Current Pharmaceutical Design - Volume 18, Issue 11, 2012

Inflammation is a crucial pathophysiological factor leading to cardiovascular comorbidities in a wide range of low- and high-grade inflammatory disorders [1-3]. High intensity of systemic inflammation underlies structural changes of the heart, coronary, cerebral and peripheral arteries in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, other connective tissue disorders and systemic vasculitides [3-6]. It triggers pathways of accelerated atherosclerosis and/or thrombosis and, combined with disease-specific factors, leads to diverse clinical presentations [7]. RA is one of the cytokinergic disorders associated with excessive cardiovascular risk due to accelerated atherosclerosis [6, 8], comparable to the risk incurred by type 2 diabetes in the general population [9]. Furthermore, RA with enhanced cardiovascular risk profile is now considered by some a coronary heart disease equivalent, requiring tight control of systemic inflammation and management of classic cardiovascular risk factors [10]. Over the past decades, treatment of RA with disease-modifying biologic and nonbiologic agents has become widely available and allowed substantially decreasing inflammatory burden in RA cohorts. In the meanwhile, numerous retrospective and small longitudinal studies have proved an association between the intensity of inflammation and a variety of cardiovascular risk markers and factors in RA [11-13]. Nevertheless, a systematic analysis of the available evidence base indicates complexity of the interrelation between inflammation and vascular dysfunction in RA [14], suggesting that systemic inflammation is not the sole factor accelerating rheumatoid vascular pathology and that future drug targets may encompass a set of disease-specific and cardiovascular abnormalities. It has become clear that previously unappreciated platelet activation may propagate the course of inflammatory arthritis and contribute to the enhanced risk of thrombosis and inflammation-induced atherosclerosis [7, 15, 16]. Moreover, entirely new prospects of research and treatment have opened after the recent studies on the role of platelets in bone remodeling [17], which may have implications for antiplatelet therapies targeting osteoporosis and cardiovascular risk in RA and other inflammatory disorders [18]. Complexity of cardiovascular risk in inflammatory disorders may be determined by variable individual responses to systemic inflammation due to age-, sex- and ethnicity-related differences [6]. It is also believed that differences in levels of systemic inflammatory markers and varying responses to daily mental stress underlie vascular dysfunction in healthy subjects and in those with established inflammatory diseases [19]. A good clinical example of complexity of inflammatory targets is Behçet disease (BD). It is a neutrophilic perivasculitis with a range of cardiovascular abnormalities such as aneurysms, pseudoaneurysms, vascular ruptures, intracardiac and venous thromboses [7, 20-22]. Lowgrade inflammation in the course of BD leads to vascular dysfunction, which can be best described within the frames of Virchow’s triad of thrombosis [23]. At the same time, systemic inflammation in BD, as in some other vasculitides [24], do not play a role in atherogenesis, and inflammatory markers such as C-reactive protein, linked to atherogenesis in SLE and RA, do not exert a vasculopathic effect in BD [1]. Differences in cardiovascular targets in inflammatory disorders have to be taken into account when efficacy and safety of antiinflammatory biologic and nonbiologic agents is evaluated. Armamentarium of antirheumatic therapies is now rapidly expanding, and a number of biologic agents are under clinical evaluation. Of these, inhibitors of tumor necrosis factor (TNF), such as infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol, are relatively well-characterized in terms of their effects on cardiovascular risk markers and factors across cohorts of patients with inflammatory rheumatic diseases [25]. Despite their apparent lipid-rising effects, occurring in the course of most antiinflammatory biologic therapies, anti-TNF agents render atheroprotective effects by altering structure of high-density lipoproteins, improving endothelial function, decreasing arterial stiffness and intima-media thickness, and possibly by alleviating insulin resistance [25, 26]. Anti-TNF agents may also prevent thrombosis by decreasing levels of plasminogen activator inhibitor, tissue-type plasminogen activator and D-dimer [25]. Importantly, shifts of some thrombotic markers, such as moderate raise of mean platelet volume in response to anti-TNF therapy, may reflect the drop of inflammatory burden and not necessarily a trend in thrombogenesis [27]. It should be, however, stressed out that currently available evidence on the effects of anti-TNF therapies on cardiovascular risk is limited by small size of the examined prospective cohorts, short duration of the studies and, consequently, lack of association with cardiovascular endpoints. Also, evidence on cardiovascular safety of some other widely used biologic therapies is still not conclusive. Recent large studies primarily focused on infections as most frequently encountered complications of antiinflammatory biologic therapies. For example, it was shown that rituximab, a B-cell-depleting agent, in combination with methotrexate is relatively safe and leads to a significant improvement in the course of arthritis in those resistant to biologic and nonbiologic therapies [28]. However, cautious approach is required in patients with cardiovascular risk factors and established cardiovascular disease as evidence suggests an increase of infusionrelated arrhythmias and hypotension [29]. It is also not clear whether statins, frequently used to halt hyperlipidemia induced by biologics, are safe when combined with rituximab and other disease-modifying agents. Initially, it was thought that antiinflammatory, immunomodulatory and a number of other pleiotropic effects of statins might have beneficial impact on the course of inflammatory arthritides [1, 30, 31]. Indeed, a few initial studies, particularly on atorvastatin, proved that these drugs reduce rheumatoid disease activity and may reduce vascular risk in high-grade inflammatory conditions [32, 33]. However, antiinflammatory effects of statins, particularly pravastatin and atorvastatin, are absent in patients with SLE [34, 35]. Results of ongoing trials on statins, particularly the Trial of Atorvastatin for the primary prevention of Cardiovascular Events in patients with Rheumatoid Arthritis (TRACE RA) [36], may shed light on the use of statins in cardiovascular prevention of RA and some other inflammatory arthritides. Large trials are also warranted to elucidate cardioprotective effects of n-3 polyunsaturated fatty acids in inflammatory rheumatic diseases [37]. Supplementation of this dietary factor proved to render lipid-lowering, antihypertensive and antithrombotic benefits which translate into the reduced risk of cardiac death in the general population [38]. It is especially important to elaborate well-tolerated and effective combinations of polyunsaturated fatty acids with antirheumatic drugs. Notably, preliminary data suggest that polyunsaturated fatty acids contained in fish oil reduce gastrointestinal toxicity of methotrexate and hypertensive effects of cyclosporine [37]. Obviously, cardiovascular protection of patients with inflammatory disorders should be based on a multidisciplinary strategy, which realized in practice by running combined rheumatology/cardiology clinics to tackle enhanced cardiovascular risks incurred by rheumatic diseases themselves and inevitable polypharmacy [39]. Evidence on cardiovascular safety of traditional and new disease-modifying drugs is accumulating [40], and there is a strong need to further advance the multidisciplinary strategy by incorporating tools to monitor heart functions, blood pressure, thrombotic and inflammatory burden to avoid preventable causes of cardiovascular morbidity and mortality. CONFLICT OF INTEREST None declared. ACKNOWLEDGMENT Efforts of all contributors to this issue, authors, numerous anonymous reviewers, editors, and the publisher, are gratefully acknowledged. It is hoped that the messages presented in the articles will successfully translate into better patient care and form a base for future research collaboration. REFERENCES [1] Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Toms TE, Douglas KM, Kitas GD. The rationale for comparative studies of accelerated atherosclerosis in rheumatic diseases. Curr Vasc Pharmacol 2010; 8: 437-49. [2] Ozcakar ZB, Yalc1nkaya F. Vascular comorbidities in familial mediterranean fever. Rheumatol Int 2011; 31: 1275-81. [3] Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 2011; 70: 8-14. [4] Mellana WM, Aronow WS, Palaniswamy C, Khera S. Rheumatoid arthritis: cardiovascular manifestations, pathogenesis, and therapy. Curr Pharm Des 2012; 18(11): 1450-56. [5] Dimitroulas T, Giannakoulas G, Karvounis H, Settas L, Kitas GD. Systemic sclerosis-related pulmonary hypertension: unique characteristics and future treatment targets. 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Rheumatoid Arthritis (RA) is a chronic progressive inflammatory joint disorder that affects 0.5% – 1% of the general population. This review article discusses cardiovascular manifestations of rheumatoid arthritis, pathogenesis of these manifestations, and therapy. This disease not only affects the joints, but it also involves other organ systems. The majority of these patients suffer significant morbidity and mortality from cardiovascular disease. Cardiovascular manifestations of RA include predilection for accelerated atherosclerosis and endothelial dysfunction resulting in coronary artery disease (CAD), stroke, congestive heart failure, and peripheral arterial disease. Some studies have shown that the risk of developing CAD in RA patients is the same as for patients with diabetes mellitus. These patients should be treated with aggressive medical therapy such as disease modifying antirheumatic drugs, tumor necrosis factor alpha inhibitors, and corticosteroids and with appropriate control of risk factors such as smoking, dyslipidemia, hypertension, and obesity. Other manifestations include pericarditis, myocarditis, and vasculitis.

Pulmonary arterial hypertension (PAH) is a severe vascular complication of connective tissue diseases. In the context of systemic sclerosis (SSc), PAH is a devastating disease with a dramatic impact on prognosis and survival. Despite advances in early diagnosis and the development of new targeted treatments, SSc-related pulmonary arterial hypertension (SScPAH) represents the leading cause of death in SSc patients with reported poorer response in therapy and worse prognosis compared with idiopathic PAH. Recent findings indicate that factors accounting for these differences may include cardiac involvement, pronounced autoimmune and inflammatory response and pulmonary venous vasculature remodeling. Deeper understanding of the underlying pathogenic mechanisms of pulmonary vascular disorders in SScPAH may lead to novel therapeutic strategies which are currently under investigation and may improve the outcome of these patients, for whom our therapeutic armamentarium is not effective enough. In this article we attempt to critically analyze the factors contributing to the unique phenotype of SScPAH focusing on future challenges for the design of novel targeted treatments which may alter the natural history of the disease.

The article reviews the evidence and extent of the excess cardiovascular risk in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis. RA entails nearly twice as high a standardized mortality ratio and is considered an equivalent of type 2 diabetes with regard to cardiovascular risk. The associated excess cardiovascular risk can only partly be explained by traditional risk factors, and the underlying inflammation is crucially involved in the pathogenesis. Data obtained from patients with early RA suggest that serum triglycerides, a proxy of disease activity as markers of systemic inflammation, impaired function of apolipoprotein A-I and HDL particles, and mediating hypertension are determinants of the excess cardiovascular risk. These changes seem to be preceded by a lowering of total cholesterol and are followed in the course of the disease by immune processes typically illustrated by positivity of rheumatoid factor. Evidence is available to postulate the notion that reduced plasma lipoprotein- associated phospholipaseA2 mass or activity, mediated by diminished hydrolysis of VLDL triglycerides and of Lp(a) phospholipids, may induce reduction or altered composition of HDL particles and apoA-I dysfunction which, along with elevated plasma triglycerides, initiate and contribute to chronic inflammation. Lifestyle modification, traditional non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors, low-dose corticosteroids, statins, tumor-necrosis-α inhibitors and, particularly, the immunosuppressive methotrexate, all have potential beneficial effects in eliciting a reduction in disease activity and cardiovascular risk. Adherence to the recent EULAR recommendations is a key in the prevention and management of cardiovascular risk among patients with rheumatic diseases.

Although inflammation-induced thrombosis is a well-known entity, its pathogenesis remains complicated. There are complex interactions between inflammation and hemostasis, involving proinflammatory cytokines, chemokines, adhesion molecules, tissue factor expression, platelet and endothelial activation, and microparticles. Inflammation increases procoagulant factors, and also inhibits natural anticoagulant pathways and fibrinolytic activity, causing a thrombotic tendency. Besides, chronic inflammation may cause endothelial damage, resulting in the loss of physiologic anticoagulant, antiaggregant and vasodilatory properties of endothelium. However, inflammation- induced venous thrombosis may develop even in the absence of vessel wall damage. On the other hand, coagulation also augments inflammation, causing a vicious cycle. This is mainly achieved by means of thrombin-induced secretion of proinflammatory cytokines and growth factors. Platelets may also trigger inflammation by activating the dendritic cells. There are many systemic inflammatory diseases characterized by thrombotic tendency, including Behçet disease (BD), antineutrophilic cytoplasmic antibody-associated vasculitides, Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus, antiphosholipid syndrome, familial Mediterranean fever, thromboangiitis obliterans (TAO) and inflammatory bowel diseases. Inflammation-induced thrombosis may respond to immunosuppressive (IS) treatment, as in the case of BD. However effectiveness of this treatment can not be generalized to all other inflammatory diseases. For instance, IS agents do not have any beneficial role in the management of TAO. Heparin, antiplatelet agents such as aspirin and clopidogrel, colchicine and statins also have some antiinflammatory activity. However, decreased responsiveness to aspirin and clopidogrel treatments may be observed in inflammatory diseases, due to antiplatelet resistance caused by systemic inflammation. In the present review, we aimed to discuss the details of the complex crosstalk between inflammation and hemostasis in the context of available data. We also intended to overview the major inflammatory diseases with thrombotic tendency, as well as to discuss the general principles of the management of inflammation-induced thrombosis.

There is evidence that mental stress can trigger myocardial infarction. Even though the underlying mechanisms remain to be determined, both inflammation and vascular responses to mental stress have been implicated as contributing factors. This review explores the effects of inflammation on the vascular responses to mental stress. First, the associations between inflammation and resting vascular function are discussed. It is known that increases in inflammation are associated with endothelial dysfunction, with a reduction in nitric oxide a common pathway through which inflammation can influence endothelial function. Second, the effects of mental stress on vascular responses are reviewed. There is ample evidence that in healthy participants, mental stress induces increases in forearm blood flow, which is impaired in those at risk for cardiovascular disease. Even though several mechanisms are discussed, there is evidence that nitric oxide plays an important role in stress-induced vasodilation. Finally, the influences of inflammation on the vascular responses are described. It is hypothesised that inflammation can alter vascular responses to mental stress, most likely due to lower levels of nitric oxide as a result of the inflammation. This poorer vascular response is thought to be an underlying factor through which mental stress can trigger myocardial infarction.

There is abundant evidence that rheumatoid arthritis (RA), a chronic inflammatory disorder, is associated with an increased risk for cardiovascular (CV) disease. While there may be several mechanisms contributing to a higher CV risk in RA patients, inflammation is considered to be the main cause explaining the excess CV burden. Inflammatory processes appear pivotal to the atherothrombotic process and are linked to endothelial dysfunction, fatty streak initiation and progression, deterioration of fatty streaks into (unstable) plaques, and plaque rupture. Moreover, systemic inflammation, through tumor necrosis factor (TNF) or related cytokines, appears to accelerate atherothrombosis either directly or via effects on conventional and novel CV risk factors, such as lipids and lipoproteins, blood pressure, haemostatic factors, and insulin resistance. New and highly specific therapeutic agents (TNF inhibitors) may significantly lower CV risk in RA. This review summarizes the evidence base supporting the notion that TNF inhibitors confer benefit CV disease risk in RA.

Accelerated development of atherosclerosis (AT) in rheumatoid arthritis (RA) stems from common immune-inflammatory mechanisms underlying the diseases. While the key role of activation of the T-cell immune system component is considered to be proved, the role of B-lymphocytes has been investigated insufficiently. Earlier experimental models demonstrated the “atheroprotective” role of B-cells. At the same time, AT development is associated with activation of the B-cell immune system component and manifested by hyperproduction of antibodies to oxidized low density lipoproteins (oxLDL), heat shock proteins, etc. Wide applications of anti-B-cell therapy stimulate active research on effects of B-lymphocytes and their depletion on AT development in RA patients that have a high risk of cardiovascular events (CVE). Experimental models demonstrated that depletion of B2 cells instead of B1 cells under anti-CD20 treatment resulted in a slower development and progression of AT. Research on cardiovascular effects of chimeric antiCD20 monoclonal antibody (rituximab, RTX) in RA is definitely of high interest. Use of RTX in a combination with methotrexate does not increase the risk of serious side effects, including CVE, compared with the sole use of methotrexate. Currently, only few pilot research reports on favorable effects of RTX on the lipid profile and endothelial function in RA patients have been published. According to other authors, the frequency of CVE in RA patients receiving RTX therapy was somewhat higher than that in patients not treated with RTX. In rare cases such side effects as hypotension and arrhythmia were reported under RTX infusion. In addition, investigation of the combined use of statins and RTX is important, since some data are available on a reduced efficacy of RTX when administered with statins. Therefore, further research is required to clarify the role of the B-cell immune system component in AT development and the impact of anti-B cell therapy on the pathogenetic mechanisms of AT and CVE in RA patients.

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the antiinflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.

Rheumatoid arthritis (RA), the most common chronic systemic inflammatory disease leading to joint destruction and disability, is associated with increased cardiovascular mortality. Systemic inflammation and increased burden of traditional cardiovascular risk factors present in RA are currently considered responsible for the accelerated atherosclerosis in these patients. Herein, we highlight a potential double effect of dietary intake of the n-3 long-chain polyunsaturated fatty acids (LCP) eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) on cardiovascular risk reduction and disease control in patients with RA. Large studies in non-RA populations provide strong evidence for the beneficial effect of n-3 LCP supplementation in primary and secondary cardiovascular prevention. Cardiovascular risk reduction is at least partly explained by n-3 LCP effects on blood pressure, dyslipidemia, thrombosis and inflammation, all important factors also in RA, whereas abnormalities in vascular function and in vascular morphology similar to those observed in RA patients may even be moderately reversed. On the other hand, there is evidence from 6 of 14 randomized controlled trials supporting a favorable effect of n-3 LCP supplementation in decreasing joint inflammation in RA. Although specific studies in RA patients are currently lacking, a double beneficial effect of n-3 LCP seems likely. The size of any such effect and how it compares with other interventions such as lifestyle changes, biologic therapies, and statin therapy, needs to be investigated prospectively in carefully designed studies.

Clinical manifestations of most rheumatic diseases have changed over the past few decades, largely due to advances in therapies targeting autoimmune and (auto)inflammatory pathways. Improvements in the management of rheumatic diseases have also now brought to the fore the issue of comorbidities. It has become evident that the burden of cardiovascular morbidity and mortality is increased in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the spondyloarthropathies, amongst other conditions. As a result, efforts have switched toward investigating the effects of conventional antirheumatic and new biologic agents on inflammationinduced atherothrombosis. Evidence is accumulating suggesting a beneficial cardiovascular profile of some antirheumatic drugs, such as methotrexate and hydroxychloroquine, but it also indicates the possibility of a variety of adverse events developing in the short- and long-term. The aim of this review is to highlight cardiovascular adverse effects of the drugs widely used in the treatment of rheumatic diseases. The literature search was performed through PubMed, the Cochrane Library, Scopus, and Web of Science databases using the following terms: “antirheumatic drugs”, “inflammation”, “rheumatic diseases”, “cardiovascular diseases”, “adverse events”, “toxicity”, “drug design”, and “drug interactions”. Adverse events ranging from infusion-related hypertension and myocardial ischemia, to restrictive cardiomyopathy and congestive heart failure have been reported in large trials and case series on most antirheumatic drugs. Clinicians should be alert of the wide variety of cardiovascular adverse effects of individual antirheumatic drugs, and should carefully monitor blood pressure and markers of inflammation, thrombosis, myocardial ischemia, electrolytes, and lipid disturbances while administering these drugs. Future prospective studies should specifically investigate the cardiovascular safety of most antirheumatic drugs as part of mono- or combination therapy in relation to different dosage regimens, duration of therapy, age, and gender.