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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Essential Hypertension (EH) is a multifactorial and polygenic syndrome with a high impact in public health. Recently, rare mendelian forms of hypertension such as glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME) and Liddle Syndrome caused by single gene mutations have been identified in which the mechanism is an increased sodium retention. Therefore, it is tempting to speculate that the most common forms of EH may be due to diverse highly prevalent molecular variants of susceptibility genes with low penetrance that are involved in arterial blood pressure (ABP) and electrolytic balance. Although a number of candidate genes such as NO synthases, ANP, ion transporters, adducins, LDL receptor, etc. can participate, renin-angiotensin system components are the most extensively studied. Although not associated with EH, the ACE D allele seems to confer a high risk of CHD or LVH. Angiotensinogen 235T and 174M variants are more likely associated with EH and positively correlate with clinical or ambulatory ABP in adolescents or adults. Individuals who carry these angiotensinogen alleles would be at 1.4 higher risk of suffering EH than homozygotes for M235 or T174 alleles. Associations of AT1 receptor variants with EH remain to be definitively defined. In conclusion, the characterization of the genetic background, although difficult at the present time, may have clear benefits in terms of defining a more rational therapy and prevention in individuals at risk. Even though this aim seems difficult to achieve since more than 150 candidate genes have been postulated as the cause of EH, with 6 to 10 SNPs in each of them, new technologies such as DNA micro-arrays will provide us with the opportunity to analyse the total genetic risk in each subject.
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PMID:[Molecular genetics of essential hypertension. Susceptibility and resistance genes]. 1083 1

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.
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PMID:Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. 1097 68

The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I-converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72; P=0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24; P=0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97; P=0.02), plasma glucose (OR=3.31; 95% CI, 3. 10 to 3.52; P=0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72; P=0.06) and increased to 3.10 (95% CI, 1.20 to 7.52; P=0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.
Hypertension 2000 Nov
PMID:Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia. 1108 47

Current gene delivery vectors demonstrate inefficient and nonselective gene transfer to vascular endothelial cells, limiting their use in cardiovascular gene transfer and therapy. The lectinlike oxidized LDL receptor (LOX-1) is expressed selectively at low levels on endothelial cells but is strongly upregulated in dysfunctional endothelial cells associated with hypertension and atherogenesis. Using LOX-1 as a target receptor, we have sought to isolate peptide ligands that mediate binding to the extracellular domain of LOX-1 as a definitive step in the development of targeted gene transfer aimed at dysfunctional endothelium. To achieve this, we ectopically overexpressed LOX-1 in cells lacking endogenous LOX-1 by using an episomally maintained expression system and designed a novel subtractive phage display strategy to identify peptides selective for LOX-1. After extensive biopanning, we sequenced individual phage and identified 60 novel peptides. This population of peptides contained a number of potential consensus motifs. To define the selectivity of individual peptides for LOX-1 with the use of an independent gene transfer system, we developed a novel adenoviral vector to overexpress LOX-1 transiently in primary cells and cell lines. We then quantified recovery of each peptide from LOX-1-positive and LOX-1-negative cells after adenovirus-mediated gene transfer. This strategy confirmed selectivity to LOX-1 for many peptides and highlighted the peptides LSIPPKA, FQTPPQL, and LTPATAI as principal candidates. These peptides will be useful for the selective targeting of viral and nonviral gene transfer vectors to endothelial cells expressing the LOX-1 receptor in vitro and in vivo and in particular dysfunctional endothelial cells associated with hypertension and atherosclerosis.
Hypertension 2001 Feb
PMID:Identification of peptides that target the endothelial cell-specific LOX-1 receptor. 1123 Mar 17

Most studies of the pathogenesis of coronary heart disease occur between gene variants and biochemical or physiological variables known to be atherogenic. In many situations, however, the gene products are not necessarily known. We studied 17 families (n = 122) with mutations in the low density lipoprotein (LDL) receptor gene as a model in which to test formally for linkage directly between an atherogenic genotype and ischemic heart disease (IHD) or aorto-coronary calcified atherosclerosis. In each family one of three different mutations was found: the Trp66-Gly mutation, the Trp23-Stop mutation, or a ten kilobase deletion removing exons 3-6 of the LDL receptor gene. Genomic DNA was used to determine these mutations by either enzymatic cleavage assays or Southern blotting. Aorto-coronary calcification was significantly associated with age and plasma cholesterol. Sex, hypertension, BMI and smoking were not associated with aorto-coronary calcification. Nonparametric analysis indicated significant linkage of the LDL receptor gene locus to aortic (p < 0.00005) and to aorto-coronary calcified atherosclerosis (p < 0.00001). Assuming a dominant mode of inheritance, significant linkage was detected for aortic (LOD = 3.89) and aorto-coronary calcified atherosclerosis (LOD = 4.10). We suggest that the atherogenicity of variations in other genes could be assessed by a similar approach.
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PMID:Linking genotype to aorto-coronary atherosclerosis: a model using familial hypercholesterolemia and aorto-coronary calcification. 1124 53

Epidemiological evidence shows that among women, the incidence of all, including less severe, coronary events is still increasing. However, owing both to diminished lethality as well as the reduction in the rate of acute myocardial infarction, mortality has globally decreased. The strong association observed between mortality and major cardiovascular risk factors as well as between their temporal changes and the occurrence of coronary disease makes the undertaking of multifactorial prevention strategies, including the formulation of risk charts for asymptomatic women and men, necessary. The different "penetrance" of risk factors in women, together with their interaction with female hormones, plays an important role in the development of cardiovascular disease. The excess risk of cigarette smoking is 2-4 times higher in women than in men and the correlation with the number of cigarettes smoked daily is distinct. However, the risk starts to decrease immediately after stopping and after 3-5 years is similar to that of non-smokers. In women, the association between hypertension, coronary artery disease and early mortality is stronger than in men: there is no threshold below which the risk disappears. Diet and lifestyle strongly influence the development of hypertension. For this reason, the American Heart Association/American College of Cardiology guidelines recommend adherence to a set of dietary and lifestyle habits including body weight control and physical activity. In particular, diet may modify the "penetrance" of risk factors in women: hence excess intake of saturated fatty acids associated with decreased cereals, fruit and vegetables does not only alter the lipid profile but also increases the risk of coronary disease. An elevated total/HDL cholesterol ratio and the presence of lipoprotein(a) constitute significant risk factors for coronary events. On the other hand, high HDL cholesterol levels (> 45 mg/dl) are considered to be protective in women. However, data on the efficacy of strategies aimed at reducing blood LDL levels in hypercholesterolemic women are limited and controversial. Pharmacological therapy is recommended in women with primary familial hypercholesterolemia and during menopause when the patient presents with two or more risk factors. Besides, pharmacological therapy is also indicated for women with a history of coronary artery disease in whom benefits exceed those observed in male patients with a similar clinical picture. In diabetic women, the risk of coronary mortality is increased 3 to 7-fold compared to the 2 to 3-fold increase observed in diabetic men. Diabetes definitely increases the effects of the other risk factors and modifies the protective effect by estrogens. However, to date, there is no evidence that keeping glucose levels within normal limits reduces the risk of coronary artery disease nor has a glycemic threshold capable of predicting mortality risk in diabetic women been established. For this reason, guidelines for such patients are aimed at keeping the other risk factors under strict control in order to significantly reduce their effect. Obesity results in a series of metabolic alterations that increase the risk of cardiovascular disease in both sexes. Although most, if not all, data confirm that obesity alone is not of predictive value, central obesity constitutes a risk factor for cardiovascular disease. A body mass index < 24.9 kg/m2 and a waist circumference < 80 cm are recommended so as to decrease the likelihood of developing a menopausal insulin-resistance syndrome. It has been demonstrated that in men, a sedentary lifestyle is correlated with a higher cardiovascular and all-cause mortality; some recent observational studies suggest a 25-30% decrease in the mortality risk for women who perform physical exercise. Current guidelines recommend at least 30 min daily of dynamic moderately vigorous activity, including brisk walking. Rather than to the reduction in the serum levels of endogenous estrogens, the increase in the incidence of disease and of mortality following menopause should be attributed to the age-related modifications in risk factors which result in an increased risk of coronary artery disease. In spite of the proved detrimental effect of estrogen deficiency on LDL- and HDL-cholesterol, on arterial smooth muscle cell proliferation and on insulin secretion and in spite of the data of numerous observational studies and of the HERS trial (all, however, with methodological limitations), clinical evidence does not justify widespread estrogen prescription, not even for purposes of secondary prevention. Besides, the dosages and the route of administration are still subject of debate. (ABSTRACT TRUNCATED)
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PMID:[Cardiovascular risk factors and prevention in women: similarities and differences]. 1125 80

Lectinlike oxidized LDL receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL (ox-LDL), is proposed to be involved in endothelial dysfunction and in the pathogenesis of atherosclerosis. Preeclampsia is a pregnancy complication diagnosed by hypertension and proteinuria, characterized by endothelial dysfunction, and supposedly caused by compounds from hypoxic uteroplacental tissues. A feature of preeclampsia is formation of foam cells in maternal arterial walls of gestational tissue ("acute atherosis"). Oxidative stress is believed to play a role in the pathophysiology of preeclampsia. 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo, is biologically active in vitro, and is elevated in preeclamptic plasma and gestational tissue. In the present article, we hypothesized that 8-iso-PGF(2alpha) could induce the expression of LOX-1 in trophoblastic cells (JAR). We demonstrated augmented cellular uptake of (125)I-tyraminylcellobiose ox-LDL in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) versus control cells. Ligand blots revealed an increased binding of ox-LDL to LOX-1 in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L). Incubation with 8-iso-PGF(2alpha) (10 micromol/L) also resulted in augmented LOX-1 protein levels (Western blots) and mRNA levels (Northern blots). JAR cells transfected with 3 copies of a nuclear factor-kappaB binding site demonstrated dose-dependent activation of the reporter gene luciferase after incubation with 8-iso-PGF(2alpha) (0 to 10 micromol/L). We also demonstrated increased accumulation of neutral fats in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) and ox-LDL compared with controls by oil red O staining. We speculate a potential role of isoprostanes and LOX-1 in preeclampsia in the development of "acute atherosis" of gestational spiral arteries.
Hypertension 2001 Apr
PMID:8-iso-prostaglandin F(2alpha) increases expression of LOX-1 in JAR cells. 1130 22

For the care of an expanding segment of the US population with multiple coronary risk factors, combination lipid-altering therapy is emerging as a treatment imperative. The most recent National Cholesterol Education Program's consensus guidelines emphasize long-term global coronary heart disease (CHD) risk status, designate patients with CHD risk equivalents (eg, diabetes, peripheral arterial disease, 20% or more 10-year absolute CHD risk) for aggressive lipid-altering therapy, and deem the metabolic syndrome (eg, obesity, insulin resistance, hypertension, elevated triglycerides, low levels of high-density lipoprotein cholesterol, small dense low-density lipoprotein particles) as a secondary target for intervention. With the advancing age of the US population and the high prevalence of diabetes, the metabolic syndrome, and CHD, increasing numbers of patients will require a more balanced metabolic attack attainable only through combination lipid-altering regimens. Many of these patients, as well as persons at heightened risk for cardiovascular disease because of a range of heritable conditions (eg, familial hypercholesterolemia, familial combined hyperlipidemia), will undoubtedly require binary or ternary regimens involving statins in concert with niacin, fibric-acid derivatives, or bile acid resins. Such approaches enable the clinician to exploit the complementary effects of these agents, allowing them to be administered at low, optimally tolerable doses that are consistent with superior efficacy and a lower risk of adverse events as compared with escalating doses of monotherapy.
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PMID:Combination lipid-altering therapy: an emerging treatment paradigm for the 21st century. 1148 48

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
Hypertension 2001 Nov
PMID:Gene therapy for cardiovascular disease: a case for cautious optimism. 1171 25

An endothelial nitric oxide synthase gene (NOS3) polymorphism in exon 7 (G894T), resulting in Glu298Asp substitution at protein level, has been associated with myocardial infarction, hypertension and coronary atherosclerosis in some populations. This polymorphism is usually identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). However, the procedures described to date do not eliminate the possibility of misclassification and either require confirmation by DNA sequencing or are time-consuming. In this study, a PCR-RFLP procedure to detect the G894T polymorphism at the NOS3 was optimized by the introduction of a constitutive cleavage site in the amplification product. This cleavage site provides an internal control for enzymatic activity to avoid mistyping. The method was validated by the study of 35 white unrelated individuals with familial hypercholesterolemia and 70 controls. The frequency of the variant allele (T) was similar between both groups (27% vs. 22%, NS), and comparable to the frequency found in other white populations. However, future studies are necessary to confirm these data. In summary, the optimized procedure for detection of the G894T NOS3 polymorphism is rapid, simple, and does not require confirmatory tests. Using this method, we found no association between this polymorphism and familial hypercholesterolemia.
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PMID:A method to detect the G894T polymorphism of the NOS3 gene. Clinical validation in familial hypercholesterolemia. 1211 83


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