EPIDEMIOLOGY

Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study. Deans KA, Bezlyak V, Ford I, Batty GD, Burns H, Cavanagh J, de Groot E, McGinty A, Millar K, Shiels PG, Tannahill C, Velupillai YN, Sattar N, Packard CJ. Department of Vascular Biochemistry, Glasgow Royal Infirmary, Glasgow G31 2ER. kevindeans@nhs.net Abstract OBJECTIVES: To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque score), and to determine whether any differences can be explained by "classic" (currently recognised) or "emerging" (novel) cardiovascular risk factors. DESIGN: Cross sectional, population based study. SETTING: NHS Greater Glasgow Health Board area. PARTICIPANTS: 666 participants were selected on the basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years). MAIN OUTCOME MEASURES: Carotid intima-media thickness and plaque score, as detected by ultrasound. RESULTS: The mean age and sex adjusted intima-media thickness was significantly higher in participants from the most deprived areas than in those from the least deprived areas (0.70 mm (standard deviation (SD) 0.16 mm) v 0.68 mm (SD 0.12 mm); P=0.015). On subgroup analysis, however, this difference was only apparent in the highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1.0 (SD 1.5) v most deprived 1.7 (SD 2.0); P<0.0001). In addition, a significant difference in plaque score was apparent in the two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P=0.0073 and P<0.001) and the highest age tertile in women (56.3-66.5 years; P<0.001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P=0.010). Adjustment for classic risk factors and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived and the least deprived individuals (adjusted odds ratio 0.94, 95% CI 0.54 to 1.65; P=0.84). CONCLUSIONS: Deprivation is associated with increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by classic or emerging risk factors. SEE FULL ARTICLE

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AUDIO

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PREVENTION

PREVENTION Try to follow these tips to prevent atherosclerosis: Quit smoking. Smoking accelerates the development of atherosclerosis, which often leads to coronary heart disease. Women who smoke are two to six times as likely to suffer a heart attack as nonsmoking women, and the risk increases with the number of cigarettes smoked per day. The good news is that quitting dramatically cuts your risk, even during the first year, no matter what your age. Lower your blood pressure. Even slightly high blood pressure levels can double your risk for heart disease. Normal blood pressure is less than 120/80 mm/Hg, according to the National Heart, Lung and Blood Institute. High blood pressure, or "hypertension," is a blood pressure reading of 140/90 mm/Hg or higher. Between 120/80 mm/Hg and 139/89 mmHg is considered prehypertension. High blood pressure also increases your chance of stroke, congestive heart failure and kidney disease. High blood pressure can be treated successfully with medication. Commonly prescribed drugs include diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta blockers and calcium channel blockers (CCBs). If your blood pressure is not too high, you may be able to control it entirely through weight loss (if you are overweight), regular physical activity and cutting down on alcohol as well as salt and sodium. Sodium is an ingredient in salt that is found in many packaged foods, carbonated beverages, baking soda and some antacids. Get regular exercise and lose weight. Regular physical activity is defined as 30 minutes of moderate-intensity physical activity, such as brisk walking, on most and preferably all days of the week, or 20 minutes of vigorous exercise, such as running, at least three days a week. Control your blood sugar if you have diabetes. Diabetes is typically diagnosed by a fasting glucose (sugar) over 126. Patients with diabetes should be treated to prevent complications from cardiovascular disease; treatment typically consists of a combination of lifestyle changes and medications. Your goal hemoglobin A1C with treatment should be less than seven percent. Those with diabetes who also have good sugar control are much less likely to develop cardiovascular complications than those with poor sugar control. Those individuals with a fasting glucose (sugar) of 100-126 may be considered pre-diabetes or glucose intolerant. This is often associated with metabolic syndrome and individuals with glucose intolerance are at high risk for developing true diabetes within the next couple years. Weight loss, healthy diet, and exercise are important to improve blood sugar levels and prevent the onset of diabetes. Lower your LDL-cholesterol level. Today, about a quarter of all American women have blood cholesterol levels high enough to pose a serious risk for atherosclerosis and heart disease. More than half of the women over age 55 need to lower their blood LDL cholesterol. Keep triglycerides in check. The lipoprotein profile that determines your cholesterol levels also measures another fatty substance called triglyceride. Produced in the liver, triglycerides are made up of saturated, polyunsaturated and monounsaturated fats. The optimal target triglyceride level for individuals without heart disease or heart disease-related risk factors is less than 150 mg/dL, with 100 mg/dL being an ideal level. For most people, cutting back on foods high in saturated fat and cholesterol will lower both total and LDL cholesterol. Regular physical activity and weight loss if you're overweight also reduces blood cholesterol levels. Losing extra weight, quitting smoking and becoming more physically active may also help boost HDL cholesterol levels. Reduce your homocysteine level. Homocysteine is an amino acid normally found in the body. Recent studies suggest that high blood levels of this substance may increase the risk of heart disease, stroke, and reduced blood flow to the hands and feet. It is believed that high levels of homocysteine may damage the arteries, making blood more likely to clot and/or making blood vessels less flexible. Homocysteine levels are affected by three vitamins—afolic acid and vitamins B6 and B12. Women who consume less than the recommended daily amounts of these vitamins are more likely to have higher homocysteine levels. Recommended daily amounts are 400 micrograms of folic acid, two mg of B6, and 2.4 mcg of B12. Good sources of folic acid include citrus fruits; tomatoes; dark green, leafy vegetables; whole-grain and fortified-grain products (whole wheat bread and oatmeal, for example) and beans and lentils. Foods high in B6 include beef, poultry, fish, fruits, vegetables and grain products. Major sources of B12 are beef, poultry, fish, milk and other dairy products. SEE WEB SITE

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Atherosclerosis

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CASE REPORT

Intravascular ultrasound of symptomatic intracranial stenosis demonstrates atherosclerotic plaque with intraplaque hemorrhage: a case report. .

Meyers PM, Schumacher HC, Gray WA, Fifi J, Gaudet JG, Heyer EJ, Chong JY. .

Department of Radiology, Columbia University, College of Physicians & Surgeons, Neurological Institute of New York, New York, New York 10032, USA. pmm2002@columbia.edu .

Abstract .

BACKGROUND: Intracranial artery stenosis is assumed to represent atherosclerotic plaque. Catheter cerebral arteriography shows that intracranial stenosis may progress, regress, or remain unchanged. It is counterintuitive that atherosclerotic plaque should spontaneously regress, raising questions about the composition of intracranial stenoses. Little is known about this disease entity in vivo. We provide the first demonstration of in vivo atherosclerotic plaque with intraplaque hemorrhage using intravascular ultrasound (IVUS). CASE DESCRIPTION: A 35-year-old man with multiple vascular risk factors presented with recurrent stroke failing medical therapy. Imaging demonstrated left internal carotid artery occlusion, severe intracranial right internal carotid artery stenosis, and cerebral perfusion failure. Cerebral arteriography with IVUS confirmed 85% stenosis of the petrous right carotid artery due to atherosclerotic plaque with intraplaque hemorrhage. Intracranial stent-supported angioplasty was performed with IRB approval. The patient recovered without complication. CONCLUSIONS: This case supports the premise that symptomatic intracranial stenosis can be caused by atherosclerotic plaque complicated by intraplaque hemorrhage similar to coronary artery plaque. IVUS provides additional characteristics that define intracranial atherosclerosis and high-risk features. To our knowledge, this is the first report of stroke due to unstable atherosclerotic plaque with intraplaque hemorrhage in vivo. .

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BLOG

http://high-fat-nutrition.blogspot.com/2010/04/arteriosclerosis-and-breeder-rat.html

HISTORY

THE NATURAL HISTORY OF ATHEROSCLEROSIS

PERSPECTIVES

Leukotrienes in atherosclerosis: new target insights and future therapy perspectives. .

Riccioni G, Zanasi A, Vitulano N, Mancini B, D'Orazio N. .

Cardiology Unit, San Camillo de Lellis Hospital, Manfredonia, Foggia, Italy. griccioni@hotmail.com .

Abstract .

Atherosclerosis represents an important chronic inflammatory process associated with several pathophysiological reactions in the vascular wall. The arachidonic acid, released by phospholipase A2, is an important substrate for the production of a group of lipid mediators known as leukotrienes, which induce proinflammatory signaling through the activation of specific BLT and CysLT receptors. The interaction of these substances in the vascular wall determines important morphological alterations like the early lipid retention and the accumulation of foam cells, the development of intimal hyperplasia, and advanced atherosclerotic lesions, and it plays an important role in the rupture of atherosclerotic plaque. Many studies regarding myocardial ischemia and reperfusion show that leukotriene signaling may be involved in the development of ischemic injury. For these, reasons both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested for inducing beneficial effects at different stages of the atherosclerosis process and may represent a new therapeutic target in the treatment of atherosclerotic vessel diseases, in particular in acute coronary syndrome. .

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EDITORIAL

Macrophage Glucocorticoid Receptors Join the Intercellular Dialogue in Atherosclerotic Lesion Calcification .

Robert Terkeltaub, M.D. .

Department of Medicine, Rheumatology Section, VA Health Care System/UCSD, San Diego, CA, 92161 Correspondence to: Robert Terkeltaub, MD, VA Medical Center, Rheumatology, 3350 La Jolla Village Drive, San Diego, CA 92161. Telephone 858-552-8585, ext 3519. Fax 858-552-7425. E-mail: rterkeltaub@ucsd.edu .

Arterial calcification is one of the potential phenotypes of vascular remodeling and repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging (1-3). Calcification decreases arterial wall compliance (4). Furthermore, deposited crystalline apatite can activate macrophages, resulting in a proinflammatory phenotype. Consequently, arterial calcification localized to the intima is a potential biomarker of atherosclerosis, and is linked to disease progression and cardiovascular mortality, while arterial calcification localized primarily to the tunica media promotes mortality in diabetes and renal failure (4). In addition, calcific stenosis of the aortic valve is a prevalent and highly significant public health problem, and shares such pathophysiological features as ectopic chondro-osseous differentiation in common with arterial calcification (5).In a study published in the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Preusch et al report the effects of lineage-specific deletion of the glucocorticoid receptor (GR) in bone marrow-donor macrophages on chondro-osseous differentiation and calcification in dietary - induced atherosclerotic lesions in lethally irradiated, bone marrow transplant recipient, LDLR knockout mice (6). Arterial calcification appears to be an active and organized multicellular process, which is switched on by chondro-osseous differentiation of a variety of progenitors in the artery wall, and regulated in part by systemic influences. Such influences include the effects of calciotropic hormones and of mineral nucleation promoters and inhibitors (1-4). In the intralesional intercellular dialogue that drives vascular calcification, potential progenitors of calcifying osteoblastic and chondrocytic cells include not only pericytes and resident and recruited vascular stem cells, but also non-terminally differentiated, phenotypically plastic adventitial myofibroblasts and smooth muscle cells (SMCs). Significantly, the latter may undergo chondro-osseous trans-differentiation (1-5,7-12).Intralesional mechanisms that drive chondro-osseous differentiation in arterial calcification include an excess of inducers of chondro-osseous commitment and maturation, such as BMP2, Pi generation and uptake by SMCs, and signaling stimulated by the wnt beta-catenin axis and by transglutaminase 2 (1-5,7-12). Conversely, intralesional deficiency of physiologic inhibitors of chondro-osseous differentiation also plays a role in arterial calcification, as exemplified by the linkage of spontaneous intra-arterial chondrogenesis and calcification with paucity of the BMP2 inhibitor and matrix calcification inhibitor MGP (13), or of the chondrogenic and matrix calcification inhibitor PPi (9,14). .

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ABSTRACT

Abstract .

An increasing number of patients under 40 years of age are being hospitalized with the diagnosis of acute myocardial infarction. This is partly due to the increased prevalance of risk factors for atherosclerosis in the younger age group; especially increased incidence of impaired fasting glucose, high triglyceride, low high-density lipoprotein levels and increased waist to hip ratio. However, non-atherosclerotic coronary artery disease or hypercoagulability should also be investigated or at least suspected in the younger patients. The pathophysiology of different clinical conditions and disease states which cause acute coronary syndromes in the young patients are reviewed, and the diagnostic modalities and therapatic options for these conditions are briefly discussed by searching for "premature atherosclerosis", "hypercoagulable states", "risk factors for atherosclerosis in youth", "novel risk factors for atherosclerosis", "non-atherosclerotic coronary artery diseases .

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INTRODUCTION

Introduction .

Atherosclerosis is a slow and progressive building up of plaque, fatty substances, cholesterol, cellular waste products, calcium and fibrin in the inner lining of an artery. This building up of plaque may lead to thickening and hardening of the arteries, subsequently blocking the blood flow either partially or totally in an artery (1). .

Atherosclerosis can affect arteries in the heart, brain, arms, legs, pelvis and intestines leading to diseases of those organs. There are four main types of Atherosclerosis which include: .

Coronary Artery Disease (CAD): When plaque builds up in the coronary arteries, supply of oxygen rich blood to heart is reduced leading to chest pain and ultimately heart attack. .

Carotid Artery Disease or Cerebrovascular Disease: When plaque builds up in carotid arteries, the supply of oxygen rich blood to the brain is reduced leading to a stroke. .

Peripheral Arterial Disease (PAD): When plaque builds up in arteries supplying blood to leg, arms and pelvis, the oxygen rich blood supply to these parts is restricted leading to numbness, pain and dangerous infections (2). .

Abdominal Angina and Bowel Infarction: Atherosclerosis leads to narrowing of arteries supplying blood to the intestines causing abdominal pain and is called abdominal angina. Complete or sudden blockage of blood supply to intestines leads to bowel infarction. .

In severe cases, atherosclerosis could also lead to narrowing of arteries of kidney leading to renal artery stenosis (3). .

Millions of Americans are diagnosed to be suffering from Atherosclerosis and millions more have the disease but are unaware it. Atherosclerosis accounts for about 75 percent of all deaths from cardiovascular disease. Men, African-Americans and all individuals over 65 years of age have the highest risk of developing advanced atherosclerosis. .

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DISCUSSION

Carotid atherosclerosis, coronary atherosclerosis and carotid intima-media thickness in patients with ischemic cerebral disease: Is there any link? .

Petar Nikic, MD MS,1 Milan Savic, MD,2 Vladimir Jakovljevic, MD PhD,3 and Dragan Djuric, MD PhD41 Department of Neurology, General Hospital, Kruševac 2 Special Hospital for Prevention and Treatment of Cerebrovascular Diseases “St Sava”, Belgrade 3 Department of Physiology, Faculty of Medicine, University of Kragujevac, Kragujevac 4 Institute of Medical Physiology, Belgrade University School of Medicine, Belgrade, Serbia and Montenegro Correspondence: Dr Dragan Djuric, Institute of Medical Physiology, Belgrade University School of Medicine, Višegradska 26\II, PO Box 783, Belgrade 11000, Serbia and Montenegro. Telephone 381-11-36-11-754, fax 381-11-684-558, e-mail drdjuric@EUnet.yu

.

Abstract .

OBJECTIVES .

The present study examined the association between carotid atherosclerosis, coronary atherosclerosis and common carotid artery intima-media thickness (CCA-IMT) in patients with incident ischemic stroke and its subtypes (75 cases and 21 controls). .

METHODS .

Cases with ischemic brain infarctions (IBIs) were consecutively recruited and classified into subtypes by computed tomography and Bamford’s classification (the size and site of the infarct) as one of the following: total anterior circulation infarcts (TACIs); partial anterior circulation infarcts (PACIs); posterior circulation infarcts (POCIs); and lacunar infarcts. Controls were recruited among individuals hospitalized for a reason other than cerebrovascular disease at the same institutions and matched for age and sex. Patients and controls underwent B-mode ultrasonographic measurements of CCA-IMT, and were evaluated by a qualified internist and neurologist for the presence of ischemic coronary disease and a history of previous stroke or transient ischemic attack. .

RESULTS .

Of the 75 patients with an acute ischemic stroke, 10 (14%) were classified as TACIs, 34 (45%) as PACIs, 12 (16%) as POCIs and 19 (25%) as lacunar infarcts. Mean CCA-IMT was higher in patients (1.03±0.18 mm) than in controls (0.85±0.18 mm; P<0.0001).>CONCLUSIONS An increased CCA-IMT as a marker of general atherosclerosis was associated with IBI and reflects cardiovascular risk. Carotid and coronary atherosclerosis were positively correlated with IBIs, with significant differences across the subtypes. .

DISCUSSION .

Atherosclerosis is consistently the cause of coronary artery disease and IBI. Stroke and myocardial infarction share common risk factors and pathological mechanisms, and are an important cause of death in older patients. Results of many studies suggest a significant positive relationship between the IMT of the CCA and vascular disease risk factors (11,12,14). This is very important in the primary prevention of cardiovascular complications (eg, sudden death, stroke and myocardial infarction), because an increased IMT can be used as an early marker of atherosclerosis (17–19,21). The present study was based on groups of patients and controls who had a large number of atherosclerosis risk factors. There was no difference in age, anthropometric data, diastolic blood pressure and total cholesterol between the two groups. All other main risk factors were identified more often in the study group. In agreement with previous reports, we found a highly significant correlation between far wall IMT of the CCA and IBI (12,16,26). Although this is a clinical study, our results are in line with observations from several previous large-scale population studies on the mean maximum far wall IMT of the CCA. However, it is important not to confuse the objectives of clinical versus epidemiological studies when reviewing our results. Epidemiological studies focus on samples or populations and not individuals. In addition, the following aspects should be carefully taken into account. First, there is no standardized method to measure the index of general atherosclerosis (CCA-IMT) by ultrasound. Moreover, there is no agreement on the carotid segments that should be investigated. Finally, many of these studies used an ultrasound scanning protocol that included carotid plaques in the measurement of the maximum IMT. The strongest data relating IMT measurement to cardiovascular events derive from the Atherosclerosis Risk in Communities (ARIC) study (15). In this prospective study, the relationship between carotid IMT and prevalent cardiovascular disease was studied over four to seven years of follow-up in 13,870 subjects aged 45 to 64 years. The results show increased IMT in participants with prevalent coronary artery disease, cerebrovascular disease and peripheral vascular disease. The carotid IMT in participants with cardiovascular disease was 10% greater in those with myocardial infarction, 6% greater in those with angina pectoris, 6% greater in those with cerebrovascular disease, 19% greater in those with peripheral vascular disease and 8% greater in those with any form of cardiovascular disease. The differences that were observed in IMT across disease groups are consistent with the associations between prevalent cardiovascular disease and carotid atherosclerosis found in previous clinical and epidemiological studies (15). In the Cardiovascular Health Study (CHS) (18), associations between the CCA-IMT and the incidence of new myocardial infarction or stroke in persons without clinical cardiovascular disease were studied in 5858 subjects older than 65 years of age. The relative risk of myocardial infarction or stroke increased linearly with IMT, and the relationship between cardiovascular events and IMT remained significant after adjustment for traditional risk factors. The study found a stronger association between IMT and stroke, possibly because IMT is a better predictor of complications on small vessels due to hypertension or due to some other aspects of physiological aging. However, some doubt still exists about the predictive power of IMT measurement as a screening tool for cardiovascular and cerebrovascular diseases, besides the well-established and easily detectable atherosclerosis risk factors (27).There are few studies that have explored the possible association between carotid artery IMT and cerebrovascular disease, and even fewer researchers have taken into account the different IBI subtypes (17,18,21,22). There is a highly significant relationship between IMT and IBI, both overall and in its four main subtypes (P<0.001).>

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LETTER TO THE EDITOR

Diabetes-Accelerated Atherosclerosis and Inflammation.

Jenny E. Kanter, Michelle M. Averill, Renee C. LeBoeuf, Karin E. Bornfeldt .

Departments of Pathology and Medicine, Diabetes and Obesity Center of Excellence, University of Washington School of Medicine, Seattle, WA, E-mail bornf@u.washington.edu .

To the Editor: .

We read with interest the Letter to the Editor by Marfella et al1 in response to our review article on the role of glucose and lipids in diabetes-accelerated atherosclerosis.2 Marfella et al1 point out that inflammation is likely to play important roles in diabetes-associated cardiovascular events. Indeed, in our review article,2 we highlighted recent data suggesting that both elevated glucose and lipids contribute to increased inflammation. There is increasing evidence that type 1 and type 2 diabetes are associated with an enhanced inflammatory state and that inflammatory cells contribute to atherosclerotic lesion initiation and lesion disruption. .

Accordingly, type 1 diabetes can cause increases in several circulating inflammatory markers, such as C-reactive protein, soluble intercellular adhesion molecule, CD40 ligand, interleukin (IL)-6, and S100A9.3–5 In addition, type 1 diabetes can promote a proinflammatory state in monocytes, associated with elevated IL-6, IL-8, IL-1, and CCL2.3–4,6 Given the inflammatory basis of atherosclerosis, these findings suggest that type 1 diabetes may accelerate atherosclerosis, in part, by stimulating inflammatory monocytes and/or systemic inflammatory mediators. Indeed, intense insulin therapy results in a coordinated reduction in certain circulating inflammatory markers and reduced risk for cardiovascular complications.7 Furthermore, type 1 diabetes might stimulate accumulation of highly inflammatory macrophage populations in atherosclerotic lesions. In a mouse model of type 1 diabetes–accelerated lesion disruption, S100A9 is upregulated in monocytes/macrophages.8 S100A9 has recently been shown to be a marker of acute coronary syndromes in humans, further supporting an augmented inflammatory state contributing to cardiovascular disease in type 1 diabetes.9 .

Likewise, circulating markers of inflammation, as well as monocyte gene expression of proinflammatory mediators are elevated in type 2 diabetes.6,10 Furthermore, the presence of inflammatory macrophages in adipose tissues in states of insulin resistance and type 2 diabetes has attracted recent interest. Saturated fatty acids released from adipocytes, such as palmitate, stimulate proinflammatory cytokine release from macrophages, potentially mediating some of the inflammation associated with both obesity and type 2 diabetes.11 Interestingly, recent data suggest that inflamed visceral adipose tissues might stimulate development of atherosclerosis.12 In this context, the hypothesis that increased activity of the ubiquitin proteasome pathway in inflammatory cells might play a role in mediating lesion instability associated with type 2 diabetes is interesting,13 although a causal relationship has not been established. Because diabetes and the metabolic syndrome indirectly affect all tissues in the body, a number of processes are likely to contribute to inflammation and the associated atherosclerosis. .

Together, there is ample data supporting an important role for inflammation in atherosclerosis associated with both type 1 and type 2 diabetes/insulin resistance. Elevated glucose and certain lipids, such as modified lipoprotein particles or saturated fatty acids, might each contribute to the enhanced inflammation, atherosclerosis, and cardiovascular events.2,10 .

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WEB SITE

http://www.athero.org/

CLASSIFICATION

A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. .

Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. Office of Scientific Affairs, American Heart Association, Dallas, TX 75231-4596, USA. .

Abstract

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This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc). .

SEE ALSO .

-Natural History and Histological Classification of Atherosclerotic Lesions .

CLINICAL TRIAL

Green Tea Catechins Improve Human Forearm Endothelial Dysfunction and Have Antiatherosclerotic Effects in Smokers .

Jun-ichi Oyama1), Toyoki Maeda1), Kazuya Kouzuma2), Ryuji Ochiai2), Ichiro Tokimitsu2), Yoshihiro Higuchi1), Masahiro Sugano1) and Naoki Makino1) 1) Department of Cardiovascular, Respiratory and Geriatric Medicine, Kyushu University Hospital at Beppu and Medical Institute of Bioregulation, Kyushu University 2) Kao Corporation (Received September 14, 2009) (Revised manuscript received December 10, 2009) (Accepted December 13, 2009) .

Background: Because green tea reduces cardiovascular and cerebrovascular risk, the purpose of this study aimed to elucidate the effect of green tea catechins (GTC) on endothelial dysfunction in smokers. Methods and Results: The 30 healthy male smokers were divided into 3 groups and given green tea beverages containing 0 mg (control group), 80 mg (medium-dose group) or 580 mg (high-dose group) of GTC daily for 2 weeks. Endothelial-dependent and- independent vasodilatation was investigated by measuring the forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside using venous occlusion strain-gauge plethysmography. The FBF response to acetylcholine significantly increased at 2 h and 1 and 2 weeks after GTC intake in the high-dose group, but no increase was observed in the other groups. FBF responses to sodium nitroprusside did not alter in any group at any time point. A significant increase in plasma nitric oxide and a decrease in asymmetrical dimethylarginine, malondealdehyde and 4-hydroxynonenal, C-reactive protein, monocyte chemotactic protein-1, and soluble CD40 ligand levels were detected after chronic consumption of high-dose GTC. Conclusions: GTC have antiatherosclerotic effects on dysfunctional vessels in smokers through increasing the level of nitric oxide and reducing oxidative stress. (Circ J 2010; 74: 578 - 588) .

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PRACTICE GUIDELINE

JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association .

SUMMARY .

The aim of these new Joint British Societies’ guidelines (JBS 2) developed by the British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, and The Stroke Association is to promote a consistent multidisciplinary approach to the management of people with established atherosclerotic cardiovascular disease (CVD) and those at high risk of developing symptomatic atherosclerotic disease. We recommend that CVD prevention in clinical practice should focus equally on (i) people with established atherosclerotic CVD, (ii) people with diabetes, and (iii) apparently healthy individuals at high risk (CVD risk of > 20% over 10 years) of developing symptomatic atherosclerotic disease. This is because they are all people at high risk of CVD. The object of CVD prevention in these high risk people is the same—namely, to reduce the risk of a non-fatal or fatal atherosclerotic cardiovascular event and to improve both quality and length of life. This can be achieved through lifestyle and risk factor interventions and appropriate drug therapies to lower blood pressure, modify lipids, and reduce glycaemia. We have set targets (see below) for lifestyle, blood pressure, lipids, and glucose for these high risk people. Cardiovascular protective drug therapies have specific clinical indications. For all high risk people a number of drugs from different classes will reduce the risk of recurrent disease and increase life expectancy: antithrombotic, blood pressure, lipid, and glucose lowering therapies. .

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META - ANALYSIS

Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries .

Stefano Cagnin,#1,2 Michele Biscuola,#3 Cristina Patuzzo,3 Elisabetta Trabetti,3 Alessandra Pasquali,3 Paolo Laveder,2 Giuseppe Faggian,4 Mauro Iafrancesco,4 Alessandro Mazzucco,4 Pier Franco Pignatti, 3 and Gerolamo Lanfranchi 1,2 1CRIBI Biotechnology Centre, University of Padova, Padova, Italy 2Department of Biology, University of Padova, Padova, Italy 3Department of Mother and Child, Biology and Genetics, Section of Biology and Genetics, University of Verona, Verona, Italy 4Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy Corresponding author. #Contributed equally. .

Abstract .

Background .

Atherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. There may be common molecular pathways sustaining this process. Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis. .

Results .

We used DNA microarrays and meta-analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression. We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis. Caveolae and JAK/STAT pathways, and S100A9/S100A8 interacting proteins are certainly involved in the development of vascular disease. We found that the system of caveolae is directly connected with genes that respond to hormone receptors, and indirectly with the apoptosis pathway.Cytokines, chemokines and growth factors released in the blood flux were investigated in parallel. High levels of RANTES, IL-1ra, MIP-1alpha, MIP-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-17, PDGF-BB, VEGF and IFN-gamma were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels. .

Conclusion .

The pattern of cytokine and S100A9/S100A8 up-regulation characterizes atherosclerosis as a proinflammatory disorder. Activation of the JAK/STAT pathway is confirmed by the up-regulation of IL-6, STAT1, ISGF3G and IL10RA genes in coronary and carotid plaques. The functional network constructed in our research is an evidence of the central role of STAT protein and the caveolae system to contribute to preserve the plaque. Moreover, Cav-1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype. .

Meta-analysis .

To compare our expression data with published expression profiles, we applied a meta-analysis approach to expression datasets of 8 carotid samples taken from Array Express database (E-MEXP-268) and 6 coronary controls retrieved from Gene Expression Omnibus (GSE3526, GSE7307), using row data only[46]. Normal coronary profiles were used as common reference for carotid plaque expression data, since no important differences emerged from the comparison between normal carotid and normal coronary expression profiles (data not shown). Moreover, since the characteristics of peripheral arteries, like thickness of intima-media layers of carotid wall, are used as surrogate markers for coronary atherosclerosis, we decided to compare directly gene expression of these two vessels. However, since it is known that atherosclerosis show some rate of artery-dependent patterns[47], it should be clarified that the comparison of diseased carotids to normal coronaries could result in some grade of under- or overestimation of differences in gene expression. Briefly, data have been normalized using the invariant probe set normalization method[48], implemented in d-chip software, and matched for the common probe set between the different platforms used in the experiments. Differentially expressed genes were calculated from normalized values by applying the fold change and t-test methods.The lists of genes differentially expressed in atherosclerotic coronaries and carotids were compared using the identification of Entrez Gene database and matching entries were classified as "atherogenes" (see the Results). Coronary specific, carotid specific and common differentially expressed genes have been functionally classified using Gene Ontology criteria as implemented in DAVID[49] and used to build networks of functionally correlated genes/protein by Cytoscape[50]. Cytoscape is an open source bioinformatic platform for visualizing molecular interaction networks and biological pathways. To retrieve interactions between differentially expressed genes and to construct the larger general interaction network (Figure ​(Figure4a),4a), we used the Biomolecular Interaction Network Database (BIND) http://bond.unleashedinformatics.com/index.jsp?pg=0, that is a collection of records documenting protein interaction, molecular complexes and pathways. We also made use of the Biological General Repository for Interaction Datasets (BioGRID) database http://www.thebiogrid.org[51] developed at the University of Toronto (Canada) to house and distribute collections of proteins and genetic interactions from major model organisms. This larger network was used to identify high interconnected nodes with the MCODE[52] Cytoscape plug-in. MCODE is an algorithm that allows the finding of clusters in interaction networks to evidence protein complexes or related pathways. Parameters used for MCODE were: Score 1.80, Nodes 76 and 170 Edges. The MCODE defines score as the product of the complex sub-graph density and the number of vertices in the complex sub-graph. With this process MCODE assigns higher values to large node and dense complexes. The inferred sub-network displayed in Figure ​Figure4b4b was that classified with the highest score.Functional classification of genes connected in the larger network (Figure ​(Figure4a)4a) was done according to Gene Ontology (GO) using the Cytoscape plug-in BINGO[53]. This is a bioinformatic tool able to determine which GO categories are statistically overrepresented in a set of genes or a sub-graph of a biological network. We used a hypergeometric test and the Benjamini and Hochberg False Discovery rate (FDR) correction with 0.05 level of significance. The results are plotted in the additional Figure S2 (see Additional file 2, Figure S2).Quantitative real-time PCR Equal aliquots of aRNA from each sample were mixed and 400 ng of this pool were used for first strand cDNA synthesis using Superscript II (Invitrogen). Four independent reactions were carried out, pooled and used for qRT-PCR with SYBR green. Each qRT-PCR was performed in triplicate using the 7500 Real Time PCR System (Applied Biosystems), and analyzed according the Pfaffl method[54]. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glucuronidase beta (GUSB), TATA box binding protein (TBP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) were used as reference transcripts. Sequences of the primers used for qRT-PCR of various mRNA are reported in the additional Table S1 (see Additional file 1, Table S1). .

SEE FULL ARTICLE

REVIEW

Monocytes in atherosclerosis: subsets and functions Kevin J. Woollard and Frederic Geissmann Center for Molecular and Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Diseases (DIIID), 1st Floor New Hunts House, Guys Campus, London SE1 1UL, UK Correspondence to: K. J. Woollard ; Email: kevin.woollard@kcl.ac.uk Abstract Chronic inflammation drives atherosclerosis, the leading cause of cardiovascular disease. Over the past two decades, data have emerged showing that immune cells are involved in the pathogenesis of atherosclerotic plaques. The accumulation and continued recruitment of leukocytes are associated with the development of ‘vulnerable’ plaques. These plaques are prone to rupture, leading to thrombosis, myocardial infarction or stroke, all of which are frequent causes of death. Plaque macrophages account for the majority of leukocytes in plaques, and are believed to differentiate from monocytes recruited from circulating blood. However, monocytes represent a heterogenous circulating population of cells. Experiments are needed to address whether monocyte recruitment to plaques and effector functions, such as the formation of foam cells, the production of nitric oxide and reactive oxygen species, and proteolysis are critical for the development and rupture of plaques, and thus for the pathophysiology of atherosclerosis, as well as elucidate the precise mechanisms involved. Introduction Atherosclerosis is a multifaceted, progressive, inflammatory disease that affects mainly large and mediumsized arteries. It is characterized by the formation and build-up of atherosclerotic plaques that consist of a well-defined structure of lipids, necrotic cores, calcified regions, inflamed smooth muscle cells, endothelial cells, immune cells and foam cells; consequently, atherosclerosis is associated with cardiovascular disease.1 In the 1970s, details of a comprehensive scheme of ‘response-to-injury’ began to emerge,1 in which endothelial activation is initiated by various triggers, such as altered blood rheology, modified LDL, increased homocysteine levels, and inflammation induced by bacterial antigens and membrane components. The presence of leukocytes within atherosclerotic arteries was characterized in the early 1980s.2 Initially, macrophages were reported as the predominant cell type present within atherosclerotic vessels, but T cells, B cells, neutrophils, mast cells, dendritic cells (DCs) and monocytes have all been observed in both mouse and human aortas.3-5 Transgenic mouse models have allowed researchers to directly investigate the molecular mechanisms that underlie the development of atherosclerosis.6 The roles of cell adhesion molecules, chemokines, cellular mediators and signaling molecules involved in lymphocyte and monocyte/macrophage activation, and the progression of atherosclerosis, have been described elsewhere.3-7 This Review focuses on monocyte biology in relation to atherosclerosis, and specifically discusses the recruitment of blood monocytes to plaques and their relationship with plaque macrophages. Whether and how distinct functional subsets of monocyte might have different roles in the pathogenesis of atherosclerosis is also discussed. SEE ARTICLE

INTERVIEW

INTERVIEW Dr Ronald Krauss speaks to Shreeya Nanda, Comissioning Editor. .

Ronald M Krauss, MD, is Director of Atherosclerosis Research at Children’s Hospital Oakland Research Institute (CA, USA), Guest Senior Scientist in the Life Sciences Division of Lawrence Berkeley National Laboratory (CA, USA), and Adjunct Professor in the Department of Nutritional Sciences at the University of California at Berkeley (CA, USA). He received his undergraduate and medical degrees from Harvard University (MA, USA) with honors and served his internship and residency on the Harvard Medical Service of Boston City Hospital (MA, USA). He then joined the staff of the National Heart, Lung, and Blood Institute in Bethesda (MD, USA), first as Clinical Associate and then as Senior Investigator in the Molecular Disease Branch. Dr Krauss is a member of the American Society for Clinical Investigation, the American Federation for Clinical Research, and the American Society of Clinical Nutrition. He has received a number of awards including the American Heart Association Scientific Councils Distinguished Achievement Award. Dr Krauss has been a Senior Advisor to the National Cholesterol Education Program and the American Heart Association Council on Nutrition, Physical Activity and Metabolism. Dr Krauss has published more than 300 research articles and reviews on genetic, dietary and drug effects on plasma lipoproteins and coronary disease risk. .

You have a degree in medicine from Harvard University: what led to your interest in the genetics of lipoproteins and coronary artery disease risk? .

I became interested in determining the causes of heart disease early on, from childhood, because my father had heart disease at a young age and I grew up with a desire to understand and cure this condition. When I reached my training, I discovered the work of a group at the NIH that had started to decipher some of the genetic contributions to heart disease and their effects on cholesterol, and at that point I decided that that was what I was going to focus on. .

What factors play a role in interindividual variations in the response to cholesterol-lowering drugs? .

This is turning out to be a very complex picture because of the many systems that are involved in regulating cholesterol and lipoprotein metabolism that have genetic influences. The drugs that we use, statins in particular (which is what my focus has been in recent years), operate in known ways to modify cholesterol metabolism, but the response is influenced by many systems that we are just beginning to understand. Genetics is only a part of the story; we know that other factors, such as age, ethnic and racial differences among individuals, which may involve genetics, play a role, and there are probably other factors, such as diet, that also come into the picture. .

You have recently published a study showing that alternate splicing of HMGCR could explain the differences in the response to treatment with statins – could you explain this work? .

We were led to study this gene, HMGCR, because it codes for the enzyme HMG-CoA reductase, which is a critical determinant of blood cholesterol synthesis and low-density lipoprotein (LDL) cholesterol levels in the blood; in particular, it is the target for statin inhibition, and this is the mechanism by which statins reduce cholesterol production. In studying this gene, we, and others, had determined that there were certain genetic variants that appeared to be associated with differing response to statins in terms of the magnitude of LDL cholesterol reduction. Once we found those variants, we wanted to try to understand the mechanisms by which the genetic variation led to a reduced response to statins, and we turned our attention to a recently described process by which the HMGCR gene is modified in the course of its transcription. When a gene is transcribed, there is splicing or clipping out of the sequences between the coding regions, and sometimes you can have alternative restitching of the remaining portions of the gene. In the case of HMGCR, we studied one such form that we determined was relatively insensitive to statin inhibition, and part of the genetic effect that we discovered was due to the fact that the genetic variation promoted an increase in the amount of the alternatively spliced enzyme. Then, when we looked at our entire population of statin-treated subjects, we found that there was splicing to varying degrees in all individuals, so there are other factors besides the specific genetic variants that influence splicing. However, overall, if an individual had a greater degree of splicing, and this was studied in cells from these individuals, they turned out to be less responsive to statins, whereas individuals with relatively low levels of splicing were more responsive. This accounted for nearly 10% of the variability in the LDL response to statins, which is a pretty significant effect, but by no means does it account for the full range of variation that we see among individuals. .

You are principal investigator of the ‘Pharmacogenomics and Risk of Cardiovascular Disease’ project of the PharmGKB – can you tell me about it? .

The NIH has a group of investigators who have grants as part of the Pharmacogenetics Research Network. My component of that, the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) grant, is one that is focused on identifying genetic modifiers of response to drugs that are used to reduce the risk of cardiovascular disease. The main focus of our current program is to better understand genetic effects on statin response, both in terms of benefits of statins and some of the adverse effects that can occur involving muscle tissue. Although the latter are relatively uncommon, they can be a clinical problem for patients, and in some cases can actually be very severe. With that mission, we have systematically examined genetic variation in genes that are considered to be involved in these processes. More recently, with the availability of genomic technology, we, as well as other groups, have utilized genome-wide screening for genetic variation in an attempt to provide a more comprehensive picture of the overall genetic contribution to statin response. This is a very ambitious effort, testing for hundreds of thousands of genetic variants in thousands of individuals. Sifting through the results using sophisticated statistical techniques is a challenge, and it is currently where our efforts are being focused: to determine not just where there might be associations, but also where we can confirm in other populations that these associations are valid. We need to replicate them because there is always a possibility for a false finding when one is carrying out that many statistical tests, and we are now assembling a number of studies that we will use to help con-firm our findings. Finally, of greatest interest, at least in my laboratory, is the proof that the variations that we come up with have effects that we can demonstrate by functional studies, such as the one I described for the HMGCR gene. It is very important to be able to draw conclusions about the genetic association findings by understanding the underlying mechanisms. In addition, this provides information that could be of value in understanding fundamental processes affecting cholesterol metabolism and heart disease risk, and could perhaps even lead to new drug targets that modify the pathways that are influenced by these genetic variants. .

What other projects are you involved in? .

A large part of my program is focused on nutrition and its effects on lipoprotein metabolism and heart disease risk, and some of the same issues come up with diet as in the case of statins and other drugs. In both cases, we are trying to understand the pathways that may influence the magnitude of the type of response that we see. We are finding individuals who actually show adverse effects on their lipid profile in their response to low-fat diets that are considered to be therapeutic, while others show beneficial effects. As in the case of pharmacogenetics, we have an interest in identifying the genetic differences among individuals that may make them more susceptible to these diet responses. This is an area that is called nutrigenomics, and between nutrigenomics and pharmacogenomics we have tried to cover a spectrum of treatment opportunities that can be used for helping to manage risk for ca-rdiovascular disease. .

When do you see the clinical translation of pharmacogenomics becoming a reality and what, in your opinion, are the main hurdles? .

Pharmacogenetics/pharmacogenomics has been around for a while and there actually have been some accomplishments that have reached the clinic, primarily in the area of genes that affect drug metabolism. In fact, there are some genetic tests that are currently being offered that help to identify people who may be susceptible to adverse reactions to certain drugs that are used in cancer treatment. Thus, that aspect of pharmacogenetics is already working its way into clinical practice. The type of work that my group is involved with is disease genetics and how drug response may be influenced by genetics in ways that could affect the disease process. That is a more challenging effort because heart disease, even cholesterol metabolism, like many other conditions that we struggle with in clinical medicine, such as obesity and diabetes, are complex genetic traits with many interactions between genes and environmental factors that require very extensive statistical analysis, as well as large amounts of data. Right now, we are fortunate that we have tools that allow us to take on this type of analysis, but this type of pharmacogenetics is far from being ready for clinical application. Within 5 or 10 years we should learn more about how this information might be used, and it may be that it will be used in a way that we have not yet anticipated. For example, the initial thinking in pharmacogenomics was that we might have a panel of genetic markers that individuals could use to help sort out their disease risk and which drugs might be most appropriate for them. That is still the goal, and it is still very much within the realm of possibility, but it may turn out that we will use genetics in a more selective way; for example, in families where there is a particular form of heart disease we may then take individuals from those families and do genetic tests to determine which form of the syndrome or disease they have and which pathways are involved. In this way we can apply genetics selectively to help refine the clinical characterization of patients, and that could lead to more rational decisions as to which drugs will be most appropriate. Thus, rather than using these tests to screen a population as a whole, I think it is more likely that we will use them to help refine the diagnoses of individuals who are being co-nsidered for treatment. .

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Where do you think your efforts will be focused in the next 5 or 10 years? We are probably going to wrap up the strictly genetic phase of our work in the next few years, and I see the next stage of research, certainly from the standpoint of my own interests, as trying to understand how the genes that we have identified function. This will require the integration of genetic knowledge with biochemistry, physiology and clinical medicine. This is what is called systems biology, in current terminology. I am very excited about the prospect of being able to take our genetic findings and apply them in clinical experiments that will allow us to work out the mechanisms and pathways by which these genetic variants are operating..

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Affiliations .

Ronald M Krauss Department of Atherosclerosis Research, 5700 Martin Luther King Junior Way, Oakland, CA 94609, USA. rkrauss@chori.org

ECONOMIC COSTS

The Vulnerable Atherosclerotic Plaque: Strategies for Diagnosis and Management .

Edited by Renu Virmani, Jagat Narula, Martin B. Leon, and James T. Willerson. 375 pp., illustrated. Malden, MA, Blackwell Futura, 2007. $174.95. ISBN 978-1-4051-5859-6 .

The disruption of atherosclerotic plaque is responsible for more than 75% of acute cardiac events, including myocardial infarction and sudden death. Heart disease has been the leading cause of death in the United States for the past 80 years, and a great majority of these deaths are caused by atherosclerotic coronary artery disease. Epidemiologists tell us that age-standardized mortality rates for myocardial infarction have declined over the past 10 to 15 years. However, the absolute number of deaths from myocardial infarction has actually increased, and now the mortality rate is even higher in women than men. In the United States, approximately 1.1 million people a year have a myocardial infarction, and sudden death occurs in an estimated 500,000 people. Worldwide, cardiovascular disease is the major cause of death in developed countries, and its prevalence is increasing in the developing countries of South America and Asia. The epidemic of obesity and associated type 2 diabetes, in addition to increased smoking among certain populations, is likely to keep atherosclerotic cardiovascular disease a major killer for years to come. The economic costs are high as well — estimated at more than $150 billion in the United States in 2007. .

Michael C. Fishbein, M.D. David Geffen School of Medicine at UCLA Los Angeles, CA 90095

BRIEF REPORT

Inflammation and Atherosclerosis

Peter Libby, MD; Paul M. Ridker, MD; Attilio Maseri, MD From the Leducq Center for Cardiovascular Research (P.L., P.M.R.) and Center for Cardiovascular Disease Prevention (P.M.R.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, and Department of Cardiovascular Disease (A.M.), University Vita-Salute San Raffaele, Milan, Italy.

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.