Marker Of Subclinical Vascular Disease Research Articles

Associations of galectin-3 levels with measures of vascular disease in patients with rheumatoid arthritis

ObjectivesGalectin-3 is a beta-galactoside-binding lectin and is a marker of cardiovascular disease (CVD) in the general population. It may also play a role in joint inflammation. We asked whether serum galectin-3 is a useful marker of subclinical vascular disease in patients with rheumatoid arthritis (RA). MethodsRA patients without clinical CVD underwent assessment of coronary artery calcium (CAC) score, aortic inflammation (using 18Fluorodeoxyglucose positron emission-computed tomography [FDG PET/CT]), and myocardial flow reserve (MFR). Aorta FDG uptake was measured as standardized uptake values (SUV). Generalized linear models were constructed to explore the associations of galectin-3 levels with CAC score, aortic SUV, and MFR. ResultsA total of 124 RA patients (mean age 57; 82 % women, 45 % Hispanic; median RA duration 6.8 years; 75 % seropositive; median CDAI 16; 33 % on prednisone; 89 % on DMARDs; median CAC score 0; median aorta SUV 2.59; mean MFR 2.86; median galectin-3 level 8.54 ng/mL) were analyzed. In univariable analysis, higher galectin-3 levels were associated with higher aortic SUV (p = 0.007) but CAC score and MFR were not. In multivariable analysis, higher galectin-3 level remained significantly associated with higher aortic SUV (ß Coefficient=0.1786, p value=0.002). ConclusionIn our cohort of RA patients without clinical CVD, higher serum galectin-3 levels were independently associated with higher levels of aortic inflammation, but not CAC score or MFR. This suggests that galectin-3 may be a biomarker for an inflammatory and potentially reversible stage, but not a later (calcified) stage, of atherosclerosis in patients with RA.

Effect of anti-inflammatory therapy on vascular biomarkers for subclinical cardiovascular disease in rheumatoid arthritis patients

ObjectiveTo assess the effect of 4 years of anti-inflammatory therapy on markers of subclinical vascular disease in rheumatoid arthritis patients.MethodsCarotid intima media thickness (IMT), augmentation index (AIx@75) and pulse wave velocity (PWV) measurements were performed repeatedly in 61 RA patients (30 early RA starting with csDMARDs and 31 established RA starting with adalimumab) for 4 years. These markers were also measured in 29 controls with osteoarthritis at baseline (BL).ResultsIMT and AIx@75 at BL were higher in RA compared to OA, while PWV was higher in OA. In RA patients, AIx@75 and PWV decreased in the first 6 months after starting anti-inflammatory therapy. At 48 M, the level of AIx@75 remained lower than before therapy, while PWV at 48 M was comparable to BL (AIx@75: BL 28% (95% confidence interval 25–30%), 6 M 23% (20–26%), 48 M 25% (22–28%); PWV: BL 8.5 (7.8–9.2), 6 M 8.0 (7.1–8.9), 48 M 8.6 (7.6–9.6) m/s). IMT remained stable. There was an effect of disease activity (longitudinally, adjusted for changes over time) on IMT, AIx@75 and PWV.ConclusionThis study suggests modest beneficial changes in some surrogate markers of subclinical vascular disease after anti-inflammatory therapy. These changes were associated with improvement in disease activity markers. Whether or not these beneficial changes ultimately predict a reduction in clinicalcardiovascular endpoints remains to be established in prospective studies.

Prognostic Role of Measurement of Renal Resistive Index in Systemic Sclerosis.

Objective:The spectrum of vascular involvement in systemic sclerosis (SSc) includes digital ulcers, gangrene, Raynaud’s phenomenon, renovascular disease, and pulmonary hypertension (PH). Recognition of markers of subclinical vascular disease in SSc is an area of active research, but such studies are limited. This study assesses the role of measurement of the renal resistive index (RRI) as an early marker of renal and systemic vasculopathy. It is a step forward towards examining the possibility of a “unified vascular phenotype’ in SSc.Methods:In this single-centre prospective study, RRI was calculated for SSc patients >18 years age. Elevated RRI (>0.7) was correlated with renal function (eGFR and proteinuria) and systemic vasculopathy manifestations like digital ulcers, digital infarcts, and PH.Results:A total of 73 patients with mean (SD) age 41.8(10.9) years were included. Mean (SD) RRI in the right and left renal artery was 0.65(0.08) and 0.66(0.07), respectively. 16 (21.9%) patients had elevated RRI (>0.7). A strong negative correlation was noted between elevated RRI and eGFR (r= −0.96, p=0.03). The percentage of patients with overt proteinuria was higher in the group with elevated RRI (20% versus 7%) (p=0.16). Similarly, digital ulcers (56% vs 33%) and digital pitting (50% vs 35%.) were numerically higher in the group with raised RRI, although statistical significance was not reached because of small numbers (p=0.09 and 0.28, respectively). No correlation of RRI with PH was identified.Conclusion:RRI correlates well with asymptomatic renal dysfunction and holds promise in the assessment of systemic vasculopathy. However, validation in studies with a larger sample size is needed.

Impaired Microcirculation in Children After Kidney Transplantation: Everolimus Versus Mycophenolate Based Immunosuppression Regimen

Background/Aims: Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown. Methods: We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycophenolate mofetil plus calcineurin inhibitor. Measurement of carotid intima-media thickness (cIMT) via ultrasound, central pulse wave velocity (PWV) by a cuff-based oscillometric technique, and skin microvascular blood flow during local heating via laser-Doppler-fluximetry (LDF) served as marker of subclinical vascular disease. Serum concentrations of angiopoietin-1 and -2, fibroblast-growth factor 23 (FGF23) and soluble klotho were measured. Results: EVR-treated patients exhibited a similar degree of hypertension, increased cIMT, elevated pro-inflammatory angiopoietin-2, and diminished endothelial survival factor angiopoietin-1 compared to healthy children but presented with a twofold more reduced skin micro-vascular function compared to standard treatment (each p< 0.001). By contrast, PWV and soluble klotho levels were normal in both groups. Conclusion: Endothelial dysfunction seems more frequent in KTx patients on EVR-based immunosuppressive regimen compared to standard immunosuppression.

Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities: The Northern Manhattan Study.

Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort. We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors. In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21-0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (β=0.046 per SD cIMT; P=0.04). Age and race/ethnicity were significant modifiers (P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (β=0.088 per SD cIMT; P=0.01) and among Hispanics (β=0.084 per SD cIMT; P=0.003). Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline.

Apolipoprotein A-IV as a marker of subclinical vascular disease among individuals with hyperalphalipoproteinemia

Apolipoprotein A-IV as a marker of subclinical vascular disease among individuals with hyperalphalipoproteinemia

Self-reported sleep duration and napping, cardiac risk factors and markers of subclinical vascular disease: cross-sectional study in older men

StudyobjectivesDaytime sleep has been associated with increased risk of cardiovascular disease and heart failure (HF), but the mechanisms remain unclear. We have investigated the association between daytime and night-time sleep...

Metabolic syndrome, hepatic steatosis, and cardiovascular risk in children

ObjectivesPediatric metabolic syndrome (MetS) is a well-recognized entity; however, there is no consensus on its exact value in predicting long-term cardiovascular (CV) risk. Hepatic steatosis (HS) is another emerging condition associated with pediatric obesity, and data have been reported suggesting a possible role of HS in CV risk linked to MetS. The aim of the present study was to evaluate the usefulness of HS and MetS cluster in predicting CV risk linked to pediatric obesity. MethodsWe studied 803 overweight and obese children (395 girls and 408 boys, mean age 9.4 ± 2.5 y, body mass index z-score 2.2 ± 0.53) with complete clinical and biological assessment. MetS was defined using the modified criteria of the American Heart Association. The diagnosis and severity of the HS was based on ultrasound. To assess CV risk, all patients underwent ultrasonography to measure carotid intima-media thickness (cIMT)—a validated marker of subclinical vascular disease. ResultsThe overall prevalence of MetS was 13.07%; HS was significantly higher in patients with MetS (40.9 versus 18.5%; P < 0.001; odds ratio, 3.059; 95% confidence interval, 1.98–4.7). Spearman's correlation between HS grade and the number of MetS criteria met by each patient was significant (r = 0.285; P < 0.001). No statistical difference was recorded in cIMT and cIMT z-scores between patients with or without MetS, until inclusion of HS as an additional criterion for the diagnosis of MetS. In this case, there was a significant difference in cIMT z-scores between the two groups. In multiple linear regression analysis, the cIMT z-score value was better predicted with HS grade and the MetS cluster (adjusted R2 = 2.6%; P = 0.002) than when using the MetS cluster only. ConclusionsHS could be used as additional criterion in detecting pediatric MetS phenotype at higher risk for long-term CV morbidity.

Liver fat is related to cardiovascular risk factors and subclinical vascular disease: the Rotterdam Study.

Increasing evidence suggests involvement of the amount of liver fat in the development of cardiovascular disease. We investigated the relation of liver fat with cardiovascular risk factors and subclinical vascular disease in the general population. Between 2003 and 2006, 2351 persons from the population-based Rotterdam Study (mean age 69.6 ± 6.7 years, 47.2% males) underwent non-enhanced computed tomography. We measured the mean liver attenuation value in Hounsfield units and quantified the following markers of subclinical vascular disease: epicardial fat volume and volumes of coronary (CAC), aortic (AAC), extracranial (ECAC), and intracranial carotid calcification (ICAC). Using linear regression, we investigated associations between traditional cardiovascular risk factors and mean liver attenuation. We also investigated relations of mean liver attenuation with markers of subclinical vascular disease, adjusting for cardiovascular risk factors. We found strong associations of waist circumference, diastolic blood pressure, and diabetes with lower mean liver attenuation [multivariable-adjusted beta per unit increase in waist circumference: -2.54 (95% CI: -3.10; -1.99); diastolic blood pressure: -0.52 (95% CI: -0.88; -0.17); and the presence of diabetes: -21.91 (95% CI: -31.76; -12.06)]. Moreover, we found that larger mean liver attenuation values were associated with smaller volumes of epicardial fat and CAC, independent of cardiovascular risk factors [beta per 1-SD increase in mean liver attenuation value: -0.05 (95% CI: -0.08; -0.02) and -0.05 (95% CI: -0.10; -0.01), respectively]. Larger amounts of liver fat are related to larger volumes of epicardial fat and CAC, independent of traditional cardiovascular risk factors, providing important novel insights into the role of liver fat as a marker of vascular disease.

Extremely elevated HDL-cholesterol levels are not associated with increased carotid intima-media thickness: data from ELSA Brasil

There is evidence that extremely elevated high-density lipoprotein cholesterol (HDL-c), that is, hyperalphalipoproteinemia (HALP) may indicate dysfunctional HDL, conferring increased cardiovascular risk. We studied carotid intima-media thickness (cIMT) a marker of subclinical vascular disease according to HDL-c distribution. cIMT was studied in subjects with "normal" HDL-c levels (HDL-c 40-50mg/dL for men; 50-60mg/dL for women, mean 49.6±5.7mg/dL, n=3226); in those with HALP (HDL-c ≥90mg/dL for both sexes, mean 101.2±10mg/dL, n=264) and according to HDL-c quintile distribution (n=9779). Multiple linear regression was used to test the association of HDL-c and cIMT. Subjects with HALP were older (54.5±9.6 vs 51.1±8.8years, P<.001); more frequently females (86.4% vs 49%, P<.001); and presented a lower burden of risk factors: hypertension (24.6% vs 32.7%, P=.009), diabetes (10.2% vs 20.4%, P<.001), and obesity (18.6% vs 37.6%, P<.001). A similar profile was seen with higher HDL-c quintiles in the whole study population. When compared to normal HDL-c values, HALP was associated with lower maximal cIMT (0.779±0.189mm vs 0.818±0.200mm, P=.002), and there was a lower prevalence of individuals with cIMT ≥ 75(th) percentile for age and gender or high cIMT (17.5% vs 26.2%, P=.003). After multivariate analysis, no association was seen between HALP and increasing cIMT values, indeed the 5(th) HDL-c quintile was associated with lower risk of high cIMT (OR= 0.80; 95% CI= 0.68-0.95). HALP is associated with lower cIMT and does not indicate a pro-atherogenic phenotype.

Depression in context of low neuroticism is a risk factor for stroke: a 9-year cohort study.

Depression predicts stroke; however, meta-analyses show significant heterogeneity. We hypothesize that the risk of depression on incident stroke is conditional upon the relative contribution of vascular disease and of neuroticism in the underlying pathways to depression in a specific patient. We examined whether depression increases stroke in persons with low neuroticism and without preexisting cardiac disease. This was a population-based cohort study with 9-year follow-up (n = 2,050; ≥55 years, 52% female). The incidence of stroke was determined by self-report data as well as data from general practitioners and death certificates. Neuroticism was measured using the Dutch Personality Questionnaire and depression using the Center for Epidemiologic Studies-Depression scale. All data were analysed by Cox proportional hazards regression. A total of 117 incident cases of stroke occurred during follow-up. Among persons with a history of cardiac disease (n = 401), depression predicted incident stroke independent of neuroticism level with a hazard ratio (HR) of 1.05 (95% confidence interval [CI] 1.01-1.10) (p = 0.02). In persons without cardiac disease (n = 1,649), depression and neuroticism interacted significantly in predicting incident stroke (p = 0.028). Stratified analyses showed that depression predicted incident stroke in those with low neuroticism, HR 1.05 (95% CI 1.00-1.09) (p = 0.033), but not in those with high neuroticism, HR 1.01 (95% CI 0.96-1.05) (p = 0.82). In persons without preexistent cardiac disease, depression is only predictive for future stroke in absence of high neuroticism. This might be explained by the hypothesis that late-life depression in context of low neuroticism is a marker of subclinical vascular disease.

Flow-mediated dilation, carotid wall thickness and HDL function in subjects with hyperalphalipoproteinemia

Background and aimsThe relationships between very high plasma HDLc and subclinical atherosclerosis are still a matter of debate. Methods and resultsTwenty subjects with primary hyperalphalipoproteinemia (HAL, with HDLc in the highest 10th percentile and absence of overt secondary causes of this condition), aged 30–65 years, were compared with 20 age and sex-matched controls. Lipid determination, lipoprotein particle distribution (Lipoprint®), Cholesterol Efflux Capacity (CEC), plasma adhesion molecule, analyses of CETP, SRB1 and LIPG genes and of different markers of subclinical vascular disease (ankle-brachial index, ABI; carotid intima-media thickness, cIMT; brachial-artery flow mediated dilation, FMD) were performed. Fasting HDLc levels were 40 mg/dl higher in HAL subjects while LDLc concentration was comparable to control group. CETP gene analysis in HAL subjects identified one novel rare Single Nucleotide Polymorphism (SNP, Asp131Asn), possibly damaging, while the common SNP p.Val422Ile was highly prevalent (50% vs. 27.4% in a control population). No rare mutations associated with HAL were found in SR-B1 and LIPG genes. Polyacrylamide gel electrophoresis in HAL subjects disclosed larger and more buoyant HDL particles than in controls, while LDL profile was much more similar. ABI, cIMT and arterial plaques did not differ in cases and controls and the two groups showed comparable FMD at brachial artery examination. Similarly, ABCA1 and ABCG1 HDL-mediated CEC, the most relevant for atheroprotection, did not discriminate between the groups and only ABCG1 pathway seemed somewhat related to arterial reactivity. ConclusionsHDL dimension, function and genetics seem scarcely related to subclinical atherosclerosis and vascular reactivity in middle-aged HAL subjects.

Asymmetric Dimethylarginine as a Surrogate Marker of Endothelial Dysfunction and Cardiovascular Risk in Patients with Systemic Rheumatic Diseases

The last few decades have witnessed an increased life expectancy of patients suffering with systemic rheumatic diseases, mainly due to improved management, advanced therapies and preventative measures. However, autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality not fully explained by traditional cardiovascular disease (CVD) risk factors. It has been suggested that interactions between high-grade systemic inflammation and the vasculature lead to endothelial dysfunction and atherosclerosis, which may account for the excess risk for CVD events in this population. Diminished nitric oxide synthesis—due to down regulation of endothelial nitric oxide synthase—appears to play a prominent role in the imbalance between vasoactive factors, the consequent impairment of the endothelial hemostasis and the early development of atherosclerosis. Asymmetric dimethylarginine (ADMA) is one of the most potent endogenous inhibitors of the three isoforms of nitric oxide synthase and it is a newly discovered risk factor in the setting of diseases associated with endothelial dysfunction and adverse cardiovascular events. In the context of systemic inflammatory disorders there is increasing evidence that ADMA contributes to the vascular changes and to endothelial cell abnormalities, as several studies have revealed derangement of nitric oxide/ADMA pathway in different disease subsets. In this article we discuss the role of endothelial dysfunction in patients with rheumatic diseases, with a specific focus on the nitric oxide/ADMA system and we provide an overview on the literature pertaining to ADMA as a surrogate marker of subclinical vascular disease.

Adiponectin and raised mortality in type 1 diabetes: any credible explanatory mechanisms?*

Adiponectin and raised mortality in type 1 diabetes: any credible explanatory mechanisms?*

Conventional and behavioral risk factors explain differences in sub-clinical vascular disease between black and Caucasian South Africans: The SABPA study

ObjectivesThere is an emerging burden of cardiovascular disease among urban black Africans in South Africa, which has been largely explained by the transition from traditional African lifestyles to more westernized behavior. We examined the role of health behaviors in explaining the excess burden of sub clinical vascular disease seen in black Africans compared to Caucasians. MethodsThis was a cross-sectional study, comprising of urban African teachers (n=192 black, 206 Caucasian) working for one of the four Kenneth Kaunda Education districts in the North West Province, South Africa. Conventional cardiovascular risk factors, 24h ambulatory blood pressure and objectively measured physical activity (Actical® accelerometers), smoking (confirmed by serum cotinine), and alcohol (serum gamma glutamyl transferase) were assessed. The main outcome was a marker of sub-clinical vascular disease, mean carotid intima media thickness (mCIMT), measured using high resolution ultrasound. ResultsCompared with Caucasians, the black Africans demonstrated higher mCIMT (age and sex adjusted β=0.044, 95% CI, 0.024–0.064mm). The blacks also had higher 24h systolic and diastolic blood pressure, triglycerides, adiposity, and C-reactive protein. In addition, blacks were less physically active (790.0kcal/d vs 947.3kcal/d, p<0.001), more likely to smoke (25% vs 16.3%, p=0.002), and demonstrated higher alcohol abuse (gamma glutamyl transferase, 66.6μ/L vs 27.2μ/L, p<0.001) compared with Caucasians. The difference in mCIMT between blacks and Caucasians was attenuated by 34% when conventional risk factors were added to the model and a further 18% when health behaviors were included. ConclusionThere is an excess burden of sub clinical vascular disease seen in black Africans compared to Caucasians, which can be largely explained by health behaviors and conventional risk factors.

Factors Associated With Low Levels of Subclinical Vascular Disease in Older Adults: Multi‐Ethnic Study of Atherosclerosis

Coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. The authors identified factors associated with low levels of subclinical vascular disease in 1824 participants 70 years and older in the Multi-Ethnic Study of Atherosclerosis. A total of 452 had low CAC (<25th percentile), 441 had low CIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all 3 parameters. This combination index was independently associated with younger age (odds ratio [OR] 2.5 per 1 SD [95% confidence interval (CI), 1.8-3.6]), female sex (OR 3.0 [95% CI, 1.9-4.8]), lower body mass index (OR 1.6 per 1 SD [95% CI, 1.2-2.0]), absence of hypertension (OR 1.8 [95% CI, 1.2-2.6]), absence of dyslipidemia (OR 1.6 [95% CI, 1.04-2.4]), and never-smoking (OR 1.7 [95% CI, 1.1-2.6]). No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging.

Abstract 6199: Relationship of Carotid Arterial Compliance and Thoracic Aorta Calcification: Multi-Ethnic Study of Atherosclerosis (MESA)

Decreased arterial compliance is one of the earliest manifestations of adverse structural and functional changes within the vessel wall. Prior studies have shown that indirect measures of arterial stiffness predict severity of atherosclerosis as well as subsequent cardiovascular events. Ultrasonography of the common carotid artery however enables a direct measurement of compliance and stiffness and may be a more sensitive marker of subclinical vascular disease. MESA is a longitudinal, population-based study of 6,814 men and women aged 45–84 without clinical cardiovascular disease at enrollment. Of these, 3,540 (62± 10 years, 47% males) individuals underwent arterial compliance assessment via calculation of the distensibility coefficient (DC, in 1/mmHg ×10 3 ), which uses carotid ultrasonographic measurements of cardiac cycle-dependent vessel size and upper arm measurements of blood pressure. All patients had their thoracic artery calcium (TAC) calculated using non-contrast cardiac CT. The cross-sectional association between decreasing quartiles of DC (4 th quartile as reference group) and TAC was assessed by multivariable relative risk regression using a generalized linear model and binomial error distribution. The mean DC in the study population was 2.51± 1.11. Overall, 1,828 (28%) individuals had detectable TAC. A lower DC was observed among those with vs. without TAC (2.06± 0.90 vs. 2.69± 1.13, p&lt;0.0001). The prevalence of TAC increased significantly across decreasing quartiles of DC (4 th : 11%, 3 rd : 21%, 2 nd : 32%, 1 st : 11%, p&lt;0.0001). The table below demonstrates the adjusted relative risk for presence of TAC with decreasing quartiles of DC. Decreased arterial compliance measured by carotid ultrasonography is independently correlated with thoracic aortic atherosclerosis. Further studies are in progress to assess the prognostic value of this marker of subclinical atherosclerosis.