Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes. This genetic approach overcomes the problem that cross-sectional studies cannot distinguish whether changes in IGF-I levels are a cause or a consequence of a disease. IGF-I is an important metabolic regulatory hormone. In addition, IGF-I suppresses myocardial apoptosis and improves myocardial function in various models of experimental cardiomyopathy. Compared with other growth factors, the 'survival' effect of IGF-I on myocardium seems rather unique.Therefore, we hypothesize that the premature and progressive decline in serum IGF-I bioactivity in ageing patients with type 2 diabetics is an important pathophysiological abnormality. It contributes not only to elevated glucose and lipid levels, but also to the progression and the poor outcome of CVD. If this hypothesis is proven to be right, treatment with IGF-I as an adjunct to insulin offers great potential and might not only improve metabolic control but also reduce the incidence and prevalence of CVD in type 2 diabetes patients. However, there is as yet no experimental evidence that long-term (replacement) treatment with IGF-I prevents, delays or reduces CVD in type 2 diabetes patients. Clinical trials are necessary to prove that long-term IGF-I treatment, preferably in the form of a better-tolerated IGF-I/IGF-binding protein-3 complex, improves the overall cardiovascular risk in type 2 diabetes.
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PMID:The role of IGF-I in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible? 1191 13

Even with modern treatment, acromegaly is associated with a 2- to 3-fold increase in mortality, mainly from vascular disease, which is probably a result of the long exposure of tissues to excess GH before diagnosis and treatment. There is accumulating evidence that effective treatment to lower serum GH levels to less than 1-2 ng/ml (glucose suppressed or random, respectively) and normalize IGF-I improves long-term outcome and survival. In addition to recognized cardiovascular risk factors of hypertension, type 2 diabetes mellitus, and dyslipidemia, there is accumulating evidence of specific structural and functional changes in the heart in acromegaly. Along with endothelial dysfunction, these changes may contribute to the increased mortality in this disease. There are specific structural changes in the myocardium with increased myocyte size and interstitial fibrosis of both ventricles. Left ventricular hypertrophy is common even in young patients with short duration of disease. Some of these structural changes can be reversed by effective treatment. Functionally, the main consequence of these changes is impaired left ventricular diastolic function, particularly when exercising, such that exercise tolerance is reduced. Diastolic function improves with treatment, but the effect on exercise tolerance is more variable, and more longitudinal data are required to assess the benefits. What scant data there are on rhythm changes suggest an increase in complex ventricular arrhythmias, possibly as a result of the disordered left ventricular architecture. The functional consequences of these changes are unclear, but they may provide a useful early marker for the ventricular remodeling that occurs in the acromegalic heart. Endothelial dysfunction, especially flow-mediated dilatation, is an early marker of atherosclerosis, and limited data imply that this is impaired in active acromegaly and can be improved with treatment. Similarly, early arterial structural changes, such as thickened intima media layer, appear more common in acromegalics, and there are hints that this may diminish with effective treatment, although more studies are required for a definite conclusion on this topic. In conclusion, impaired cardiac and endothelial structure and function in acromegaly are risk factors for vascular mortality and should be regarded as legitimate therapeutic targets in the overall management of this condition.
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PMID:Cardiovascular function in acromegaly. 1278 99

We investigated the impact of GH administration on endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, in vivo and in vitro. Soluble VCAM-1, E-selectin, and C-reactive protein concentrations were measured before and after treatment in 25 healthy subjects and 25 adult GH-deficient (GHD) patients randomized to GH treatment or placebo. Furthermore, we studied the direct effect of GH and IGF-I and serum from GH-treated subjects on basal and TNF alpha-stimulated expression of VCAM-1 and E-selectin on cultured human umbilical vein endothelial cells. Baseline levels of VCAM-1, but not E-selectin, were significantly lower in GHD patients than in healthy subjects (362 +/- 15 microg/liter vs. 516 +/- 21 microg/liter, P < 0.001) and increased in GHD patients during GH treatment, compared with placebo [net difference between groups 151.8 microg/liter (95% confidence interval: 95.0-208.7 microg/liter); P < 0.0001]. In human umbilical vein endothelial cells, there was no direct stimulatory effect of either GH or IGF-I on the expression of VCAM-1 and E-selectin, but serum from GH-treated healthy subjects significantly increased the expression of VCAM-1 (P < 0.01). Our findings are compatible with the notion that GH may stimulate the expression of VCAM-1 indirectly through modulation of circulating factors. VCAM-1-mediated leukocyte extravasation is implicated in several illnesses including atherosclerosis and multiple-organ failure in sepsis, and we hypothesize that enhanced expression of VCAM-1 may contribute to the detrimental effects of GH in critically ill patients.
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PMID:Growth hormone increases vascular cell adhesion molecule 1 expression: in vivo and in vitro evidence. 1476 13

GH deficiency is associated with increased prevalence of atherosclerosis, and recent data indicate a proatherogenic role for macrophage lipoprotein lipase (LPL) in the arterial wall. In this pilot study, we determined LPL expression and foam cell formation in monocyte-derived macrophages of 12 control subjects and nine patients with GH deficiency without GH replacement therapy. LPL mRNA levels, mass, and activity were increased in macrophages of patients with GH deficiency. In these subjects, macrophage LPL activity correlated with body mass index and fat mass. Incubation of patient macrophages with IGF-I for 24 h or differentiation of monocytes isolated from GH-deficient patients into macrophages in the presence of this growth factor decreased the amount of LPL mass. Compared with control cells, macrophages derived from GH-deficient patients took up and stored increased amounts of proatherogenic lipoproteins and were more easily converted to foam cells. In the supernatants of these cells, increased levels of free fatty acids and TNFalpha were also documented. These results demonstrate that macrophages of patients with GH deficiency secrete increased amounts of proatherogenic cytokines and are more susceptible to foam cell formation. These alterations may contribute to the increased cardiovascular risk in patients with GH deficiency.
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PMID:Enhanced lipoprotein lipase secretion and foam cell formation by macrophages of patients with growth hormone deficiency: possible contribution to increased risk of atherogenesis? 1476 24

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.
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PMID:Systemic complications of acromegaly: epidemiology, pathogenesis, and management. 1476 29

Vascular dementia (VaD) and Alzheimer's disease (AD) are the most common causes of dementia in the elderly. The aim of this study was to investigate carotid atherosclerosis, serum lipid profiles, and atherogenic hormone levels in nondiabetic Japanese men with VaD or AD. Carotid artery intima-media thickness (IMT) and plaque, serum lipid and lipoprotein profiles, including low-density lipoprotein (LDL) particle size, as well as insulin-like growth factor-I (IGF-I, somatomedin C) and testosterone levels, were determined in 34 patients with AD, 37 patients with VaD, and 63 healthy male controls. Age, body mass index, systolic and diastolic blood pressure, and fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), triglyceride, high-density lipoprotein (HDL)-cholesterol, and apolipoproteins (apo) A-I, B, and E levels did not differ significantly among the 3 groups. However, the mean value of carotid IMT, the frequency of atherosclerotic plaque deposition, the serum levels of LDL-cholesterol, lipoprotein(a), and lipid peroxides, and the incidence of small dense LDL (particle diameter </= 25.5 nm) were increased significantly in VaD patients compared with AD patients or controls. VaD patients had a close reverse correlation between carotid IMT and LDL particle diameter, which were statistically proven independent risk factors for VaD. In contrast, AD patients had significantly lower serum levels of IGF-I and testosterone than either VaD patients or controls. Our results indicate that VaD is associated with atherogenic dyslipidemia, in particular, small dense LDL and carotid atherosclerosis, whereas AD is associated with hyposomatomedinemia and hypogonadism rather than atherosclerosis.
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PMID:Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. 1504 95

IGF-I is a multipotent growth factor with important actions on normal tissue growth and regeneration. In addition, IGF-I has been suggested to have beneficial effects on glucose homeostasis due to its glucose lowering and insulin sensitizing actions. However, not all effects of IGF-I are considered to be favorable; thus, epidemiological studies suggest that IGF-I is also involved in the development of common cancers, atherosclerosis and type 2 diabetes. The biological actions of IGF-I are modulated by at least six IGF-binding proteins, which bind approximately 99% of the circulating IGF-I pool. So far, most in vivo studies have used serum or plasma total (extractable IGF-I) as an estimate of the bioactivity of IGF-I in vivo. However, within the last decade, validated assays for measurement of free IGF-I have been described. This review aims to discuss the current assays for free IGF-I and their advances in relation to the traditional measurement of total IGF-I. The literature overview will focus on the role of circulating free versus total IGF-I in the feedback regulation of GH release, and the possible involvement of the circulating IGF-system in glucose homeostasis.
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PMID:Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. 1533 29

Atherosclerosis and insulin resistance are common complications of adult growth hormone deficiency (GHD) and acromegaly. Circulating adiponectin, an adipocyte-derived protein, has both anti-atherogenic and insulin-sensitising effects. In this study, we measured serum adiponectin levels in patients with either adult GHD or acromegaly to clarify the impact of GH secretory states on the regulation of serum adiponectin levels. Serum adiponectin level was measured by radioimmunoassay in 32 patients with adult GHD, 49 patients with acromegaly and 25 normal subjects. The relationships between adiponectin and insulin sensitivity index assessed as quantitative insulin sensitivity check index (QUICKI), BMI, and serum GH and IGF-I levels were then investigated. The values of QUICKI were significantly lower in patients with acromegaly or adult GHD compared to normal subjects (0.33 +/- 0.03, P < 0.01, 0.35 +/- 0.04, P < 0.05 and 0.36 +/- 0.01, respectively). While patients with adult GHD had significantly lower serum adiponectin levels than patients with acromegaly (6.5 +/- 3.9, 9.2 +/- 5.0, P < 0.01) these levels were not significantly different from those found in normal subjects (7.8 +/- 4.3 mug/ml). There was an inverse correlation between serum adiponectin levels and BMI in both patient groups (GHD r = -0.39, P < 0.05; Acromegaly r = -0.35, P < 0.05). However, serum adiponectin levels correlated positively with QUICKI (R(s) = 0.37, P < 0.05) only in patients with adult GHD. In patients with acromegaly, the levels of circulating adiponectin showed an inverse correlation with serum IGF-I levels (R(s) = -0.34, P < 0.05), but not with basal GH levels. These results demonstrate that adiponectin levels are significantly lower in patients with adult GHD than in patients with acromegaly. Adiponectin levels are similar in patients with GHD and healthy controls, whereas in patients with acromegaly, insulin resistance appears to be not closely related to adiponectin levels compared with BMI. The different relationship between adiponectin and QUICKI observed in the adult GHD and acromegaly groups presumably reflects differences in the mechanisms of insulin resistance under states of GH deficiency or excess.
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PMID:Serum adiponectin levels in adult growth hormone deficiency and acromegaly. 1551 53

Insulin-like growth factor-1 (IGF-I), the primary mediator of growth hormone (GH) effects, is an important regulator of cell growth, differentiation, and apoptosis. GH and IGF-I deficiency is known to be associated with premature atherosclerosis and elevated cardiovascular disease mortality. Recent evidence suggests that cardiovascular disease risk may also be elevated among apparently healthy individuals who have serum IGF-I levels in the low-normal range. In this review, we appraise the epidemiologic and clinical studies implicating low IGF-I level as a risk factor for incident myocardial infarction and other manifestations of coronary heart disease. Potential mechanisms that may underlie this association include beneficial effects of IGF-I on myocyte survival after ischemia, stability of atherosclerotic lesions, and endothelial function. We conclude that additional confirmatory data from prospective studies are needed to confirm low IGF-I level as an independent cardiovascular risk factor. However, if this finding is confirmed, this would support the rationale for intervention trials aimed at reducing cardiovascular disease morbidity and mortality among older adults by targeting the GH/IGF-I pathway.
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PMID:Insulin-like growth factors and coronary heart disease. 1559 27

To explore early effects of GH treatment or deprivation on cardiovascular risk factors and carotid intima-media thickness (IMT), we designed this randomized, cross-over study in 34 adult patients with severe GH deficiency. At study entry, the patients were randomized into two groups (A and B); group A (n = 17) received appropriate replacement therapy including GH at standard doses for 6 months and then were withdrawn from GH for the subsequent 6 months; group B (n = 17) received appropriate replacement therapy excluding GH for 6 months with the addition of GH in the subsequent 6 months. After the first 6 months, we observed a significant increase in IGF-I levels and of high-density lipoprotein (HDL)-cholesterol together with a significant decrease in diastolic blood pressure, the total/HDL-cholesterol ratio, and C-reactive protein in the patients in group A, whereas vascular parameters did not significantly change. In the patients in group B, none of the parameters studied significantly changed. After 6 months of GH withdrawal in the patients in group A, a significant decrease in IGF-I levels, a significant increase in the total/HDL-cholesterol ratio and C-reactive protein, and a trend toward an impairment of carotid IMT and peak velocities were observed. In the patients in group B, the addition of GH to the standard replacement induced a significant increase in IGF-I levels together with a decrease in systolic and diastolic blood pressure, total cholesterol and total/HDL-cholesterol ratio, and C-reactive protein, and an increase in HDL-cholesterol levels with a trend toward an improvement of vascular parameters. At the end of the study, mean IMT was significantly lower than at baseline both in group A (from 0.88 +/- 0.28 to 0.85 +/- 0.27 mm, P = 0.0003) and in group B (from 0.83 +/- 0.21 to 0.80 +/- 0.20 mm, P = 0.003). In conclusion, 6 months of GH replacement has beneficial effects whereas 6 months of GH deprivation has detrimental effects on cardiovascular risk factors and atherosclerosis. These findings support the indication for GH replacement in severe GH deficiency adult patients.
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PMID:Short-term effects of growth hormone (GH) treatment or deprivation on cardiovascular risk parameters and intima-media thickness at carotid arteries in patients with severe GH deficiency. 1567 Oct 89


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