Articles on Inflammation & Atherosclerosis 

1. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction.
2. Vascular risks and complications in diabetes mellitus: the role of helicobacter pylori infection. Journal of Stroke & Cerebrovascular Diseases.
3. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice.
4. Inflammatory mechanisms: the molecular basis of inflammation and disease.
5. Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery.
6. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation.
7. Endothelial dysfunction in obesity: etiological role in atherosclerosis.
8. Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links.
9. Anti-inflammatory drugs and atherosclerosis.
10. The two faces of the 15-lipoxygenase in atherosclerosis.
11. The macrophage at the crossroads of insulin resistance and atherosclerosis.
12. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia.
13. Zinc and inflammatory/immune response in aging.
14. Olive oil and the cardiovascular system.
15. Clustering of cardiovascular risk factors in rheumatoid arthritis: the rationale for using statins.
16. Intertwining of thrombosis and inflammation in atherosclerosis.
17. Metabolic syndrome, inflammation and atherosclerosis.
18. Inflammation and disease progression. 
19. Molecular and signaling mechanisms of atherosclerosis in insulin resistance.
20. Arteries, inflammation and insulin resistance.
21. Links between inflammation and thrombogenicity in atherosclerosis.
22. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease.
23. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization.
24. Inflammation: a pivotal link between autoimmune diseases and atherosclerosis.
25. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence.
26. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin.
27. Inflammation and cardiovascular disease mechanisms.

Hamed SA. Amine NF. Galal GM. Helal SR. Tag El-Din LM. Shawky OA. Ahmed EA. Abdel Rahman MS. Vascular risks and complications in diabetes mellitus: the role of helicobacter pylori infection. Journal of Stroke & Cerebrovascular Diseases. 17(2):86-94, 2008. Patients with diabetes mellitus (DM) are at risk for Helicobacter pylori infection. This infection has been linked to atherosclerosis and its vascular complications. The aim of this study was to evaluate the: (1) prevalence of H pylori infection in patients with DM; (2) association between diabetic vascular complications and H pylori infection; and (3) influence of H pylori infection on atherosclerosis and inflammatory biomarkers. In this study, we evaluated 80 patients with DM for atherosclerosis; cardiac, cerebral, and peripheral vascular diseases; retinopathy; neuropathy; and nephropathy. We estimated the blood levels of glucose, glycosylated hemoglobin, complete blood cell count, erythrocytic sedimentation rate, lipid profile, tumor necrosis factor-alpha, interleukin (IL)-6, and anti-H pylori IgG antibodies. H pylori infection was detected in 85% of patients versus 76.7% for control subjects. Carotid artery intima-media thickness was significant in H pylori-infected patients. IL-6 and tumor necrosis factor-alpha were significantly associated with H pylori infection. In multivariate analysis, blood glucose, triglycerides, erythrocytic sedimentation rate, IL-6, and tumor necrosis factor-alpha increased the odds for atherothrombotic cause of cerebral ischemia in H pylori infection. We concluded that H pylori infection is common in DM and seems to be linked to the presence of atherosclerosis and ischemic cerebrovascular stroke. This effect could be mediated by increasing cytokine levels. 

Harja E. Bu DX. Hudson BI. Chang JS. Shen X. Hallam K. Kalea AZ. Lu Y. Rosario RH. Oruganti S. Nikolla Z. Belov D. Lalla E. Ramasamy R. Yan SF. Schmidt AM. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. Journal of Clinical Investigation. 118(1):183-94, 2008. Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall. 

Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. [Review] [55 refs] Nutrition Reviews. 65(12 Pt 2):S140-6, 2007. Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues. Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation. Mastery of the inflammatory response should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of chronic diseases associated with aging, such as atherosclerosis. 

Watanabe M. Sangawa A. Sasaki Y. Yamashita M. Tanaka-Shintani M. Shintaku M. Ishikawa Y. Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery. Journal of Atherosclerosis & Thrombosis. 14(6):325-31, 2007. AIM: Since atherosclerosis was recognized as an inflammatory disease in 1990, the infiltration of macrophages and T lymphocytes has been reported to be predominant in human atherosclerotic lesions. Although adventitis accompanying atherosclerosis was also described in many reports, it is still unclear whether T lymphocytes or B lymphocytes are predominant in the adventitis. In this study, the authors immunohistochemically investigated the correlation between the transition of infiltrating inflammatory cells in the adventitia with atherosclerosis and the type of coronary atherosclerosis. METHODS: Sixty-four coronary atherosclerotic lesions from a surgical specimen and 47 autopsy cases were used for immunohistochemical study of CD45RO, CD20, CD68 and others. Atherosclerosis was classified into type I, II, III, IV according to the 1995 AHA classification. RESULTS: T lymphocyte infiltration in the adventitia was predominantly recognized in about 80% (38/48) of cases, but B lymphocyte infiltration was occasionally recognized in about 20% (10/48). Among 10 cases with B lymphocyte infiltration, small lymph follicles formed in 3 cases. This inflammatory response in adventitia subsided in type III and augmented again in type IV.CONCLUSION: This result suggested that other inflammatory stimuli were induced in the adventitia in type IV coronary atherosclerosis. 

Hannawi S. Haluska B. Marwick TH. Thomas R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Research & Therapy. 9(6):R116, 2007. Rheumatoid arthritis (RA) patients have increased mortality and morbidity as a result of cardiovascular and cerebrovascular disease. What is not clear, however, is either how early accelerated atherosclerosis begins in RA or how soon risk factors must be rigorously controlled. Furthermore, given the strong relationship of vascular disease to RA mortality and of inflammation to the accelerated atherosclerosis associated with RA, it is important to evaluate indices that could serially and noninvasively quantify atherosclerotic disease in RA patients. The carotid intima-media thickness (cIMT) and plaque, measured by ultrasound, correlate closely with direct measurement of the local and systemic atherosclerotic burden. To investigate the presence of subclinical atherosclerosis in the early stages of RA, the cIMT and plaque were measured using carotid duplex scanning in 40 RA patients with disease duration < 12 months and in 40 control subjects matched for age, sex and established cardiovascular risk factors. Patients with RA had significantly higher average cIMT values and more plaque than the control group (cIMT 0.64 +/- 0.13 mm versus 0.58 +/- 0.09 mm, respectively; P = 0.03). In RA patients, the cIMT was predicted by age and C-reactive protein level at first presentation to the clinic (R2 = 0.64). C-reactive protein was associated with age of disease onset and history of smoking. Since inflammation has been shown to predate onset of clinical RA, the accelerated atherogenic process related to inflammation may precede RA symptom onset. 

Meyers MR. Gokce N. Endothelial dysfunction in obesity: etiological role in atherosclerosis. [Review] [58 refs] Current Opinion in Endocrinology, Diabetes & Obesity. 14(5):365-9, 2007. PURPOSE OF REVIEW: To review studies of vascular endothelial dysfunction in obesity, discuss potential mechanisms of disease, and address the therapeutic effects of weight loss interventions on arterial health. RECENT FINDINGS: Endothelial dysfunction represents the earliest abnormality in the development of vascular disease, and is pathophysiologically linked to subsequent atherosclerosis progression and cardiovascular disease events. Obesity is closely associated with a number of established cardiovascular risk factors, including diabetes mellitus, insulin resistance, dyslipidemia, and hypertension that are cumulatively damaging to the endothelium. In addition, there is now a growing recognition of non-traditional risk factors as potential modulators of the endothelial phenotype in obesity, including fat tissue production of proatherogenic adipokines, oxidative stress, and chronic inflammation. Clinical studies have demonstrated that even modest weight loss reverses endothelial dysfunction, and the restoration of arterial homeostasis could potentially reduce cardiovascular risk. SUMMARY: Obesity is associated with altered arterial homeostasis and endothelial dysfunction. Mechanisms of disease are related to a complex interplay of metabolic and inflammatory factors that coordinately improve along with arterial function in response to weight loss interventions. 

Vlachopoulos C. Rokkas K. Ioakeimidis N. Stefanadis C. Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. [Review] [75 refs] European Urology. 52(6):1590-600, 2007. OBJECTIVE: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. METHODS: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. RESULTS: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial-prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. CONCLUSIONS: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events. 

Moubayed SP. Heinonen TM. Tardif JC. Anti-inflammatory drugs and atherosclerosis. [Review] [65 refs] Current Opinion in Lipidology. 18(6):638-44, 2007. PURPOSE OF REVIEW: Inflammation contributes to the formation and progression of atherosclerosis and the therapeutic potential of some anti-inflammatory drugs has been evaluated for possible antiatherosclerotic effects. This review will briefly describe the mechanisms underlying the inflammation-atherosclerosis connection, the effect of various anti-inflammatory therapies on atherosclerotic disease and a sampling of the potential targets and agents under evaluation. RECENT FINDINGS: Some agents with anti-inflammatory properties appear to have beneficial effects on atherosclerosis or subsequent risk for cardiovascular events, while others have been disappointing. The anti-inflammatory actions of statins have been linked retrospectively with their favorable effects on atherosclerosis progression and clinical outcomes. The cardiovascular safety of COX-2 inhibitors is being assessed prospectively in patients with atherosclerosis. Potential new therapeutic agents targeting other inflammatory mechanisms and oxidative stress are being evaluated in animal models and clinical trials. SUMMARY: Due to the contributory inflammatory pathways in atherosclerosis, the properties of existing and novel anti-inflammatory agents are being carefully and actively evaluated in cardiovascular disease. Advances in our understanding of both atherosclerosis and the inflammatory contributors may play an important role in future strategies to decrease the incidence of atherosclerotic cardiovascular disease. 

Wittwer J. Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. [Review] [118 refs] Prostaglandins Leukotrienes & Essential Fatty Acids. 77(2):67-77, 2007. Chronic inflammation plays a major role in atherogenesis and understanding the role of inflammation and its resolution will offer novel approaches to interfere with atherogenesis. The 15(S)-lipoxygenase (15-LOX) plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell cultures and primary cells and even opposite effects on atherosclerosis in two different animal species. There is evidence for a pro-atherosclerotic effect of 15-LOX including the direct contribution to LDL oxidation and to the recruitment of monocytes to the vessel wall, its role in angiotensin II mediated mechanisms and in vascular smooth muscle cell proliferation. In contrast to the pro-atherosclerotic effects of 15-LOX, there is also a broad line of evidence that 15-LOX metabolites of arachidonic and linoleic acid have anti-inflammatory effects. The 15-LOX arachidonic acid metabolite 15-HETE inhibits superoxide production and polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium and can be further metabolized to the anti-inflammatory lipoxins. These promote vasorelaxation in the aorta and counteract the action of most other pro-inflammatory factors like leukotrienes and prostanoids. Anti-atherogenic properties are also reported for the linoleic acid oxidation product 13-HODE through inhibition of adhesion of several blood cells to the endothelium. Furthermore, there is evidence that 15-LOX is involved in the metabolism of the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) leading to a family of anti-inflammatory resolvins and protectins. From these cell culture and animal studies the role of the 15-LOX in human atherosclerosis cannot be predicted. However, recent genetic studies characterized the 15-LOX haplotypes in Caucasians and discovered a functional polymorphism in the human 15-LOX promoter. This will now allow large studies to investigate an association of 15-LOX with coronary artery disease and to answer the question whether 15-LOX is pro- or anti-atherogenic in humans. 

Liang CP. Han S. Senokuchi T. Tall AR. The macrophage at the crossroads of insulin resistance and atherosclerosis. [Review] [124 refs] Circulation Research. 100(11):1546-55, 2007. The macrophage has emerged as an important player in the pathogenesis of both atherosclerosis and insulin resistance. Cross-talk between inflammatory macrophages and adipocytes may be involved in insulin resistance in peripheral tissues. Defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis. Insulin resistant macrophages are more susceptible to endoplasmic reticulum stress and apoptosis in response to various stimuli such as nutrient deprivation, free cholesterol loading, and oxidized LDL. Increased apoptosis of insulin resistant macrophages and impaired phagocytic clearance of apoptotic cells by insulin resistant macrophages in atherosclerotic lesions may lead to enhanced postapoptotic necrosis, larger lipid-rich cores, increased inflammation, and more complex vulnerable plaques. Williams MD. Nadler JL. Inflammatory mechanisms of diabetic complications. [Review] [69 refs] Current Diabetes Reports. 7(3):242-8, 2007Activation of inflammatory processes may contribute to the development of type 2 diabetes mellitus. In addition, inflammation appears to be a major mechanism responsible for vascular damage leading to the clinically well-recognized complications of diabetes. Inflammatory cytokine and chemokine mediators released from visceral fat contribute to atherosclerotic plaque formation and increased risk for myocardial infarction and stroke. Activation of growth factors and adhesion molecules may promote the movement of inflammatory cells into the renal microvasculature, predisposing to the development of diabetic nephropathy. Emerging evidence also indicates that markers of inflammation are associated with the more severe forms of diabetic retinopathy. Future approaches to the treatment of diabetic complications may involve regulation of inflammatory processes, specifically targeting factors that contribute to vascular damage. 

Hahn BH. Grossman J. Chen W. McMahon M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. [Review] [37 refs] Journal of Autoimmunity. 28(2-3):69-75, 2007. As patients with autoimmune rheumatic diseases live longer due to improved therapies and preventive measures, death and disability from atherosclerosis, particularly myocardial infarcts, are increasing. The relative risks for atherosclerosis vary from approximately 1.6 in ankylosing spondylitis and psoriatic arthritis to 3.0 in rheumatoid arthritis (RA), and 6.0 in systemic lupus erythematosus (SLE). Increased risks are found when analyzed by atherosclerotic events, causes of death, or surrogate measures of atherosclerosis, such as carotid artery plaque, intimal-media thickness, or coronary artery calcification. At all ages among adults, atherosclerosis is increased in patients with SLE or RA compared to healthy controls. For example, in women with SLE under the age of 40 years, approximately 13% have carotid plaque compared to 2% of controls; over age 59 the percentages are 71 and 45, respectively. For patients with RA, prevalence is 7% under the age of 40 in patients compared to zero in controls; over 59 years the prevalences are 80% and 44%, respectively. In this review we will discuss the mechanisms involved as well as an overview of the natural history in pathobiology. 

Vasto S. Mocchegiani E. Malavolta M. Cuppari I. Listi F. Nuzzo D. Ditta V. Candore G. Caruso C. Zinc and inflammatory/immune response in aging. [Review] [49 refs] Annals of the New York Academy of Sciences. 1100:111-22, 2007. Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of refined wheat products that lack zinc and other critical nutrients as a consequence of the refining process. On the other hand, plasma zinc concentration is influenced by proinflammatory cytokines (IL-6 and TNF-alpha) and by metallothioneins (MT) homeostasis, which is in turn affected by proinflammatory cytokines. MT increase in aging and chronic inflammation allowing a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon leads to an impaired inflammatory/immune response in the elderly. A major target of zinc is NF-kappaB, a transcription factor critical for the expression of proinflammatory cytokines whose production is regulated by extra- and intracellular activating and inhibiting factors interacting with the regulatory elements on cytokine genes. Effects of zinc on translocation of NF-kappaB have been attributed to the suppression of phosphorylation and degradation of the inhibitory proteins (A20) that normally sequester it in the cytoplasm. Moreover, this factor and A20 are regulated by specific genes involved in inflammation and by intracellular zinc ion availability. So, it is not so surprising that zinc deficiency is constantly observed in chronic inflammation, such as in old individuals. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms are associated with atherosclerosis and diabetes type 2. Therefore, zinc turnover, via MT homeostasis, in individuals genetically predisposed to a dysregulation of the inflammatory/immune response may play a crucial role in causing possible adverse events with the appearance of age-related diseases. 

Covas MI. Olive oil and the cardiovascular system. [Review] [153 refs] Pharmacological Research. 55(3):175-86, 2007. Olive oil is the primary source of fat in the Mediterranean diet which is associated with a low mortality for cardiovascular disease. In spite of this, data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for cardiovascular disease. The benefits of olive oil consumption are beyond a mere reduction of the low density lipoprotein cholesterol. Here, we review the state of the art concerning the knowledge of the most important biological and clinical effects related to the intake of olive oil rich diets on lipoprotein metabolism, oxidative damage, inflammation, endothelial dysfunction, blood pressure, thrombosis, and carbohydrate metabolism. The extent to which we possess evidence of the health benefits of olive oil minor components is also assessed. The wide range of anti-atherogenic effects associated with olive oil consumption could contribute to explain the low rate of cardiovascular mortality found in Southern European Mediterranean countries, in comparison with other western countries, despite a high prevalence of coronary heart disease risk factors. 

Gazi IF. Boumpas DT. Mikhailidis DP. Ganotakis ES. Clustering of cardiovascular risk factors in rheumatoid arthritis: the rationale for using statins. [Review] [200 refs] Clinical & Experimental Rheumatology. 25(1):102-11, 2007. Atherosclerosis may be more prevalent and more extensive in individuals with rheumatoid arthritis (RA) compared with the general population. Despite the fact that traditional and novel cardiovascular disease (CVD) risk factors are clinically important in these patients, it seems that inflammation--a key feature of RA--plays a crucial role in atherogenesis. Reducing the CVD burden in patients with RA is a more complex process than in the general population, mostly due to inadequate inflammation suppression as well as multiple concomitant drug therapy. Furthermore, there is no current consensus on whether RA patients should be treated as individuals at high-risk for vascular events. Statins have proved their efficacy in reducing CVD events in the general population. Despite the fact that they are not specifically indicated in RA, there is evidence supporting a beneficial effect on CVD risk factors as well as disease activity and progression. The present review considers the traditional and novel as well as the RA-specific CVD risk factors. The current evidence supporting the use of statins in this patient population is also discussed. 

Croce K. Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. [Review] [76 refs] Current Opinion in Hematology. 14(1):55-61, 2007. PURPOSE OF REVIEW: The aim of this article is to highlight the importance of thrombotic processes in the development and complications of atherosclerotic vascular disease. RECENT FINDINGS: Thrombin generated at sites of vascular inflammation activates major atheroma-associated cells including endothelial cells, platelets, smooth muscle cells, monocytes, and macrophages. Thrombin-activated cells produce a plethora of inflammatory mediators, such as regulated upon activation normal T cell expressed presumed secreted, macrophage migration inhibitory factor, and CD40 ligand, that promote atherosclerotic lesion formation and atherothrombotic complications of vascular disease. Additionally, thrombin-induced inflammatory mediators stimulate tissue factor procoagulant activity within atheroma to initiate a positive feedback loop where thrombin activation launches inflammatory signals that lead to further thrombin activation. Platelets, the main cellular effectors of the thrombotic system, also play a central role in the biology of atherosclerosis by producing inflammatory mediators and directing leukocyte incorporation into plaques through platelet-mediated leukocyte adhesion. SUMMARY: New research has identified signaling pathways that intertwine thrombotic and inflammatory pathways with the development and progression of atherosclerosis. These signaling pathways contain positive feedback loops that propagate atherogenesis. Targeting molecular regulators at the interface of thrombosis and inflammation simultaneously may reduce thrombosis and inflammation, thus breaking pathological cycles that promote atherosclerosis and associated thrombotic complications. 

Paoletti R. Bolego C. Poli A. Cignarella A. Metabolic syndrome, inflammation and atherosclerosis. [see comment]. [Review] [52 refs] Vascular Health & Risk Management. 2(2):145-52, 2006.The inflammatory component of atherogenesis has been increasingly recognized over the last decade. Inflammation participates in all stages of atherosclerosis, not only during initiation and during evolution of lesions, but also with precipitation of acute thrombotic complications. The metabolic syndrome is associated with increased risk for development of both cardiovascular disease and type-2 diabetes in humans. Central obesity and insulin resistance are thought to represent common underlying factors of the syndrome, which features a chronic low-grade inflammatory state. Diagnosis of the metabolic syndrome occurs using defined threshold values for waist circumference, blood pressure, fasting glucose and dyslipidemia. The metabolic syndrome appears to affect a significant proportion of the population. Therapeutic approaches that reduce the levels of proinflammatory biomarkers and address traditional risk factors are particularly important in preventing cardiovascular disease and, potentially, diabetes. The primary management of metabolic syndrome involves healthy lifestyle promotion through moderate calorie restriction, moderate increase in physical activity and change in dietary composition. Treatment of individual components aims to control atherogenic dyslipidemia using fibrates and statins, elevated blood pressure, and hyperglycemia. While no single treatment for the metabolic syndrome as a whole yet exists, emerging therapies offer potential as future therapeutic approaches. 

Krishnamoorthy S. Honn KV. Inflammation and disease progression. [Review] [71 refs] Cancer & Metastasis Reviews. 25(3):481-91, 2006. Inflammation is a physiological response to a foreign organism such as bacteria, dust particles, and viruses. Recent studies have enlightened the role of inflammation in the progression of a variety of diseases such as cancer, atherosclerosis, asthma, and psoriasis. This article is a brief overview of the inflammatory processes involved in the progression of these common diseases. Knowledge about these mechanisms can shed light into development of newer therapeutic agents that are aimed at the eradication of these diseases. 

Schwartz EA. Reaven PD. Molecular and signaling mechanisms of atherosclerosis in insulin resistance. [Review] [176 refs] Endocrinology & Metabolism Clinics of North America. 35(3):525-49, viii, 2006. Although the prevalence of cardiovascular complications is increased in insulin-resistant individuals, the underlying causes of this link have been elusive. Recent work suggests that several intracellular signal transduction pathways are inappropriately activated by hyperinsulinemia, hyperglycemia, increased free fatty acids, dyslipidemia, various inflammatory cytokines and adipokines--factors that are increased in insulin resistance. Once activated, substantial cross talk occurs between these pathways, especially a self-reinforcing cascade of vascular inflammation and cell dysfunction, greatly increasing the risk and severity of atherosclerosis in the insulin-resistant individual. We review several key cell-signalling pathways, describe how they are activated in they insulin-resistant state and the damage they induce, and discusses possible therapeutic approaches to limit vascular damage. 

Amar J. Perez L. Burcelin R. Chamontin B. Arteries, inflammation and insulin resistance. [Review] [21 refs] Journal of Hypertension - Supplement. 24(5):S18-20, 2006. Inflammation plays a role in all stages of atherosclerosis from the formation to the rupture of the plaque. Guided by inflammatory mediators, monocytes bind to an endothelium damaged by cardiovascular risk factors, and then migrate towards the intima where, after incorporating oxidized low-density lipoprotein particles, they are transformed into foam cells. The lipid streak forms and develops as an atherosclerotic plaque, which is susceptible to erosion and rupture. Inflammation fed by excess adipose tissue decreases insulin sensitivity, which is the central feature of the metabolic syndrome. Inflammation therefore appears to be a common factor of atherosclerosis and the metabolic syndrome. The factors triggering this inflammation have yet to be determined. One line of thought would appear to point to diet. 

Viles-Gonzalez JF. Fuster V. Badimon JJ. Links between inflammation and thrombogenicity in atherosclerosis. [Review] [129 refs] Current Molecular Medicine. 6(5):489-99, 2006. Plaque disruption and subsequent thrombus formation play a critical role in the clinical manifestations of atherothrombosis. Vulnerable lesions are characterized by the existence of core rich in lipid, macrophages and tissue factor (TF). Plaque disruption facilitates the interaction between flowing blood with the inner components (TF) of disrupted atherosclerotic lesions triggering the coagulation cascade. TF, thrombin, platelets, fibrin and inflammatory cells are involved in this process of acute thrombus formation. This pathologic process is significantly accelerated by several "cardiovascular risk factors" such as diabetes, smoking, dyslipemia, etc. We will review on the role of TF, plaque cell apoptosis and blood thrombogenicity acting as a thread of inflammatory and prothrombotic mediators. We will also review the role of activated platelets as source for pro-inflammatory cytokines and enunciation of thrombotic process. Overall, we will try to emphasize the most recent understanding of the concepts involved in the interaction between inflammation and coagulation within the setting of atherothrombotic disease. 

Chapman MJ. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. [Review] [149 refs] Pharmacology & Therapeutics. 111(3):893-908, 2006. Innovative pharmacological approaches to raise anti-atherogenic high-density lipoprotein-cholesterol (HDL-C) are currently of considerable interest, particularly in atherogenic dyslipidemias characterized by low levels of HDL-C, such as type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia, but equally among individuals with or at elevated risk for premature cardiovascular disease (CVD). Epidemiological and observational studies first demonstrated that HDL-C was a strong, independent predictor of coronary heart disease (CHD) risk, and suggested that raising HDL-C levels might afford clinical benefit. Accumulating data from clinical trials of pharmacological agents that raise HDL-C levels have supported this concept. In addition to the pivotal role that HDL-C plays in reverse cholesterol transport and cellular cholesterol efflux, HDL particles possess a spectrum of anti-inflammatory, anti-oxidative, anti-apoptotic, anti-thrombotic, vasodilatory and anti-infectious properties, all of which potentially contribute to their atheroprotective nature. Significantly, anti-atherogenic properties of HDL particles are attenuated in common metabolic diseases that are characterized by subnormal HDL-C levels, such as type 2 diabetes and metabolic syndrome. Inhibition of cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism and transport, constitutes an innovative target for HDL-C raising. In lipid efficacy trials, 2 CETP inhibitors-JTT-705 and torcetrapib-induced marked elevation in HDL-C levels, with torcetrapib displaying greater efficacy. Moreover, both agents attenuate aortic atherosclerosis in cholesterol-fed rabbits. Clinical trial data demonstrating the clinical benefits of these drugs on atherosclerosis and CHD are eagerly awaited. 

Stoll G. Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. [Review] [136 refs] Stroke. 37(7):1923-32, 2006. BACKGROUND AND PURPOSE: The simplistic view of atherosclerosis as a disorder of pathological lipid deposition has been redefined by the more complex concept of an ongoing inflammatory response. SUMMARY OF REVIEW: Apolipoprotein E and low-density lipoprotein (LDL)-receptor-deficient mice develop accelerated atherosclerosis allowing in-depth pathophysiological investigations. Atherosclerotic plaques in these mice contain large numbers of T cells and macrophages. Crossbreeding apolipoprotein E-deficient mice with T-cell-deficient mice and mice with impaired macrophage function (osteopetrotic op/op mice) disclosed the important impact of immune cells on atherosclerotic lesion development. In contrast to the detrimental role of T cells and macrophages, B cells appear to be atheroprotective. These basic experimental findings have partly been confirmed in studies of the human carotid artery system. Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder. Humoral factors involved in internal carotid artery destabilization include cytokines, cyclooxygenase-2, matrix metalloproteinases, and tissue factor. Antibodies to oxidized LDL can reflect disease activity on one hand, but can also confer atheroprotection. Novel MRI techniques may aid in the in vivo assessment of acute plaque inflammation in humans. CONCLUSIONS: The impact of inflammation on the development of atherosclerotic plaques and their destabilization opens new avenues for treatment. The effects of statins, acetylsalicyclic acid and angiotensin-converting enzyme inhibitors on stroke prevention may partly be attributable to their profound anti-inflammatory actions. Vaccination against modified LDL and heat shock proteins halt plaque progression in experimental atherosclerosis. Their potential for prevention of human atherosclerosis is currently under investigation. 

Abou-Raya A. Abou-Raya S. Inflammation: a pivotal link between autoimmune diseases and atherosclerosis. [Review] [40 refs] Autoimmunity Reviews. 5(5):331-7, 2006. Premature coronary heart disease has emerged as a major cause of morbidity and mortality in systemic autoimmune diseases. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and that of atherosclerosis. Some of the most remarkable data in support of a link between autoimmunity and atherosclerosis comes from epidemiological studies of patients with autoimmune disorders (RA and SLE). Many epidemiologic observations have linked systemic inflammation with the cardiovascular events in autoimmune disease such as RA and SLE. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Systemic inflammation may be regarded as accelerating the atherosclerotic process. Systemic levels of soluble inflammatory mediators such as C-reactive protein (CRP) have been associated with cardiovascular risk in the general population. CRP, or more specifically high sensitivity-hsCRP, is a marker of systemic inflammation that has been identified as a valid biomarker of cardiovascular risk. Furthermore, the immunomodulatory and anti-inflammatory actions of statins may affect their utility in the context of chronic inflammatory autoimmune disease. Thus, effective control or dampening of inflammation, with such agents, should be included in the therapeutic armamentarium of autoimmune diseases with the aim of protecting against cardiovascular disease. 

Mozaffarian D. Trans fatty acids - effects on systemic inflammation and endothelial function. [Review] [15 refs] Atherosclerosis Supplements. 7(2):29-32, 2006. Consumption of trans fatty acids (TFA) predicts higher risk of coronary heart disease, sudden death, and possibly diabetes mellitus. These associations are greater than would be predicted by effects of TFA on serum lipoproteins alone. Systemic inflammation and endothelial dysfunction may be involved in the pathogenesis of atherosclerosis, acute coronary syndromes, sudden death, insulin resistance, dyslipidemia, and heart failure. Evidence from both observational and experimental studies indicates that TFA are pro-inflammatory. Limited evidence suggests that pro-inflammatory effects may be stronger for trans isomers of linoleic acid (trans-C18:2) and oleic acid (trans-C18:1), rather than of palmitoleic acid (trans-C16:1), but further study of potential isomer-specific effects is needed. TFA also appear to induce endothelial dysfunction. The mechanisms underlying these effects are not well-established, but may involve TFA incorporation into endothelial cell, monocyte/macrophage, or adipocyte cell membranes (affecting membrane signaling pathway relating to inflammation) or ligand-dependent effects on peroxisome proliferator-activated receptor (PPAR) or retinoid X receptor (RXR) pathways. Activation of inflammatory responses and endothelial dysfunction may represent important mediating pathways between TFA consumption and risk of coronary heart disease, sudden death, and diabetes. Further study is indicated to define these effects of TFA and the implications of such effects for cardiovascular health. 

Zambon A. Gervois P. Pauletto P. Fruchart JC. Staels B. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence. [Review] [113 refs] Arteriosclerosis, Thrombosis & Vascular Biology. 26(5):977-86, 2006. Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-alpha is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-alpha is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-alpha agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-alpha agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-alpha activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-alpha agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state. 

McCaffery JM. Frasure-Smith N. Dube MP. Theroux P. Rouleau GA. Duan Q. Lesperance F. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin.[see comment]. [Review] [233 refs] Psychosomatic Medicine. 68(2):187-200, 2006. OBJECTIVE: Although it is well established that depressive symptoms are associated with recurrent cardiac events among cardiac patients and novel cardiac events among participants with no known coronary artery disease (CAD), the nature of this association remains unclear. In this regard, little attention has been paid to the possibility that common genetic vulnerability contributes to both depressive symptoms and CAD. In this paper, we review the existing evidence for common genetic contributions to depression and CAD, primarily using evidence from twin and family studies, followed by a review of two major pathophysiological mechanisms thought to underlie covariation between depressive symptoms and CAD: inflammation and serotonin. We conclude with an overview of select candidate genes within these pathways. METHODS: Literature review. RESULTS: In twin studies, both depression and CAD appear heritable. In the only twin study to consider depression and CAD jointly, the correlation across heritabilities was 0.42, suggesting that nearly 20% of variability in depressive symptoms and CAD was attributable to common genetic factors. In addition, although it is plausible that genetic variation related to inflammation and serotonin may be associated with both depression and CAD, genetic variation related to inflammation has been primary examined in relation to CAD, whereas genetic variation in the serotonin system has been primarily examined in relation to depression. CONCLUSIONS: It appears that the covariation of depressive symptoms and CAD may be attributable, in part, to a common genetic vulnerability. Although several pathways may be involved, genes within the inflammation and serotonin pathways may serve as good candidates for the first steps in identifying genetic variation important for depression, CAD or both. 

Libby P. Inflammation and cardiovascular disease mechanisms. [Review] [54 refs] American Journal of Clinical Nutrition. 83(2):456S-460S, 2006. The traditional view of atherosclerosis as a lipid storage disease crumbles in the face of extensive and growing evidence that inflammation participates centrally in all stages of this disease, from the initial lesion to the end-stage thrombotic complications. Investigators now appreciate that narrowing arteries do not necessarily presage myocardial infarction and that simply treating narrowed blood vessels does not prolong life. Although invasive approaches such as angioplasty and coronary artery bypass will remain necessary in some cases, we now understand that at least some of the cardiovascular benefits attributable to medical treatment and lifestyle modification (diet and physical activity) may result from reductions in inflammatory processes.