Inflammation and Accelerated Atherosclerosis: Basic Mechanisms

To assess mortality rates (MRs), standardized mortality ratios, and causes of death in systemic lupus erythematosus (SLE) in a population-based study.

We analyzed linked administrative health databases of the Veneto Region (Italy, 4,900,000 residents). SLE was defined by any hospital diagnosis or healthcare copayment exemption for SLE. We analyzed mortality from January 1st, 2012, until December 31st, 2021. MRs per 1000 were stratified by year, sex, and age group. Standardized mortality ratios were derived by comparing MRs of the general regional population. Causes of death were coded using the ICD-10 coding system and they were grouped in: SLE, infectious diseases, cardiovascular diseases (CVD), cancer, or others.

Among 4283 SLE prevalent cases, 603 deaths occurred, corresponding to an average annual standardized MR of 18.6 per 1000 person/year (95% CI 17.0-20.2). Out of 1092 incident SLE patients, 90 died with a peak in the first year after diagnosis (MR 26.5 per 10,000 person/month). Standardized mortality ratio was 2.65 (95% CI 2.13-3.26) overall, and highest among younger patients (<45 years: 5.59, 95% CI 2.05-12.4). Five- and 8-year survival were 91% and 89%, respectively. About half of the deaths had CVD or cancer as underlying cause, whereas infections were less frequently reported.

Although the medium-term survival since diagnosis is good, SLE mortality is still higher than that of the general population, especially in youngest patients. Nowadays, CVD seems to be the major cause of deaths in SLE, whereas infections account for a low proportion of deaths, at least in Western countries.

Atherosclerosis is one of the potential causes of death in patients with cardiovascular disease. With the discovery of new anti atherosclerotic drugs becoming the pursuit of the pharmaceutical industry, natural products have attracted more and more attention because of their unique efficacy in the treatment of atherosclerosis. More and more studies have shown that esculetin, a coumarin mainly found in cortex fraxini, can improve atherosclerosis by participating in cellular antioxidant responses and reducing inflammation related pathogenesis. This paper summarizes the researches of esculetin on anti-atherosclerosis in the past two decades. Esculetin plays an anti atherosclerotic role through reducing blood triglyceride level, preventing the proliferation of vascular smooth muscle cells (VSMC) and the production of matrix metallopeptidase 9 (MMP-9), inhibiting the oxidation of low density lipoprotein (LDL) and the secretion of adhesion factors and chemokines, and increasing the outflow level of high density lipoprotein cholesterol (HDL-C). Esculetin is safe and reliable, easy to be absorbed by the body and can be synthesized in a variety of ways. Although there are still few clinical studies on anti-atherosclerosis, in vivo experiments have proved that esculetin has high bioavailability. From the current research, the anti-atherosclerotic effect of esculetin is positive and encouraging. However, much work remains to be done to clarify the molecular mechanism of esculetin in the treatment of atherosclerosis.

Cardiovascular disease (CVD) are a major public health problem, as they are among the leading causes of mortality worldwide. Tripodanthus acutifolius (TA) is a hemiparasite plant used for medicinal purposes with great antioxidant capacity. However, little is known about its hypolipemic effect. Thus, the aim of this study was to evaluate the effects of the hydroalcoholic extract of Tripodanthus acutifolius leaves in hypercholesterolemic Wistar rats. The animals were divided into: (1) NC (Normocaloric Control); (2) HC (Hypercaloric Control); (3) Oral Simvastatin Suspension 10 mg/kg (SIM); (4) TA extract 50 mg/kg (TA 50 mg/kg) and (5) TA 100 mg/kg. The in vitro antioxidant activity assay demonstrated that TA shows high antioxidant capacity. The in vivo findings demonstrated that TA supplementation resulted in significant decreases (p < 0.05) in Total Cholesterol (TC), Triglycerides (TG) and Low density lipoprotein (LDL) levels, whereas High density lipoprotein (HDL) levels increased significantly in all TA-supplemented groups in relation to the HC group. Hepatic, renal and cardiac function markers improved during supplementation. Serum adiponectin levels increased significantly, whereas C-reactive protein (PCRus) levels decreased in the TA-supplemented in relation to the HC group. Catalase (CAT), superoxide dismutase (SOD) and gluthatione peroxidase (GPx) activities, as well as polyphenols, vitamin C (Vit C) and total gluthatione (GSH), increased significantly in the TA-supplemented groups treated when compared to the HC group. Concerning oxidative damage to biomolecules, TA showed a protective effect on lipids, proteins and DNA. Regarding the histological analysis of the aortic artery, TA treatment was able to decrease aortic vasculature. Therefore, TA is rich in antioxidant compounds and may be an alternative for the treatment of hypercholesterolemia.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, characterized by the production of autoantibodies by autoreactive B cells, which are capable of inducing inflammatory changes in various organs and systems by several mechanisms. In patients with SLE, all the cardiac structures can be involved. Pericarditis is the most common cardiac abnormality, but lesions of the valves, myocardium, and coronary vessels may also occur. Nowadays, cardiac manifestations can be frequently recognized by echocardiography and other noninvasive tests, such as cardiac computed tomography or cardiac magnetic resonance imaging. Echocardiography is a nonexpensive, sensitive, and specific technique in detecting cardiac abnormalities, particularly mild pericarditis, valvular lesions, and myocardial dysfunction. Premature atherosclerosis is the most frequent cause of coronary artery disease in SLE patients. Efforts should be made to control traditional risk factors as well as all other factors, which could contribute to atherosclerotic plaque development.

Evidence collected in the last 2 decades suggests that, compared to the general population, patients affected by systemic autoimmune rheumatic diseases (SADs) carry an increased risk of developing cardiovascular (CV) comorbidities in a context of accelerated atherosclerosis. Moreover, CV manifestations occur earlier than in the general population, thus having a relevant effect on mortality of patients with SADs. This is explained by the coexistence in this group of patients of a high prevalence of traditional (such as hypertension, dyslipidemia, diabetes) and specific disease-related risk factors that accelerate the progression of vascular damage. In this context, not only inflammatory mechanisms and immunologic abnormalities, but also genetic factors and treatment effects may contribute to CV comorbidities. However, the processes that are responsible for accelerated atherosclerosis in SADs remain incompletely understood.

Pentraxin 3 (PTX3) plays an important role in the inflammatory processes. Recently it has been reported to be involved in autoimmune diseases. Many studies have investigated the serum/plasma levels of PTX3 in autoimmune diseases, but the results are contradictory or inconclusive among those findings. The purpose of this meta-analysis was to investigate whether serum/plasma levels of PTX3 were associated with autoimmune diseases by comparing the serum/plasma levels of PTX3 in the autoimmune diseases and healthy controls.

PubMed, ELSEVIER ScienceDirect and Cochrane Library databases (up to December 26, 2015) were used to obtain all relative published literatures. The study quality was assessed by the Newcastle-Ottawa scale. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by random-effect model analysis.

A total of 20 studies including seven studies of systemic lupus erythematosus (SLE), four studies of ankylosing spondylitis (AS), five studies of rheumatoid arthritis (RA), three studies of systemic sclerosis (SSc) and one study of multiple sclerosis (MS) were finally included in the meta-analysis. The results revealed that the serum/plasma levels of PTX3 in autoimmune diseases were significantly higher than in normal controls (SMD = 0.496 ng/mL, 95% CI = 0.107–0.886, p <0.001; I² = 91.9, p <0.001). The subgroup analysis showed that the serum/plasma levels of PTX3 in AS and SSc were higher than in healthy controls (pooled SMD = 0.926 ng/mL, 95% CI = 0.174–1.677, p <0.001, I² = 77.0, p = 0.013; pooled SMD = 0.546 ng/mL, 95% CI = 0.136–0.957, p <0.001; I² = 30.9, p = 0.299, respectively).

Serum/plasma levels of PTX3 in autoimmune diseases were higher than in normal controls.