Images in clinical medicine. Homozygous familial hypercholesterolemia.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
J Genest
Publications and source records attributed to J Genest.
Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child.
We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele.
Adolescent↗
Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate RNA editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(Honduras-1) [LDL-R1061(-1) G-->C].
Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern Honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative RNA editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate RNA editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.
Adult↗
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).
ATP Binding Cassette Transporter 1↗
Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.
Familial high density lipoprotein (HDL) deficiency (FHD) is a genetic lipoprotein disorder characterized by a severe decrease in the plasma HDL cholesterol (-C) level (less than the fifth percentile). Unlike Tangier disease, FHD is transmitted as an autosomal dominant trait. FHD subjects have none of the clinical manifestations of Tangier disease (lymphoid tissue infiltration with cholesteryl esters and/or neurological manifestations). Plasmas from FHD subjects contain pre-beta-migrating HDLs but are deficient in alpha-migrating HDLs. We hypothesized that a reduced HDL-C level in FHD is due to abnormal transport of cellular cholesterol to the plasma membrane, resulting in reduced cholesterol efflux onto nascent HDL particles, leading to lipid-depleted HDL particles that are rapidly catabolized. Cellular cholesterol metabolism was investigated in skin fibroblasts from FHD and control subjects. HDL3- and apolipoprotein (apo) A-I-mediated cellular cholesterol and phosphatidylcholine efflux was examined by labeling cells with [3H]cholesterol and [3H]choline, respectively, during growth and cholesterol loading during growth arrest. FHD cells displayed an approximately 25% reduction in HDL3-mediated cellular cholesterol efflux and an approximately 50% to 80% reduction in apoA-I-mediated cholesterol and phosphatidylcholine efflux compared with normal cells. Cellular cholesterol ester levels were decreased when cholesterol-labeled cells were incubated with HDL3 in normal cells, but cholesterol ester mobilization was significantly reduced in FHD cells. HDL3 binding to fibroblasts and the possible role of the HDL binding protein/vigilin in FHD were also investigated. No differences were observed in 125I-HDL3 binding to LDL-loaded cells between FHD and control cells. HDL binding protein/vigilin mRNA levels and its protein expression were constitutively expressed in FHD cells and could be modulated ( approximately 2-fold increase) by elevated cellular cholesterol in normal cells. In conclusion, FHD is characterized by reduced HDL3- and apoA-I-mediated cellular cholesterol efflux. It is not associated with abnormal cellular HDL3 binding or a defect in a putative HDL binding protein.
Adult↗
High density lipoproteins in health and in disease.
Explore the source record for details and available documents.
Apolipoprotein A-I↗
Hyperhomocyst(e)inemia--determining factors and treatment.
Elevated homocyst(e)ine levels are associated with an increased risk of vascular disease, particularly aorto-iliac, coronary and cerebrovascular disease. In patients with confirmed disease, plasma homocyst(e)ine is a strong predictor of death. In addition to B vitamins, folic acid and certain genotypes, renal function is an independent determinant of plasma homocyst(e)ine level. There also may be a polygenic component contributing to elevated homocyst(e)ine levels in confirmed vascular disease. Possible mechanisms of homocyst(e)ine-induced vascular change include proliferation of vascular smooth muscle cells, endothelial cell dysfunction and a procoagulant state. The definition of hyperhomocyst(e)inemia is based on arbitrary cut-points (eg, the 90th percentile). In most populations, this is approximately 15 microM/L. Patients with hyperhomocyst(e)inemia should be treated with at least 400 micrograms of folic acid per day. Alternative treatments are vitamin B6 and B12 supplementation, although optimal doses have yet to be identified.
Animals↗
Contribution of traditional risk factors to coronary artery disease in patients with systemic lupus erythematosus.
OBJECTIVE: Several factors have been implicated in the high prevalence of premature coronary artery disease (CAD) in patients with systemic lupus erythematosus (SLE). We hypothesize that variables independent of traditional risk factors contribute significantly to the development of CAD in SLE. We investigated the relative contribution of traditional risk factors in SLE patients with CAD compared to non-SLE patients with premature CAD. METHODS: An age matched retrospective cohort analysis. The prevalence of traditional cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes, smoking, family history) in patients with SLE who developed CAD during the course of their illness was compared to a group of age matched non-SLE subjects with premature CAD. Sexes were analyzed separately using Fisher's exact test and unpaired t tests. RESULTS: Thirty-five patients with SLE (27 women, 8 men) with definite ischemic heart disease were identified along with 397 non-SLE subjects (83 women, 314 men). In women with SLE the mean number of CAD risk factors per cardiac event was 2.0 +/- 0.77 versus 2.90 +/- 1.19 for the comparison group (p = 0.0008). In men with SLE the mean number of CAD risk factors was 1.87 +/- 0.83 versus 2.73 +/- 0.99 in the comparison group (p = 0.016). CONCLUSION: SLE patients with a cardiac event have fewer traditional risk factors than non-SLE patients with premature CAD. Thus premature CAD in SLE cannot be attributed solely to an excess of traditional risk factors.
Adult↗
Contribution of the -455G/A polymorphism at the beta-fibrinogen gene to erythrocyte aggregation in patients with coronary artery disease.
BACKGROUND: A high level of red blood cell (RBC) aggregation has been consistently found in patients with coronary artery disease (CAD) in case-control studies. Plasma fibrinogen has been shown to promote RBC aggregability. The purpose of this study was to investigate the influence of the genetic variability of the beta-fibrinogen gene on RBC aggregation in patients with CAD. METHODS AND RESULTS: The genotype of the beta-fibrinogen gene locus was determined by polymerase chain reaction using the restriction enzyme HaeIII for a G to A substitution at position -455 upstream from the transcriptional start site in 135 French Canadians with premature CAD (age: 51+/-7 years). Indices measuring the RBC aggregation kinetics (S10) and shear resistance of the aggregates (gammaS) were obtained by laser reflectometry. Patients were separated into groups by using the medians of S10 and gammaS. Using chi2 analyses, the distribution of the -455GG, -455GA, and -455AA genotypes in the groups with high levels of S10 (0.43, 0.49, and 0.08) and gammaS (0.45, 0.49, and 0.06) were found to be significantly distinct from those in the groups with low levels of S10 (0.67, 0.27, and 0.06; p<0.05) and gammaS (0.70, 0.23, and 0.07; p<0.01). High levels of RBC aggregation were closely associated with the rare -455A allele. Multivariate linear regression analyses showed that S10 was positively correlated with the linear combination of the fibrinogen concentration, age, and the -455G/A genotype (adjusted r = 0.63, p<0.0001). Fibrinogen and age were positive determinants, and HDL-cholesterol was a negative predictor of gammaS (adjusted r = 0.51, p<0.0001). CONCLUSION: These findings support the hypothesis that RBC hyperaggregation in premature CAD may be associated with the beta-fibrinogen -455G/A polymorphism. This association may be explained by a change in the concentration and/or the functional properties of the fibrinogen protein.
5' Untranslated Regions↗
Emerging risk factors associated with cardiovascular diseases.
Explore the source record for details and available documents.
Adult↗
Clinical comparison of acoustic and electronic stethoscopes and design of a new electronic stethoscope.
This clinical study was performed to evaluate the advantages and limitations of 3 acoustic stethoscopes and 3 electronic stethoscopes. It shows that it is possible to design a new electronic stethoscope by considering the advantages of both the acoustic and electronic stethoscopes.
Acoustics↗
Atherogenic, hemostatic, and other potential risk markers in subjects with previous isolated myocardial infarction compared with long-standing uncomplicated stable angina.
BACKGROUND: Several atherogenic, hemostatic, inflammatory, and genetic parameters and markers have been implicated as risk factors in coronary artery disease, although whether they are risk factors for acute as opposed to chronic coronary disease is unclear. METHODS AND RESULTS: Fifty subjects with an isolated myocardial infarction >3 months previously were compared with 50 subjects with a minimum 3-year history of stable angina, documented coronary artery disease, normal electrocardiogram and normal ventricular wall motion, and no episode suggesting infarction or unstable angina. Biologic variables analyzed included apolipoprotein B (apo B), lipoprotein (a), C-reactive protein (CRP), fibrinogen, factor VII, tissue plasminogen activator (TPA) and inhibitor (PAI-1), thrombin-antithrombin (TAT), fragment 1+2 (F1+2), von Willebrand factor (vWF), activated protein C resistance, homocyst(e)ine, anticardiolipin antibodies, blood group, and the angiotensin-converting enzyme insertion/deletion (I/D) and angiotensin II receptor gene polymorphisms. There were no significant differences between the 2 groups for any of the variables studied, although fibrinogen and F 1+2 tended to be slightly higher in the angina group (P = .09 for each). These significant correlations were present: age with fibrinogen, homocyst(e)ine, and vWF; factor VII with apo B, homocyst(e)ine, and TPA; apo B with TPA and CRP; CRP with fibrinogen, TPA, PAI-1, and factor VII; fibrinogen with vWF. CONCLUSIONS: Examination of atherogenic, hemostatic, inflammation, and genetic variables in the clinically quiescent state permitted no distinction between subjects with a previous isolated myocardial infarction in contrast to those with long-standing uncomplicated stable angina, favoring the notion that acute coronary events occur at random on a varying background of atherosclerosis. The multiple correlations found among these variables also underscore their complex interaction in the atherosclerotic process.
Adult↗
Genetics of lipoprotein disorders.
The study of lipoprotein metabolism has led to major breakthroughs in the fields of cellular physiology, molecular genetics, and protein chemistry. These advances in basic science are reflected in medicine in the form of improved diagnostic methods and better therapeutic tools. Perhaps the greatest benefit is the improved ability to identify at an early stage patients who are at high risk for atherosclerosis, providing clinicians the opportunity to proceed swiftly with intensive lipid-lowering therapy for the prevention of cardiovascular complications. Recent clinical trials have shown that such an approach is not only cost-effective but saves lives while improving the quality of life. They also emphasize the important role physicians can have in prevention. More than half of patients with premature CAD have a familial form of dyslipoproteinemia. This review of the genetics of atherogenic lipoprotein disorders underscores the importance of identifying major genetic defects. It also stresses the need to take into account multifactorial etiologies and clustering of risk factors, as well as gene-gene and gene-environment interactions in assessing the atherogenic potential of a lipid transport disorder. Table 2 summarizes the key points in the diagnosis, clinical implications, and treatment of the major inherited atherogenic dyslipidemias.
Diagnosis, Differential↗
Plasma acylation stimulating protein (ASP) as a predictor of impaired cellular biological response to ASP in patients with hyperapoB.
BACKGROUND: The objective of this study was to examine specific membrane binding of [125I]-acylation stimulating protein (ASP) in cultured human skin fibroblasts obtained from normal subjects and patients with hyperapoB. ASP is a small basic protein isolated from human plasma that stimulates triglyceride synthesis (TGS) and glucose transport (GT) in human skin fibroblasts and adipocytes. DESIGN: In the present study, three groups were studied: normal (NASP-NB) subjects, hyperapoB subjects with normal plasma ASP (NASP-HB) and hyperapoB subjects with high plasma ASP (HASP-HB). RESULTS: ASP-induced TGS in fibroblasts from HASP-HB subjects was significantly less than in the two control groups with normal plasma ASP (NASP-NB and NASP-HB). Similarly, ASP stimulation of GT was less in HASP-HB fibroblasts than in the NASP-HB fibroblasts or the NASP-NB subjects. Insulin-induced TGS was similar in all three groups as was insulin-stimulated GT. As well, protein kinase C-mediated stimulation was equivalent among the three groups both for GT and for TGS. There was no significant difference in the binding affinity (Kd) of [125I]-ASP to intact cells in any group. By contrast, binding of [125I]-ASP revealed a significantly lower Bmax of the HASP-HB cell lines than the NASP-NB cells and the NASP-HB cells. CONCLUSION: A decrease in the ASP cell-surface receptor concentration is responsible for decreased ASP stimulation of TGS, and GT and may contribute to the inefficient postprandial triglyceride (TG) clearance in HASP-HB subjects.
Adult↗
Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I.
We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126+/-18 mg/dL, mean+/-SD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5+/-1.7 mg x kg[-1] x d[-1]). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32+/-1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9+/-2.6 mg x kg[-1] x d[-1]) and proapoA-I RTs (0.18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24+/-0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7+/-0.2 mg x kg[-1] x d[-1]). Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I.
Apolipoprotein A-I↗
Rationale for and outline of the recommendations of the Working Group on Hypercholesterolemia and Other Dyslipidemias: interim report. Dyslipidemia Working Group of Health Canada.
A panel consisting of lipidologists, epidemiologists, cardiologists, internists, general practitioners, and public health and government representatives used the evidence-based approach to examine the rationale for a draft of recommendations for medical management of lipid disorders. The proposed recommendations deal with assessment of cardiovascular risk based on history, physical examination and laboratory findings; assessment of the fasting lipid profile; diagnosis and treatment of secondary risk factors; calculation of the 10-year risk of a cardiac event; initiation of lifestyle modifications in patients in whom low density lipoprotein cholesterol (LDL-C), total:high density lipoprotein cholesterol (HDL-C) ratio or triglycerides exceeds target values based on a patient's risk category; follow-up; treatment with drugs; and choices of drugs. In contrast to previous recommendations, there are new, considerably lower, cholesterol level targets for secondary prevention, with a less important emphasis on total cholesterol value than on LDL-C or total:HDL-C ratio and triglyceride levels, and an emphasis on determining the likelihood of a cardiac event by evaluating all relevant risk factors and sharpening the focus on nondrug treatment, which should result in treating a greater percentage of at-risk patients.
Anticholesteremic Agents↗
Lipoprotein lipase gene mutations in coronary artery disease.
BACKGROUND: Genetic lipoprotein disorders are frequently associated with premature coronary artery disease (CAD). Functional mutations of the lipoprotein lipase (LPL) gene are associated with altered plasma lipoprotein profiles and are relatively common in French Canadians. OBJECTIVE: To investigate the prevalence of LPL gene mutations in a group of patients with premature CAD and in a healthy control group. METHODS: A total of 636 subjects (337 [82% men] with angiographically documented CAD and 299 controls [63% men]) were examined for the presence of mutations LPL(Gly188-->Glu), LPL(Pro207-->Leu), LPL(Asp250-->Asn) and LPL(Asn291-->Ser) of the LPL gene. These mutations represent over 97% of LPL mutations in familial hyperchylomicronemia in Quebec. RESULTS: The prevalence of heterozygosity for defective LPL alleles was eight of 337 (2.4%) in the CAD group and five of 299 (1.7%) in the control group (chi(2) = 0.118, P = 0.73; power [P] for alpha = 0.05, P = 0.60). In the six CAD patients heterozygous for LPL(Asn291-->Ser), fasting plasma lipoprotein lipid levels did not differ significantly from those of the rest of the CAD group or markedly from those of control subjects. The two CAD patients heterozygous for the LPL(Gly188-->Glu) mutation, however, had hypertriglyceridemia and low plasma high density lipoprotein levels. No CAD or control subjects were identified with the LPL(Pro207-->Leu) or LPL(Asp250-->Asn) alleles. CONCLUSIONS: In this selected population of premature CAD subjects, the prevalence of heterozygosity for defective LPL alleles was slightly higher (but not significantly so) than that in a group of healthy subjects. The LPL(Gly188-->Glu) and LPL(Asn291-->Ser) mutations may confer genetic susceptibility to premature CAD in a small number (approximately 2.4%) of patients; overall these four LPL alleles do not appear to contribute significantly to CAD risk in French Canadians.
Adult↗
Angiotensin converting enzyme insertion/deletion polymorphism in French Canadian subjects with premature coronary artery disease.
The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been postulated to be associated with CAD in some populations of European descent. As part of a study investigating metabolic and genetic factors in subjects with premature coronary artery disease (CAD), we examined the I/D polymorphism of the ACE gene in 134 subjects with premature CAD (105 men and 29 women, mean age 49 +/- 6 years) and 116 control subjects selected for health (71 men, 45 women; mean age 39 +/- 7 years). Both patients and controls were of French Canadian descent. As expected, significant differences were found between cases and controls with respect to age, plasma lipoprotein cholesterol, presence of smoking, diabetes and high blood pressure after correction for age. Multivariate analysis confirms the importance of age, HDL-C levels, smoking and apo B levels as determinants of CAD. Allele frequencies of the I and D polymorphism were 43.1% and 57.9% in controls, and 48.5% and 51.5% in CAD cases (chi 2 = 0.622, p = 0.430). No significant association between the I/D polymorphism and conventional cardiovascular risk factors, including plasma levels of lipids, lipoprotein cholesterol, diabetes or smoking, was found in cases or controls. Furthermore, the presence of the I/D polymorphism did not correlate with a history of hypertension or a family history of premature CAD in CAD patients. We conclude that, in our selected population, the I/D polymorphism of the ACE gene is not associated with CAD, conventional risk factors, or a family history of CAD. Although our sample size does not allow sufficient power to ascertain that the ACE I/D polymorphism is not associated with CAD, we do not recommend the routine measurement of the ACE polymorphism in our population to determine cardiovascular risk.
Adult↗