Current Vascular Pharmacology - Volume 18, Issue 5, 2020

In the current Thematic Issue of Current Vascular Pharmacology (CVP), entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, presented in two parts, Part 1 and Part 2, review articles are included from specialists in cardiology, rheumatology, immunology and related fields. These reviews discuss the cardiovascular complications of the main systemic Autoimmune Rheumatic Diseases (ARDs). For example, the underlying pathogenetic mechanisms, the role of cardiovascular imaging and recommendations for prevention and management. These articles place inflammation as the key process, linking cardiovascular complications with ARDs. From all these reviews, the conclusion is the need for collaboration between the disciplines of Rheumatology and Cardiology to establish the emerging field of Cardio- Rheumatology. This will aid to fine-tune risk stratification and optimize preventive strategies and pharmacological therapies for patients with ARDs.

Rheumatoid arthritis (RA) is an autoimmune inflammatory arthritis. Inflammation, however, can spread beyond the joints to involve other organs. During the past few years, it has been well recognized that RA associates with increased risk for cardiovascular (CV) disease (CVD) compared with the general population. This seems to be due not only to the increased occurrence in RA of classical CVD risk factors and comorbidities like smoking, obesity, hypertension, diabetes, metabolic syndrome, and others but also to the inflammatory burden that RA itself carries. This is not unexpected given the strong links between inflammation and atherosclerosis and CVD. It has been shown that inflammatory cytokines which are present in abundance in RA play a significant role in every step of plaque formation and rupture. Most of the therapeutic regimes used in RA treatment seem to offer significant benefits to that end. However, more studies are needed to clarify the effect of these drugs on various parameters, including the lipid profile. Of note, although pharmacological intervention significantly helps reduce the inflammatory burden and therefore the CVD risk, control of the so-called classical risk factors is equally important. Herein, we review the current evidence for the underlying pathogenic mechanisms linking inflammation with CVD in the context of RA and reflect on the possible impact of treatments used in RA.

Sjögren’s syndrome is a rheumatic autoimmune disease that primarily affects middle-aged women and runs a slowly progressing course with sicca symptoms being the prevalent manifestation. Premature atherosclerosis and increased cardiovascular (CV) morbidity and mortality are frequently encountered in rheumatic diseases characterized by significant systemic inflammation, such as the inflammatory arthritides, systemic vasculitides and systemic lupus erythematosus. In the same context, chronic inflammation and immune aberrations underlying Sjögren’s syndrome are also reported to be associated with augmented risk of atherosclerosis. Increased CV disease (CVD) frequency has been found in recent meta-analyses. The involvement of the CV system is not a common feature of Sjögren’s syndrome; however, specific manifestations, such as autoantibody-mediated heart block, pericarditis, pulmonary arterial hypertension and dysautonomia, have been described. This review focuses on studies addressing CV morbidity in Sjögren’s syndrome and presents current data regarding distinct CV features of the disease.

Patients with rheumatoid diseases have an increased risk of cardiovascular disease (CVD) and CVD-related death compared with the general population. Both the traditional cardiovascular risk factors and systemic inflammation are contributors to this phenomenon. This review examines the available evidence about the effects of synthetic, non-biologic disease-modifying antirheumatic drugs (DMARDs) on CVD risk. This is an important issue for clinicians when deciding on individual treatment plans in patients with rheumatic diseases. Evidence suggests that synthetic, non-biologic DMARDs such as methotrexate, sulfasalazine, hydroxychloroquine, leflunomide and tofacitinib show decreased CVD morbidity and mortality. However, the strongest data in favour of a reduction in CVD events in rheumatoid patients are shown with methotrexate, which has been the focus of most studies. Adequate proof for a favourable effect also exists for hydroxychloroquine. Larger, prospective studies and randomized clinical trials are needed to better characterize the effect of synthetic, non-biologic DMARDs on CVD outcomes in these patients. Design of future studies should include areas with lack of evidence, such as the risk for heart failure, arrhythmias and valvular heart disease. The clinically relevant question whether synthetic, non-biologic DMARDs are inferior to biologic DMARDs in terms of CVD outcomes remains not adequately addressed.

The vasculitides are a heterogeneous group of disorders, characterized by inflammatory cell infiltration and necrosis of blood vessels that cause vascular obstruction or aneurysm formation, affecting various organs such as lungs, kidneys, skin and joints. Cardiac involvement is commonly encountered in primary systemic vasculitis and it is associated with increased morbidity and mortality. Depending on the dominant pathophysiological mechanism, heart complications may manifest in different ways, including myocardial ischemia due to impaired micro- or macrovascular circulation, progressive heart failure following valvular heart disease and myocardial dysfunction, (sub) clinical myocarditis, pericarditis, pulmonary hypertension as well as arteritis of coronary vessels. Beyond cardioprotective regimens, aggressive immunosuppression reduces the inflammatory burden and modulates the progression of cardiovascular complications. Perioperative management of inflammation, when surgical treatment is indicated, improves surgical success rates and postoperative long-term prognosis. We aim to provide an overview of the pathogenetic, diagnostic and therapeutic principles of cardiovascular involvement disease in the various forms of systemic vasculitis.

The spondyloarthritides are a group of chronic systemic inflammatory joint diseases, the main types being ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Evidence accumulating during the last decades suggests that patients with AS or PsA carry an increased risk for cardiovascular disease and cardiovascular death. This risk appears to be mediated by systemic inflammation over and above classical cardiovascular risk factors. The excess cardiovascular risk in those patients has been formally acknowledged by scientific organizations, which have called physicians’ attention to the matter. The application by Rheumatologists of new effective anti-rheumatic treatments and treat-to-target strategies seems to benefit patients from a cardiovascular point of view, as well. However, more data are needed in order to verify whether anti-rheumatic treatments do have an effect on cardiovascular risk and whether there are differences among them in this regard. Most importantly, a higher level of awareness of the cardiovascular risk is needed among patients and healthcare providers, better tools to recognize at-risk patients and, ultimately, commitment to address in parallel both the musculoskeletal and the cardiovascular aspect of the disease.

The risk of cardiovascular (CV) disease is increased among patients with systemic autoimmune rheumatic diseases and remains an underserved area of medical need. Although traditional risk factors for CV disease, such as hypertension, smoking, dyslipidemia and obesity contribute to endothelial dysfunction in rheumatoid arthritis (RA), they are not enough on their own to explain the observed excess CV risk. Rather, systemic inflammation seems to play a pivotal role in both disease states. Considering the inflammatory process in autoimmune diseases, scientific interest has focused on recently introduced biologic disease-modifying agents (bDMARDS) such as inhibitors of Tumor Necrosis Factor- α (TNF-α), Interleukins -1 (IL-1) and -6 (IL-6). Despite the widespread use of bDMARDS in RA and other chronic autoimmune inflammatory diseases, their precise impact on CV disease and outcome remains to be elucidated, while prospective randomized control trials assessing their impact on hard CV endpoints are scarce. In this review, we summarize current knowledge concerning the effect of bDMARDs on CV outcome and on the risk of developing CV disease in patients with systemic autoimmune rheumatic diseases.

Objective: Restenosis is a frequent complication of angioplasty. It consists of a neointimal hyperplasia resulting from progression and migration of vascular smooth muscle cells (VSMC) into the vessel lumen. microRNA miR-223 has recently been shown to be involved in cardiovascular diseases including atherosclerosis, vascular calcification and arterial thrombosis. In this study, our aim was to assess the impact of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. Methods: The over and down-expression of miR-223 was induced by adenoviral vectors, containing either a pre-miR-223 sequence allowing artificial miR-223 expression or a sponge sequence, trapping the native microRNA, respectively. Restenosis was quantified on stained rat carotid sections. Results: In vitro, three mRNA (Myocyte Enhancer Factor 2C (MEF2C), Ras homolog gene family, member B (RhoB) and Nuclear factor 1 A-type (NFIA)) reported as miR-223 direct targets and known to be implicated in VSMC differentiation and contractility were studied by RT-qPCR. Our findings showed that down-expression of miR-223 significantly reduced neointimal hyperplasia by 44% in carotids, and was associated with a 2-3-fold overexpression of MEF2C, RhoB and NFIA in a murine monocyte macrophage cell line, RAW 264.7 cells. Conclusion: Down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty.

Objective: Sudomotor dysfunction is a feature of Diabetic Peripheral Neuropathy (DPN). The indicator plaster Neuropad can provide an easy and accurate way to diagnose DPN. The aim of the present study was to evaluate Neuropad’s specificity, sensitivity and accuracy in detecting DPN in patients with Diabetes Mellitus (DM). Methods: A total of 174 patients with DM (79 with type 1 DM, 88 women), mean age 49.8 ± 16.1 years and mean DM duration 17.3 ± 7.7 years were included in the present study. The following methods were used to diagnose DPN: the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively), application of 10 g monofilament (MONO) and measurement of vibration perception threshold with biothesiometer (BIO). Neuropad was applied to both feet in all patients and according to the presence or absence of color change of the sticker, patients were divided in two groups: group A (n = 82, complete change in color from blue to pink, depicting normal perspiration) and group B (n = 92, incomplete or no change, depicting abnormal perspiration). Results: MNSIQ and MNSIE were positive for DPN in 111 and 119 patients, respectively. BIO was abnormal in 109 and MONO in 59 patients. Sensitivity of Neuropad testing was 95% vs. MONO, 73% vs. BIO, 73% vs. MNSIE and 75% vs. NSIQ. Specificity was 69, 81, 90 and 92%, respectively and accuracy of the test was 78, 76, 78 and 83%, respectively. Conclusion: Neuropad has a high sensitivity and specificity in detecting DPN vs. MNSIQ, MNSIE and BIO. Neuropad has a high sensitivity but moderate specificity vs. MONO. The accuracy of the test was high in all measurements.

Background: Osteoprotegerin and osteopontin have recently emerged as key factors in both vascular remodelling and atherosclerosis progression. Interleukin-6 (IL-6) is an inflammatory cytokine with a key role in atherosclerosis. The relationship of osteoprotegerin, osteopontin, and IL-6 serum levels with endothelial function and arterial stiffness was evaluated in patients with coronary artery disease (CAD). Methods: We enrolled 219 patients with stable CAD and 112 control subjects. Osteoprotegerin, osteopontin and IL-6 serum levels were measured using an ELISA assay. Endothelial function was evaluated by flow-mediated dilation (FMD) in the brachial artery and carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. Results: There was no significant difference between control subjects and CAD patients according to age and sex. Compared with control subjects, CAD patients had significantly impaired FMD (p<0.001) and increased PWV (p=0.009). CAD patients also had significantly higher levels of osteoprotegerin (p<0.001), osteopontin (p<0.001) and IL-6 (p=0.03), compared with control subjects. Moreover, IL-6 levels were correlated with osteoprotegerin (r=0.17, p=0.01) and osteopontin (r=0.30, p<0.001) levels. FMD was correlated with osteoprotegerin levels independent of possible confounders [b coefficient= - 0.79, 95% CI (-1.54, -0.05), p=0.04]. Conclusion: CAD patients have increased osteoprotegerin, osteopontin and IL-6 levels. Moreover, there is a consistent association between osteoprotegerin and osteopontin serum levels, vascular function and inflammation in CAD patients. These findings suggest another possible mechanism linking osteoprotegerin and osteopontin serum levels with CAD progression through arterial wall stiffening and inflammation.