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PubMed2000

Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia.

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.

Adolescent↗
PubMed1994

Enhanced collagen-induced responses of platelets from rabbits with diet-induced hypercholesterolemia are due to increased sensitivity to TxA2. Response inhibition by chronic ethanol administration in hypercholesterolemia is due to reduced TxA2 formation.

The effects of dietary cholesterol and chronic administration of moderate amounts of ethanol on collagen-induced platelet responses were investigated. Three groups of rabbits were fed the following diets for 8 weeks: a normal chow diet, a cholesterol-enriched (0.25% wt/wt) chow diet, and a cholesterol-enriched chow diet plus 6% ethanol in the drinking water for the final week of the dietary period. Cholesterol feeding enhanced collagen-induced responses-aggregation, secretion of [14C]serotonin from prelabeled platelets, and thromboxane formation--of suspensions of washed platelets, and chronic ethanol treatment significantly reduced these enhanced responses. These effects are mediated by thromboxane A2 (TxA2) rather than ADP. Experiments with collagen-stimulated platelets in which feedback amplification of TxA2 was blocked with the prostaglandin H2/TxA2 receptor blocker BM 13.177 and experiments with aspirin-treated platelets stimulated with the stable TxA2 mimetic U46619 showed that cholesterol feeding enhanced platelet sensitivity to TxA2 rather than formation of TxA2 by platelets that had interacted with collagen. Without BM 13.177 or aspirin, TxA2 increased the amount of TxA2 formed by feedback amplification. In contrast, decreased responsiveness to collagen by platelets from cholesterol-fed rabbits given ethanol was due to inhibition of TxA2 formation rather than reduced sensitivity to TxA2. Platelets from cholesterol-fed rabbits given ethanol did not develop tolerance to the acute inhibitory effects of ethanol. Our results indicate that administration of moderate amounts of ethanol to cholesterol-fed rabbits inhibits enhanced collagen-induced responses of platelets by a TxA2-dependent pathway that involves reduction of TxA2 formation rather than reduction of platelet responses to TxA2.

Alcoholism↗
PubMedDate not supplied

DEAE-Dextran in the treatment of primary hypercholesterolemia and/or hypercholesterolemia combined with hypertriglyceridemia. A multicentric randomized study on the efficacy of DEAE-Dextran compared with Cholestyramine.

This study was carried out to verify the therapeutic homogeneity between DEAE-Dextran and Cholestyramine. Blood levels of total cholesterol, HDL, LDL and triglycerides were evaluated in 202 patients affected by dyslipidemia and treated with DEAD-D at 2.5 g/day or with Cholestyramine at 12 g/day for 30 days. At the end of treatment both drugs caused significant reduction of total cholesterol, LDL and triglycerides blood levels; DEAD-D was generally more effective than Cholestyramine, in particular on triglycerides values (30.6% and 13.7% of reduction respectively), and produced also a significant increase in HDL cholesterol, differently from Cholestyramine that was ineffective on this parameter.

Anticholesteremic Agents↗
PubMed2006

Prevalence, treatment, and control of combined hypertension and hypercholesterolemia in the United States.

Hypertension and hypercholesterolemia are important modifiable risk factors for cardiovascular disease (CVD). We examined the prevalence, treatment, and control of combined hypertension and hypercholesterolemia in United States adults aged>or=20 years (n=2,864, projected to 118 million, 52% women) from the National Health and Nutrition Examination Survey 2001 to 2002 by gender, age group, ethnicity, and co-morbidities (metabolic syndrome, diabetes mellitus [DM], and preexisting CVD). Hypertension was defined as blood pressure of >or=140/90 mm Hg (>or=130/80 mm Hg if DM was present) or on treatment. Hypercholesterolemia was defined as a low-density lipoprotein cholesterol level of >or=130 mg/dl (>or=100 mg/dl if DM or CVD was present) or on treatment. The overall prevalence of hypertension, hypercholesterolemia, and hypertension and hypercholesterolemia combined was 30%, 47%, and 18%, respectively. The incidence of the 2 combined was 20% in women versus 16% in men (p<0.05), ranging from 1.9% in those aged 20 to 29 years to 56% in those aged>or=80 years (p<0.001). Combined hypertension and hypercholesterolemia was least prevalent in Hispanics (9.8% compared with 19% in whites and 22% in African-Americans, p<0.01) and highest in those with CVD plus DM or metabolic syndrome (69%), CVD only (44%), DM only (41%), and metabolic syndrome only (37%). Of those with combined hypertension and hypercholesterolemia, 29% were being treated (8.3% in those aged 20 to 29 years to 38% in those aged 70 to 79 years, p<0.01). Treatment was least prevalent in Hispanics (12% vs 24% in African-Americans and 30.4% in whites, p<0.01). Overall control of hypertension and hypercholesterolemia was only 9% and was low in all disease groups (5.5% to 16%). In conclusion, treatment and control of combined hypertension and hypercholesterolemia are suboptimal. Increased efforts to improve treatment of these conditions are needed.

Adult↗
PubMedDate not supplied

Diabetes attenuates the alterations in both venous endothelial and smooth muscle cell function induced by prolonged hypercholesterolemia in an experimental model.

The systemic effects of the combination of diabetes and hypercholesterolemia on venous vasomotor function are poorly understood. This study examines in vitro vasomotor responses of New Zealand White rabbit jugular veins from control, diabetic, hypercholesterolemic, and hypercholesterolemic with diabetes groups. Hypercholesterolemia was induced with a diet supplemented with 1% cholesterol, while diabetes was induced by alloxan. Cumulative dose response curves to norepinephrine, bradykinin, and histamine were performed. After precontraction with norepinephrine to give 80% maximal contraction, relaxation in response to acetylcholine and sodium nitroprusside was determined. Potency of the agonist responses were compared. The contractile responses to all agonists were significantly increased in hypercholesterolemia. Only the response to norepinephrine was increased in diabetes. However, when diabetes and hypercholesterolemia were combined the contractile response to bradykinin was increased, the response to histamine was significantly decreased, but the norepinephrine response was unchanged. There was dose-dependent, endothelium-mediated relaxation in precontracted control and diabetic veins. Hypercholesterolemia and hypercholesterolemia with diabetes interfered with endothelium-mediated relaxation, producing a multiphasic response: relaxation at low concentrations followed by contraction at higher concentrations. Non-endothelium-dependent relaxation to sodium nitroprusside of precontracted veins was unaffected by the presence of diabetes or hypercholesterolemia. This study suggests that the combined presence of diabetes and hypercholesterolemia attenuated the altered contractile responses induced by hypercholesterolemia alone without further alterations in endothelial-mediated responses. The mechanism for these alterations remains to be determined.

Acetylcholine↗
PubMed1991

Metabolic basis of primary hypercholesterolemia.

BACKGROUND: Hypercholesterolemia is a well-established risk factor for coronary heart disease. However, the mechanisms underlying hypercholesterolemia, elevated low density lipoprotein (LDL) in particular, are not well understood. To determine these mechanisms, we studied LDL kinetics in a group of men with primary hypercholesterolemia. METHODS AND RESULTS: LDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol, 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol, more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in LDL apolipoprotein (apo) B levels but had abnormally high LDL cholesterol-to-apo B ratios; 14 patients had very low fractional catabolic rates (FCRs) for LDL, similar to FH patients; 35 patients had FCRs for LDL in the borderline range but high production rates for LDL; and 22 patients had a high flux of LDL (high production rates and high FCRs). In general, patients with severe hypercholesterolemia resembled those with moderate LDL elevations, except that their LDL particles were enriched with cholesterol. CONCLUSIONS: Data from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia. These patterns can serve as the basis for further investigation to determine the molecular defects responsible for each pattern.

Adult↗
PubMed2001

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

The aims of this study were to examine the presence of mutations in the low-density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.

Adult↗