[Show abstract][Hide abstract] ABSTRACT: Objective
Low levels of IgM anti- phosphorylcholine (anti-PC) increase the risk of cardiovascular events (CVE). Here we investigate the association of low anti-PC with the progression of carotid intima media thickness (C-IMT) and incidence of CVE in a large cohort of individuals at high risk of CVE, the IMPROVE, a prospective multicenter European study.
3711 subjects (54-79 years) with at least three established cardiovascular risk factors were enrolled. Baseline serum levels of IgM anti-PC were measured by ELISA. Carotid ultrasound investigations were performed at baseline and after 15 and 30 months of follow-up. The risk of C-IMT progression and ischemic CVE associated with low anti-PC levels was tested by logistic regression and Cox regression analysis, respectively. Risk estimates were adjusted by center and conventional cardiovascular risk factors.
3670 study participants were included in the present analysis and 213 CVE were recorded during a 3 year follow up. Anti-PC levels (U/ml) were classified into quartiles [Q1≤ 40, Q2 >40-≤64, Q3 >64-≤102, Q4 >102]. In men, low levels of anti-PC (Q1) were associated with the highest (> 90th) percentile of the fastest C-IMT progression, i.e. the segment showing the fastest progression over 30 months in the whole carotid tree, with an OR of 1.41 (95%CI, 1.02-1.9) and with an increased risk of CVE with a multivariable adjusted HR of 1.85 (95%CI, 1.1-3.1). No significant associations were found in women.
Low anti-PC levels increase the risk of CVE in men. This effect may be partly mediated by a fast C-IMT progression.
[Show abstract][Hide abstract] ABSTRACT: Background
The aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments.
Patients and methods
We used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis.
Of the 1380 patients enrolled, 27.9% had HF (age 80 ± 7, BMI 27 ± 6 kg/m2) and 17.4% CKD (age 81 ± 7, BMI 26.8 ± 6 kg/m2). Both groups were significantly older (P < 0.0001) with BMI higher than the patients without those diagnosis (P < 0.02). Patients with a history of CKD showed higher non-fasting glycaemia (140 ± 86 vs. 125 ± 63 mg/dL, P < 0.001). CKD was significantly associated with HF (P < 0.0001). Patients with HF had an estimated GFR lower than patients without HF (P < 0.0001). Comorbidity and severity indices were significantly higher in subjects with HF (P < 0.0001) and CKD (P < 0.0001) than in those without. Multivariable analysis showed a significant association between HF and age (for five years increase OR 1.13, P < 0.009), BMI (for each 3 kg/m2 increase OR 1.15, P < 0.001), GFR (for each decrease of 10 mL/min increase OR 0.92, P < 0.002) and severity index (IS) (for each 0.25 units increase OR 1.43, P < 0.001).
HF on admission is strongly associated with CKD, older age, BMI, and SI. These data focus the value of epidemiological studies such REPOSI in identifying and monitoring multimorbidity in elderly.
European geriatric medicine 10/2014; · 0.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic inflammation and imbalance between endothelial injury and repair, the latter referred to as vascular incompetence, are associated with atherosclerosis and cardiovascular risk. Psoriasis, an inflammatory disease of the skin, has been associated with atherosclerosis. We investigated whether, in psoriasis, inflammation and vascular incompetence are associated with carotid intima-media thickness (cIMT) irrespective of metabolic syndrome and other established cardiovascular risk factors.
European Journal of Preventive Cardiology 06/2014; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima-media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question.
The multicentre, longitudinal Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes.
SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia.
SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.
[Show abstract][Hide abstract] ABSTRACT: Objective
Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals.
Approach and results
IgG-p210nat and IgM-p210MDA were quantified in baseline plasma samples of 3430 participants in the IMPROVE study and related to composite and segment-specific measures of severity and rate of progression of carotid intima-media thickness (cIMT) determined at baseline and after 30 months. IgM-p210MDA autoantibody levels were independently related to several cIMT measures both in the common carotid artery and in the carotid bulb, including measures of cIMT progression, higher levels being associated with lower cIMT or slower cIMT progression. Consistent inverse relationships were also found between plasma levels of IgG-p210nat and baseline composite measures of cIMT. These associations disappeared when adjusting for established and emerging risk factors, and there were no associations with rate of cIMT progression besides in certain secondary stratified analyses.
The present study provides further evidence of involvement of autoantibodies against native and MDA-modified apoB-100 peptide 210 in cardiovascular disease in humans and demonstrates that these associations are present already at a subclinical stage of the disease.
[Show abstract][Hide abstract] ABSTRACT: Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk.
Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere-Terpstra χ=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment-specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals.
Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals.
Arteriosclerosis Thrombosis and Vascular Biology 09/2013; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial progenitor cells (EPCs) are believed to play a role in promoting abnormal vascularization in neoplastic sites. We measured the number of circulating EPCs in treatment-naïve patients with early non-small-cell lung cancer (NSCLC) and healthy controls. The prospective influence of baseline and post-surgery EPC levels on cancer recurrence and survival was investigated.
Circulating EPCs were quantified by FACS analysis in 34 patients with Stage I-II NSCLC and 68 healthy age- and sex-matched controls. Measurement of EPCs was repeated 48 h after thoracic surgery and at the hospital discharge. Cancer recurrence and survival was evaluated after 446 ± 106 days of follow-up (range 182-580 days).
The base 10 logarithmic [log] number of circulating EPCs was comparable between patients with NSCLC and controls [mean ± standard deviation (SD): 2.3 ± 0.32 vs 2.3 ± 0.26 n/ml, P = 0.776]. In regression analysis, smoking status [standardized coefficient beta (β) = -0.26, 95% confidence interval (CI) for B -0.29/-0.03, P = 0.014] and systolic blood pressure [β = -0.23, 95% CI for B -0.011/-0.001, P = 0.018] were independent predictors of the number of EPCs, irrespective of the NSCLC status. The mean number of EPCs did not change after surgical treatment. However, a post-surgery EPC increase was observed in 44% patients. Patients with a 48 h post-surgery EPC increase had a higher rate of cancer recurrence/death than patients with either stable or decreased post-surgery EPC levels [hazard ratio (HR) 4.4, 95% CI 1.1-17.3; P = 0.032], irrespective of confounders.
Circulating EPC levels are comparable between patients with early-stage NSCLC and healthy controls. Overall, surgical cancer resection was not associated with a significant early EPC change. However, an early post-surgery EPC increase is able to predict an increased risk of cancer recurrence and death.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 07/2013; · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statin therapy is followed by reductions in carotid intima-media thickness (CIMT) and C-reactive protein (CRP) levels, but a significant number of treated patients still have increased CIMT. We investigated whether on-treatment levels of CRP is associated with CIMT in hypercholesterolemic patients receiving statin therapy. The influence of blood pressure and anti-hypertensive therapy on the association between CRP and CIMT was evaluated.
Assessment of cardiovascular risk factors, CRP and CIMT was performed in a cross-sectional study of 240 hypercholesterolemic patients at intermediate cardiovascular risk under statin therapy; 125 patients received only a statin (Statin Group) and 115 also anti-hypertensive therapy (Combined Therapy Group).
Logarithmically transformed CRP (β=0.17, p=0.01) and HDL cholesterol levels (β=-0.27, p<0.001) were correlates of CIMT, irrespective of confounders. High CRP levels (>3 mg/L) were associated with a 2.7-fold increased risk of having high CIMT (>1.25 mm). High CIMT was present in a high percentage of patients not at target for cholesterol and blood pressure levels (61%). Patients in the Statin Group had lower Framingham risk and CIMT than those in the Combined Therapy Group. In the Statin Group, logarithmically transformed CRP (β=0.28, p=0.004) and HDL cholesterol (β=-0.21, p=0.03) were associated with CIMT. In the Combined Therapy Group, HDL cholesterol was the only significant CIMT correlate (β=-0.33, p=0.001).
On-treatment CRP and HDL cholesterol levels are associated with CIMT among hypercholesterolemic patients under statin therapy. In patients receiving both statin and anti-hypertensive therapy, HDL cholesterol remains the main covariate of CIMT.
Life sciences 07/2013; 93(8). · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate whether several different measures of carotid intima-media thickness (IMT) progression are associated with subsequent vascular events and whether such associations are independent of baseline carotid atherosclerotic profile and Framingham risk factors.
A longitudinal cohort study (the IMPROVE study) was performed in 7 centers in 5 European countries (Finland, France, Italy, the Netherlands, and Sweden). Three thousand four hundred eighty-two subjects (median age 64.1 years; 47.8% men) with ≥3 vascular risk factors were recruited and monitored for a postprogression median follow-up of 21.5 months, during which time 129 subjects experienced a first vascular event (incidence of 20.4 per 1000 person-years). The 15th month progression of mean and maximum carotid IMT of the left and right common carotids, bifurcations, internal carotid arteries, and their composite measures, as well as the fastest IMTmax progression (Fastest-IMTmax-progr) detected in the whole carotid tree regardless of location, were used in statistical analyses. All carotid IMT measures showed significant progression during the first 15 months (P<0.001), but only the Fastest-IMTmax-progr was significantly associated with the risk of subsequent vascular events. The Fastest-IMTmax-progr association persisted after Bonferroni correction for multiple comparisons and after adjustments for Framingham risk factors and pharmacological treatments (all P<0.005). The use of Framingham Risk Score in place of Framingham risk factors provided almost identical results (P=0.003).
The Fastest-IMTmax-progr, a novel approach to assess carotid IMT progression, identifies focal increases of carotid IMT and, in contrast to other progression variables, is associated with cardiovascular risk.
Arteriosclerosis Thrombosis and Vascular Biology 07/2013; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aimsEctopic artery calcification has been documented in women with postmenopausal osteoporosis, in whom an imbalance in the number of circulating osteoprogenitor cells (OPCs) has been identified. Circulating OPCs form calcified nodules in vitro; however, it remains unknown whether an association exists between the number of circulating OPCs and aortic calcifications. We investigated the relationship between OPCs and aortic calcifications in women with postmenopausal osteoporosis.Methods and resultsThe number of circulating OPCs was quantified by FACS analysis in 50 osteoporotic postmenopausal women. OPCs were defined as CD15-/alkaline-phosphatase(AP)+ cells coexpressing or not CD34. Participants underwent measurement of markers of bone metabolism, bone mineral density and abdominal aortic calcium (AAC) by 64-slice computed tomography.Patients with AAC were older, had lower 25(OH)vitamin D levels and higher circulating CD15-/AP+/CD34- cells than those without AAC. Significant correlates of AAC included age (rho = 0.38 p = 0.006), calcium (rho = 0.35 p = 0.01), 25(OH)vitamin D (rho = −0.31, p = 0.03) and the number of CD15-/AP+/CD34- cells (rho = 0.55 p < 0.001). In regression analyses, the log-transformed number of CD15-/AP+/CD34- cells was associated with the presence (OR = 6.45, 95% CI 1.03–40.1, p = 0.04) and severity (β = 0.43, p < 0.001) of AAC, independent of age, 25(OH)vitamin D, calcium and other potential confounders. Patients with low 25(OH)vitamin D and high CD15-/AP+/CD34- cells had higher median AAC than other patients (1927/μL, 862–2714/μL vs 147/μL, 0–1665/μL, p = 0.003).Conclusion
In women with postmenopausal osteoporosis, the number of circulating CD15-/AP+/CD34- cells is significantly associated with increased aortic calcifications, that appear to be correlated also with reduced 25(OH)vitamin D levels.
[Show abstract][Hide abstract] ABSTRACT: To investigate the influence of the silent mutation c.816C > G (L272) of Niemann-Pick C1-like 1 (NPC1L1) and of apolipoprotein (APO) E alleles on cholesterol absorption markers, sitosterol and campesterol, in 87 patients with primary hyperlipidemias.
In all subjects genotyped for silent polymorphism in NPC1L1 gene c.816C > G (L272L) and for APO E polymorphism, campesterol and sitosterol were measured by gas chromatography coupled to mass spectrometry.
Thirty-eight patients carrying the G allele of NPC1L1 showed significantly greater concentrations (log values) of campesterol (1.86 ± 0.3 vs 1.61 ± 0.3 10(2) μmol/mmol cholesterol, p < .001) and sitosterol (2.03 ± 0.2 vs 1.94 ± 0.2 10(2) μmol/mmol cholesterol, P = .05). Patients with at least one E4 allele showed values of sitosterol greater than those carrying E3E3 or E3E2 (2.05 ± 0.2 10(2) μmol/mmol cholesterol vs 1.95 ± 0.2 10(2) μmol/mmol cholesterol, P = .004). The presence of the G allele (β = .379, P < 0.001) and high-density lipoprotein cholesterol (β = .242, P = .019) was an independent predictor of campesterol values (R of the model = 0.473, P < .001). The E4 allele (β = .293, P = .005) and high-density lipoprotein cholesterol (β = .311, P = .003) were independent predictors of sitosterol values (R 0.416, P of the model <.001).
In patients with hyperlipidemias, G allele of NPC1L1 and APO E4 could account for some of the inter-individual variability in cholesterol absorption.
Journal of Clinical Lipidology 03/2013; 7(2):147-52. · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: -Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. METHODS AND RESULTS: -In order to identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3,430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE study. Segment-specific IMT measurements of common carotid (CC), bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analysed. A replication stage investigating 42 single nucleotide polymorphisms (SNPs) for association with CC-IMT was undertaken in five independent European cohorts (total n=11,590). A locus on chromosome 16 (lead SNP rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple-testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMT(max); replication P=7.24x10(-6) for CC-IMT; adjustments for sex, age and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120), and lower coronary artery disease (CAD) risk in two case-control studies of subjects with European ancestry (odds ratio [95%CI] 0.83 [0.77-0.90], P=6.53x10(-6); n=13,591, and 0.95 [0.92-0.98], P=1.83x10(-4), n=82,297, respectively). Queries of human biobank datasets (n=126-138) revealed associations of rs4888378 with nearby gene expression in vascular tissues. CONCLUSIONS: -This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and CAD risk in individuals of European descent.
[Show abstract][Hide abstract] ABSTRACT: Objectives – To compare the performance of several measures of carotid intima-media thickness (C-IMT) as predictors of cardiovascular events (CVEs), and to investigate whether they add to the predictive accuracy of Framingham risk factors (FRFs).
Background – Various markers of subclinical atherosclerosis have been identified as predictors of CVEs, but the most powerful variable is still under debate.
Method – A cohort study was carried out in 5 European countries. 3703 subjects (median age 64.4 years; 48% men) were followed-up for a median of 36.2 months, and 215 suffered a first CVE (incidence: 19.9/1000 person-years).
Results – All measures of C-IMT and the inter-adventitia common carotid artery diameter (ICCAD) were associated with the risk of CVEs, after adjustment for FRFs and therapies (all P<0.005). The average of 8 maximal IMT measurements (IMTmean-max), alone or combined with ICCAD, classified events and non-events better than the common carotid mean IMT (net reclassification improvement, NRI: +11.6% and +19.9%, respectively; both P<0.01). Compared to classification based on FRFs alone, the NRI resulting from the combination of FRFs+ICCAD+IMTmean-max was +12.1% (P<0.01). The presence of at least one plaque (maximum IMT>1.5 mm) performed significantly worse than composite IMTs which incorporated plaques (P<0.001). Adjusted Kaplan-Meier curves showed that individuals with a FRS=22.6% (cohort average), and both IMTmean-max and ICCAD above the median, had a 6.5% risk to develop a CVE over 3 years versus a 3.4% risk for those with the same FRS, and both IMTmean-max and ICCAD below the median.
Conclusions – A risk stratification strategy based on C-IMT and ICCAD as an adjunct to FRFs is a rational approach to prevention of cardiovascular disease.
Journal of the American College of Cardiology 09/2012; 60(16):1489-1499. · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study.
Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMT(mean), IMT(max) and IMT(mean-max)) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden.
In multivariate regression analysis, gender (p < 0.001), age (p < 0.001), systolic blood pressure (IMT(mean), p = 0.01; IMT(mean-max), p = 0.05) and serum LDL conjugated dienes (p = 0.02 for both IMT(mean) and IMT(mean-max)) were the strongest determinants of IMT variation, adjusted for study center, ultrasound videotape reader and serum LDL cholesterol. Pack-years of smoking, added into the regression model, did not destroy the significant association between increased serum LDL conjugated dienes and IMT. Ratio of LDL conjugated dienes to LDL particle cholesterol was higher in subjects of Northern recruiting centers than of Southern centers (r = 0.39, p < 0.0001).
There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries.