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- Volume 20, Issue 4, 2014
Current Pharmaceutical Design - Volume 20, Issue 4, 2014
Volume 20, Issue 4, 2014
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Will Antirheumatic Treatment Improve Cardiovascular Outcomes in Patients with Rheumatoid Arthritis?
Authors: Herwig Pieringer, Max Pichler, Erich Pohanka and Uta C. HoppeIn recent years, the scientific community has gained significant insight into the complex interaction between inflammation and the cardiovascular system in patients with rheumatoid arthritis (RA), which leads to increased cardiovascular (CV) morbidity and mortality in these patients. Our common understanding of this association is that persistent inflammation contributes to the development of premature atherosclerosis. Consequently, the question arises whether control of inflammation with antirheumatic treatment will be able to improve CV outcome. While there are a lot of data that demonstrate improvement of numerous CV surrogate markers in patients treated with virtually all antirheumatic drug classes, there is much less information about the possible translation of these beneficial effects into improved CV outcome. In summary, the published evidence suggests that tumor necrosis factor (TNF) alpha inhibitors may improve CV outcome. The same is true for methotrexate (MTX). However, it is not clear whether MTX works via suppression of inflammation or through drug specific mechanisms. For other traditional disease-modifying antirheumatic drugs and biologic therapies, there are no convincing data for improved CV outcome. Only a few drugs (glucocorticoids and NSAIDs) have been associated with increased CV risk. Treating RA aggressively, as recommended by current guidelines, is likely to have a beneficial effect on CV outcomes.
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Myocardial Infarction after Rituximab Treatment for Rheumatoid Arthritis: Is there a Link?
Authors: Alper M. van Sijl, Wilfred van der Weele and Michael T. NurmohamedRituximab is an anti-CD20 monoclonal antibody often used in the treatment of rheumatoid arthritis (RA). Infusion reactions sometimes develop following rituximab administration. Delayed complications are rare. Acute coronary syndromes are listed as sideeffects of rituximab therapy. We report two cases of acute myocardial infarction following rituximab therapy for RA and review the literature regarding cardiac events in patients treated with rituximab. We would like to raise awareness of this possible complication in patients treated with rituximab.
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Effects of Biologic Agents and Other Disease-Modifying Antirheumatic Drugs on Cardiovascular Outcomes in Psoriasis and Psoriatic Arthritis: A Systematic Review
More LessBackground: Whether systemic treatments for psoriasis or psoriatic arthritis affect cardiovascular comorbidities is a clinically significant question. Objective: To examine the effects of biologic agents and other Disease-Modifying Antirheumatic Drugs (DMARDs) used to treat psoriasis and psoriatic arthritis on cardiovascular risk factors and adverse cardiovascular outcomes. Methods: MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for studies evaluating biologic and other DMARD therapy for psoriasis and psoriatic arthritis that reported cardiovascular events as primary outcomes. Results: From 20 studies that met the search criteria for the review, 81,469 patients with psoriasis and/or psoriatic arthritis were included in the data synthesis of the current literature. While the data on the cardioprotective effect of methotrexate exist in patients with rheumatoid arthritis, its effect on the psoriasis and psoriatic arthritis populations with regards to cardiovascular outcomes are inconclusive at this time. The association of hypertension with long-term cyclosporine use prompts discontinuation of cyclosporine in selected patients. The use of TNF inhibitors may be associated with reduced risk of adverse cardiovascular events in preliminary epidemiologic studies; however, large randomized controlled trials and epidemiologic studies with well-characterized populations will be necessary to elucidate their exact effects. The short-term data regarding the safety of IL-12/23 inhibitors showed that, to date, there are no increased cardiovascular events compared to the general population. Conclusions: To date, epidemiologic data is insufficient to reach definitive conclusions with regards to the effects of biologics and other DMARDs on cardiovascular outcomes in psoriasis and psoriatic arthritis patients. Adequately powered, long-term, controlled studies are necessary to determine the cardioprotective effects of TNF inhibitors observed in preliminary studies on psoriasis and psoriatic arthritis populations.
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Endothelial Dysfunction and the Effects of TNF Inhibitors on the Endothelium in Psoriasis and Psoriatic Arthritis: A Systematic Review
More LessBackground: Epidemiologic data support the association of psoriasis and psoriatic arthritis with adverse cardiovascular outcomes. Shared pathogenesis in endothelial dysfunction may underlie psoriasis and atherosclerosis. Tumor necrosis factor (TNF) inhibitors may modulate endothelial dysfunction seen in patients with psoriasis and psoriatic arthritis. Objective: To perform a systematic review that investigated endothelial function in psoriasis and psoriatic arthritis and the effect of TNF inhibitors on endothelial function in psoriasis and psoriatic arthritis. Methods: MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for cross-sectional or longitudinal studies that 1) examined endothelial function in patients with psoriasis or psoriatic arthritis, or 2) investigated the effect of TNF inhibitor therapy on endothelial function. Results: Twenty articles and four abstracts with 2261 patients evaluated endothelial function in psoriasis and psoriatic arthritis, which was measured by pulse wave velocity, flow-mediated dilation, nitroglycerine-induced vasodilation, carotid intima-media thickness, peripheral arterial tonometry, or aortic stiffness parameters. The majority of the data suggests that patients with psoriasis and psoriatic arthritis have significantly increased arterial stiffness, impaired endothelial-dependent vasodilation, increased carotid intima-media thickness, and decreased aortic elasticity compared to the general population. Two out of three studies showed that TNF inhibitors improved endothelial function in psoriasis and psoriatic arthritis. Limitations: Measurements of endothelial function were not standardized across studies. Conclusions: The preponderance of literature suggests that endothelial function is significantly impaired in patients with psoriasis and psoriatic arthritis compared to the general population. Preliminary evidence suggests that TNF inhibitors may improve endothelial function in the psoriasis and psoriatic arthritis populations.
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Psoriasis and Atherosclerosis: Is There a Need For Novel Biomarkers Assessing Cardiovascular Risk?
Authors: Murat Sunbul and Mehmet AgirbasliEpidemiological studies indicate increased mortality rates in cohorts of patients with psoriatic arthritis (PsA). Psoriasis is associated with an enhanced cardiovascular risk. The excess mortality in psoriasis and PsA is predominantly due to coronary artery disease. The aim of this review is to overview the biomarkers and/or mediators of increased cardiovascular risk in patients with psoriasis and PsA. We searched through Medline/PubMed to retrieve sources on cardiovascular disease (CVD), related risk factors and inflammatory markers in psoriasis and PsA. We analyzed the relationship between psoriasis and novel vascular biomarkers with potential use for preventive studies. Studies underline the importance of considering psoriatic patients as a high-risk population in terms of CVD. Novel biomarkers of inflammation, thrombosis, oxidative stress and atherosclerosis can provide risk stratification and strategies for early detection and treatment of CVD in patients with psoriasis. A better understanding of the association between psoriasis and vascular risk can help the clinician to manage the increased morbidity and mortality related to CVD.
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Micro- and Macrovascular Treatment Targets in Scleroderma Heart Disease
Cardiac involvement in systemic sclerosis (SSc) is a frequent visceral complication that considerably affects the prognosis of the disease. The pathophysiologic hallmark is myocardial fibrosis which can progress leading to arrhythmia, right and/or left heart dysfunction and failure. Symptoms range from unusual to prominent and from mild to dramatic, but clinically overt disease is a poor prognostic factor. Primary myocardial involvement is related to focal ischemia due to transient coronary spasm, and the available data support that microvascular functional and structural abnormalities rather than macrovascular coronary involvement represent the main underlying mechanism of the disease. However, the existence and prevalence of atherosclerotic coronary artery disease in SSc remain to be determined, as several studies have generated conflicting reports. Despite the lack of effective targeted therapy for SSc itself, sensitive and quantitative techniques have demonstrated the ability of vasodilators to improve myocardial function and perfusion and to prevent the evolution of subclinical heart involvement to decompensated heart failure. Further research will provide a better understanding of the disease by detecting the potent contribution of coronary artery involvement, explaining differences in accelerated atherosclerosis between SSc and other autoimmune disorders, and opening directions for the development of novel treatment strategies for this life-threatening complication of SSc.
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Primary Antiphospholipid Syndrome and Pulmonary Hypertension
Authors: Aibek E. Mirrakhimov and Nicholas S. HillPrimary antiphospholipid syndrome (APS) is a disease characterized by the presence of autoantibodies reacting with proteins bound to phospholipids, leading to thrombosis and gestation abnormalities. Prothrombotic states and impaired clot dissolution are believed to contribute to the occurrence of chronic thromboembolic pulmonary hypertension (CTEPH) in APS. Whether preventive anticoagulation therapy in patients with antiphospholipid autoantibodies without a history of thrombosis reduces the risk of thrombosis is currently unclear. The diagnosis and treatment of CTEPH in APS is similar to CTEPH complicated by other predisposing conditions, with surgical treatment being the most effective. However, not every patient with CTEPH is suitable for pulmonary thromboendartarectomy and such individuals may benefit from pharmacotherapy of pulmonary hypertension, given the presence of pulmonary microvascular abnormalities similar to those in idiopathic pulmonary hypertension. Anticoagulation therapy is the mainstay of management because of the high risk of recurrent embolization and local in-situ thrombosis.
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Platelets in Rheumatic Diseases: Friend or Foe?
Authors: Armen Yuri Gasparyan, Lilit Ayvazyan, Etheresia Pretorius and George D. KitasPlatelets are intimately involved in hemostasis, inflammation, innate and adaptive immunity, tissue regeneration and other physiological and pathological processes. Their granular structure is programmed to release a wide range of bioactive substances in response to agonists. Upon activation, platelet membranes display thrombotic and inflammatory agents, which may take an active part in the pathophysiology of autoimmune and autoinflammatory disorders. The aim of this review is to analyze current evidence of platelet (dys)function in inflammatory rheumatic diseases and overview platelettargeting mechanisms of antirheumatic drug therapies. A comprehensive search through Medline/PubMed, SciVerse/Scopus and Web of Science was performed for English-language original research papers, using the keywords related to platelets in autoimmune and autoinflammatory rheumatic disorders. Additionally, the Cochrane Collaboration database was searched for the literature on the effects of antirheumatic drugs on platelet function. A variety of platelet markers have been tested in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, spondyloarthropathies, vasculitides, and some autoinflammatory disorders. It has been shown that platelets circulate in an activated state in most of these disorders and tend to form complexes with other inflammatory and immune cells. Thrombotic and inflammatory agents, released from platelets, may trigger disease-specific complications (e.g., extraarticular features, fibrosis in systemic sclerosis) and propagate endothelial dysfunction. Whether platelet activation is a primary or secondary feature in rheumatic disorders remains to be elucidated. Some widely used antirheumatic drugs may suppress thrombopoiesis and platelet activity, however the clinical implications of this effect have yet to be examined in specifically designed prospective studies. Large retrospective cohort studies supported the use of low-dose aspirin for suppressing platelet function and preventing cerebrovascular events in giant-cell arteritis. However, emerging data suggest that the release rate of activated platelets applied topically to the inflamed cartilage in arthritis or skin ulcers in scleroderma may suppress the inflammation and facilitate tissue repair. Taken together, current evidence necessitates a balanced approach to platelet-activating and suppressing drug therapies in inflammatory rheumatic diseases.
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Targeting Platelet-Neutrophil Interactions in Giant-Cell Arteritis
Authors: Mattia Baldini, Angelo A. Manfredi and Norma MaugeriGiant-cell arteritis (GCA) is the most common vasculitis affecting large vessels in the elderly. It is associated with ischemic events that account for important disability. Despite the increasing insight in the mechanisms involved in the arterial wall inflammation, the events that lead to eventual occlusion of the vessels lumen are unknown. Cohort studies on risk factors for ischemic events and aspirin efficiency in GCA provide inconsistent results. Corticosteroids, which prevent the worsening or the recurrence of ischemia in the majority of patients, are slow-acting and not effective in all patients. The interaction between circulating activated platelets and leukocytes contributes in acute myocardial infarction and other ischemic diseases to determine the prothrombotic and inflammatory characteristics of blood cells. The activation of circulating platelets, their interaction with leukocytes and the expression of tissue factor by circulating leukocytes frequently occur in patients with GCA. The molecular characterization of the cross-talk between blood cells and the inflamed vessel wall could yield molecular targets for novel therapeutics, more effective than aspirin in preventing ischemic events and more specific than steroids in their treatment.
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Enhanced Proinflammatory State and Autoimmune Activation: a Breakthrough to Understanding Chronic Diseases
Authors: Altan Onat and Gunay CanInsight is provided herein into the novel mechanisms of cardiometabolic risk. Previous reports, including the epidemiological work of the Turkish Adult Risk Factor study, indicated that proinflammatory state and oxidative stress are crucial for evaluating cardiometabolic risk. Autoimmune pathways in the course of oxidative stress are major determinants of cardiorenal and metabolic risk. The latter encompasses metabolic syndrome, type 2 diabetes, coronary heart disease, and chronic kidney disease (CKD). Along with platelet-activating factor acetylhydrolase, creatinine, thyroid stimulating hormone, acylation-stimulating protein, asymmetric dimethylarginine, and serum lipoprotein[Lp](a) are triggers of systemic low-grade inflammation and enhanced autoimmune reactions. Related studies are analyzed in the current review. Lp(a) plays a crucial role by taking part in the immune activation, thereby accelerating the course of diabetes, CKD, and other chronic disorders. Populations prone to impaired glucose tolerance, and particularly peri- and postmenopausal women, are at high risk of developing related vascular complications.
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The Relationship between Inflammatory and Oxidative Stress Biomarkers, Atherosclerosis and Rheumatic Diseases
Authors: Corina Serban and Simona DraganAtherosclerotic cardiovascular disease is the leading cause of death in many developed countries. It is characterized by complex endocrine, paracrine and juxtacrine interactions between immune and vascular cells, as well as several tissues and organs. Oxidative stress and inflammation have an important role in the promotion of atherosclerotic cardiovascular disease. Considering the complicated mechanisms and signals involved in atherosclerosis, research is focused on blood-based biomarkers, gene-based markers, metabolomics and other potentially interesting approaches for biomarker discovery. These biomarkers can be introduced as routine diagnostic tests if they prove to be cost-effective and to predict future cardiovascular events. Given the overlap of circulating inflammatory and oxidative stress biomarkers in atherosclerosis and rheumatic diseases, we aim to overview their potential to screen cardiovascular risk and also to predict the evolution of associated rheumatic diseases.
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Leptin-Induced Endothelial Dysfunction: A Target for Therapeutic Interventions
Authors: Gregory A. Payne, Johnathan D. Tune and Jarrod D. KnudsonLeptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.
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Role of C Reactive Protein (CRP) in Leptin Resistance
Authors: Marta Letizia Hribal, Teresa Vanessa Fiorentino and Giorgio SestiIncreased plasma levels of both leptin and C reactive protein (CRP) have been reported in a number of conditions, including obesity, and have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk; interestingly these two biomarkers appear to be able to reciprocally regulate their bioavailability, through complex mechanisms that have not been completely clarified yet. Here we first review clinical evidence suggesting not only that the circulatory levels of CRP and leptin show an independent correlation, but also that assessing them in tandem may result in an increased ability to predict cardiovascular disease. We summarize also molecular studies showing that leptin is able to promote CRP production from hepatocytes and endothelial cells in vitro and discuss the studies addressing the possibility that in vivo leptin administration may be able to modulate plasma CRP levels. Furthermore, we describe two studies demonstrating that CRP directly binds leptin in extra-cellular settings, thus impairing its biological actions. Finally we report genetic evidence that common variations at the leptin receptor locus are associated with CRP blood levels. Overall, the data reviewed here show that the chronic elevation of CRP observed in obese subjects may worsen leptin resistance, contributing to the pathogenesis of cardiovascular disease, and highlight a potential link between conditions, such as leptin resistance and endothelial dysfunction, that may be amenable of pharmacological treatment targeted to the disruption of leptin-CRP interaction.
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Transactivation of ErbB Receptors by Leptin in the Cardiovascular System: Mechanisms, Consequences and Target for Therapy
Authors: Jerzy Beltowski and Anna Jazmroz-WisniewskaMany experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as “transactivation”. Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.
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Leptin and Vascular Smooth Muscle Cells
This review concerns the influence of leptin on vascular smooth muscle cells (VSMC). VSMC express different isoforms of the leptin receptor (Ob-R) able to activate a wide range of intracellular signalling pathways, mediating many relevant biological actions. In particular, leptin promotes processes deeply involved in atherogenesis, such as VSMC migration, hypertrophy, proliferation, osteogenic differentiation and metalloproteinase expression. The intracellular signalling molecules involved are JAK/STAT, PI3K/Akt, ERK 1/2, p38 MAPK, mTOR, and RhoA/ROCK. Some of these leptin actions are particularly evident in stretching conditions; others are mediated by the NAD(P)H-induced increase of Reactive Oxygen Species. A leptin-induced activation of angiotensin and endothelin systems, with up-regulation of the synthesis of the two hormones and of their receptors, has also been demonstrated. Other studies, however, showed that leptin increases in VSMC the nitric oxide production by activating the inducible nitric oxide synthase, and, via nitric oxide, exerts a vasodilating effect and impairs the proliferative and vasoconstricting actions of angiotensin II. Both the potentially harmful and the potentially beneficial effects exerted by leptin in VSMC are lost in VSMC from animal models of genetically determined leptinresistance. Cultured VSMC from leptin-resistant animals are also resistant to insulin and to nitric oxide. It is not known, however, whether in human obesity, a condition characterized by hypothalamic leptin resistance and by compensatory hyperleptinemia, VSMC are sensitive or resistant to leptin: only in the first case the predictive role of circulating leptin on cardiovascular events could support a pathogenetic influence of the hormone on atherosclerosis.
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Mechanisms Linking Leptin to Arterial and Venous Thrombosis: Potential Pharmacological Targets
Authors: Katrin Schafer and Stavros KonstantinidesEpidemiological evidence strongly links excess body weight with an increased risk to develop atherothrombotic complications. Obesity is frequently associated with systemic and local inflammation as well as elevated circulating leptin levels, and clinical studies found hyperleptinemia to correlate not only with measures of adiposity, but also with circulating biomarkers of an increased metabolic and cardiovascular risk or surrogate markers of subclinical atherosclerosis. Moreover, experimental studies in mice with systemic disruption of the leptin-leptin receptor system as well as after administration or neutralization of the adipokine demonstrated that leptin promotes both arterial and venous thrombosis. In addition to directly binding to and activating platelets and thus potentiating their aggregation in response to agonist stimulation, leptin enhances the expression of prothrombotic and anti-fibrinolytic proteins in vascular and inflammatory cells. On the other hand, its ability to mobilize and recruit vascular progenitor cells from the bone marrow to sites of vascular injury was found to be impaired in hyperleptinemic, obese humans and rodents. Thus, leptin promotes thrombus formation and resolution by several different mechanisms involving primary hemostasis, the coagulation cascade as well as the integrity of the vessel wall. Dissection of the molecular mechanisms underlying each of its actions may pave the road for novel therapeutic options in targeting the increased risk of thrombosis associated with obesity, keeping in mind unresolved issues of a cell-specific leptin resistance as well as individual differences in the responsiveness to leptin.
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Leptin in Thrombosis and Atherosclerosis
Authors: Hui Wang, Wei Luo and Daniel T. EitzmanA world-wide obesity epidemic is threatening to have a major impact on the prevalence of chronic and acute vascular diseases. In addition to weight loss interventions, which have met with modest success to date, it will be important to understand mechanisms by which obesity promotes vascular disease processes. Studies of leptin, a hormone produced by the adipocyte, have supported the concept that adipocyte-specific products may be mediating some of the vascular risk associated with obesity. This mini-review provides an overview of some of the preclinical studies demonstrating causal relationships between leptin and vascular endpoints. Therapeutic strategies designed to block leptin-mediated signaling events in cells contributing to vascular disease may prove beneficial in obese subjects at risk for vascular complications.
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Leptin as a Cardiac Pro-Hypertrophic Factor and its Potential Role in the Development of Heart Failure
Authors: Morris Karmazyn and Venkatesh RajapurohitamThe identification of the adipocyte as a source of production of biologically-active peptides has materialized into an active area of research related to the role of these peptides in physiology and pathophysiology. Moreover, this research has resulted in the identification of the adipocyte as an endocrine organ producing potent bioactive compounds. An increasing number of these adipokines are being identified, the first of which was leptin, a product of the obesity gene whose primary function is to act as a satiety factor but which is now known to exert a myriad of effects. It is now recognized that virtually all adipokines produce effects on numerous organ systems including the heart and many of these, including leptin, are produced by cardiac tissue. Here we focus primarily on the diverse effects of leptin on the heart especially as it pertains to hypertrophy and discuss the potential cell signaling mechanisms underlying their actions. Current evidence suggests that leptin is a cardiac hypertrophic factor and from clinical studies there is evidence that hyperleptinemia is associated with cardiovascular risk especially as it pertains to heart failure. While more substantial research needs to be carried out, leptin may represent a potential link between obesity, which is associated with hyperleptinemia, and increased cardiovascular risk.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)