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Low serum 25 hydroxyvitamin D3 (vitamin D3) is known to perturb cellular function in many tissues, including the endocrine pancreas, which are involved in obesity and type II diabetes mellitus (TIIDM). Vitamin D3 insufficiency has been linked to obesity, whether obesity is assessed by body mass index (BMI) or waist circumference (waist). Central obesity, using waist as the surrogate, is associated with the metabolic syndrome (MetSyn), insulin resistance, TIIDM and atherosclerotic cardiovascular disease (CVD). We tested how vitamin D3 was related to measures of fat mass, MetSyn markers, haemoglobin A1c (HbA1c) and MetSyn in a cross-sectional sample of 250 overweight and obese adults of different ethnicities. There were modest inverse associations of vitamin D3 with body weight (weight) (r = -0.21, p = 0.0009), BMI (r = -0.18, p = 0.005), waist (r = -0.14, p = 0.03), [but not body fat % (r = -0.08, p = 0.24)], and HbA1c (r = -0.16, p = 0.01). Multivariable regression carried out separately for BMI and waist showed a decrease of 0.74 nmol/L (p = 0.002) in vitamin D3 per 1 kg/m2 increase in BMI and a decrease of 0.29 nmol/L (p = 0.01) per 1 cm increase in waist, with each explaining approximately 3% of the variation in vitamin D3 over and above gender, age, ethnicity and season. The similar relationships of BMI and waist with vitamin D3 may have been due to associations between BMI and waist, or coincidental, where different mechanisms relating hypovitaminosis D3 to obesity occur concurrently. Previously reviewed mechanisms include that 1) low vitamin D3, may impair insulin action, glucose metabolism and various other metabolic processes in adipose and lean tissue 2) fat soluble-vitamin D3 is sequestered in the large adipose compartment, and low in serum, 3) obese people may be sensitive about their body shape, minimising their skin exposure to view and sunlight (not tested). We showed evidence for the first theory but no evidence to support the second. In the current study, serum vitamin D3 was inversely related to weight, BMI and markers of TIIDM (large waist, raised HbA1c) but not to adipose mass nor to MetSyn per se.
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PMID:Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. 1822 57

The main components of the metabolic syndrome (MS) are abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance with or without glucose intolerance, and proinflammatory and prothrombotic states. The clustering of these metabolic risk factors significantly increases the risk of type 2 diabetes and promotes vascular endothelial dysfunction, inflammation, and increased oxidative stress. The net result is an increase in the risk of atherosclerotic cardiovascular disease. Therefore, management of MS is of utmost importance, especially considering its rapidly increasing prevalence in a population with rising obesity rates and its significant cardiovascular implications. The primary management of this syndrome involves the correction of the underlying risk factors--obesity, physical inactivity, and an atherogenic diet--with lifestyle modifications including increased physical activity and dietary modification. Smoking cessation also should be encouraged. However, pharmacologic therapies are often required to address cardiovascular risk factors. These agents can be categorized broadly into 1) anorectic agents, 2) insulin-sensitizing agents, 3) statins, and 4) renin-angiotensin system antagonists. Emerging therapies include adipokines, endocannabinoid inhibitors, and metabolic modulators, such as perhexiline and trimetazidine. To date, these therapies have not been shown to normalize the metabolic and cardiovascular burden of MS, and there still is no single therapeutic agent for its management.
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PMID:Management of the metabolic syndrome in cardiovascular disease. 1832 5

Metabolic syndrome is a cluster of interrelated cardiometabolic risk factors that are associated with an increased risk for both type 2 diabetes and atherosclerotic cardiovascular disease. These risk factors include visceral obesity, atherogenic dyslipidemia (elevated triglycerides and low HDL cholesterol), elevated blood pressure, dysglycemia (pre-diabetes or diabetes) and a prothrombotic and proinflammatory state. The condition is progressive, beginning with borderline risk factors, and worsens over time. Primary treatment is lifestyle therapy--weight loss, increased physical activity and antiatherogenic diet. But, as the metabolic syndrome progresses, drug therapy directed at individual risk factors may be needed.
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PMID:Metabolic syndrome: an evolving concept. 1833 69

Atherosclerotic cardiovascular disease (A-CVD) is preventable. Major causal risk factors are known, and effective and safe treatments exist. However, A-CVD remains the leading cause of death and severe disability not only in affluent countries, but also globally. The burden of A-CVD is growing faster in poor and developing countries threatening their future economic development. Traditional methods for prevention of A-CVD have proven largely insufficient. Although many societal factors contribute to the epidemic of A-CVD (eg, smoking, obesity, diabetes, insufficient physical activity, and so on) and deserve renewed attention, early detection of the asymptomatic vulnerable patient who has significant subclinical atherosclerosis presents as a low hanging fruit in primary prevention of A-CVD. The Screening for Heart Attack Prevention and Education (SHAPE) Task Force, comprised of an international group of experts, has proposed the First SHAPE Guideline to address a major shortcoming in the existing guidelines in primary prevention of A-CVD. It is based on the observation that most heart attacks and strokes occur in people who are not classified as high risk by the traditional risk factor-based approach recommended in the United States (Framingham Risk Score) and Europe (SCORE). Unfortunately, these guidelines provide inadequate warning to asymptomatic individuals with subclinical atherosclerosis who are unaware of their high-risk status and are not aggressively treated by their physicians who follow the existing recommendations. Consequently, most of these asymptomatic individuals, who are vulnerable to a near-future heart attack, are not offered the benefit of existing prophylactic therapies. Unlike decades ago when screening for risk factors of A-CVD was the only available risk stratification method in primary prevention, today, noninvasive detection of atherosclerosis is feasible and widely available. It provides a direct and individualized method for risk assessment. A large body of evidence has been compiled in recent years showing the superior prognostic value of detecting atherosclerosis rather than risk factors of atherosclerosis. The First SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45 to 75 years old and asymptomatic women 55 to 75 years old (except those defined as very low risk) to detect and treat individuals with subclinical atherosclerosis. The intensity of treatment should correlate with the severity of the disease. Among existing tools for detection of subclinical atherosclerosis, the SHAPE Task Force has created the SHAPE Flow Chart based on the following 2 noninvasive imaging techniques: coronary artery calcium scoring using computed tomography and carotid intima media thickness and plaque using B-mode ultrasonography.
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PMID:The first SHAPE (Screening for Heart Attack Prevention and Education) guideline. 1834 Feb 36

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.
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PMID:Identifying the vulnerable patient with rupture-prone plaque. 1854 69

The metabolic syndrome is a constellation of metabolic risk factors and physical conditions that are accompanied by an enhanced propensity toward the development of type 2 diabetes, atherosclerosis, and cardiovascular disease. It presents a combination of atherosclerosis risk including atherogenic dyslipidemia, hypertension, elevated plasma glucose, hypercoagulability, and a proinflammatory state. The 2 major underlying risk factors for the metabolic syndrome are obesity and insulin resistance. Exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. Associated hyperinsulinemia, hyperglycemia, and elevated adipokine levels (adipose cytokines) lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease. In this 2-part series, the authors present an up-to-date and detailed systematic review of the literature on this important topic.
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PMID:The metabolic syndrome and cardiovascular disease: Part I. 1860 51

Recent researches have shown that adipocytokines secreted by adipose tissue play an important role in inflammation which is considered to be a crucial step in the pathogenesis of atherosclerosis. Leptin, one of the earlier adipocytokines, is known to play a major role in cardiovascular disease and recent observations suggest that leptin is an independent risk factor for coronary heart disease. Resistin, another recently discovered adipocytokine, has been related to risk factors of atherosclerosis, and in diabetic individuals serum resistin levels correlate well with inflammatory markers and are predictive for the development of cardiovascular disease. Adiponectin, another adipocytokine of interest in recent years, seems to be the most promising one studied to date. In contrast to leptin and resistin, adiponectin seems to be beneficial for health and it is a protective factor and decreased in obesity. However, many other factors derived from adipose tissue have also been discovered, such as interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein 1, apelin, visfatin and probably others awaiting discovery in the near future. In this paper, we discussed the role of adipocytokines in the pathogenesis of atherosclerotic cardiovascular disease.
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PMID:A new frame in thromboembolic cardiovascular disease: Adipocytokine. 1837 21

Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor.
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PMID:Leptin and mechanisms of endothelial dysfunction and cardiovascular disease. 1895 28

Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll-like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro-inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator-activated receptor-gamma and NFkappaB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin-resistant state promoting meta-bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity.
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PMID:Adipose inflammation, insulin resistance, and cardiovascular disease. 1897 44

Despite remarkable progress in diagnosis and understanding of risk factors, cardiovascular disease (CVD) remains still the leading cause of morbidity and mortality in the world's developed countries. The metabolic syndrome, a cluster of risk factors (visceral obesity, insulin resistance, dyslipidaemia, and hypertension), is increasingly being recognized as a new risk factor for type 2 diabetes and atherosclerotic cardiovascular disease. Nevertheless, there is wide variation in both the occurrence of disease and age of onset, even in individuals who display very similar risk profiles. There is now compelling evidence that a complex interplay between genetic determinants and environmental factors (still largely unknown) is the reason for this large inter-individual variation in disease susceptibility. The purpose of the present review is to describe the current status of our knowledge concerning the gene-environment interactions potentially implicated in the pathogenesis of metabolic syndrome, diabetes and cardiovascular disease. It focuses predominantly on studies of genes (peroxisome proliferator-activated receptor-gamma, alcohol dehydrogenase type 1C, apolipoprotein E, glutathione S-transferases T1 and M1) that are known to be modified by dietary and lifestyle habits (fat diet, intake of alcohol and smoking habit). It also describes the limited current understanding of the role of genetic variants of xenobiotic metabolizing enzymes and their interactions with environmental toxicants. Additional studies are needed in order to clarify whether inter-individual differences in detoxification of environmental toxicants may have an essential role in the development of CVD and contribute to the emerging field of "environmental cardiology". Such knowledge may be particularly relevant for improving cardiovascular risk stratification and conceiving the development of "personalized intervention program".
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PMID:Metabolic syndrome, diabetes and atherosclerosis: influence of gene-environment interaction. 1902 10


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