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Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Patients with rheumatic diseases are at an increased risk of mortality and fatal cardiovascular events. Several rheumatic diseases rheumatoid arthritis [RA], osteoarthritis [OA], ankylosing spondylitis [AS], and systemic lupus erythematosus [SLE] have been associated with an increase in the prevalence of cardiovascular diseases CVDs.
Visceral fat accumulation and incompletely clarified genetic determinants have been suggested to play an essential role in the development of the coexistent disorders in the metabolic syndrome, such as hyperglycemia, hypertension, hyperlipidemia, and proinflammatory states, which will determine an increased risk of developing CVD. The predisposition to coexist for these risk factors suggests a single etiologic basis.
However, although traditional cardiovascular risk factors sex, smoking, dyslipidemia, age, and hypertension have been involved in the pathogenesis of CVDs in patients with rheumatic diseases, such features do not clearly and fully for the enhanced cardiovascular risk in this population.
Metabolic syndrome and obesity or, much more correctly, pathologic alteration of fat mass, is likely the link between CVDs and rheumatic diseases. Indeed, the incidence of CVDs is increased when obesity and associated clinical metabolic manifestations such as hyperlipidemia, diabetes mellitus, hypertension, and forced sedentary style is present in patients with rheumatic disorders. Although it has been recently evidenced that dysfunctional adipose tissue secretes inflammatory mediators that are able to influence relevant tissue for rheumatic diseases such as cartilage and synovium, this review summarizes recent evidence on the central role of adipokines, specifically leptin and adiponectin, produced by fat tissue in the modulation of CVDs in the general population, but also analyzes the role of adipokine in a special environment that is represented by rheumatic diseases Figure 1.
Summary of the current knowledge of leptin and adiponectin activities in cardiovascular and rheumatic diseases. Treatments in patients with rheumatic disorders principally involve the management of t disease, but also target serious associated illnesses such as infections and malignancies, and mainly CVDs.
Such comorbidities have a great impact on patient quality of life, chronic disability, life expectancy, and mortality. Classic risk factors, such as hypertension, dyslipidemia, insulin resistance, and obesity metabolic syndromeappear to cluster in patients with RA and are highly prevalent 3. Actually, RA is characterized by hyperproduction of proinflammatory cytokines and adipokines that create a specific milieu that contributes to the worst patient conditions by also establishing a complex metabolic state called rheumatoid cachexia.
This latter state is characterized by loss of muscle mass with progressively increased fat mass. Paradoxically, as a result, a patient with RA may have a higher percentage of body fat when compared to a healthy control with the same body mass index; this increased body fat may contribute further to the development of CVD 45.
However, it is noteworthy to mention that Escalante et al 6 described a paradoxical effect of body mass on mortality in patients with RA. Actually, in this cohort, a higher body mass index BMI seems to diminish the death risk. Nevertheless, some cautions, i. The increase of fat mass is also related to the occurrence of OA and to the plethora of cardiovascular comorbidities. The relationship between obesity and OA is an important public health issue. Actually, the increase of disability associated with the increase of a dysfunctional fat mass in these patients enhances the severity of clinical conditions and is perhaps also responsible for disease promotion and progression 7.
Regarding the influence of fat mass on OA, it is evident that biomechanical aspects are of weight in the pathogenesis of diseases. However, OA is more common in women and exists in non—weight-bearing ts, indicating that a metabolic component is present. A link between SLE and metabolic syndrome also exists reviewed by Pereira et al [ 8 ].
Most of these reports showed a major prevalence of experiencing metabolic syndrome in lupus patients than in healthy controls. Moreover, a higher risk of experiencing CVDs in lupus patients with a concomitant metabolic syndrome is also reported in some of these studies. The link between metabolic syndrome and rheumatic diseases is also at play in AS. Moreover, in these patients, the metabolic syndrome was associated with higher disease activity. It is noteworthy that hypertriglyceridemia and diabetes mellitus were found to be associated with an increased risk of extraglandular findings These adipokines follow the canonical definition of a cytokine having pleiotropic effects according to the site of production, the site of action, the environmental context, and the concentration.
Although initially confined to metabolic activities, adipokines represent a new family of compounds that can be currently considered as key players in the complex network of soluble mediators involved in the pathophysiology of rheumatic diseases. Actually, research aimed to study the complex interactions between metabolism and rheumatic disorders soon identified leptin and adiponectin as relevant adipokines involved in these pathologies, particularly in OA and RA. Nevertheless, new adipokines have emerged as potential players in rheumatic diseases.
Resistin is elevated after traumatic t injuries and induces production of inflammatory cytokines and loss of proteoglycans in cartilage. The injection of resistin into mice ts induces arthritis-like conditions. NAmPRTase seems to have a proinflammatory effect on chondrocytes and synovial fibroblasts In the majority of obese patients, a dysfunctional adipose tissue mechanistically links obesity to other manifestations such as CVDs, fatty liver, and type 2 diabetes mellitus.
This dysfunction is caused by a complex disequilibrium between genetic and environmental factors, which is characterized by adipocyte hypertrophy, hypoxia, and inflammation. The direct consequence of this dysfunction is that adipokine secretion is shifted to an atherogenic, diabetogenic, and proinflammatory secretion pattern.
According to the recent literature, all known adipokines are markedly dysregulated when an abnormal abdominal fat accumulation is present, thereby promoting metabolic and cardiovascular complications. Adipokines, such as leptin, also contribute ificantly to the promotion of proinflammatory and prothrombotic states in cardiovascular complications of rheumatic diseases. Indeed, the main mechanisms of CVDs, particularly those related to the atherogenic process atherosclerosis, inflammation, thrombosisare deeply influenced by adipokines.
Notably, visceral fat accumulation associated with adipokine dysregulation affects both atherosclerotic plaque development and, more importantly, plaque disruption. Clearly, when the advanced plaque becomes unstable, ruptures can occur, establishing an acute coronary syndrome that is aggravated by the adipokine-induced prothrombotic and inflammatory state, which can further worsen syndromes.
Although it has been recently evidenced that dysfunctional adipose tissue secretes inflammatory mediators that are able to influence relevant tissue for rheumatic diseases such as cartilage and synovium 13here we present an updated overview of the function played by 2 of the main fat mass—induced adipokines, leptin and adiponectin, with particular emphasis on their role as mediators of cardiometabolic risk factors in the general population, but also analyzing their role in the most relevant rheumatic diseases.
Leptin is a kd nonglycosylated peptide encoded by the obese ob gene homolog of human LEP gene mainly produced by adipocytes that act at the hypothalamic central level by inducing a decrease in food intake and an increase in energy consumption, and whose circulating levels directly correlate with adipose tissue mass Leptin exerts its biologic actions through the activation of its cognate receptors, which are encoded by the diabetes db gene Various tissues produce leptin and express its cognate receptors, including those of the cardiovascular system such as blood vessels and cardiomyocytes Food intake, energy status, and several hormones but also inflammatory mediators mainly regulate leptin gene expression 15 Genetic deficiency in the gene encoding for leptin or its receptors provokes severe obesity and diabetes mellitus.
Indeed, in obese patients, leptin concentrations are high in consequence of the increased fat mass, and it has been suggested that high leptin levels themselves are able to induce leptin resistance Elevated serum leptin concentrations in humans are associated with myocardial infarction and stroke independently of traditional cardiovascular risk factors and obesity status 18as well as with insulin resistance, inflammation, disturbances in hemostasis 19hypertension 20and the extent of coronary artery calcification in women On the other hand, leptin has been proven to be an efficient vasodilator in humans with coronary artery disease It has been proposed that leptin could play a role in the pathogenesis of atheromatous plaques acting synergistically with other inflammatory mediators The proposed proatherogenic actions of leptin are supported by the demonstration that, in vitro, leptin stimulates the proliferation and hypertrophy of vascular smooth muscle cells and the production of matrix metalloproteinase 2 MMP-2promotes vascular production of proliferative and profibrotic cytokines, increases the secretion of the proatherogenic lipoprotein lipase by cultured human and murine macrophages, enhances platelet aggregation 14and is able to induce C-reactive protein expression in human coronary artery endothelial cells At the cardiac level leptin regulates cardiac contractile function 25metabolism 26and cell dimension and production of extracellular matrix components 27 in cardiomyocytes; reduces reperfusion-induced cardiac cell death 28 ; and induces elongation of cardiac myocytes causing eccentric dilatation with compensation A role for leptin in the regulation of cardiomyocyte hypertrophy has been also suggested It is well known that leptin exerts direct actions on immune response, as reviewed by Matarese et al In addition to these actions, leptin has also been related to rheumatic diseases due to its ability to regulate bone metabolism via the central sympathetic nervous system It seems that leptin plays a role in several autoimmune diseases such as RA.
This idea is underpinned by several in vivo and in vitro findings: in RA patients, circulating leptin levels have been found to be higher than in healthy controls 3334 ; however, other studies reported unchanged levels. Moreover, leptin has been involved in RA-induced hypoandrogenicity, since leptin levels were negatively correlated to androstenedione Therefore, since leptin acts as a proinflammatory agent and androgens are generally considered as antiinflammatory molecules, the preponderance of leptin and hypoandrogenicity may help to perpetuate chronic rheumatic diseases such as RA.
However, neither infliximab nor adalimumab treatment was able to affect plasma or serum leptin levels 37 On the other hand, experiments carried out in arthritis animal models also strengthen the involvement of leptin in RA disease. Together with in vivo experiments, in vitro experiments also revealed a proinflammatory facet of leptin. In comparison to RA, OA has a lower immune component. Despite this aspect, leptin has also been related to this pathology. It is known that leptin expression is much higher in human OA cartilage than in normal cartilage.
Moreover, leptin expression in chondrocytes, as in synovial fluid, correlates with the severity of the disease 42 - Considering the sexual dimorphism of leptin circulating levels, it has been hypothesized that the increased predisposition of women to develop OA could be due to the higher circulating levels observed in women in comparison with men In vivo experiments also support the involvement of leptin in OA.
Very recently it has been reported that induced obesity due to impaired leptin aling is able to induce alterations in subchondral bone morphology without increasing the incidence of knee OA. These imply that only adiposity is insufficient to develop OA, pointing to a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems In agreement with these data, intraarticular injection of leptin in rat ts suggested that leptin plays a catabolic role on cartilage metabolism, since it induced cartilage levels of MMP-2, MMP-9, and proteoglycan depletion As for RA, in vitro experiments also pointed to a role of leptin in OA.
Leptin has also been involved in bone metabolism. Actually, it has been suggested that abnormal production of leptin by OA osteoblasts could be responsible for an altered osteoblast function in OA Regarding the role of leptin in SLE, some controversy exists. At present most of the studies pointed to a role for leptin in this pathology. Circulating leptin levels have been found to be increased in SLE patients compared to healthy controls, even after BMI correction 50 - To note, in some of these studies, the hyperleptinemia coexists with CVDs and with several features of the metabolic syndrome.
Indeed, in a lupus animal model, both high-fat diet and leptin increase proinflammatory high-density lipoproteins scores, atherosclerosis, and proteinuria, suggesting that factors typically associated with the metabolic syndrome can accelerate the disease and its cardiovascular complications Moreover, leptin has been involved in SLE-induced hypoandrogenicity, since leptin levels were negatively correlated with androstenedione In contrast to these studies, other groups have reported lower or unchanged circulating leptin levels in SLE patients compared to healthy controls 57 The role of leptin in AS is still unclear and the data available are somewhat scarce and contradictory.Women in need 49 Fontana mass 49
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