Ivana Hollan

Cardiovascular disease in autoimmune rheumatic diseases

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA). Ischemic events in APA are more likely to be caused by pro-thrombotic state than by enhanced atherosclerosis. Cardiovascular disease (CVD) in ARDs is caused by traditional and non-traditional risk factors. Besides other factors, inflammation and immunologic abnormalities, the quantity and quality of lipoproteins, hypertension, insulin resistance/hyperglycemia, obesity and underweight, presence of platelets bearing complement protein C4d, reduced number and function of endothelial progenitor cells, apoptosis of endothelial cells, epigenetic mechanisms, renal disease, periodontal disease, depression, hyperuricemia, hypothyroidism, sleep apnea and vitamin D deficiency may contribute to the premature CVD. Although most research has focused on systemic inflammation, vascular inflammation may play a crucial role in the premature CVD in ARDs. It may be involved in the development and destabilization of both atherosclerotic lesions and of aortic aneurysms (a known complication of ARDs). Inflammation in subintimal vascular and perivascular layers appears to frequently occur in CVD, with a higher frequency in ARD than in non-ARD patients. It is possible that this inflammation is caused by infections and/or autoimmunity, which might have consequences for treatment. Importantly, drugs targeting immunologic factors participating in the subintimal inflammation (e.g., T- and B-cells) might have a protective effect on CVD. Interestingly, vasa vasorum and cardiovascular adipose tissue may play an important role in atherogenesis. Inflammation and complement depositions in the vessel wall are likely to contribute to vascular stiffness. Based on biopsy findings, also inflammation in the myocardium and small vessels may contribute to premature CVD in ARDs (cardiac ischemia and heart failure). There is an enormous need for an improved CVD prevention in ARDs. Studies examining the effect of DMARDs/biologics on vascular inflammation and CV risk are warranted.

Increased levels of serum pentraxin 3, a novel cardiovascular biomarker, in patients with inflammatory rheumatic disease.

Pentraxin 3 (PTX3), a key component of innate immunity, is a strong marker of disease severity in coronary artery disease (CAD). The aim of this study was to compare levels of serum PTX3 in CAD patients with and without inflammatory rheumatic disease (IRD) and in healthy controls.

Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients

Objective: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM) is associated with endothelial dysfunction in patients with rheumatoid arthritis (RA). Methods: We studied the presence of anti-CCP antibodies and RF IgM and endothelial function in terms of the reactive hyperaemic index (RHI) in 53 consecutive RA patients. Endothelial function was measured by using a finger plethysmograph. Results: RHI was significantly lower in anti-CCP-positive RA patients (n  =  33, RHI  =  1.78, SD  =  0.30) than in anti-CCP-negative RA patients (n  =  20, RHI  =  2.19, SD = 0.59; p  =  0.008). A similar result was found in RF IgM-positive patients (n  =  34, RHI  =  1.77, SD  =  0.30) vs. RF IgM-negative patients (n  =  19, RHI  =  2.23, SD  =  0.58; p  =  0.003). There were no significant differences between the groups regarding age, gender, traditional cardiovascular risk markers, Disease Activity Score using 28 joint counts (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), extra-articular manifestations (EAMs), use of glucocorticosteroids, statins, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). Conclusion: The presence of anti-CCP antibodies and RF IgM was related to impaired endothelial function independent of other cardiovascular risk factors in RA patients. Thus, these autoantibodies might reflect an early reversible stage of the atherosclerotic process, and may indicate increased risk of cardiovascular disease (CVD). Further studies are needed to explore whether anti-CCP antibodies and RF IgM may act directly or indirectly to cause endothelial dysfunction, or merely reflect endothelial dysfunction in RA patients.

Prevention of cardiovascular disease in rheumatoid arthritis

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs.

Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism.

Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti–tumor necrosis factor α agents in RA is considered secondary to their anti‐inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high‐density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol‐loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling.

Irisin in Blood Increases Transiently after Single Sessions of Intense Endurance Exercise and Heavy Strength Training

Purpose Irisin is a recently identified exercise-induced hormone that increases energy expenditure, at least in rodents. The main purpose of this study was to test the hypothesis that Irisin increases acutely in blood after singular sessions of intense endurance exercise (END) and heavy strength training (STR). Secondary, we wanted to explore the relationship between body composition and exercise-induced effects on irisin, and the effect of END and STR on muscular expression of the irisin gene FNDC5. Methods Nine moderately trained healthy subjects performed three test days using a randomized and standardized crossover design: one day with 60 minutes of END, one day with 60 minutes of STR, and one day without exercise (CON). Venous blood was sampled over a period of 24h on the exercise days. Results Both END and STR led to transient increases in irisin concentrations in blood, peaking immediately after END and one hour after STR, before gradually returning to baseline. Irisin responses to STR, but not END, showed a consistently strong negative correlation with proportions of lean body mass. Neither END nor STR affected expression of FNDC5, measured 4h after training sessions, though both protocols led to pronounced increases in PGC-1α expression, which is involved in transcriptional control of FNDC5. Conclusion The results strongly suggest that single sessions of intense endurance exercise and heavy strength training lead to transient increases in irisin concentrations in blood. This was not accompanied by increased FNDC5 expression, measured 4h post-exercise. The results suggest that irisin responses to resistance exercise are higher in individuals with lower proportions of lean body mass.

Spondyloarthritis: a strong predictor of early coronary artery bypass grafting

Objectives: The main aim of the study was to examine whether patients with spondyloarthritides underwent their first coronary artery bypass grafting (CABG) at a younger age than those without spondyloarthritides. Methods: Patients who underwent their first CABG at the Feiring Heart Clinic during 2001–2005 were preoperatively screened for spondyloarthritides, and the cardiological assessment was registered. We compared the characteristics of patients with and without spondyloarthritides. Results: Of the 3852 patients undergoing their first CABG, 30 (0.78%) had spondyloarthritides. No statistically significant differences in traditional cardiovascular risk factors were found. The mean ages of patients with and without spondyloarthritides were 60.1 (SD = 8.7) and 66.9 (SD = 10.1) years, respectively. Spondyloarthritis was found by multivariate analysis to be a stronger independent predictor of early CABG than traditional cardiovascular risk factors [adjusted beta −6.2, p<0.001, 95% confidence interval (CI) −9.5 to −2.8]. Sixty per cent of spondyloarthritis patients and 52% of control patients had already suffered a myocardial infarction (p = 0.4). Conclusion: Spondyloarthritis was a stronger predictor of early CABG than most of the registered traditional cardiovascular risk factors. The prevalence of spondyloarthritis seemed to be higher in the CABG population than in the general population. These findings may indicate accelerated coronary artery disease (CAD) in spondyloarthritides.

Strength training improves performance and pedaling characteristics in elite cyclists.

The purpose was to investigate the effect of 25 weeks heavy strength training in young elite cyclists. Nine cyclists performed endurance training and heavy strength training (ES) while seven cyclists performed endurance training only (E). ES, but not E, resulted in increases in isometric half squat performance, lean lower body mass, peak power output during Wingate test, peak aerobic power output (Wmax), power output at 4 mmol L−1 [la−], mean power output during 40‐min all‐out trial, and earlier occurrence of peak torque during the pedal stroke (P < 0.05). ES achieved superior improvements in Wmax and mean power output during 40‐min all‐out trial compared with E (P < 0.05). The improvement in 40‐min all‐out performance was associated with the change toward achieving peak torque earlier in the pedal stroke (r = 0.66, P < 0.01). Neither of the groups displayed alterations in VO2max or cycling economy. In conclusion, heavy strength training leads to improved cycling performance in elite cyclists as evidenced by a superior effect size of ES training vs E training on relative improvements in power output at 4 mmol L−1 [la−], peak power output during 30‐s Wingate test, Wmax, and mean power output during 40‐min all‐out trial.

Inflammatory markers in patients with coronary artery disease with and without inflammatory rheumatic disease

OBJECTIVES Patients with inflammatory rheumatic diseases (IRDs) have a higher morbidity and mortality from accelerated atherosclerosis than the general population. We hypothesized that patients with the combination of IRD and coronary artery disease (CAD) would have a certain inflammatory phenotype compared with CAD patients without this comorbidity. METHODS Four groups of patients were included: patients with IRD, referred to coronary artery bypass grafting (CABG) (CAD-IRD, n = 67), patients without IRD, referred to CABG (CAD, n = 52), patients with IRD without CAD (IRD, n = 32) and healthy controls (n = 30). Plasma levels of several inflammatory markers were analysed by enzyme immunoassays. RESULTS (i) Plasma levels of markers of endothelial cell activation [i.e. vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor] and osteoprotegerin (OPG) were significantly increased and plasma levels of CCL21 significantly decreased in CAD-IRD patients as compared with CAD patients without IRD. (ii) Within the CAD-IRD group, acute coronary syndrome was a significant predictor of OPG, suggesting an enhanced inflammatory response during plaque destabilization in CAD-IRD patients. (iii) Plasma levels of VCAM-1, OPG and CCL21, but not lipid parameters, IRD characteristics and several other inflammatory markers (e.g. CRP), were significant predictors of CAD-IRD as opposed to CAD in two logistic regression models. CONCLUSION Our findings further support a role for inflammation in the accelerated form of atherosclerosis in IRD patients, and suggest that certain inflammatory pathways, such as the enhanced endothelial cell activation and the RANK ligand/RANK/OPG system, may be of particular importance.

Cardiovascular disease in patients with inflammatory rheumatic disease is associated with up‐regulation of markers of inflammation in cardiac microvessels and cardiomyocytes

OBJECTIVE Various inflammatory rheumatic diseases (IRDs) are associated with increased mortality due to cardiovascular disease. The aim of this study was to investigate heart biopsy specimens obtained from patients undergoing coronary artery bypass grafting and compare markers of inflammation and endothelial cell activation in the cardiac and skeletal muscle of patients with and those without IRD. METHODS Paired biopsy specimens of cardiac and skeletal muscle were obtained from 22 consecutive patients with IRD and 8 patients without IRD, all of whom were undergoing coronary artery bypass grafting. The biopsy specimens were evaluated in a blinded manner by conventional microscopy and digital image analysis for cell markers (CD3, CD4, CD8, CD68, CD163, and CD31), HLA (HLA-ABC, HLA-DR, and HLA-DQ), adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), and proinflammatory cytokines (interleukin-1alpha, interleukin-1beta, and tumor necrosis factor). RESULTS Patients with IRD had significantly higher expression of adhesion molecules, proinflammatory cytokines, and all classes of HLA on cardiomyocytes and endothelial cells but no increase on mononuclear cells in the myocardium compared with patients without IRD. Furthermore, cardiac muscle from patients with IRD displayed significantly higher local expression of inflammation and activation of cardiac microvessels compared with skeletal muscle from the same patients. CONCLUSION Patients with cardiovascular disease had increased expression of adhesion molecules, HLA, and proinflammatory cytokines in heart tissue, indicating local inflammation involving microvessels and cardiomyocytes that could play a role in the pathogenesis of cardiovascular disease. The more pronounced changes in patients with IRD compared with patients without IRD might contribute to the increased risk of cardiovascular disease and premature death in patients with IRD.