attributable risk of severe psoriasis.
We performed a cohort study in the General Practice Research Database. Severe psoriasis was defined as receiving a psoriasis diagnosis and systemic therapy (N=3,603). Up to 4 patients without psoriasis were selected from the same practices and start dates for each patient with psoriasis (N=14,330).
Severe psoriasis was a risk factor for major adverse cardiac events (hazard ratio 1.53; 95% confidence interval 1.26, 1.85) after adjusting for age, gender, diabetes, hypertension, tobacco use and hyperlipidemia. After fully adjusted analysis, severe psoriasis conferred an additional 6.2% absolute risk of 10-year major adverse cardiac events.
Severe psoriasis confers an additional 6.2% absolute risk of 10-year rate of major adverse cardiac events compared to the general population. This potentially has important therapeutic implications for cardiovascular risk stratification and prevention in patients with severe psoriasis. Future prospective studies are needed to validate these findings.
Psoriasis; major adverse cardiac events; inflammation; risk factors
Objectives. The objectives of this study were to determine the prevalence of PsA in The Health Improvement Network (THIN), a large population-based medical records database in the UK, to examine factors associated with prevalent PsA among patients with psoriasis and to describe the use of DMARDs in patients with PsA.
Methods. Two cohorts were derived from THIN to examine the prevalence of PsA in a cross-sectional study among all patients aged 18–90 years and among a subcohort of 4900 psoriasis patients aged 45–65 years. Prescription codes were used to describe therapies after the diagnosis of PsA. Associations for prevalent PsA among psoriasis patients were assessed using logistic regression analysis.
Results. Among 4.8 million patients in THIN between the ages of 18 and 90 years, 9045 patients had at least one medical code for PsA, giving an overall prevalence of 0.19% (95% CI 0.19%, 0.19%). Of those patients, 45.9% with PsA have been prescribed DMARDs. Among the 4064 confirmed psoriasis patients, the prevalence of PsA was 8.6% (95% CI 7.7%, 9.5%). PsA was more prevalent among patients with severe psoriasis [odds ratio (OR) 3.34; 95% CI 2.40, 4.65], obesity (OR 1.77; 95% CI 1.30, 2.41) and duration of psoriasis for ≥10 years (OR 7.42; 95% CI 3.86, 14.25) in the fully adjusted model.
Conclusion. The prevalence of PsA in THIN is consistent with previous population-based estimates. Limitations include a definition of PsA based on a diagnostic code rather than Classification Criteria for Psoriatic Arthritis (CASPAR) criteria. Given the large population of PsA patients, THIN is an important resource for the study of PsA.
spondyloarthritis (including psoriatic arthritis); epidemiology; DMARDs; primary care rheumatology
Moderate-to-severe psoriasis is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD); however, the link is poorly understood.
Skin and serum from patients with psoriasis were evaluated to understand if there was evidence of dysregulation in a targeted group of inflammatory and lipid genes related to ASCVD. Microarray analyses of expression of targeted ASCVD genes from skin in 89 patients with moderate-to-severe psoriasis from the ACCEPT trial were compared with non-diseased skin from healthy controls (n = 25). Serum (n = 149) was tested at baseline for monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), and apolipoprotein-A1 (Apo-A1) comparing to healthy controls (n=162).
An increase in skin gene expression for MCP-1 (7.98-fold) and MDC (6.66-fold) (p < 0.001 each) was observed in lesional versus healthy skin. Significant decreases in liver X receptor-alpha (LXR-α) (−5.94-fold), a protective lipoprotein metabolism gene, and in peroxisome proliferator-activated receptor-alpha (PPAR-α) (−7.58-fold), a protective anti-inflammatory and lipid modulating gene, were observed in lesional versus healthy skin (p < 0.001 each). Serum analyses revealed that MCP-1 (502 vs. 141 pg/mL) and MDC (1240 vs. 409 pg/mL) levels were significantly elevated in psoriasis compared with healthy controls (p < 0.001 each). Dysregulated lipid metabolism was also evident in the serum, as Apo-A1, a protein product related to PPAR-α activation, was significantly decreased in patients with psoriasis compared with healthy controls (25.2 vs. 38.9 mg/dL; p < 0.001).
Analyses of targeted genes and their products known to be associated with ASCVD revealed dysregulation of inflammatory (MCP-1 and MDC) and lipid metabolism (LXR-α, PPAR-α) genes in psoriasis. These findings provide evidence of a potential shared pathophysiology linking psoriasis to cardiometabolic diseases.
Inflammation; Atherosclerosis; Lipid metabolism; Psoriasis
Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans.
Methods and Results
We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (-32.2 ± 9.3% at 24h, p<0.05) as well as small (-23.0 ± 5.1%, p<0.01, at 24h) and medium (-57.6 ± 8.0% at 16h, p<0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (~36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (-20.8 ± 3.4% at 24h, p<0.01) and cholesterol ester transfer protein mass (-22.2 ± 6.8% at 24h, p<0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models.
These data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.
inflammation; atherosclerosis; cholesterol; lipoproteins; macrophages
Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia.
The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female).
Baseline clinical, metabolic, and inflammatory biomarkers by race and gender were consistent with epidemiological literature; pre-LPS cytokines (e.g. median (IQR) IL-6, 2.7 (2) vs.2.1 (2) pg/ml, P=0.001) were higher in AA than EA. In contrast, acute cytokine responses during endotoxemia were lower in AA than EA (e.g. median (IQR) peak IL-1RA, 30 (38) vs.43 (45) ng/ml P=0.002) as was the induction of hepatic acute-phase proteins (e.g. median (IQR) peak CRP 12.9 (9) vs.17.4 (12) mg/L P=0.005). Further, baseline levels of cytokines were only weakly correlated with peak inflammatory responses (all rs <0.2) both in AA and in EA. There were less pronounced and less consistent differences in the response by gender, with males having a higher AUC for CRP response compared to females (median (IQR) AUC: 185 (112) vs. 155 (118), P=0.02).
We observed lower levels of evoked inflammation in response to endotoxin in AA compared with EA, despite similar or higher baseline levels of inflammatory markers in AA. Our data also suggest that levels of inflammatory biomarkers measured in epidemiological settings might not predict the degree of acute stress-response or risk of diseases characterized by activation of innate immunity.
FDA clinicaltrials.gov registration number NCT00953667
To examine the role of lipoprotein-associated phospholipase A2 (Lp-PLA2/PLA2G7) in human inflammation and coronary atherosclerosis.
Lp-PLA2 has emerged as a potential therapeutic target in coronary heart disease (CHD). Data supporting Lp-PLA2 are indirect and confounded by species differences; whether Lp-PLA2 is causal in CHD remains in question.
We examined inflammatory regulation of Lp-PLA2 during experimental endotoxemia in human, probed the source of Lp-PLA2 in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA2, with coronary artery calcification (CAC).
In contrast to circulating TNFα and CRP, blood and monocyte Lp-PLA2 mRNA decreased transiently, and plasma Lp-PLA2 mass declined modestly during endotoxemia. In vitro, Lp-PLA2 expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foam like-cells. Despite only a marginal association of SNPs in PLA2G7 with Lp-PLA2 activity or mass, numerous PLA2G7 SNPs were associated with CAC. In contrast, several SNPs in CRP were significantly associated with plasma CRP levels but had no relation with CAC.
Circulating Lp-PLA2 did not increase during acute phase response in human, while inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2. Common genetic variation in PLA2G7 is associated with sub-clinical coronary atherosclerosis. These data link Lp-PLA2 to atherosclerosis in human while highlighting the challenge in using circulating Lp-PLA2 as a biomarker of Lp-PLA2 actions in the vasculature.
Lp-PLA2; PLA2G7; CAC
Psoriasis is a model Th1-mediated inflammatory disease associated with increased incidence of stroke and cardiovascular disease (CVD). The mechanism behind these associations is unknown, however abnormal HDL particle composition measured by nuclear magnetic resonance (NMR) spectroscopy has been shown to be associated with CVD. Using [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT), a validated surrogate marker of CVD, we assessed whether HDL particle size and concentration were associated with vascular inflammation in patients with psoriasis. Patients with psoriasis were prospectively enrolled (439 aortic samples from 10 patients). Lipoprotein profiles using NMR spectroscopy were obtained and the relationship between vascular inflammation within the thoracic aorta by FDG-PET/CT was analyzed for association with lipoprotein particle characteristics. The plasma total cholesterol (206 mg/dL (IQR 154-229)), LDL (105 (90-161)), and triglyceride levels were within normal range (151 (94-191)) while HDL levels were low (28.9 (27.2-31.3)); however, the NMR profile demonstrated an atherogenic profile with increased small LDL and HDL particles. Total HDL particle concentration (p<0.001) and HDL particle size (p<0.001) were associated with decreased aortic inflammation, while concentration of small HDL particles was associated with increased inflammation (p<0.001). The association of total HDL particle concentration (β -0.0113, p=0.002) and small HDL particle concentration (β 0.026, p<0.001) with aortic inflammation persisted following adjustment for CVD risk factors. Total HDL particle concentration and small HDL particle concentration were associated with vascular inflammation within the thoracic aorta in psoriasis. These findings suggest that HDL particle characteristics may play an important role in psoriatic vascular inflammation and CVD.
Psoriasis; inflammation; atherosclerosis; high-density lipoprotein cholesterol particle; FDG PET CT
Introducing the Cardiovascular, metabolic and lipoprotein translation section of journal of translational medicine.
The relationship between glycemic control and lipid abnormalities with urinary albumin-creatinine ratio (ACR) in chronic kidney disease (CKD) patients with diabetes mellitus (DM) is unknown. We sought to investigate the association of dyslipidemia and glycemic control with levels of albuminuria in the National Kidney Foundation (NKF) Kidney Early Evaluation Program (KEEP) participants with DM and CKD stage 3 or higher.
We performed a cross-sectional study of 6639 eligible KEEP patients with DM and CKD Stage 3 to 5 from June 2008 to December 2009. Multivariate logistic regression was used to evaluate the association of lipid parameters (per 10 mg/dl change in serum level) and glycosylated hemoglobin (HbA1c) values with three degrees of albuminuria normo (<30 mg⁄g), micro (30 to 300 mg⁄g) and macro (>300 mg⁄g).
2141 KEEP participants were included. HbA1c levels were strongly associated with micro-albuminuria (compared to normo-albuminuria) and macro-albuminuria (compared to normo-albuminuria and micro-albuminuria). Each 1.0% increase in HbA1c increased the odds of micro-albuminuria by 32% (OR 1.32, 95% CI 1.23-1.42) and the odds of macro-albuminuria (vs. microalbuminuria) by 16% (OR 1.16, 95% CI 1.05-1.28). Only increases in serum HDL were associated with decreased odds of micro-albuminuria; otherwise, the association between other components of the serum lipid profile with urinary ACR did not reach statistical significance.
In this cross-sectional study of 2141 KEEP participants with DM and CKD stages 3–5, overall glycemic control but not lipids were associated with abnormal urinary albumin excretion, a marker of increased risk for progressive disease.
Chronic Kidney Disease; Diabetes Mellitus; Proteinuria; Dyslipidemia; Glycosylated hemoglobin
Increasing epidemiological evidence suggests independent associations between psoriasis and cardiovascular and metabolic disease. Our objective was to test the hypothesis that directly-assessed psoriasis severity relates to the prevalence of metabolic syndrome and its components.
Population-based, cross-sectional study using computerized medical records from The Health Improvement Network Study population included individuals aged 45-65 years with psoriasis and practice-matched controls. Psoriasis diagnosis and extent were determined using provider-based questionnaires. Metabolic syndrome was defined using National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria.
44,715 individuals were included: 4,065 with psoriasis and 40,650 controls. 2,044 participants had mild psoriasis (≤2% body surface area (BSA)), 1,377 had moderate (3-10% BSA), and 475 had severe psoriasis (>10% BSA). Psoriasis was associated with metabolic syndrome, adjusted odds ratio (OR) 1.41 (95% CI 1.31-1.51), varying in a “dose-response” manner, from mild (adj. OR 1.22, 95% CI 1.11-1.35) to severe psoriasis (adj. OR 1.98, 95% CI 1.62-2.43).
Psoriasis is associated with metabolic syndrome and the association increases with increasing disease severity. Furthermore, associations with obesity, hypertriglyceridemia and hyperglycemia increase with increasing disease severity independent of other metabolic syndrome components. These findings suggest that screening for metabolic disease should be considered for psoriasis, especially when extensive.
The Psoralen plus Ultraviolet-A (PUVA) cohort study has been a tremendous success in determining how a novel treatment (i.e. PUVA) impacts the long-term risk of keratinocyte carcinoma. The ability to follow patients from the initial multi-center clinical trial for over three decades has been a remarkable achievement in dermatoepidemiology. In this issue, Stern and Huibregste report results from the PUVA follow-up study and conclude that only patients with exceptionally severe psoriasis have an increased overall mortality risk and that there is no significant risk of cardiovascular mortality associated with psoriasis. The results are in contrast to a large and growing body of literature that suggests patients with more severe psoriasis have a clinically significant increased risk of mortality in general, and cardiovascular disease in particular. In addition, the authors found no association between severe psoriasis and obesity or between obesity and cardiovascular mortality, despite extensive literature establishing these associations. Basic principles of epidemiological study design may explain these discrepancies. Ultimately, however, , randomized clinical trials will be necessary to determine whether severe psoriasis is in fact a “visible killer”, as four decades ago (after many years of controversy), hypertension was recognized to be a “silent killer”.
eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
Methods and Results
In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3).
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.
coronary artery disease; genome-wide association studies; gene expression; genetic variation; genomics; eQTL; eSNP; LIPA
Data conflict with regard to whether peroxisome proliferator–activated receptor-α agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator–activated receptor-α agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation.
Methods and Results
In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m2, 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily. After 6 to 8 weeks of treatment, subjects underwent a low-dose LPS challenge. Clinical and blood measurements were collected at randomization, before LPS administration, and serially for 24 hours after LPS administration. We examined area under the curve for evoked responses by treatment group. Compared to placebo, but before LPS challenge, fenofibrate reduced total cholesterol and tended to decrease triglycerides, consistent with achieved therapeutic plasma levels of fenofibric acid. In the placebo group, LPS induced a modest inflammatory response with increased cytokines and chemokines (2- to 4-hour post-LPS 8-fold increase in tumor necrosis factor-α, 9-fold increase in interleukin-6, 9-fold increase in interleukin-10, and 10-fold increase in monocyte chemotactic protein-1; all P<0.001) and acute-phase reactants (24-hour post-LPS 15-fold increase in serum amyloid A and 9-fold increase in C-reactive protein; both P<0.001). Compared to placebo, however, fenofibrate did not significantly attenuate LPS-induced levels of plasma cytokines, chemokines, or acute-phase proteins.
These data suggest a lack of systemic antiinflammatory properties of fenofibrate at clinically relevant dosing in humans.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ct2/show/NCT01048502. Unique identifier: NCT01048502. (J Am Heart Assoc. 2012;1:e002923 doi: 10.1161/JAHA.112.002923.)
clinical trials; cytokines; endotoxemia; fenofibrate; inflammation