Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males: the Helsinki Sudden Death Study

ObjectiveThe increased plasma concentrations of pro-atherogenic and cardiomyocyte hypertrophic cytokine interleukin 18 (IL-18) predict mortality in patients with coronary heart disease (CHD) in addition to predicting the outcome of heart failure. The IL-18 gene has a functional ?137 G/C polymorphism (rs187238) in the promoter region. The C allele carriage is associated with attenuated IL-18 production. The effect of IL-18 genotype on SCD is unknown. We studied the association of the IL-18 gene ?137 G/C polymorphism with the occurrence of sudden cardiac death (SCD).MethodsUsing the TaqMan 5′ nuclease assay, we genotyped two independent consecutive and prospective autopsy series which were included in the Helsinki Sudden Death Study.ResultsOf the 663 men, 359 (54.1%) had the wild-type GG-genotype, 261 (39.4%) were heterozygotes (CG) and 43 (6.5%) were CC homozygotes. Compared to the GG homozygotes, the C allele carriers (i.e. subjects having CC or CG genotypes) had a lower adjusted risk for SCD from any cause (odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31–0.77, p = 0.002), for SCD due to CHD (OR 0.51; 95% CI, 0.32–0.82, p = 0.005), and for SCD caused by non-coronary heart diseases (OR 0.34; 95% CI 0.13–0.90, p = 0.030).ConclusionIL-18 promoter ?137 G/C polymorphism, which regulates the expression of IL-18, is an important predictor of SCD from any cause as well as SCD in patients with and without underlying CHD.     

Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men

ObjectiveTo compare the prevalence of subclinical atherosclerosis between postmenopausal women and men of similar age early after the onset of menopause.MethodsIn the first part of this cross-sectional study 186 non-diabetic young postmenopausal women (n = 101, menopausal age ≤10 years) and men (n = 85) aged 40–60 years without overt CVD were consecutively recruited from the outpatients clinics of an academic hospital. Subclinical carotid atherosclerosis was assessed by high-resolution ultrasonography. The presence of carotid atherosclerosis was defined as either increased carotid intima-media thickness (IMT > 0.9 mm) and/or the presence of plaques. In the second part, 1:1 matching for age and traditional risk factors (hyperlipidemia, smoking, hypertension and BMI) was performed between men and women of this cohort resulting in a matched sub-sample of 76 subjects.ResultsBy multivariate analysis, gender was not an independent determinant of any measure of carotid atherosclerosis. In the matched sub-sample, carotid IMT and the number of segments with atherosclerosis did not significantly differ between women and men (0.734 ± 0.119 mm and 1.47 ± 1.6 versus 0.717 ± 0.138 mm and 1.47 ± 1.5, p = 0.575 and p = 0.999, respectively). Also, the prevalence of increased IMT (60.5% in both genders), carotid plaques and subclinical atherosclerosis (31.6% and 63.2% versus 28.9% and 65.8%, p = 0.803 and p = 0.811, respectively) was similar between men and women.ConclusionsThe prevalence and severity of carotid atherosclerosis was similar between men and young postmenopausal women matched for traditional risk factors. Whether these women may be better risk stratified irrespective of gender should be further assessed in prospective studies.     

Correlation of peripheral Th17 cells and Th17-associated cytokines to the severity of carotid artery plaque and its clinical implication

ObjectiveAtherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets. Th17 cells reportedly play important roles in the development of inflammatory and autoimmune diseases. In this study, we investigated the contributions of circulating Th17 cells and plasma Th17-associated cytokines to carotid artery plaques.MethodsBased on carotid artery ultrasonography, 280 atherosclerosis patients were categorized both by: (1) 4 levels for extent and severity of plaques (Level 1 = least severe; Level 4 = most severe) and (2) 5 groups for ultrasound features of carotid artery plaques (none, flat, soft, hard, ulcerated). Peripheral blood Th17 cell frequencies and plasma concentrations of Th17-associated cytokines (IL-17, IL-6, and TNF-α) were also determined.ResultsFor groups categorized by the extent and severity of carotid artery plaques, Th17 cell frequencies, common carotid artery intima-media thickness (CCA-IMT), and Crouse scores were significantly increased in higher level groups (Levels 3 and 4) than in lower level groups (Levels 1 and 2), and plasma concentrations of IL-17, IL-6, and TNF-α increased with increased levels of plaque severity. The same pattern was found for groups categorized by ultrasound features of carotid artery plaques. The results of Pearson correlation and multiple linear regression analyses showed that both CCA-IMT and Crouse scores for carotid artery plaques were significantly and positively correlated with Th17 cell frequencies and plasma Th17-associated cytokine concentrations.ConclusionThese results suggest that increased frequencies of circulating Th17 cells and Th17-associated cytokines are correlated to the severity and progression of carotid artery plaques.     

Brain natriuretic peptide is related to carotid plaques and predicts atherosclerosis in pre-dialysis patients with chronic kidney disease

BackgroundAlthough brain natriuretic peptide (BNP) concentration has been associated with atherosclerosis and ischemic cardiovascular diseases (CVD) in the general population, less is known about this relationship in pre-dialysis chronic kidney disease (CKD) patients.MethodsWe prospectively analyzed 227 pre-dialysis patients with CKD [median estimated glomerular filtration rate (eGFR): 28.82 (11.65–48.20) ml/min/1.73 m²]. At enrollment, BNP concentrations, biochemical and echocardiographic parameters were measured, and carotid artery ultrasound was performed. Patients were prospectively followed for a mean 31.8 months (range 0.5–57.0 months). Ischemic CV events and patient outcomes were recorded.ResultsMedian BNP concentration at enrollment was significantly higher in the CKD patients than in a control group [53.9 (16.2–181.0) pg/ml vs. 9.4 (7.0–15.3) pg/ml, P < 0.01]. BNP concentration was positively related with the carotid intima–media thickness of the common carotid artery (CCA-IMT) and left ventricular mass index (LVMI) and was significantly higher in patients with than without carotid plaques (P < 0.01). Logistic regression analysis confirmed that lgBNP concentration was independently correlated with carotid plaques. Thirty-two patients experienced ischemic cardiovascular (ICV) events during follow-up. Kaplan–Meier analysis showed that cumulative survival without new ICV events was better in patients with lower than with higher BNP concentrations (P < 0.01). Cox regression analysis showed that BNP was an independent risk factor for ICV events (HR = 3.167, 95%CI = 1.398–7.171, P < 0.01).ConclusionsSimilar to findings in the general population, elevated BNP level is related to atherosclerosis and an increased risk of ICV events in pre-dialytic CKD patients.     

Coronary calcification is more predictive of carotid intimal medial thickness in black compared to white middle aged men

BackgroundRace-specific data for the association between coronary artery calcification (CAC) and carotid intimal medial thickness (IMT) are limited. We sought to compare black-white specific associations of these two measures.MethodsWe conducted a population-based study of 379 randomly selected men aged 40–49 years (84 black and 295 white) from Allegheny County, US (2004–2006). Agatston CAC score was evaluated by electron-beam tomography and carotid IMT was evaluated by ultrasonography.ResultsCompared to white men, black men had similar prevalence of CAC (p = 0.56) and higher total carotid IMT (p < 0.001). In black and white men, CAC score had significant positive correlations with total carotid IMT (r = 0.47 and r = 0.24, respectively, p < 0.001 for both) as well as the IMT for the common carotid artery (CCA), internal carotid artery and carotid bulb. The associations of CAC with total and CCA IMT were significantly stronger in black (β = 0.07 and β = 0.05, respectively) than white men (β = 0.03 and β = 0.01, respectively) after adjustment for traditional coronary risk factors (p = 0.046 and p = 0.036, respectively).ConclusionsIn black and white middle aged men, CAC score had significant positive correlations with total and segmental carotid IMT. CAC was more predictive of total and CCA IMT in black than white men independent of coronary risk factors.     

Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and proinflammatory ligand for RAGE (EN-RAGE) are associated with carotid atherosclerosis in patients with peritoneal dialysis

ObjectivesThe soluble receptor for advanced glycation end products (sRAGE) exerts a protective effect on the development of atherosclerotic vascular complications by inhibiting RAGE-mediated inflammatory response. In contrast, extracellular newly identified RAGE-binding protein (EN-RAGE) contributes to increased atherosclerosis as a pro-inflammatory ligand for RAGE. We determined the levels of sRAGE and EN-RAGE in peritoneal dialysis (PD) patients and evaluated their relationship with carotid atherosclerosis.MethodsA cross-sectional study was performed in 91 PD patients and 29 control subjects. Carotid IMT (cIMT) and abdominal aortic vascular calcification score (VCS) were evaluated using high-resolution B-mode ultrasonography and plain radiographic film of the lateral abdomen.ResultsPlasma sRAGE and EN-RAGE levels were more than twice as higher in PD patients compared to controls. EN-RAGE showed a strong positive correlation with serum high-sensitivity CRP (p = 0.007) and IL-6 (p = 0.002), whereas sRAGE was negatively associated with those inflammatory markers (p = 0.001, p = 0.031). Even after adjustments for traditional cardiovascular risk factors, both sRAGE and EN-RAGE were independently associated with cIMT (β = ?0.230, p = 0.037, β = 0.155, p = 0.045) and VCS (β = ?0.205, p = 0.049, β = 0.197, p = 0.156). Multivariate logistic analysis revealed that old age (OR 1.14, 95% CI 1.03–1.25, p = 0.009), presence of diabetes (OR 13.4, 95% CI: 1.20–150.18, p = 0.035) and elevated plasma EN-RAGE (OR 2.26, 95% CI: 1.05–5.11, p = 0.048) were significant predictors for the occurrence of carotid atherosclerosis (cIMT > 1.0 mm and/or plaque formation).ConclusionsOur findings suggest that elevated plasma EN-RAGE and decreased sRAGE level could play a crucial role in systemic inflammation and carotid atherosclerosis in PD patients.     

Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia

Background and objectivesDefects in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a highly atherogenic condition. The effect of different LDLR mutations on coronary heart disease (CHD) risk is insufficiently defined. We assessed carotid intima-media thickness (IMT), a surrogate marker of CHD, in relation to LDLR mutational class in FH.MethodsIn 436 Spanish FH patients (223 men and 213 women, age 44 ± 14 years) with known LDLR mutations, alleles were classified by standard criteria as null (n = 269), defective (n = 162), or undetermined (n = 5). LDLR defects were detected using a microarray (Lipochip^®) designed to uncover prevalent mutations in Spain and gene sequencing when no mutations were detected. Carotid IMT and plaque were assessed in FH patients and 268 healthy subjects.ResultsAll carotid measurements were increased in FH patients versus controls (p < 0.05), irrespective of genotype. After adjustment for gender and age, patients with null alleles compared with defective alleles had similar mean and maximum common carotid artery (CCA) IMT, but higher maximum IMT at any carotid segment, with median values (95% confidence interval) of 1.25 mm (1.19–1.31) and 1.11 mm (1.05–1.18), respectively. Multivariate analysis showed that null alleles were independently associated with maximum CCA-IMT (β = 0.09, p = 0.033) with an impact similar to that of gender (β = 0.10, p = 0.035).ConclusionsFH patients show advanced carotid atherosclerosis in relation to LDLR mutational class. The findings support the utility of genetic testing in FH beyond providing a secure diagnosis.     

A pathobiologic link between risk factors profile and morphological markers of carotid instability

ObjectiveAlthough cardiovascular risk factors have been strongly linked to carotid intimal-media thickness, their association with plaque progression towards instability is poorly understood.We evaluated a large database of endarterectomy specimens removed from symptomatic and asymptomatic patients to determine the correlation between major cardiovascular risk factors and carotid plaque morphology.MethodsIncidence of thrombotic, vulnerable and stable plaques together with the degree of plaque inflammatory infiltration was evaluated in 457 carotid atherosclerotic lesions. Clinical records were reviewed in all cases for risk factors profile.ResultsThrombotic plaques were more frequently observed in patients affected by stroke (66.9%) as compared to TIA (36.1%) and asymptomatic patients (26.8%, p < 0.001). Out of 457 carotid plaques removed during carotid endarterectomy, 181 (39.6%) were represented by thrombotic plaques, 72 (15.8%) by vulnerable plaques (thin cap fibroateroma) and 204 (44.6%) by stable plaques. At the multivariate analysis, a strong association was observed between hypertension, low HDL-cholesterol (HDL-C) and ratio of total to HDL-C >5 with vulnerable and thrombotic carotid plaques. Hypertension (p = 0.001), hypercholesterolemia (p = 0.05) and low HDL-C (p = 0.001) significantly also correlated with the presence of high inflammatory infiltrate of the plaque. When multivariate analysis was restricted to asymptomatic patients, hypertension (p = 0.009, OR 2.29), low HDL-cholesterol (p = 0.01 OR 2.21) and the ratio of total to HDL-C >5 (p = 0.03, OR 2.07) were confirmed to be the risk factors most significantly associated to unstable plaques. The relative risk to carry an unstable plaque for asymptomatic patients with high Framingham Risk Score as compared with those with low risk score was 2.06 (95% C.I., 1.26–3.36).ConclusionsThe present histopathological study identifies risk factors predictive of increased risk of carotid plaque rupture and thrombosis. Asymptomatic patients with high risk factors profile may constitute a specific target to reduce the likelihood of cerebrovascular accidents even in the presence of non-flow-limiting plaque.     

Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease

Background and aimsApolipoprotein E (apoE) polymorphism plays a significant role in the development of atherosclerosis and cardiovascular disease. Therefore, the aim of the present study was to examine the association between apoE polymorphism and carotid intima-media thickness (IMT), and severity and extent of coronary artery disease (CAD).Methods and resultsB-mode ultrasound and quantitative coronary angiography (QCA) were used to assess carotid, and coronary artery atherosclerosis in 91 patients with clinically suspected CAD referred for cardiac catheterization. Two apoE phenotype groups were defined: apoE3 (E3/E3) and apoE4 (including E4/E3, E4/E4 phenotypes). Maximum IMT was higher in the apoE4 group than in the apoE3 group (p = 0.022). The global atheroma burden index was similarly higher in the apoE4 group than in the apoE3 group (p = 0.033). ApoE4 subjects had higher levels of apolipoprotein B (apoB) (p = 0.008), triglycerides (p = 0.006), remnant lipoprotein-cholesterol (RLP-C) (p = 0.023), and lipoprotein(a) [(Lp(a)] (p = 0.041) than apoE3 subjects. The mean LDL particle size was smaller in the apoE4 group than in the apoE3 group (p = 0.041).ConclusionsApoE polymorphism was associated with both carotid and coronary atherosclerosis. Patients with the apoE4 isoform had an increased carotid IMT and a more severe and extensive CAD than patients with the apoE3 isoform.     

Impact of prehypertension on carotid artery intima–media thickening: Actual or masked?

BackgroundRecent studies have reported that prehypertension is associated with increased values of common carotid artery intima–media thickness (CCA-IMT). The aim of this study was to assess the impact of daytime ambulatory blood pressure (BP) levels on the association of prehypertension with CCA intima–media thickening in prehypertensive subjects.MethodsA total of 807 subjects with office systolic BP < 140 and diastolic BP < 90 mmHg, underwent 24 h ambulatory BP (ABP) monitoring and carotid artery ultrasonographic measurements. The study population was divided into 3 groups according to office and daytime ABP levels: (1) normotensives: subjects with office BP < 120/80 mmHg and daytime ambulatory BP values within the normal range, (2) actual prehypertensives: individuals with office SBP (120–139 mmHg) and/or DBP (80–89 mmHg) and daytime ambulatory BP values within the normal range and (3) prehypertensives with masked hypertension (MH): patients with office SBP (120–139 mmHg) and/or DBP (80–89 mmHg) and elevated daytime ambulatory BP values.ResultsPrehypertensive patients with MH had higher (p < 0.01) CCA-IMT values (0.712 mm; 95%CI: 0.698–0.725) than actual prehypertensives (0.649 mm; 95%CI: 0.641–0.656) and normotensives (0.655 mm; 95%CI: 0.641–0.670) even after adjustment for baseline characteristics. Normotensives and actual prehypertensives did not differ significantly regarding CCA-IMT values (p > 0.05). After adjusting for potential confounders, (including demographic characteristics, vascular risk factors, and office BP) prehypertension with MH was independently (p < 0.01) associated with a 0.06 mm increment in CCA-IMT (95%CI: 0.03–0.09).ConclusionsPatients with office BP levels in the prehypertensive range, who also have elevated daytime ABP levels, had higher CCA-IMT values than patients with prehypertension with normal daytime ABP values and normotensive individuals.     

The risk factors associated with ultrasonic tissue characterization of carotid plaque in type 2 diabetic patients

AimsLittle is known about the related factors of plaque echogenicity in diabetic subjects.MethodsThis was a single-center, retrospective, study investigating a subgroup of patients of a previously published trial. We enrolled 179 middle-aged and older Japanese type 2 diabetic patients with carotid plaque, and examined the parameters related with echogenicity of carotid plaque evaluated by gray-scale median (GSM).ResultsProportion of males and body mass index (BMI) were significantly higher and HDL-cholesterol was significantly lower in the patients with low GSM (< 48) plaques (n = 89) as compared to those without it (n = 90). A multiple logistic regression analysis with gender, BMI, and HDL-cholesterol as independent variables and the presence of low GSM plaques as an objective variable showed that male (odds ratio (OR) 2.36, 95%CI 1.05–5.31, p = 0.037) and BMI (OR 1.12 [1.01–1.24], p = 0.029) were independently associated with low GSM plaques. Another multiple logistic regression analysis with gender, BMI, and low-HDL–cholesterolemia (HDL-C < 40 mg/dl) as independent variables showed that low-HDL–cholesterolemia (OR 2.30 [1.03–5.13], p = 0.042) and BMI (OR 1.11 [1.00–1.22], p = 0.046) were independently associated with low GSM plaques.ConclusionsOur study suggests that gender, BMI and low-HDL-cholesterol are important determinants of the content of the vascular wall in diabetic subjects.     

Slow heart rate recovery after exercise is associated with carotid atherosclerosis

ObjectiveSlow heart rate recovery (HRR) after exercise is an estimate of impaired parasympathetic tone and predictor of all-cause and cardiovascular mortality. Carotid atherosclerosis is associated with high risk of developing coronary heart disease (CHD) and stroke. We tested the hypothesis that slow HRR is associated with carotid atherosclerosis in a cross-sectional study of 12,712 middle-aged men (age 49.1 ± 8.9 years).MethodsCarotid atherosclerosis was measured using B-mode ultrasonography and defined as stenosis >25% and/or intima–media thickness >1.2 mm. HRR was calculated as the difference between peak heart rate during a graded exercise treadmill test and heart rate 2 min after cessation of exercise.ResultsThe prevalence of carotid atherosclerosis was 8.4%. The prevalence of atherosclerosis was significantly higher among subjects in the lowest (<44 bpm) versus the highest (>61 bpm) quartile of HRR (14.4% versus 4.1%, p < 0.001). In multivariable logistic regression models adjusted for established CHD risk factors, inflammatory markers, and exercise capacity, subjects in the lowest quartile of HRR (<44 bpm) were 1.50 times (95% CI: 1.13–2.00) more likely to have carotid atherosclerosis than subjects in the highest quartile (HRR >61 bpm).ConclusionsSlow heart rate recovery after exercise, an index of decreased parasympathetic activity, is associated with carotid atherosclerosis independent of established risk factors in middle-age men.     

The effect of WNT5B IVS3C>G on the susceptibility to type 2 diabetes in UK Caucasian subjects

Background and aimsThe wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status.Methods and resultsTwo thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C > G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022–0.031) in controls and 0.031 (0.025–0.039) in patients with diabetes, p = 0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m² had significantly higher T2D hazard risk [3.46 (1.34–8.96), p = 0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06–2.12), p = 0.02 in subjects with BMI lower than 30 kg/m². Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C > T SNP (rs7903146) was evaluated, a 2.07 (1.40–3.07), p < 0.0001 fold higher OR was observed in carriers of both the rare alleles.ConclusionVariation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D.     

Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

ObjectiveTo determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether this GRS also predicts incident stroke.MethodsGenotypes at nine CHD-relevant SNPs were determined in 494 cases of incident CHD, 320 cases of incident stroke and 1345 unaffected controls drawn from the population-based Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. An additive GRS was calculated for each study participant by adding one unit for the presence of each high-risk allele multiplied by the estimated effect size of that allele in the discovery samples. Statistical analysis was performed using logistic regression.ResultsThe GRS was significantly associated with the incidence of CHD where the odds of CHD incidence in the highest quintile of the GRS were 1.74 times higher (95% confidence interval [CI] = 1.25–2.43, p for trend = 0.0004), compared to the lowest quintile. With respect to stroke, a weaker and non-significant positive association with GRS was apparent as the odds of stroke incidence in the highest quintile of the GRS were 1.36 times higher (95% CI = 0.90–2.06, p for trend = 0.188), compared to the lowest quintile.ConclusionA GRS relying on nine documented “CHD-specific” SNPs is significantly predictive of CHD but it was not found to be statistically significantly associated with incident stroke.     

High serum levels of remnant lipoproteins predict ischemic stroke in patients with metabolic syndrome and mild carotid atherosclerosis

Background and objectiveMetabolic syndrome is prevalently associated with stroke. Triglyceride-rich lipoproteins contribute to atherothrombotic complications in metabolic syndrome. This study examined whether high levels of remnant lipoprotein, atherogenic triglyceride-rich lipoprotein, may be associated with future ischemic stroke in metabolic syndrome.Methods and resultsWe followed up 292 consecutive patients with metabolic syndrome meeting ATP III criteria and mild carotid plaques for a period of ≤24 months until occurrence of an ischemic stroke. Remnant lipoprotein (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. Twenty-two ischemic stroke events occurred during follow-up. A multivariate Cox proportional hazards models showed that high RLP-C levels were a significant and independent predictor of ischemic stroke events (p < 0.01). Echolucent carotid plaques were also a significant predictor of ischemic stroke that was independent of other carotid ultrasound parameters in Cox proportional hazards models (p < 0.01). High RLP-C levels were intimately and independently associated with carotid plaque echolucency (p < 0.01).ConclusionsHigh RLP-C levels are an independent risk factor for future ischemic strokes in metabolic syndrome. High RLP-C levels may be related to echolucent carotid plaque, partly accounting for high risk for ischemic stroke in metabolic syndrome.     

Periodontitis and diabetes associations with measures of atherosclerosis and CHD

ObjectiveDiabetes has been linked with more severe periodontal disease and with coronary heart disease (CHD). The purpose of this study was to determine if periodontal infection was a significant modifier in the risk that diabetes poses for increased carotid artery intimal–medial wall thickness (IMT) and more advanced atheroma lesions as reflected in atherosclerotic plaque calcification measured by acoustic shadowing.Methods and resultsComparisons for analyses of cardiovascular outcomes were performed based upon periodontitis and diabetes status. Periodontitis was measured using pocket depth and attachment loss at six sites per tooth. Cross-sectional data on 6048 persons aged 52–74 years were obtained from the Dental Atherosclerosis Risk in Communities Study. Participants without diabetes (n = 5257) were compared to those with diabetes (n = 791). Dependent variables were thick IMT (>1 mm), presence of acoustic shadowing, and prevalent CHD. All models were adjusted for the following covariates: gender, age, race/center, LDL and HDL cholesterol, BMI, triglycerides, hypertension, smoking, income and education. For multivariate model building, all non-normally distributed variables were transformed and multivariable logistic regression analyses were performed to evaluate the relationship between periodontal infection, diabetes, and cardiovascular outcomes. Individuals with diabetes and with severe periodontitis were found to be significantly more likely to have IMT > 1 mm [OR = 2.2, (1.4–3.5)], acoustic shadowing [OR = 2.5, (1.3–4.6)], and CHD [OR = 2.6, (1.6–4.2)] compared to those without diabetes or periodontal disease.ConclusionResults from this study suggest that among people with diabetes, periodontal disease may increase the likelihood of subclinical atherosclerotic heart disease and CHD.     

Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization

Background and purposePlacenta growth factor (PlGF) mediates angiogenesis and inflammation, but its role in human atherosclerosis is unknown. This study was designed to test the hypothesis that PlGF-expression in human atherosclerotic carotid plaques is related to inflammation, vascularization and clinical plaque instability.MethodsThe expression of PlGF, C-reactive protein (CRP) and CD40L was analyzed with Western blots in carotid plaques of 60 patients. Cellular infiltration (CD68, CD3) and vascularization (von-Willebrand-factor) was assessed by immunohistochemistry.ResultsSymptomatic patients showed higher levels of PlGF than asymptomatic patients (115.4 ± 8.2 versus 83.6 ± 10.5 densitometric units (DU), p < 0.05) and higher grading for inflammatory cells and microvessels (CD3: 2.3 ± 0.1 versus 0.6 ± 0.1, p < 0.001, CD68: 2.4 ± 0.1 versus 0.8 ± 0.1, p < 0.001, microvessels: 2.3 ± 0.1 versus 1.5 ± 0.1, p < 0.01). PlGF-expression showed a positive correlation to the expression of CRP (r = 0.5, p < 0.001) and CD40L (r = 0.4, p < 0.01).ConclusionsPlGF-expression within human atherosclerotic lesions is associated with plaque inflammation and microvascular density, suggesting a role for PlGF in plaque destabilization and, thus, in clinical manifestation of the disease.     

Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris

ObjectiveNeopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP).MethodsWe measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells.ResultsPlasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2–39.3] nmol/L vs. 19.4 [11.9–25.1] nmol/L; P = 0.01) or without any plaques (18.8 [14.9–23.6] nmol/L; P = 0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13–4.33, P = 0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions.ConclusionThese findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.     

Age and coumarin-type anticoagulation are associated with the occurrence of intraplaque hemorrhage, while statins are associated less with intraplaque hemorrhage: a large histopathological study in carotid and femoral plaques

IntroductionIntraplaque hemorrhage (IPH) is an important determinant of progression and destabilization of atherosclerotic plaque. We recently demonstrated that IPH is an independent predictor of future cardiovascular events after carotid endarterectomy. Thus far, it is unknown whether clinical patient characteristics, such as medication use, are associated with the occurrence of IPH. The purpose of this study was to examine the association of IPH with clinical patient characteristics.Methods and results1070 consecutive patients who underwent a carotid (n = 794) or femoral (n = 276) endarterectomy were included. Endarterectomy specimens were subjected to histopathological examination. IPH was observed in 644/794 (81%) carotid and 175/276 (63%) femoral plaques. Carotid IPH was positively correlated with advanced age (69 years [IQR: 62–75] vs. 65 years [IQR: 57–73]; P = 0.002) and coumarin-type anticoagulation use prior to operation (104/116 [90%] with coumarin derivatives vs. 540/678 [80%] without coumarin derivatives; P = 0.01). Carotid IPH was less frequently observed in patients that used statins prior to endarterectomy (468/595 [79%] with statin vs. 176/199 [88%] without statin; P = 0.002). In multivariate analysis, age, coumarin-type anticoagulation use and statin use were independently correlated with carotid IPH. No association was observed between femoral IPH and clinical patient characteristics.ConclusionAdvanced age and coumarin-type anticoagulation use are associated with the occurrence of IPH, while statin use is associated with less IPH.     

Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis

ObjectiveThere is controversy over whether or not chronic HIV infection contributes to atherosclerosis. We investigated the relationship between HIV infection, antiretroviral medication and ultrasound evidence of early atherosclerosis in the context of vascular risk factors.DesignA case–control design with 292 HIV-positive subjects and 1168 age- and sex-matched controls.MethodsWe assessed vascular risk factors, blood pressure, serum lipids and carotid intima media thickness (IMT) in cases and controls. With multivariate regression models, we investigated the effects of HIV status and antiretroviral medication on IMT.ResultsThe common carotid artery (CCA) IMT value was 5.70% (95% confidence interval [3.08–8.38%], p < 0.0001) or 0.044 mm [0.021–0.066 mm] (p = 0.0001) higher in HIV-positives, adjusted for multiple risk factors. In the carotid bifurcation (BIF), the IMT values were 24.4% [19.5–29.4%] or 0.250 mm [0.198–0.303 mm] higher in HIV patients (p < 0.0001). An investigation of antiretroviral substances revealed higher CCA- and BIF-IMT values in patients receiving combination antiretroviral therapy (HAART).ConclusionsHIV infection and HAART are independent risk factors for early carotid atherosclerosis. Assuming a risk ratio similar to that in large population-based cohorts, the observed IMT elevation suggests that vascular risk is 4–14% greater and the “vascular age” 4–5 years higher in HIV-positive subjects. The underlying mechanisms remain to be clarified.