Theodoros Dimitroulas

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.

Neuropathic pain in osteoarthritis: A review of pathophysiological mechanisms and implications for treatment

OBJECTIVES Osteoarthritis (OA) is the leading cause of musculoskeletal pain and functional disability worldwide, affecting a growing number of individuals in the western society. Despite various conservative and interventional treatment approaches, the overall management of the condition is problematic, and pain-the major clinical problem of the disease-remains sub-optimally controlled. The objectives of this review are to present the pathophysiologic mechanisms underlying the complexity of pain in OA and to discuss the challenges for new treatment strategies aiming to translate experimental findings into daily clinical practice. METHODS A narrative literature review of studies investigating the existence of a neuropathic component in OA pain was conducted. We searched PubMed, Embase and Scopus for English language publications. A hand-search of reference lists of relevant studies was also performed. RESULTS Recent advances have shed additional light on the pathophysiology of osteoarthritic pain, highlighting the contribution of central pain pathways together with the sensitisation of peripheral joint receptors and changes of the nociceptive process induced by local joint inflammation and structural bone tissue changes. Thus, a neuropathic pain component may be predominant in individuals with minor joint changes but with high levels of pain refractory to analgesic treatment, providing an alternative explanation for osteoarthritic pain perception. CONCLUSION A growing amount of evidence suggests that the pain in OA has a neuropathic component in some patients. The deeper understanding of multiple mechanisms of OA pain has led to the use of centrally acting medicines that may have a benefit on alleviating osteoarthritic pain. The ineffective pain management and the increasing rates of disability associated with OA mandate for change in our treatment paradigm.

N-Terminal Pro-Brain Natriuretic Peptide Levels Are Elevated in Patients with Acute Ischemic Stroke

Brain natriuretic peptide (BNP) is a counterregulatory hormone released by the ventricles of the heart. Its main actions are natriuresis and vasodilation. The authors studied N-terminal pro-brain natriuretic peptide (NT-proBNP) levels soon after an acute ischemic stroke. They compared plasma NT-proBNP concentrations in 30 patients with an acute ischemic stroke with those of 30 controls. The 2 groups were adjusted for age and gender, and there were no significant differences in vascular risk factors and left ventricular systolic and diastolic function. Venous samples were collected within the first 11.8 ±1.2 hours after the onset of symptoms and again on day 6. Brain computed tomography/magnetic resonance imaging (CT/MRI) was performed on the same days (day 0 and day 6) in order to assess the site (carotid or vertebrobasilar), cause (atherothrombotic, cardioembolic, or lacunar), and size (large, medium, or small) of the brain infarct. NT-proBNP levels were elevated in patients with acute stroke (129.9 ±9.9 fmol/mL) compared with the controls (90.8 ±6.3 fmol/mL, p<0.05). These levels remained elevated at day 6 (113.5 ±13.0 fmol/mL). NT-proBNP at admission was significantly higher in cardioembolic compared with atherothrombotic infarctions. There was no correlation between circulating NT-proBNP and stroke topography, infarct size, or severity as assessed by the National Institutes of Health Stroke Scale (NIHSS) at any of the 2 time points (admission and day 6). NT-proBNP levels were raised in patients with acute ischemic stroke; this effect persisted until day 6. The authors suggest that neurohumoral activation occurs in patients with acute ischemic stroke, either reflecting a counterbalancing vasodilating response to the cerebral ischemia or direct myocardial dysfunction.

Biologic therapies and systemic bone loss in rheumatoid arthritis

Chronic inflammation affects bone metabolism leading to disequilibrium in the rates of bone resorption and repair and subsequently to local and generalized bone loss. Osteoporosis represents an important co-morbidity of rheumatoid arthritis (RA) patients, which exhibit increased fracture risk. Osteoclasts play a pivotal role in the development and progression of bone loss, while resident synovial cells such as T cells, monocytes and synovial fibroblasts have been identified as sources of osteoclast differentiation signals in RA. This process is mainly mediated through the receptor activator of nuclear-kappa B ligand (RANKL) signalling system, which is upregulated by numerous proinflammatory cytokines involved in the pathogenesis of RA. Improved knowledge of the association between cells and cytokines of the immune system and their relationship to bone remodeling has revealed several promising targets for the treatment of inflammatory bone loss in RA. In this respect, initiation of biologic therapies targeting inflammatory cytokines and/or lymphocyte activation has modified RA therapy not only by blocking local and systemic inflammatory cascades but also by providing beneficial effects against bone and joint degradation. In this article we briefly present the modern view of the mechanisms that govern inflammatory bone loss, highlighting the role of cytokine-induced molecular pathways, and discuss in detail the effects of different biologic treatment strategies on bone mass in RA patients.

Early Detection of Cardiac Involvement in Systemic Sclerosis Assessed by Tissue-Doppler Echocardiography: Relationship with Neurohormonal Activation and Endothelial Dysfunction

Objective. Cardiopulmonary complications are common in patients with systemic sclerosis (SSc). We assessed cardiac involvement in patients with SSc using echocardiography and investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) with echocardiographic measures of myocardial function in sera of patients with SSc who had no symptoms of heart failure. Methods. We prospectively studied 52 patients with SSc (mean age 55.7 ± 10.1 yrs, 51 women), with conventional and tissue-Doppler echocardiography. Plasma NT-proBNP and ADMA levels were measured in all patients. Data were compared with those obtained from 25 healthy controls comparable for age and sex. Results. Patients with SSc had impaired left ventricular (LV) and right ventricular diastolic function expressed by inverted ratio of peak early to peak late transmitral (Mit E/A) and transtricuspid velocity and increased left atrial diameter compared with controls. Peak systolic mitral lateral annular motion velocity and peak early diastolic mitral lateral annular motion velocity (LV Em) were lower, while LV E/Em ratio was higher, in patients with SSc compared to controls. ADMA was significantly related with LV Em and E/Em ratio. NT-proBNP was associated with Mit E, Mit E/A ratio and mitral deceleration time. Significant correlation was also observed between NT-proBNP and ADMA levels. Conclusion. Depressed cardiac function is common, even in asymptomatic patients with SSc. NT-proBNP and ADMA are significantly correlated with echocardiographic abnormalities, providing a potent link for cardiac function, neuroendocrine derangement, and endothelial dysfunction in patients with SSc who have cardiac disease.

Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension

OBJECTIVES SSc is a CTD characterized by vascular involvement, with generalized disturbance of the microcirculation, which may lead to pulmonary artery hypertension (PAH). Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor. Increased concentrations of plasma ADMA may also contribute to endothelial dysfunction in patients with pulmonary vascular disease. The aim of our study was to elucidate the possible relationship between serum ADMA and PAH in patients with SSc. Moreover, we sought to investigate the effect of ADMA levels on the functional capacity of these patients. METHODS Plasma ADMA levels were measured in 66 patients with SSc (63 females, mean age 57.8 +/- 12.8 yrs, median duration of disease 9.9 yrs, 47 with lcSSc and 19 with dcSSc disease) and 30 healthy controls (29 females, mean age 58.2 +/- 8.4 yrs). Systolic pulmonary artery pressure (sPAP) assessed by echocardiography, lung function tests, 6-min walk test (6MWT) and serum ADMA levels were recorded from patients. RESULTS In 24 patients, the diagnosis of PAH was established. Mean value of ADMA for SScPAH patients was 0.44 +/- 0.22 micromol/l compared with 0.26 +/- 0.18 micromol/l for patients without PAH and 0.25 +/- 0.20 micromol/l for controls (P = 0.001). ADMA levels were inversely correlated with the 6MWT (r = -0.55, P = 0.005). CONCLUSIONS In patients with SScPAH, increased ADMA serum levels and their negative association with exercise capacity suggests that the NO pathway is involved in the development of pulmonary vascular disease.

Imaging modalities for the diagnosis of pulmonary hypertension in systemic sclerosis

Patients with systemic sclerosis (SSc) are at considerable risk of developing pulmonary arterial hypertension (PAH). PAH has a dramatic impact on the natural history of the disease and overall survival of the patient. Despite progress made in elucidating the pathogenesis of PAH and introduction of novel therapies, SSc-related PAH (SScPAH) remains a devastating disease that responds poorly to therapy. Although early diagnosis is of paramount importance, there are no available validated strategies for assessing SScPAH because reliable evaluation of the structure and function of the right ventricle is difficult owing to its complex geometry. Additionally, myocardial fibrosis might affect cardiac contractility and contribute to heart failure. Modern imaging modalities, such as novel echocardiographic techniques and cardiac MRI, are highly sensitive, quantitative and reproducible methods that allow noninvasive assessment of regional and global myocardial performance without relying on geometric assumptions. In this Review, we examine the imaging modalities currently available, focusing on evolving diagnostic imaging methodologies and their possible clinical implications in the SScPAH setting.

Cardiovascular magnetic resonance in rheumatology: Current status and recommendations for use.

Targeted therapies in connective tissue diseases (CTDs) have led to improvements of disease-associated outcomes, but life expectancy remains lower compared to general population due to emerging co-morbidities, particularly due to excess cardiovascular risk. Cardiovascular magnetic resonance (CMR) is a noninvasive imaging technique which can provide detailed information about multiple cardiovascular pathologies without using ionizing radiation. CMR is considered the reference standard for quantitative evaluation of left and right ventricular volumes, mass and function, cardiac tissue characterization and assessment of thoracic vessels; it may also be used for the quantitative assessment of myocardial blood flow with high spatial resolution and for the evaluation of the proximal coronary arteries. These applications are of particular interest in CTDs, because of the potential of serious and variable involvement of the cardiovascular system during their course. The International Consensus Group on CMR in Rheumatology was formed in January 2012 aiming to achieve consensus among CMR and rheumatology experts in developing initial recommendations on the current state-of-the-art use of CMR in CTDs. The present report outlines the recommendations of the participating CMR and rheumatology experts with regards to: (a) indications for use of CMR in rheumatoid arthritis, the spondyloarthropathies, systemic lupus erythematosus, vasculitis of small, medium and large vessels, myositis, sarcoidosis (SRC), and scleroderma (SSc); (b) CMR protocols, terminology for reporting CMR and diagnostic CMR criteria for assessment and quantification of cardiovascular involvement in CTDs; and (c) a research agenda for the further development of this evolving field.

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.

Multimodality imaging and the emerging role of cardiac magnetic resonance in autoimmune myocarditis.

Autoimmune responses and inflammation are involved in the excess cardiovascular risk observed in patients with systemic inflammatory diseases. Autoimmune myocarditis is a presentation of an inflammatory reaction of the heart during the course of autoimmune disorders, with most cases seen in systemic lupus erythematosus. Early diagnosis is of great significance because of the likelihood of progression to severe and potentially fatal complications such as arrhythmias, heart block, and heart failure. The clinical presentation of the disease is silent leading to delayed diagnosis when dilated cardiomyopathy or heart failure has already advanced. Therefore, a major issue is whether the diagnosis of myocarditis will continue to require invasive procedures such as endomyocardial biopsy or can be achieved with non-invasive methods. There is increasing evidence that noninvasive cardiac imaging, including tissue Doppler echocardiography and cardiac magnetic resonance (CMR), is able to detect subclinical cases and aid in the initiation of specific treatment when it is more likely to be effective. CMR in particular, has emerged as an important technique in the evaluation of myocarditis using three types of images: T2-weighted (T2-W), early T1-weighted (EGE) images taken after 1 min, and delayed enhanced images (LGE) taken 15 min after the injection of contrast agent. If 2/3 of the imaging sequences are positive, myocardial inflammation can be predicted or ruled out with a diagnostic accuracy of 78%. As our understanding of disease mechanisms improves, multimodality imaging may aid in the development of new diagnostic and therapeutic strategies for this potentially devastating complication of systemic inflammation, but further studies are needed to formally evaluate this.