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PubMed1996

Reduced coronary flow reserve in familial hypercholesterolemia.

UNLABELLED: Familial hypercholesterolemia (FH) presents the highest risk for coronary artery disease (CAD) among patients with hyperlipidemia. Therefore, early detection of coronary arterial atherosclerosis is important for the treatment of FH patients. The aim of this study was to detect early coronary arterial abnormalities that may relate to future atherosclerosis in asymptomatic FH patients by measuring coronary flow reserve (CFR) using PET and 13N-ammonia. METHODS: Twenty-five patients with FH (14 men, 11 women) without a history of myocardial ischemia and 14 control subjects (9 men, 5 women) were studied. Total serum cholesterol (mmole/liter) was 5.33 +/- 0.66 in control subjects and 7.90 +/- 0.77 in FH patients (p < 0.01 versus control subjects). RESULTS: Myocardial blood flow (MBF) at rest and during dipyridamole loading was measured using PET, and CFR was calculated. MBF (ml/min/100 g weight heart) at rest in the FH group (79.0 +/- 20.0) was comparable to that in control subjects (70.0 +/- 17.0). However, MBF during dipyridamole loading was significantly lower in FH patients (163.0 +/- 67.0) than in control subjects (286.0 +/- 120.0, p < 0.01). CFR in FH patients (2.09 +/- 0.62) was also significantly lower than that in control subjects (4.13 +/- 1.38, p < 0.01). CFR showed a gender-specific variance in FH patients (1.85 +/- 0.40 in men versus 2.55 +/- 0.74 in women p < 0.05) but not in control subjects. Significant inverse correlations between CFR and the total plasma cholesterol level as well as plasma LDL cholesterol were observed. CONCLUSION: The CFR was reduced in patients with FH. This abnormality was more prominent in men than in women patients. Noninvasive assessment of CFR by 13N-ammonia PET was useful to detect early abnormalities of the coronary arteries in asymptomatic patients with FH.

Ammonia↗
PubMed1998

VLDL and IDL apolipoprotein B-100 kinetics in familial hypercholesterolemia due to impaired LDL receptor function or to defective apolipoprotein B-100.

Mutations in the apolipoprotein (apo) B, E (LDL) receptor gene and in the apolipoprotein B-100 gene are the cause of familial hypercholesterolemia (FH) and of familial defective apo B-100 (FDB), respectively. Whether these abnormalities lead to altered production or uptake of very low density lipoprotein (VLDL) or intermediate density lipoprotein (IDL) has not been established previously. Therefore VLDL and IDL apo B-100 kinetics were measured in seven subjects with FH, in six subjects with FDB, and in five normocholesterolemic controls using primed-constant infusions of [1-13C]leucine. Absolute production rates (APR) of VLDL apoB were higher in FH than in controls (27.1+/-1.9 vs. 17.9+/-2.1 mg/kg/day P < 0.03). VLDL APR in FDB were between those of FH and controls (24.3+/-4.8 mg/kg/day), and demonstrated a relatively large inter-individual variability. The increase in VLDL APR in FH resulted in higher fasting serum triglyceride concentrations than in controls (P < 0.05), whereas in FDB triglycerides were between those observed in FH and in controls. A significant correlation was observed between VLDL apoB APR and serum triglycerides in FH and in FDB; the correlation coefficient for all subjects was r = 0.84 (P < 0.0001), indicating that the major determinant of serum triglyceride concentrations was VLDL apoB APR. IDL apoB APR was lower in FH and in FDB compared to controls (P < 0.03 P < 0.02, respectively): and its fractional catabolic rate (FCR) was slightly lower in FH and in FDB, resulting in similar plasma IDL apoB concentrations in all three groups of subjects. IDL apoB APR in FH were negatively correlated with LDL cholesterol concentrations (r = -0.89; P < 0.001); LDL cholesterol concentrations correlated positively with the part of VLDL that did not appear in IDL (r = 0.82 P < 0.02), by-passing therefore the delipidation cascade. In conclusion the data demonstrate increased VLDL apoB production rates in FH. VLDL and IDL kinetics differ when LDL concentrations are elevated either due to a LDL receptor defect or due to defective apolipoprotein B-100.

Adult↗
PubMed2006

An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations.

Factor H (FH) is a central complement regulator comprised of 20 short complement repeat (SCR) domains. Nucleotide changes within this gene (CFH) have been observed in patients with hemolytic uremic syndrome (HUS), and also membranoproliferative glomerulonephritis and age-related macular degeneration. All parts of FH are affected, but many mutations are clustered in the C-terminal part of FH. Up to now, structural analyses of HUS have been based on SCR-20, a domain that is involved in FH interactions with C3b, heparin, and endothelial cells. In order to identify the structural and functional consequence of HUS mutations, further disease-associated mutations were analyzed in terms of homology and nuclear magnetic resonance (NMR) models for factor H SCR domains. An interactive web database of 54 human HUS-associated mutations and others was created from the literature (www.FH-HUS.org). This has comprehensive search and analysis tools, integrating phenotypic and genetic data with structural analysis. Each mutation can be highlighted on the SCR structure together with the patient FH and C3 levels where available. Two new insights were obtained from our collection of data. First, phenotypic data on FH clarify our previously-proposed classification of Type I and Type II disorders that both lead to HUS, where Type I affects FH secretion and folding, and Type II leads to expressed protein in plasma that is functionally defective. Second, the new mutations show more clearly that SCR domains from SCR-16 to SCR-19 are important for the ligand binding activities of FH as well as SCR-20. This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH.

Amino Acid Sequence↗
PubMed1993

A clinicopathological analysis of breast cancer in patients with a family history.

A study was conducted to investigate the clinical and pathological characteristics of breast cancer in patients with a family history (FH). Among 4,481 primary breast cancer patients, 394 (8.8%) had families which included two or more breast cancer patients within three generations (FH(+)group). This group was compared with the remaining 3,969 patients (FH(-) group) with the following results: (1) The tumor diameter in the FH(+) group was slightly less than that in the FH(-) group [not significant (NS)], with fewer lymph node metastases (P < 0.05); (2) the positive rates for the estrogen receptor were 52% (138/266) and 49% (1,216/2,481), respectively (NS); (3) expression of the c-erbB-2 protein was observed in 14 out of 40 (35%) and 32 out of 100 cases (32%), respectively (NS); (4) the relative risk of bilateral occurrence in the FH(+) group was 1.4, with a 95% confidence interval of 0.9-2.4; (5) the 15-year survival rate was 72% and 60%, respectively, suggesting a better prognosis for the FH(+) group (P < 0.01); and (6) multivariate analysis showed that the contribution of FH to postoperative survival was marginal (P = 0.07). Factors related to the hormonal environment such as age at menarche (P = 0.08) and age at menopause (P = 0.08) made a greater but non-significant contribution to the prognosis of the FH(+) group than to that of the FH(-) group. However, further genetic and molecular biological analyses of familial breast cancer are needed in order to clarify the mechanisms of cancer accumulation within families.

Adult↗
PubMed2000

Looking forward and back: distress among women at familial risk for breast cancer.

Healthy women with family histories of breast cancer in a first-degree relative (FH+) have been reported to exhibit higher levels of breast cancer-related distress than women without family histories of breast cancer (FH-). Recent data suggest that this may be particularly true for women who had a parent die of cancer. In line with theories emphasizing the psychological impacts of past stressors and concerns for the future, the present study examined the hypotheses that past cancer stressors (i.e. maternal breast cancer caregiving and death, "Looking Back") and perceptions of one's own heightened future risk for developing the disease ("Looking Forward") would predict current levels of distress. One hundred forty-eight healthy women (57 FH+, 91 FH-) recruited from large medical centers in the New York City area completed measures of breast cancer-related distress, general psychological distress, and items assessing whether or not they had taken care of their mother with breast cancer or had had their mother die from the disease. Consistent with previous research, results indicated that FH+ women whose mothers had died of breast cancer had significantly higher breast cancer-related distress than either FH+ women whose mothers had not died of breast cancer or FH- women (p < .05). Further analyses revealed that FH+ women who had cared for their mothers with breast cancer had higher cancer-related distress than women who did not (p < .01), and that FH+ women whose experience included both caregiving and the death of their mother from breast cancer had the highest levels of cancer-related distress (p < .01) and depressive symptoms (p < .05). Findings also indicated that FH+ women with heightened perceptions of risk for breast cancer had higher levels of distress, independent of past stressors. These findings suggest that psychosocial interventions for women with family histories of breast cancer might be appropriately focused on these issues.

Adult↗
PubMed2001

A Chinese homozygote of familial hypercholesterolemia: identification of a novel C263R mutation in the LDL receptor gene.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene; it is characterized by a high concentration of LDL, which frequently gives rise to tendon xanthomas and premature coronary artery disease (CAD). Individuals with heterozygous FH in China often exhibit a milder phenotype than those in other countries. The diagnosis of heterozygous FH relies on the clinical phenotype and this does not always permit unequivocal diagnosis of the disease. In the course of investigation of FH in a Chinese population sample, we found a family whose proband showed a markedly raised concentration of LDL cholesterol in plasma, and the presence of skin and tendon xanthomata. We used single-strand conformation polymorphism (SSCP) analysis to screen all the 18 exons and the exon-intron boundaries of the LDLR gene. One novel homozygous mutation, replacing T by C at nucleotide 850 in exon 6 was identified. This change substituted cysteine for arginine at codon 263 (C263R) of the LDLR. By means of mutant allele-specific amplification, we unequivocally diagnosed six heterozygotes with this novel mutation in the proband's family. forms of heterozygous FH are characterized by high serum LDL cholesterol levels, which are usually associated with premature coronary heart disease (CHD) and tendon xanthomas in early middle age, while homozygous FH individuals frequently suffer fatal CHD by their third decade (Goldstein et al. 1995). To date, more than 200 different mutations of the LDLR gene have been characterized worldwide (Hobbs et al. 1990; Hobbs et al. 1992; Varret et al. 1997). Chinese individuals with heterozygous FH are often recognized by virtue of their being parents of offspring with mutations in both alleles of the LDLR gene (Mak et al. 1998). Unlike their heterozygous parents, the Chinese homozygous FH patients are as severely affected, as are those elsewhere (Sun et al. 1994). In this article, we present an investigation of a Chinese family whose proband, with severe hypercholesterolemia, carried a novel mutation of the LDLR gene in a homozygous form, while the other six patients in the family, who carried this mutation in a heterozygous form, have a milder phenotype of FH. The main objective of our analysis was to delineate the full spectrum of mutations that underline FH in the Chinese population; our work represents a first step towards the implementation of nationwide DNA testing for this disease.

Base Sequence↗
PubMed1993

Documented need for more effective diagnosis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah.

A project to help Utah residents with heterozygous familial hypercholesterolemia (FH) identified affected individuals by collecting detailed questionnaires from: (1) very high-risk persons in computer files of screening data (very high cholesterol levels, very early coronary artery disease, and strong positive family history); (2) confirmed FH index cases from a university lipid clinic; and (3) relatives of any confirmed FH cases. Questionnaires were received from 2,143 persons identifying 101 living index cases and 502 relatives meeting the criteria for the diagnosis of FH. Finding new FH heterozygotes was about one fourth as expensive by tracing relatives of confirmed FH cases by evaluating very high-risk persons. Of those meeting criteria for the diagnosis of heterozygous FH, only 31% reported being told by their physicians that they had FH, only 42% indicated that they were taking a cholesterol-lowering prescription medication, and only 23% had reasonably controlled cholesterol levels (below the 90th percentile). However, the data also suggest that good control is achievable in motivated patients. Among 106 FH heterozygotes who were early responders to a second follow-up questionnaire, 79% were taking prescription medications, of whom 49% had achieved cholesterol levels below the 90th percentile, and 17% even achieved cholesterol levels below the 50th percentile. We conclude that most patients with heterozygous FH are not diagnosed and not adequately treated. We demonstrated how many of these persons needing help could be identified efficiently by tracing relatives of known index cases.

Adolescent↗
PubMed1990

Frequency and role of apo E phenotype in familial hypercholesterolemia and non-familial hyperlipidemia in the Japanese.

The frequencies of the major apolipoprotein E(apo E) phenotypes in 65 normal, 426 hyperlipidemics, and 92 familial hypercholesterolemic Japanese subjects (FH) were studied, and features of hyperlipidemia compared between non-FH hyperlipidemia and FH. The frequencies of apo E phenotypes 3/3, 4/3, 3/2, 4/4 were almost the same in normal, non-FH hyperlipidemic, and FH subjects. The incidence of apo E7 was about 0.5% of total subjects. In type IV and V hyperlipidemias, incidence of E4/3 was higher than in any other hyperlipidemia. Incidence of E3/2 was also high in types III and V. In type II non-FH hyperlipidemia, incidence of E3/2 in type IIb was higher than in type IIa. VLDL-triglyceride, VLDL-cholesterol, apo C-II, apo C-III, and apo E levels were higher in E3/2 than in E3/3. But, in type IIa FH and type IIb FH, the incidence of E3/2 was the same, and lipid and apolipoprotein levels between 3/2 and 3/3 in FH were the same. These results indicate that allele epsilon 2 may be involved in the retention of VLDL or IDL, but not in FH.

Apolipoproteins E↗
PubMed1995

Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study.

We have measured the hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B) in 6 patients with heterozygous familial hypercholesterolaemia (FH) (4 males, 2 females, age 47.0 +/- 2.7 years (mean +/- S.E.M.), weight 71.0 +/- 5.3 kg) and 6 normocholesterolaemic subjects matched for age, weight and sex (4 males, 2 females, age 47.5 +/- 3.1 years, weight 70.0 +/- 4.4 kg) using a stable isotope method. Each subject received a primed, constant infusion of [I-13C]leucine and isotopic enrichment of VLDL apo B was determined using gas-chromatography mass-spectrometry (GCMS). Mean plasma low-density-lipoprotein (LDL) cholesterol and apo B concentrations in the FH group were more than twice that in the control group (FH, 8.5 +/- 0.5 mmol/l vs. controls, 3.3 +/- 0.2 mmol/l, P < 0.001; and FH, 2.0 +/- 0.1 g/l vs. controls, 1.0 +/- 0.04 g/l, P < 0.0001, respectively). Plasma triglyceride (TG) and high-density-lipoprotein (HDL) cholesterol concentrations were not significantly different between the two groups. Although the fractional secretion rates of VLDL apo B were similar (FH, 14.3 +/- 3.6 pools/day vs. controls, 11.6 +/- 1.7 pools/day, P = 0.53), VLDL apo B pool size and VLDL apo B absolute secretion rates (ASR) were significantly higher in the FH group (FH, 234.2 +/- 27.8 mg vs. controls, 66.3 +/- 13.5 mg, P < 0.001; and FH, 51.4 +/- 17.9 mg/kg per day vs. controls, 9.4 +/- 1.1 mg/kg per day, P < 0.02, respectively). We conclude that FH is associated with increased hepatic secretion of VLDL apo B and that this may contribute to the elevated concentration of LDL-cholesterol. The findings are also consistent with the hypothesis that in FH increased hepatic cholesterol availability (due to increased uptake of LDL-cholesterol via the receptor-independent pathway) stimulates hepatic secretion of VLDL apo B.

Adult↗
PubMed1996

Heterozygous familial hypercholesterolemia in children: low-density lipoprotein receptor mutational analysis and variation in the expression of plasma lipoprotein-lipid concentrations.

The phenotypic expression of heterozygous familial hypercholesterolemia (FH) is variable form biochemical and clinical standpoints and several genetic and environmental factors could contribute to explain this variability. We have compared, in a cohort of 266 heterozygous FH children and adolescents (1-19 years), the variation in plasma lipoprotein-lipid levels among patients defined by three mutations in the low density lipoprotein receptor (LDLR) gene. Comparison of the plasma total and LDL-cholesterol (LDL-C) levels among the three mutation groups revealed significant differences. Plasma total and LDL-C levels were significantly higher (P < 0.05) in the group bearing the French-Canadian delta > 15 kb null allele mutation (8.17 +/- 1.45 and 6.58 +/- 1.42 mmol/l) and in the group with the defective allele C646Y missense mutation (8.18 +/- 1.53 and 6.65 +/- 1.50 mmo/l) compared to the group with the defective allele W66G missense mutation (7.19 +/- 1.23 and 5.62 +/- 1.16 mmol/l). Comparisons of other lipoprotein-lipid parameters between FH heterozygotes and normolipemic (n = 120) children indicated that all mutation groups had significantly (P = 0.0001) lower plasma HDL-cholesterol (HDL-C) levels and a higher total cholesterol (TC) to HDL-C ratio (P < 0.05). Among FH heterozygote groups, the W66G group had the lowest TC to HDL-C ratio. Multivariate analyses revealed that in FH heterozygotes as well as in controls, HDL-C levels contributed to a greater proportion of the variation in TC to HDL-C ratio than TC. In order to examine the age effect, control and FH heterozygote delta > 15 kb groups were then subdivided into four groups (1-4; 5-8; 9-13, and 14-19 years). The variation in HDL-C and triglycerides with age in heterozygous FH children showed a pattern which was similar to the one noted in the control group. In conclusion, the present study demonstrated that the overall contribution of age to variation in the lipoprotein profile of heterozygous FH children is similar to the effect observed among healthy children. The effect of LDLR gene in FH is dominant and there was no difference in plasma TC and LDL-C due to gender. Finally, this study indicates that the LDLR gene type mutations are a modulator of the magnitude of the increase in plasma TC and LDL-C levels noted among FH heterozygote children.

Adolescent↗
PubMed2004

Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor.

The effect of simvastatin therapy on the biologic characteristics of the electronegative low-density lipoprotein (LDL) subfraction of patients with familial hypercholesterolemia (FH) was studied. Total LDL, isolated from FH plasma at 0, 3 and 6 months of simvastatin treatment, was subfractionated into electropositive LDL (LDL[+]) and electronegative LDL (LDL[-]) by anion exchange chromatography. LDL isolated from healthy normolipemic (NL) subjects was used as a control. The LDL(-) proportion was twofold higher in patients with FH than in NL subjects (17.6 +/- 1.6% vs 7.8 +/- 1.5%, respectively; p <0.05) and was progressively reduced by simvastatin therapy (15.7 +/- 1.6% at 3 months; 13.8 +/- 2.5% at 6 months; p <0.05). Both LDL subfractions from patients with FH had a higher relative cholesterol content and decreased apolipoprotein B and triglycerides than NL subfractions. Simvastatin progressively induced changes in lipid content of both LDL subfractions in patients with FH, and lipid composition was closer to these subfractions in NL subjects after 6 months of therapy. Binding displacement experiments in human fibroblasts demonstrated that LDL(-) from both groups of subjects had a lower affinity of binding to the LDL receptor that LDL(+). In addition, LDL(+) in patients with FH presented an intermediate binding affinity between LDL(-) and LDL(+) in NL subjects. Simvastatin-induced changes in LDL composition were accompanied by a progressive increase in affinity of LDL(+) and LDL(-) in patients with FH. After 6 months of therapy, LDL(+) in FH had an affinity similar to that of LDL(+) in NL subjects. The LDL(-)-induced release of chemokines interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells was twofold higher compared with that of LDL(+). No difference in chemokine release between patients with FH and NL subjects or the effect of simvastatin were observed. We conclude that simvastatin therapy was able to modify LDL subfraction composition in subjects with FH and increase their affinity to the LDL receptor. This improvement could contribute to the observed reduction in LDL(-) proportion induced by simvastatin.

Adult↗
PubMed2006

Identification of mildly oxidized low-density lipoprotein (electronegative LDL) and its auto-antibodies IgG in children and adolescents hypercholesterolemic offsprings.

BACKGROUND: Oxidative modification of low-density lipoproteins (LDL) is an essential step in atherogenesis, generating minimally oxidized LDL, also called electronegative LDL [LDL(-)], which has chemotactic, cytotoxic and immunogenic properties. METHODS AND RESULTS: Serum LDL(-) and anti-LDL(-) auto-antibodies (IgG) were evaluated in 28 children and adolescents with familial hypercholesterolemia (FH) antecedents, with or without early coronary artery disease in first-degree relatives (eCAD), hypercholesterolemic (hc) or normocholesterolemic (nc) versus a control group of normocholesterolemic children without pathologic antecedents (C). ELISA method was used for detection of LDL(-) and anti-LDL(-) IgG. LDL(-) serum levels did not differ among the four groups (FH-eCAD-hc 41.4 +/- 24.9 microg/dl; FH-hc 38.3 +/- 11.2 microg/dl; FH-nc 47.3 +/- 17.0 microg/dl and C 44.2 +/- 28.8 microg/dl, p = 0.659). However, IgG anti-LDL(-) auto-antibodies were significantly higher in the control group in comparison to the FH groups with or without eCAD, independent of hypercholesterolemia or normocholesterolemia (FH-eCAD-hc 0.825 +/- 0.289 microg/dl; FH-hc 0.667 +/- 0.307 microg/dl; FH-nc 0.763 +/- 0.204 microg/dl and C 1.105 +/- 0.233 microg/dl, p = 0.006). When the auto-antibodies of groups with FH, with or without eCAD and with or without hypercholesterolemia were compared, no differences were found (p = 0.509). CONCLUSION: These results showed that FH and/or eCAD children and adolescents have lower titers of auto-antibodies anti-LDL(-) than children from normal families, independent of serum LDL-cholesterol or serum LDL(-).

Adolescent↗
PubMed2006

Altered hemostatic balance and endothelial activation in pregnant women with familial hypercholesterolemia.

INTRODUCTION: Patients with familial hypercholesterolemia (FH) are prone to premature cardiovascular disease. During pregnancy plasma lipids reach higher absolute values in FH than in healthy women. Pregnancy is associated with activation of coagulation and possibly also of vascular endothelium, which might further increase the risk of cardiovascular disease in FH. However, whether hemostatic and endothelial activation markers are increased in pregnant FH women compared with non-FH pregnancies, is unknown. MATERIALS AND METHODS: Activation markers of hemostasis and endothelium were analyzed in blood samples collected prospectively from 22 heterozygous FH women during pregnancy and compared with those of a reference group of 149 healthy, pregnant women. RESULTS: A procoagulant pattern was detected in both groups, but was more evident among FH women at least partly due to their enhanced thrombin generation, and because tissue factor pathway inhibitor type 1 increased in the reference group only. Furthermore, plasminogen activator inhibitor type 2 antigen increased more in FH than in the reference group. Whereas C-reactive protein, intercellular adhesion marker-1 and E-selectin did not change appreciably, vascular endothelial cell adhesion molecule 1 rose markedly in FH. CONCLUSION: Increased lipid levels as well as a net procoagulant activity and an enhanced endothelial activation possibly confer additional risks of cardiovascular disease among pregnant FH women.

Adult↗
PubMed1999

Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia.

BACKGROUND: The aortic valve dysfunction of patients with homozygous familial hypercholesterolemia (FH) suggests that hypercholesterolemia affects not only coronary arteries but also the aortic valve. We studied the aortic root of patients with homozygous FH and those of patients with heterozygous FH to characterize the premature atherosclerotic lesions by using histopathologic specimens. METHODS AND RESULTS: The aortic roots of 10 patients with homozygous FH, age 9 to 58 years, were studied by cardiac catheterization with several angiographies. The aortic roots of 39 patients with heterozygous FH under age 60 years were also examined for aortic and mitral valvular functions by color Doppler echocardiography, and 30 normocholesterolemic patients with coronary artery disease were examined as control subjects. In addition, in 22 patients with FH and 20 control subjects, the internal diameter of the aortic annulus and the aortic ridge in cardiac cycles were measured. Of the 10 homozygotes with FH, 8 patients had aortic regurgitation demonstrated by aortography; 3 of them showed significant transvalvular pressure gradients. Stenotic changes of coronary ostia were observed in 8 of the 10 homozygotes with moderate coronary atherosclerosis. Of the 39 heterozygotes with FH, 10 patients had aortic regurgitation shown by Doppler echocardiography, as did only 1 of the 30 control subjects (P <.05). The average diameter and distensibility of the ascending aorta were significantly reduced in the heterozygotes compared with the control subjects. The surgically resected cusp specimens of aortic valves obtained from 1 homozygous and 1 heterozygous patient showed significant thickening of the cusp with foam cell infiltration. CONCLUSIONS: Premature atherosclerosis in FH had a characteristic distribution, affecting the aortic root dominantly. The involvement of the aortic valve indicating "hypercholesterolemic valvulopathy" was a peculiar feature of FH, especially its homozygous form, but was reminiscent of ubiquitous processes caused by hypercholesterolemia.

Adolescent↗
PubMed1998

Psychobiological heterogeneity of familial and sporadic schizophrenia.

BACKGROUND: Although schizophrenia is presumed to be heterogeneous, there has been limited success distinguishing familial from sporadic cases. We used psychobiological measures to examine heterogeneity, as they may be closer to neurobiology than symptoms. Smooth pursuit eye movement quality (SPEM) and dichotic listening (DL) tests to tones and words were used to assess hemispheric laterality asymmetry. METHODS: Forty-six research unit patients participated in assessments of family history (FH) and physiological measures. FH was categorized by three exclusive groups: FH-1 patients had a chronic schizophrenia-related psychosis in a first-degree relative, FH-2 had it in second-degree relative, and FH-3 had no family member with a reoccurrence. RESULTS: Analysis of variance showed a significant group difference for SPEM and DL tones. SPEM was significantly worse in all three schizophrenia groups than for the normal comparison subjects. Among the schizophrenia groups, the nonfamilial group (FH-3) had the worst SPEM quality, FH-2 had intermediate quality, and FH-1 had the best quality. Conversely, only the nonfamilials (FH-3) had normal right hemispheric lateralization for tones, whereas familials did not, and FH-2 again had intermediate values. The lateralization quotient for DL words did not significantly differ among the groups. CONCLUSIONS: SPEM was affected most in sporadic, not familial schizophrenia, whereas dichotic listening was most affected in familial schizophrenia. This double dissociation supports the utility of the familial/sporadic distinction and suggests that etiological factors in different forms of schizophrenia may impact principally on distinct neurobiological substrates, despite similar patient phenomenology.

Adult↗
PubMed2003

A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.

BACKGROUND: Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. METHODS: A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. FINDINGS AND DISCUSSION: A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30-50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.

Cholesterol↗
PubMed1997

Reduced platelet serotonin content and release in familial hypercholesterolaemia.

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (-37%, P < 0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH, patients were combined (r = -0.48, P = 0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r = -0.59, P = 0.03; normal and FH data, r = -0.49, P = 0.004) but positively with high-density lipoprotein (HDL) (FH r = 0.79, P = 0.001; normal and FH, r = 0.37, P = 0.03). Collagen (5-160 micrograms/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 micrograms/ml collagen, -40%, P < 0.05) and accompanied by increased collagen EC50 values (P < 0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.

Adult↗
PubMed2002

[Influence of plasma lipids, APOE genotype and type of LDL receptor gene mutations on myocardial infarction in subjects with familial hypercholesterolemia].

BACKGROUND: Our goal was to analyze the relationship of lipids and lipoproteins, APOE genotype and mutations of the LDL receptor gene with the prevalence of myocardial infarction (MI) in patients with familial hypercholesterolemia (FH) from a Southern European FH population. PATIENTS AND METHOD: We studied 108 heterozygous FH subjects aged > 35 years (41 males). It was a cross-sectional study comparing individuals with FH and MI with individuals with FH without MI. In 88 FH subjects, a mutation of the LDL receptor gene was detected. These FH subjects were divided in carriers of null mutation or no null mutations. We compared lipids and lipoproteins and prevalences of LDL receptor type mutation and APOE genotype. RESULTS: Parameters associated with MI were: age, presence of xanthomas and arcus cornealis, plasma concentrations of total cholesterol (TC), LDLc, TC/HDLc ratio > 5.3 and *4 genotype of the APOE gene. Odds ratio for MI were as follows: presence of xanthomas and arcus cornealis, 1.36 (CI 95%, 1.08-1.71; P = 0.01), age > 54 years (50 th of FH group), 1.56 (CI 95%, 1.19-2.04; P = 0.001) and plasma TC values > 332 mg/dl (50 th of FH group), 1.34 (CI 95%, 1.05-1.71; P = 0.019). In the logistic regression model, only age and TC were significantly associated with MI. CONCLUSIONS: In FH subjects aged over 35 years from a Southern European population, MI is associated with age, plasma TC and LDLc values, TC/HDLc ratio and the *4 genotype. In addition, MI is related with age and TC plasma levels on an independent basis.

Adult↗