Current Vascular Pharmacology - Volume 18, Issue 6, 2020

In Part 1 of this Thematic Issue entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, a panel of specialists and experts in cardiology, rheumatology, immunology and related fields discussed the cardiovascular complications of spondyloarthritides, rheumatoid arthritis, Sjogren’s syndrome and vasculitides, as well as relevant cardiovascular issues related to non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), and provided their recommendations for prevention and management of these complications. In part 2 of this Thematic Issue, experts discuss the enhanced cardiovascular risk conferred by additional autoimmune rheumatic diseases (ARDs), including systemic lupus erythematosus, the antiphospholipid syndrome, psoriasis and psoriatic arthritis and juvenile idiopathic arthritis. These, and the previous articles, place inflammation as the key common link to explain the enhanced risk of cardiovascular complications in patients with ARDs. It follows that treatment should probably target inflammation. From all these contemporary reviews, the conclusion that is derived further supports the notion of the emerging field of Cardio- Rheumatology where physicians and experts from these two disciplines collaborate in risk stratification and optimization of preventive strategies and drug therapies in patients with ARDs.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. This review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options. Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings. Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.

Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.

The increased risk of cardiovascular disease (CVD) among patients with autoimmune rheumatic diseases such as rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus has been extensively documented. Sub-clinical atherosclerosis can be assessed using various non-invasive imaging techniques. However, the mechanisms underlying the higher risk of atherosclerotic CVD in patients with autoimmune rheumatic diseases are not fully known, although they seem to include chronic low-grade systemic inflammation leading to prolonged endothelial activation, accompanied by a pro-thrombotic/pro-coagulant and autoantibody state. Furthermore, sub-clinical atherosclerosis is also influenced by other traditional risk factors for CVD. Including the individual components of the metabolic syndrome (MetS: obesity, impaired glucose metabolism, dyslipidemia and high blood pressure), the degree of which is higher in these patients than in controls. The aim of this narrative review is to discuss the CV manifestations and risk factors involved in the increased risk of CVD among patients with autoimmune rheumatic diseases.

Juvenile idiopathic arthritis (JIA), is a term used to describe a group of inflammatory disorders beginning before the age of 16 years. Although for the majority of children remission is achieved early, those with systemic or polyarticular form of the disease may present persistent symptoms in adulthood. Considering that there is overlap in the pathogenesis of JIA with adult rheumatic diseases, concerns have been raised as to whether JIA patients could be at increased cardiovascular (CV) risk in the long-term. In this review, we summarize evidence for CV involvement in JIA and present data on CV risk factors and surrogate markers of arterial disease. We also provide information on beneficial and harmful CV effects of anti-inflammatory medications in the context of JIA and suggest strategies for CV screening. Overall, patients with systemic forms of JIA demonstrate an adverse lipid profile and early arterial changes relevant to accelerated arterial disease progression. Although there is paucity of data on CV outcomes, we recommend a holistic approach in the management of JIA patients, which includes CV risk factor monitoring and lifestyle modification as well as use, when necessary, of antiinflammatory therapies with documented CV safety.

Psoriasis; a chronic inflammatory disease is characterized by symmetric hyperkeratotic plaques affecting any part of the body. Psoriasis is nowadays considered as a systemic inflammation linked with several comorbidities as metabolic syndrome, depression, anxiety and increased prevalence of cardiovascular (CV) disease. The hypothesis that psoriasis is an independent CV risk factor leading to atherosclerosis via inflammation is now widely accepted. Deciphering the underlying mechanisms interconnecting psoriasis and CV disease may have significant implications in treatment decisions. Accumulating evidence suggests that systematic therapies and recently introduced biologic agents, that control psoriasis by suppressing the chronic and systemic inflammation, may alter the progression of CV disease. We herein attempt a review of current evidence analysing the relationship between psoriasis and CV comorbidities, comment on the mechanisms underlying this association and investigate the consequences for the management of psoriasis.

Background: Several studies showed a close link between metabolic syndrome (MetS), type 2 diabetes (T2DM) and cerebrovascular diseases. There is considerable debate regarding the role of uric acid (UA) as a risk factor in these conditions. Objective: The aim of this narrative review is to discuss the links between UA, MetS, T2DM and cerebrovascular disease. Methods: An extensive review has been conducted based on the scientific literature published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and Google Scholar from January to May 2019. Additional relevant studies published after the initial review were also considered during the period of June 2019-October 2019, during which, this manuscript was written. The Mesh Terms considered were: uric acid, antioxidant, oxidant, metabolic syndrome, diabetes, cerebrovascular diseases, stroke, haemorrhagic stroke, neurocognitive disorders, and their combinations. Results: The literature review shows a dose-dependent inflammatory action of UA, which occurs with serum concentrations >4 mg/dl (>0.24 mmol/l), representing one of the contributors to the chronic inflammatory process that underlies metabolic and cerebrovascular diseases. Conclusion: UA, which is associated with arterial hypertension and cardiovascular diseases, represents one of the indicators of oxidative homeostasis. Increasing concentrations represent a status of active inflammation which is observed with metabolic and cerebrovascular diseases.

The endothelial glycocalyx is a complex mesh of proteoglycans, glycoproteins and other soluble components, which cover the vascular endothelium. It plays an important role in many physiological processes including vascular permeability, transduction of shear stress and interaction of blood cells and other molecules with the vascular wall. Its complex structure makes its precise assessment challenging, and many different visualization techniques have been used with varying results. Diabetes, one of the main disease models where disorders of the glycocalyx are present, causes degradation of the glycocalyx through a variety of molecular pathways and especially through oxidative stress due to the action of reactive oxygen species. As the glycocalyx has been primarily studied in the glomerular endothelium, more evidence points towards a vital role in albumin handling and, consequently, in diabetic nephropathy. Therefore, the maintenance or restoration of the integrity of the glycocalyx seems a promising therapeutic target. In this review, we consider the structural and functional capacities of the endothelial glycocalyx, the available methods for its evaluation, the mechanisms through which diabetes leads to glycocalyx degradation and albuminuria, and possible treatment options targeting the glycocalyx.

Background: Antipsychotic (AP) medications are the cornerstone treatment for schizophrenia and some other psychiatric diseases. However, some observational studies suggest that these medications might increase the risk of venous thromboembolism (VTE) and pulmonary embolism (PE). Objectives: The aim of this study was to assess whether AP medications are associated with the development of VTE or PE, and to assess the risk based on any type of AP drugs, quality of studies and after adjustment of risk factors. Data Sources: To identify relevant studies, we searched PubMed and EMBASE databases up to February 2019. We also searched the reference lists of relevant articles for related studies. Study Selection: Twenty studies fulfilled the eligibility criteria and were included in our meta-analysis after screening relevant observational cohort and case-control studies. Primary Outcome: The primary outcome of our meta-analysis was the occurrence of all VTE or PE only attributed to exposure to AP medications compared with non-exposure to AP medications. Results: Exposure to AP drugs was associated with a significant increase in the risk of VTE (RR 1.53, 95% CI 1.30-1.80, I2 = 85%) and PE (RR 3.69, 95% CI 1.23-11.07, I2 = 90%). In the subgroup metaanalysis, the use of low-potency AP drugs was associated with a higher risk of VTE, (RR 1.90, 95% CI 1.04-3.47, I2 = 78%). Conclusion: AP exposure was associated with a 1.5-fold increase in the risk of VTE and a 3.7-fold increase in the risk of PE. Low-potency AP drugs were associated with a higher risk of VTE. However, high heterogeneity among studies limits the generalizability of the results.

The prognostic impact of beta-blockers (BB) in coronary artery disease (CAD) is controversial, especially in the post-reperfusion era. We studied in-hospital cardiovascular events in patients hospitalized for acute HF, a previous history of CAD and a left ventricular ejection fraction (LVEF) ≥40%, in relation to BB on admission; and 1-year outcome in relation to BB on discharge, in the GULF aCute heArt failuRe (GULF-CARE) registry. From a total of 5005 patients included in the GULF-CARE registry, 303 patients with a previous history of CAD and a LVEF ≥40% on BB were propensity-matched to 303 patients without BB on admission. In-hospital mortality (OR= 0.82; 95% CI [0.35-1.94]), stroke and cardiogenic shock were not reduced by BB. On discharge, 306 patients on BB, including the ones newly diagnosed with myocardial infarction as a precipitating cause of HF, were propensity-scored matched with 306 patients without BB. Mortality (OR= 0.86; 95%CI [0.51-1.45], hospitalization for HF or PCI/CABG at 1 year were also not reduced by BB at discharge. In summary, our data show that BB have a neutral effect on in-hospital and 1-year outcomes in acute heart failure patients with a previous history of CAD and a LVEF ≥40%.

Atherosclerosis is the main cause of cardiovascular and cerebrovascular diseases. In advanced atherosclerotic plaque, macrophage apoptosis coupled with inflammatory cytokine secretion promotes the formation of necrotic cores. It has also been demonstrated that the long-noncoding Ribonucleic Acid (lnc RNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), with its potent function on gene transcription modulation, maintains oxidized low-density lipoprotein (ox-LDL)- induced macrophage autophagy (i.e., helps with cholesterol efflux). It also showed that MALAT1 activated Sirtuin 1 (SIRT1), which subsequently inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-ΚB) signaling pathways. ox-LDL has been used to incubate human myeloid leukemia mononuclear cells (THP-1)-derived macrophages to establish an in vitro foam cell model. Quantitative reverse-transcription polymerase chain reaction and Western blot analyses confirmed the increased expression level of MALAT1 and the autophagy-related protein Microtubuleassociated protein light chain 3 (LC-3), beclin-1. The small interfering RNA study showed a significant decrease in autophagy activity and an increase in apoptotic rate when knocking down MALAT1. Further study demonstrated that MALAT1 inhibited the expression of MAPK and NF-ΚB (p65) by upregulating SIRT1.