Evidence Of Premature Atherosclerosis Research Articles

Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice-Brief Report.

Women with a history of preeclampsia have evidence of premature atherosclerosis and increased risk of myocardial infarction and stroke compared with women who had a normotensive pregnancy. Whether this is due to common risk factors or a direct impact of prior preeclampsia exposure has never been tested in a mouse atherosclerosis model. Pregnant LDLR-KO (low-density lipoprotein receptor knockout; n=35) female mice were randomized in midgestation to sFlt1 (soluble fms-like tyrosine kinase 1)-expressing adenovirus or identical control adenovirus. Postpartum, mice were fed high-fat diet for 8 weeks to induce atherogenesis. Comparison between the control and preeclampsia models was made for metabolic parameters, atherosclerosis burden and composition by histology, plaque inflammation by flow cytometry, and aortic cytokines and inflammatory markers using a cytokine array. In pregnant LDLR-KO mice, sFlt1 adenovirus significantly induced serum sFlt1, blood pressure, renal endotheliosis, and decreased pup viability. After 8 weeks of postpartum high fat feeding, body weight, fasting glucose, plasma cholesterol, HDL (high-density lipoprotein), and LDL (low-density lipoprotein) were not significantly different between groups with no change in aortic root plaque size, lipid content, or necrotic core area. Flow cytometry demonstrated significantly increased CD45+ aortic arch leukocytes and CD3+T cells and aortic lysate contained more CCL (CC motif chemokine ligand) 22 and fetuin A and decreased expression of IGFBP6 (insulin-like growth factor-binding protein 6) and CCL21 in preeclampsia-exposed mice compared with controls. In atherogenic LDLR-KO mice, exposure to sFlt1-induced preeclampsia during pregnancy increases future atherosclerotic plaque inflammation, supporting the concept that preeclampsia directly exacerbates atherosclerotic inflammation independent of preexisting risk factors. This mechanism may contribute to ischemic vascular disease in women after preeclampsia pregnancy.

Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers

Age-associated telomere shortening leads to replicative senescence of human endothelial cells (EC). Risk factors for cardiovascular disease (CVD) accelerate ageing, while there is a concomitant rise in oxidative stress known to promote stress-induced senescence (SIS) in vitro. Of all risk factors for CVD, smoking is most associated with the development of inflammation and accelerated atherosclerosis due to a prooxidant-antioxidant imbalance. We tested the hypothesis that SIS predominates in EC isolated from chronic smokers with premature atherosclerosis undergoing coronary artery bypass graft surgery (CABG). We isolated and cultured EC from segments of internal mammary arteries from smoker, former smoker, and nonsmoker coronary patients. Senescence of EC was induced by serial passage and quantified by the measurement of telomere length and senescence-associated beta-galactosidase activity. Compared with nonsmokers, smoker patients were 10 years younger at the time of CABG, evidence of premature atherosclerosis. Cellular senescence was independent of telomere length and directly related to oxidative damage. EC exhibited higher expression levels of markers of oxidative stress (lipid peroxydation level and caveolin-1 mRNA), inflammation (angiopoietin-like 2 mRNA), hypoxia (vascular endothelial growth factor (VEGF)-A mRNA), and cell damage (p53 mRNA). In conclusion, a high oxidative stress environment in EC isolated from atherosclerotic chronic smokers predisposes to SIS rather than replicative senescence.

Relationship between carotid intima-media thickness and arterial stiffness in children after Kawasaki disease

Background: Evidence of premature atherosclerosis and systemic arterial stiffening in patients after Kawasaki disease is accumulating. Aim: To test the hypothesis that carotid intima-media thickness (IMT), a surrogate marker of...

Lack of Evidence of Premature Atherosclerosis in Untreated Severe Isolated Growth Hormone (GH) Deficiency due to a GH-Releasing Hormone Receptor Mutation

GH deficiency (GHD) acquired at adult age as a result of pathological processes of the pituitary gland or the hypothalamus causes changes that are associated with worsening cardiovascular risk. They include increase in abdominal obesity, total and low- density lipoprotein cholesterol, and C-reactive protein. GHD adults also have thickening of the carotid arteries. It has been postulated that GHD is the link between hypopituitarism and the increase in cardiovascular and cerebrovascular mortality observed in hypopituitarism. However, several confounding factors exist, such as associated pituitary deficits and replacement of other hormones or surgical or radiological therapies used to treat the underlying pituitary of hypothalamic pathologies. The aim of this study was to determine the consequences of lifetime isolated GHD (IGHD) on the metabolic and cardiovascular status of adult members of a large Brazilian cohort with severe IGHD due to a homozygous mutation in the GHRH receptor gene. Twenty-two GH naive adult dwarfs (10 men and 12 women; aged 44 +/- 12 yr) were compared with 22 healthy volunteers (10 men and 12 women; aged 45 +/- 12 yr) living in the same area. GHD subjects had increased abdominal obesity, higher total and low-density lipoprotein cholesterol, and higher C-reactive protein than controls. They did not have an increase in carotid wall thickness, and there was no evidence of premature atherosclerosis as evaluated by exercise echocardiography. In this homogeneous cohort residing in a rural area of Brazil, lifetime, untreated severe IGHD is not associated with evidence of premature atherosclerosis despite unfavorable cardiovascular risk profile.

Hyperhomocysteinemia, Enzyme Polymorphism and Thiobarbituric Acid Reactive System in Children with High Coronary Risk Family History

Objectives: To investigate both the frequency and the genetic background of hyperhomocysteinemia and the frequency of increased plasma thiobarbituric acid reactive system (TBARS) levels in children and adolescents whose parents had premature coronary heart disease (CHD).Methods: The study was performed on children and adolescents aged 4–18 years (105 offspring of parents with CHD before age 45 and 74 referents from families without any evidence of premature atherosclerosis). Fasting serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and total triglyceride (TG) levels were measured by enzymatic methods. Low density lipoprotein cholesterol (LDL-C) level was calculated by the Friedewald formula. Plasma total homocysteine (THCy) level was measured by fluorescence polarisation immunoassay. Plasma TBARS level was determined by fluorimetric method. 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme polymorphism was analyzed by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP).Results: Hyperhomocysteinemia was found in 32 cases and in 4 controls. Increased plasma THCy level was found in 10 children and adolescents from 12 cases homozygous for the C677T polymorphism of the MTHFR gene. No similar high frequency was observed in heterozygous subjects. Elevated fasting plasma TBARS levels were found in 38 cases and in 8 controls. The frequency differences were significant (p < 0.01). Allele frequency of the MTHFR polymorphism among cases and controls was similar. Significant correlation (r = 0.53, p < 0.02) was detected between plasma THCy and TBARS levels. One child had high serum TC level, 5 had low serum HDL-C level and all other children had normal serum TC, LDL-C, HDL-C and TG levels from children with hyperhomocysteinemia and/or high plasma TBARS levels. A significant correlation (r = 0.64, p < 0.01) was observed between plasma THCy levels of parents and children in the case group.Conclusion: The measurement of plasma THCy and TBARS levels may contribute to the detection of the risk of children and adolescents with high CHD risk family history.

The importance of oestrogens in males.

For a long time oestrogens in the human male have been regarded as a mere by-product of testosterone synthesis. Only since the description of an oestrogen-resistant man (Smith et al ., 1994) has it been fully realized that oestrogens play an import role in bone homeostasis, cardiovascular health and pituitary–gonadal interactions in men. Due to a disruptive homozygous oestrogen receptor alpha (ER α ) mutation, this man was virtually insensitive to oestrogens which lead to osteoporosis, unfused epiphyses resulting in linear growth into adulthood, increased gonadotrophin levels and evidence of premature atherosclerosis (Sudhir et al ., 1997a) and endothelial dysfunction (Sudhir et al ., 1997b). Additionally, there was low viability of sperm and glucose intolerance with acanthosis nigrans. Two adult aromatase-deficient men showed, besides undetectable oestrogen levels, low bone mass, unfused epiphyses, increased gonadotrophins and a unfavourable lipid profile (Morishima et al ., 1995; Carani et al ., 1997). Earlier, Korach (1994) described similar observations in ER α knockout mice. Heterozygous mice exhibited no obvious phenotypic abnormalities. Homozygous male mice proved to be infertile, showing smaller testes with dysmorphic seminiferous tubules and a sperm count of less than 10% compared to normal mice. Finally, bone mineral density was 20–25% lower in male and female mutants compared to wild-type animals. These reports indicate that oestrogens also play a central role in several metabolic processes in men. The interrelation between testosterone and oestrogen biosynthesis makes it difficult to separate their respective biological effects. Therefore, it is not unlikely that biological effects formerly attributed to testosterone actually represent effects of oestrogens. In light of the observations in oestrogen-resistant or -deficient males, and because of the wealth of evidence for the role of oestrogens in the (patho)physiology of bone and lipid metabolism, cardiovascular disease and the hypothalamo–pituitary– gonadal axis in women, this review will discuss these areas, focusing on the clinical importance of oestrogens in males.

Hypopituitarism and atherosclerosis

In the last decade, retrospective cohort data has provided evidence of premature atherosclerosis in patients with hypopituitarism which may account for the recently observed increased death rate from vascular events in these patients. The exact mechanism(s) for such propensity to atherosclerotic vascular disease is not yet completely clear. It is possible that hormonal factors may be the initiating mechanisms with subsequent secondary metabolic abnormalities acting as risk factors for development of atherosclerosis. This seems to be more evident in female hypopituitary patients compared with their male counterparts. Female patients have higher frequency and more pronounced abnormalities of various risk factors as well as surrogate markers of early vascular disease. This may explain why morbidity and mortality in women is in excess of men in retrospective epidemiological studies. Addressing abnormal hormonal factors, especially in females, is a primary objective in managing these patients both in the clinical arena as well as in trials designed to reduce the risk of atherosclerotic vascular disease in these patients. While short-term growth hormone treatment may ameliorate some of the vascular risk factors and improve endothelial function, it remains to be shown whether this translates into long-term reduction in morbidity and mortality from vascular, especially cerebrovascular, disease.

Increased High-Density Lipoprotein Levels Caused by a Common Cholesteryl-Ester Transfer Protein Gene Mutation

The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7.01 +/- 0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.