oa Editorial [Hot Topic: Cardiovascular Risk and Inflammation: Pathophysiological Mechanisms, Drug Design, and Targets Executive (Guest Editor: Armen Yuri Gasparyan)]

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. 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