The effect of exercise on vascular health in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. This increased risk cannot be fully explained by traditional risk factors such as hypertension. Endothelial dysfunction and arterial stiffness have been suggested as factors that explain some of the increased risk and are independently associated with important cardiovascular outcomes in patients with CKD. Studies in other disease populations have shown the positive effects of exercise on vascular dysfunction. The aim of this review was to determine whether exercise training interventions improve measures of vascular function and morphology in patients across the spectrum of CKD and which exercise training interventions are most efficacious. A systematic search of Medline, Embase, and the Cochrane Central Register identified 25 randomized controlled trials. Only randomized control trials using an exercise intervention with a nonexercising control group and at least one measure of vascular function or morphology were included. Participants were patients with nondialysis CKD or transplant patients or those requiring dialysis therapy. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis was completed for pulse wave velocity, augmentation index, and measures of endothelium-dependent vasodilation. Data from 25 studies with 872 participants showed that exercise training reduced pulse wave velocity and augmentation index but had no effect on endothelium-dependent vasodilation. Subgroup analyses suggested that exercise interventions of at least moderate intensity were more likely to be effective. Limitations included the absence of observational studies or other interventions aimed at increasing habitual physical activity. Further studies are warranted to investigate which are the most effective exercise interventions.NEW & NOTEWORTHY A thorough systematic review and meta-analysis of the effects of exercise training on measures of vascular function in patients with chronic kidney disease, including arterial stiffness and endothelial function, were conducted. Subgroup analyses investigated how differences in exercise training, according to frequency, intensity, type, and timing, have an impact on the efficacy of the intervention.

The deleterious effects of acute hypoxia on microvascular and large vessel endothelial function.

NEW FINDINGS: What is the central question of this study? The aim was primarily to determine the effect of hypoxia on microvascular function and secondarily whether superior cardiorespiratory fitness is protective against hypoxia-induced impairment in vascular function. What is the main finding and its importance? Hypoxia reduced endothelium-dependent but not endothelium-independent microvascular function. The extent of impairment was twofold higher in the microcirculation compared with the large blood vessels. This study suggests that individuals with superior cardiorespiratory fitness might preserve microvascular function in hypoxia. These findings highlight the sensitivity of the microvascular circulation to hypoxia. ABSTRACT: Hypoxia is associated with diminished bioavailability of the endothelium-derived vasodilator, nitric oxide (NO). Diminished NO bioavailability can have deleterious effects on endothelial function. The endothelium is a heterogeneous tissue; therefore, a comprehensive assessment of endothelial function is crucial to understand the significance of hypoxia-induced endothelial dysfunction. We hypothesized that acute hypoxia would have a deleterious effect on microvascular and large vessel endothelial function. Twenty-nine healthy adults [24 (SD = 4 ) years of age] completed normoxic and hypoxic [inspired O2  fraction = 0.209] trials in this double-blinded, counterbalanced crossover study. After 30 min, we assessed the laser Doppler imaging-determined perfusion response to iontophoresis of ACh as a measure of endothelium-dependent microvascular function and iontophoresis of sodium nitroprusside as a measure of endothelium-independent microvascular function. After 60 min, we assessed brachial flow-mediated dilatation as a measure of large vessel endothelial function. Thirty minutes of hypoxia reduced endothelium-dependent microvascular function determined by the perfusion response to ACh (median difference (x̃∆) = -109% {interquartile range: 542.7}, P < 0.05), but not endothelium-independent microvascular function determined by the perfusion response to sodium nitroprusside (x̃∆ = 69% {interquartile range: 453.7}, P = 0.6). In addition, 60 min of hypoxia reduced allometrically scaled flow-mediated dilatation compared with normoxia ( x¯Δ=-1.19 [95% CI = -1.80, -0.58 (Confidence Intervals)]%, P < 0.001). The decrease in microvascular endothelial function was associated with cardiorespiratory fitness (r  = 0.45, P = 0.02). In conclusion, acute exposure to normobaric hypoxia significantly reduced endothelium-dependent vasodilatory capacity in small and large vessels. Collectively, these findings highlight the sensitivity of the microvascular circulation to hypoxic insult, particularly in those with poor cardiorespiratory fitness.

Bilateral regional extracranial blood flow regulation to hypoxia and unilateral duplex ultrasound measurement error.

NEW FINDINGS: What is the central question of this study? Is blood flow regulation to hypoxia different between the internal carotid arteries (ICAs) and vertebral arteries (VAs), and what is the measurement error in unilateral extracranial artery assessments compared to bilateral? What is the main finding and its importance? ICA and VA blood flow regulation to hypoxia is comparable when factoring for vessel type and vessel side. Compared to bilateral assessment, vessels assessed unilaterally had individual measurement errors of up to 37%. Assessing the vessel with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error. ABSTRACT: Whether blood flow regulation to hypoxia is similar between left and right internal carotid arteries (ICAs) and vertebral arteries (VAs) is unclear. Extracranial blood flow is regularly calculated by doubling a unilateral assessment; however, lateral artery differences may lead to measurement error. This study aimed to determine extracranial blood flow regulation to hypoxia when factoring for vessel type (ICAs or VAs) and vessel side (left or right) effects, and to investigate unilateral assessment measurement error compared to bilateral assessment. In a repeated-measures crossover design, extracranial arteries of 44 participants were assessed bilaterally by duplex ultrasound during 90 min of normoxic and poikilocapnic hypoxic (12.0% fraction of inspired oxygen) conditions. Linear mixed model analyses revealed no Condition × Vessel Type × Vessel Side interaction for blood flow, vessel diameter and flow velocity (all P > 0.05) indicating left and right ICA and VA blood flow regulation to hypoxia was similar. Bilateral hypoxic reactivity was comparable (ICAs, 1.4 (1.0) vs. VAs, 1.7 (1.1) Δ%·Δ SpO2-1 ; P = 0.12). Compared to bilateral assessment, unilateral mean measurement error of the relative blood flow response to hypoxia was up to 5%, but individual errors reached 37% and were greatest in ICAs and VAs with the smaller resting blood flow due to a ratio-scaling problem. In conclusion, left and right ICA and VA regulation to hypoxia is comparable when factoring for vessel type and vessel side. Assessing the ICA and VA vessels with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error.

Subclinical atherosclerosis in systemic sclerosis and rheumatoid arthritis: a comparative matched-cohort study.

Systemic autoimmune inflammatory disorders confer a higher risk of cardiovascular (CV) disease leading to increased morbidity and mortality and reduced life expectancy compared to the general population. CV risk in systemic sclerosis (SSc) has not been studied extensively but surrogate markers of atherosclerosis namely carotid intima media thickness (cIMT) and pulse wave velocity (PWV) are impaired in some but not all studies in SSc patients. The aim of this study was to investigate the prevalence of subclinical atherosclerosis assessed by cIMT and PWV between two well-characterized SSc and Rheumatoid Arthritis (RA) cohorts. Consecutive SSc patients attending the Scleroderma Clinic were compared with RA patients recruited in the Dudley Rheumatoid Arthritis Co-morbidity Cohort (DRACCO), a prospective study examining CV burden in RA. Augmentation Index (Aix75) and cIMT were measured in all participants. Propensity score matching was utilised to select patients from the two cohorts with similar demographic characteristics, CV risk factors and inflammatory load. Unpaired analysis was performed using unpaired t test for continuous variables and χ2 test for dichotomous variables. Statistical analysis was repeated using paired t test for continuous normal variables and McNemar's test for dichotomous variables. Fifty five age- and sex-matched SSc and RA patients were included in the analysis. No difference was demonstrated between SSc and RA subjects regarding cIMT (0.66 mm vs 0.63 mm, respectively) and Aix75% measurements (33.4 vs 31.7, respectively) neither in paired (p = 0.623 for cIMT and p = 0.204 for Aix%) nor in unpaired t test analysis (p = 0.137 for cIMT and p = 0.397 for AIx%). The results of this comparative study show that subclinical atherosclerosis is comparable between SSc and RA, a systemic disease with well-defined high atherosclerotic burden. Such findings underscore the importance of CV risk management in SSc in parallel with other disease-related manifestations.

Comparison of the effects of exercise and anti-TNF treatment on cardiovascular health in rheumatoid arthritis: results from two controlled trials.

People with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Both pharmacological treatment and exercise are suggested in the management of CVD risk in RA. This study explored the effects of exercise and anti-TNF treatment on CVD risk in RA. Twenty RA patients (70% female, 50 (10) years) completed a 3-month exercise intervention and 23 RA patients (65% female, 54 (15) years) started anti-TNF treatment. Markers of disease activity, CVD risk, and vascular function were assessed before and after 3-months of intervention/treatment. Both exercise and anti-TNF treatment improved functional ability and fatigue, anti-TNF treatment was more successful in improving inflammation, disease activity, functional ability and pain. Exercise induced a reduction in overall CVD risk and improvement in vascular function, which was significantly different from anti-TNF treatment where no such changes were found. These findings showed that exercise and anti-TNF had differential effects on CVD risk in RA, and should be combined for optimal CVD risk reduction. Whereas anti-TNF treatment is likely to impact on CVD risk through reducing the systemic inflammatory load, exercise should be recommended to people with RA as an effective self-management strategy to reduce CVD risk further. Once RA patients have responded successfully to anti-TNF treatment, increasing exercise should be encouraged to reduce the risk for CVD. Thus, supporting exercise programmes when the disease is controlled, is likely to enhance the uptake and the maintenance of exercise, which will result in additional benefits to cardiovascular health and wellbeing in people with RA.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Sitting time is negatively related to microvascular endothelium-dependent function in rheumatoid arthritis.

BACKGROUND: Sedentary behaviour is linked to increased cardiovascular disease risk in Rheumatoid Arthritis (RA), but the biological processes underlying this relationship are not understood. OBJECTIVES: To investigate the cross-sectional associations of habitual sedentary behaviour, with endothelial function in RA. METHODS: Sixty-eight RA patients (Mage = 55 ±â€¯12 years) underwent Laser Doppler Imaging with iontophoresis, to assess microvascular endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) function. Large-vessel endothelium-dependent and endothelium-independent functions were measured via flow-mediated dilation (FMD) and glyceryl trinitrate dilation (GTN), respectively. Habitual sedentary behaviour (hours/week sitting) was self-reported (International Physical Activity Questionnaire). RESULTS: Regressions revealed sitting time significantly negatively predicted microvascular endothelium-dependent function (ACh, unstandardizedß = -3.25, p = .02, 95% CI [-6.07, -.42], R2 = 0.06), but did not associate with other endothelial function outcomes (SNP, FMD, GTN). CONCLUSION: Habitual sedentary behaviour (sitting time) appears to be adversely linked to microvascular endothelium-dependent function among people living with RA.

Genetic variations in the alanine-glyoxylate aminotransferase 2 (AGXT2) gene and dimethylarginines levels in rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with high rates of cardiovascular events mainly due to coronary and cerebrovascular atherosclerotic disease. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines are endogenous inhibitors of nitric oxide synthase and have been repeatedly linked with adverse cardiovascular outcomes in the general population and various disease settings. Alanine-glyoxylate aminotransferase 2 (AGTX2) is considered an alternative metabolic pathway contributing to the clearance of dimethylarginines in humans. The aim of the current study was to investigate the effect of specific AGXT-2 gene polymorphisms on circulating levels of ADMA or SDMA in patients with RA. Serum ADMA and SDMA levels were measured in 201 individuals with RA [median age: 67 years (IQR: 59-73), 155 females]. Two single nucleotide polymorphisms (SNPs) in the AGXT-2 gene-rs37369 and rs28305-were genotyped. Distributions of SDMA and ADMA were skewed, hence comparisons across the gene polymorphisms were performed using Kruskal-Wallis tests, and summarized using medians and interquartile ranges. Univariable analysis did not demonstrate a significant difference in the levels of SDMA or ADMA amongst the different genotypic groups of either rs37369AGXT2 (p = 0.800, 0.977) or rs28305AGXT2 (p = 0.463, 0.634). In multivariable analyses, ADMA levels were found to be significantly associated with erythrocyte sedimentation rate and estimated glomerular filtration rate, whilst SDMA levels were significantly associated with estimated glomerular filtration rate and quantitative insulin sensitivity check index. After adjustments for these factors, the relationship between the AGXT2 gene variants and both ADMA and SDMA remained non-significant. Our study in a well-characterized RA population did not show an association between serum concentrations of dimethylarginines and genetic variants of the AGXT2 gene.

In vivo microvascular and macrovascular endothelial function is not associated with circulating dimethylarginines in patients with rheumatoid arthritis: a prospective analysis of the DRACCO cohort.

OBJECTIVES: To examine associations between asymmetric (ADMA), symmetric dimethylarginine (SDMA) and ADMA:SDMA ratio with assessments of endothelial function and coronary artery perfusion in RA patients. METHODS: ADMA and SDMA levels were measured in 197 RA individuals [144 (77.4%) females, median age: 66 years (quartiles: 59-73)]. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-dependent and endothelium-independent function and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Coronary perfusion was assessed by subendocardial viability ratio (SEVR). RESULTS: SEVR correlated with SDMA (r = 0.172, p = 0.026) and ADMA:SDMA (r = -0.160, p = 0.041) in univariable analysis, but not in multivariable analysis accounting for confounding factors. Neither ADMA:SDMA ratio nor SDMA were significantly correlated with microvascular or macrovascular endothelial function, or with arterial stiffness and cIMT. Within subgroup of patients (n = 26) with high inflammatory markers, a post-hoc analysis showed that SDMA and the ADMA:SDMA ratio were significantly associated with endothelium-dependent microvascular function in univariable analysis, with Pearson's r correlation coefficients of -0.440 (p = 0.031) and 0.511 (p = 0.011), respectively. Similar finding were established between ADMA:SDMA ratio and arterial stiffness in univariable analysis, with Pearson's r of 0.493, (p = 0.024). CONCLUSION: Dimethylarginines were not found to be significantly associated with several assessments of vascular function and morphology in patients with RA, however, post-hoc analysis indicates that there may be associations in patients with raised inflammatory markers. Our results suggest that dysregulated NO metabolism may not be the sole mechanism for the development of preclinical atherosclerosis in RA.

Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study.

OBJECTIVE: The aim of the present study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular disease (CVD) risk factors with asymmetric dimethylarginine (ADMA) in a large prospective cohort of patients with established RA. METHODS: Two hundred and one RA patients [155 females, median age 67 years (range 59-73)] were assessed at baseline (2006) for the presence of classical CVD risk factors and determination of systemic inflammation by CRP and ESR. Global CVD risk was identified by the Framingham Risk Score and the Reynolds Risk Score. At follow-up (2012), ADMA levels were measured by ELISA. A quarterly measurement of CRP and ESR for each year the patient was in the study was used to produce an average area under the curve (AAUC) for ESR and CRP. RESULTS: Regression analysis revealed that baseline ESR in 2006 and the AAUC of ESR and CRP all had significant positive relationships with current ADMA (P = 0.004, P < 0.001 and P = 0.002, respectively). Baseline CRP in 2006 was not a significant predictor of ADMA (P = 0.093), although this relationship was in the same direction as the other factors. These results remained consistent after adjustment for classical CVD risk factors. CONCLUSION: Cumulative inflammatory burden is positively associated with ADMA levels, suggesting a potential pathogenic mechanism through which chronic systemic inflammation exerts deleterious effects on nitric oxide metabolism and endothelial homeostasis. This association is independent of classical CVD risk factors.

Symmetric dimethylarginine (SDMA) serum levels in rheumatoid arthritis: correlations with insulin resistance and disease activity scores.

Vascular abnormalities predisposing to atherosclerosis are present in patients with rheumatoid arthritis (RA) and associate with excess cardiovascular risk. Symmetric dimethylarginine (SDMA), an endogenous inhibitor of nitric oxide (NO) synthase activity, has been recognised as novel risk factor for endothelial dysfunction and cardiovascular disease. We aimed to compare SDMA levels in RA patients and controls and to investigate whether they are influenced by demographic, inflammatory or metabolic factors. Serum SDMA levels were measured in 197 RA individuals [median age: 67 years (quartiles: 59-3), 153 (78 %) females] and 82 controls [median age: 44 years [quartiles: 33-55, 50 (61 %) females]. Routine biochemistry tests, lipid profile, glycemic profile [glucose, insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI)], as well as inflammatory markers were measured in all patients. Paired analysis was employed for the comparison of SDMA in two groups and multivariable regression models were performed to identify predictors of SDMA in the RA cohort. SDMA was significantly lower in RA than control patients in both unpaired and paired analyses (P < 0.001 and P = 0.005, respectively), with the magnitude of the difference being similar in both models. QUICKI (P = 0.005) and disease activity score-28 (P = 0.007) were positively related to SDMA in the RA cohort, whilst a negative correlation with renal function (eGFR) was detected (P = 0.005). The molecular explanation of lower serum SDMA is unclear, but the established relationships with indices of disease activity and insulin resistance, may underline the pathogenetic role of the L-arginine/NO pathway dysregulation in the development of atherosclerosis in RA. The biological and clinical importance of SDMA in RA remains to be evaluated in clinical and experimental studies.

Symmetric Dimethylarginine Is Not Associated with Cumulative Inflammatory Load or Classical Cardiovascular Risk Factors in Rheumatoid Arthritis: A 6-Year Follow-Up Study.

Symmetric dimethylarginine (SDMA) indirectly inhibits nitric oxide (NO) synthesis and predicts cardiovascular and all-cause mortality in high-risk patients. The aim of our study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular (CV) disease risk factors with SDMA in RA patients. 201 RA patients (155 females, median age 67 (59-73)) were assessed at baseline (2006). Classical CV disease risk factors were recorded and systemic inflammation was determined by the measurement of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) SDMA levels were measured by enzyme-linked immunosorbent assay. Mean SDMA levels in RA population were 0.40 (0.40-0.53) µmol/L. No significant association between SDMA and cumulative inflammatory load was established in the analysis. SDMA levels were not found to be significantly related to CV disease risk factors. We explored the potential relationship between SDMA and cumulative inflammatory burden in patients with RA and obtained negative results. SDMA did not relate to CV disease risk factors in our population and its clinical significance as a surrogate marker of endothelial dysfunction in patients with RA remains to be determined.

Individualised exercise improves endothelial function in patients with rheumatoid arthritis.

BACKGROUND: We investigated the effects of individualised combined resistance and aerobic exercise on microvascular and macrovascular function in rheumatoid arthritis (RA) patients. METHODS: Forty age-matched, gender-matched and body mass index (BMI)-matched patients were allocated to either an exercise group, receiving a 6 months tailored aerobic and resistance exercise intervention, or controls receiving only information about the benefits of exercise. Participants were assessed for microvascular (acetylcholine (Ach) and sodium nitroprusside (SNP)) and macrovascular (flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)) endothelial function, maximal oxygen uptake, disease activity and severity (C-reactive protein (CRP), disease activity score 28 and health assessment questionnaire). Data were collected at baseline, 3 months and at the end of the intervention (6 months). RESULTS: At baseline, demographic, anthropometric, disease-related characteristics and endothelial function parameters were similar between the exercise and control groups (p>0.05). Repeated measures analysis of variance revealed a significant improvement in endothelial function parameters at 3 (GTN: p<0.001) or 6 months (Ach: p=0.016, SNP: p=0.045, FMD: p=0.016) in the exercise but not in the control group. Generalised estimated equations detected that maximal oxygen uptake was a strong predictor for the observed changes in Ach (p=0.009) and GTN (p<0.001) whereas logCRP for SNP (p=0.017) and GTN (p=0.008). CONCLUSIONS: An exercise programme designed to meet individual needs and physical abilities significantly improves microvascular and macrovascular function in parallel with disease-related characteristics in RA patients. The potential long-term beneficial effects of such interventions at reducing cardiovascular risk in these patients merit further exploration. CLINICAL TRIAL REGISTRATION: ISRCTN50861407.

Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden.

OBJECTIVE: RA associates with an increased rate of sudden cardiac death (SCD). A prolonged QTc interval has been associated with arrhythmogenic and SCD in patients with long QT syndrome. Despite the previously reported contemporary association of CRP with SCD, thus far no studies have examined the association of QTc with mortality in RA, a condition characterized by high inflammatory burden. The aim of this study was to examine the role of electrocardiography (QT corrected interval) in predicting all-cause mortality in patients with RA who have an increased rate of SCD and a high inflammatory burden. METHODS: Three hundred and fifty-seven RA patients with detailed baseline clinical characterization and 12-lead ECGs were followed up for a mean of 73.0 (S.D. 18.3) months. Linear and Cox regression analyses were used to identify variables that associate with QTc and examine its association with all-cause mortality. RESULTS: The patients' mean age was 60.6 (S.D. 12.0) years, 267 (74.8%) were females and 54 (15.1%) died during the follow-up period. Age (ß = 0.231, P < 0.001), gender (ß = 0.137, P = 0.008) and CRP (ß = 0.144, P = 0.006) associated independently with QTc in RA patients. The crude hazard ratio (HR) for total mortality per 50-ms increase in QTc was 2.17 (95% CI 1.21, 3.90). This association remained significant [HR = 2.18 (95% CI 1.09, 4.35)] after adjustment for identified confounders (cardiovascular and RA specific), but was lost [HR = 1.73 (95% CI 0.83, 3.62)] when CRP was included in the model. CONCLUSION: A 50-ms increase in QTc interval associates with a doubling of the hazard for all-cause mortality in patients with RA. The observed contemporary association of QTc with CRP levels indicates a potentially hazardous interplay between inflammation and arrhythmogenesis. Future studies are needed to confirm the above findings and explore underlying mechanisms.

The relationship between cardiovascular disease risk prediction scores and vascular function and morphology in rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD) resulting from impairments in vascular function and morphology. CVD risk prediction scores can identify patients at high risk of CVD, but little is known about whether they relate with assessments of vascular function and morphology which provide early indication of subclinical atherosclerosis. The objective of the present study was to examine the relationship of several CVD risk prediction scores with assessments of vascular function and morphology in patients with RA. METHODS: Framingham risk score, Systematic Coronary Risk Evaluation for total cholesterol and ratio of total cholesterol to high-density lipoprotein, as well as Reynolds Risk Score, and QRISK2 were calculated in 201 RA patients (155 females, median (25th to 75th percentile) age: 61 (53-67)) who were examined at baseline (2006). The European League Against Rheumatism (EULAR) multiplication factor was also applied to the algorithms. At a 6-year follow-up (2012) visit the patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. RESULTS: All five CVD risk prediction scores measured at baseline were significantly correlated with vascular function and morphology at follow-up. Application of the EULAR multiplication factor did not change any of the associations. CONCLUSIONS: Five commonly used CVD risk prediction scores associate with assessments of vascular function and morphology over a 6-year follow-up period suggesting that these CVD risk prediction scores may also reflect subclinical atherosclerotic changes.

Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a pilot study.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-α (anti-TNFα) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. METHODS: Twenty-three RA patients starting on anti-TNFα treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. RESULTS: Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. CONCLUSION: Anti-TNFα therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function.

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.

Vascular function and morphology in rheumatoid arthritis: a systematic review.

OBJECTIVES: RA associates with significantly increased morbidity and mortality from cardiovascular disease (CVD). This may be due to complex interactions between traditional CVD risk factors, systemic rheumatoid inflammation and the vasculature. We reviewed the current literature to answer: (i) whether there is sufficient evidence that patients with RA have altered vascular function and morphology compared with normal controls; (ii) whether there is sufficient evidence to determine if such changes relate predominantly to systemic inflammation; and (iii) whether any changes of vascular function and morphology in RA can be modified with therapy. METHODS: The MEDLINE database was searched to identify publications from 1974 to 1 November 2010 pertaining to vascular function and morphology in RA. The total number of articles included in the present review was 93. This included 57 cross-sectional studies, 27 longitudinal studies without randomization and 9 longitudinal studies with randomization. RESULTS: Vascular function and morphology was impaired in RA relative to healthy controls. The majority of studies reported no associations between systemic inflammation and vascular function. Treatment with anti-inflammatory medication resulted in both transient and long-term improvements in the vasculature, but only a few studies reported associations between change in inflammation and change in vascular function and morphology. CONCLUSION: The link between systemic inflammation and vascular function and morphology is not wholly supported by the available literature. Long-term studies examining specific predictors (including CVD risk factors) on the vasculature in RA are needed.

Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study.

OBJECTIVE: The extent to which atherosclerosis is accelerated in chronic inflammatory diseases is not established. We compared preclinical atherosclerosis in rheumatoid arthritis with diabetes mellitus, a known coronary heart disease equivalent. METHODS AND RESULTS: Endothelial function, arterial stiffness, carotid intima-media thickness, and analysis of atheromatous plaques were examined in 84 rheumatoid arthritis patients without cardiovascular disease versus healthy controls matched for age, sex, and traditional cardiovascular disease risk factors, as well as in 48 diabetes patients matched for age, sex, and disease duration with 48 rheumatoid arthritis patients. Rheumatoid arthritis duration associated with arterial stiffening, whereas disease activity associated with carotid plaque vulnerability. All markers of preclinical atherosclerosis were significantly worse in rheumatoid arthritis compared to controls, whereas they did not differ in comparison to diabetes despite a worse cardiovascular risk factor profile in diabetics. Both diseases were associated independently with increased intima-media thickness; rheumatoid arthritis, but not diabetes, was independently associated with endothelial dysfunction. CONCLUSIONS: Preclinical atherosclerosis appears to be of equal frequency and severity in rheumatoid arthritis and diabetes of similar duration with differential impact of traditional risk factors and systemic inflammation. Cardiovascular disease risk factors in rheumatoid arthritis may need to be targeted as aggressively as in diabetes.