Apolipoprotein B gene polymorphisms: prevalence and impact on serum lipid concentrations in hypercholesterolemic individuals from Brazil.

Genetic polymorphisms at the apolipoprotein B (apo B) have been associated with elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol, atherosclerosis and increased risk for coronary artery disease (CAD). In the present study, four apo B gene polymorphisms (MspI, XbaI, Ins/Del and 3'HVR) have been investigated to determine their frequencies and influence on the lipid profile of 177 hypercholesterolemic white Brazilian subjects (HG) and 100 control individuals (CG). The genotype distribution and allele frequency of MspI, XbaI and Ins/Del polymorphisms of apo B gene were similar between HG and CG groups. The frequency of the alleles smaller than 43 repeats (< or =43) of 3'HVR polymorphism in the HG group was higher when compared to controls (16.4 vs. 8.5%, P<0.05). Moreover, these alleles were associated with higher total cholesterol concentrations in serum of hypercholesterolemic individuals (P<0.05). In addition, an association between Ins/Del and 3'HVR polymorphism was observed. The alleles < or =43 and Del were more frequent in the HG when compared to the CG individuals (P<0.05). We concluded that 3'HVR polymorphism at the apo B gene may be an important genetic marker to evaluate atherosclerotic disease risk.

Polymorphisms of the low-density lipoprotein receptor gene in Brazilian individuals with heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low-density lipoprotein (LDL) level. The disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the techniques available for determining the number of the functional LDL receptor molecules are difficult to carry out and expensive. Polymorphisms associated with this gene may be used for unequivocal diagnosis of FH in several populations. The aim of our study was to evaluate the genotype distribution and relative allele frequencies of three polymorphisms of the LDL receptor gene, HincII1773 (exon 12), AvaII (exon 13) and PvuII (intron 15), in 50 unrelated Brazilian individuals with a diagnosis of heterozygous FH and in 130 normolipidemic controls. Genomic DNA was extracted from blood leukocytes by a modified salting-out method. The polymorphisms were detected by PCR-RFLP. The FH subjects showed a higher frequency of A+A+ (AvaII), H+H+ (HincII1773) and P1P1 (PvuII) homozygous genotypes when compared to the control group (P<0.05). In addition, FH probands presented a high frequency of A+ (0.58), H+ (0.61) and P1 (0.78) alleles when compared to normolipidemic individuals (0.45, 0.45 and 0.64, respectively). The strong association observed between these alleles and FH suggests that AvaII, HincII1773 and PvuII polymorphisms could be useful to monitor the inheritance of FH in Brazilian families

Polymorphisms of the low-density lipoprotein receptor gene in Brazilian individuals with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low-density lipoprotein (LDL) level. The disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the techniques available for determining the number of the functional LDL receptor molecules are difficult to carry out and expensive. Polymorphisms associated with this gene may be used for unequivocal diagnosis of FH in several populations. The aim of our study was to evaluate the genotype distribution and relative allele frequencies of three polymorphisms of the LDL receptor gene, HincII(1773) (exon 12), AvaII (exon 13) and PvuII (intron 15), in 50 unrelated Brazilian individuals with a diagnosis of heterozygous FH and in 130 normolipidemic controls. Genomic DNA was extracted from blood leukocytes by a modified salting-out method. The polymorphisms were detected by PCR-RFLP. The FH subjects showed a higher frequency of A+A+ (AvaII), H+H+ (HincII(1773)) and P1P1 (PvuII) homozygous genotypes when compared to the control group (P<0.05). In addition, FH probands presented a high frequency of A+ (0.58), H+ (0.61) and P1 (0.78) alleles when compared to normolipidemic individuals (0.45, 0.45 and 0.64, respectively). The strong association observed between these alleles and FH suggests that AvaII, HincII(1773) and PvuII polymorphisms could be useful to monitor the inheritance of FH in Brazilian families.

Clinical outcome of patients with familial hypercholesterolemia and coronary artery disease undergoing partial ileal bypass surgery.

Familial hypercholesterolemia is characterized by high serum levels of total cholesterol and LDL-cholesterol. It may be homozygous or heterozygous. In homozygous patients, LDL-cholesterol levels range from 500 to 1000 mg/dL and coronary artery disease is precocious, usually manifesting itself between the 2nd and 3rd decades of life. The diagnosis is often made by the presence of xanthoma tuberosum and tendinous xanthomas that appear between the 1st and 2nd decades of life. The use of high doses of statins or even unusual procedures (apheresis, partial ileal bypass surgery, liver transplantation, gene therapy), or both, is necessary for increasing survival and improving quality of life, because a reduction in cholesterol levels is essential for stabilizing the coronary artery disease and reducing xanthomas. We report our experience with 3 patients with xanthomatous familial hypercholesterolemia and coronary artery disease, who underwent partial ileal bypass surgery. Their follow-up over the years (approximately 8 years) showed a mean 30% reduction in total cholesterol, with a significant reduction in the xanthomas and stabilization of the coronary artery disease.

Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease.

The possible association of genetic markers at the apolipoprotein E (HhaI polymorphism), apolipoprotein B (XbaI, EcoRI and Ins/Del polymorphisms), and low-density lipoprotein receptor (LDLR) (AvaII, HincII and PvuII polymorphisms) with coronary artery disease (CAD) was evaluated in 50 Brazilian women with CAD diagnosed by angiography and in 100 healthy women (controls). The frequency of E3/E4 genotype for HhaI polymorphism at the Apo E gene was significantly higher in CAD patients than in controls (40% vs. 14%, respectively, P<0.001). Similarly, the X-X- genotype for XbaI polymorphism was more frequent in CAD individuals than controls (42% vs. 12%, P<0.0001). The A+A+ and P1P1 genotypes for AvaII and PvuII polymorphisms at the LDLR locus were also higher in CAD subjects than controls (44% vs. 16%, P<0.001 and 64% vs. 39%, P<0.05, respectively). The estimated relative risks for CAD in women carrying the E3/E4, X-X-, A+A+ and P1P1 genotypes were 4.1 [95% confidence interval (CI), 3.0-5.6], 5.3 (95% CI, 3.8-7.5), 4.1 (95% CI, 3.0-5.5), and 2.8 (95% CI, 2.2-3.6), respectively. This study demonstrates that Apo E, Apo B and LDLR gene polymorphisms are associated with CAD in Brazilian Caucasian women.

Pvu II intron 15 polymorphism at the LDL receptor gene is associated with differences in serum lipid concentrations in subjects with low and high risk for coronary artery disease from Brazil.

Coronary artery disease (CAD) has a high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CAD in this country have not been sufficiently conducted. We used the Pvu II polymorphism (intron 15) at the low-density lipoprotein receptor (LDLR) gene to study the effect of variation at this locus in determining plasma lipid concentrations in 128 white subjects presenting a lipid profile suggesting high risk for CAD (HRG) and 100 white normolipidemic individuals (controls, CG). The Pvu II polymorphism was detected by PCR-RFLP. The P1P1 genotype for Pvu II polymorphism (homozygous for absence of restriction site) was greater in HRG individuals than in CG subjects (57% vs. 38%, P<0.05). Moreover, the P1P1 genotype was strongly associated with high concentrations of total cholesterol (P=0.0001), triglycerides (P=0. 0295), LDL-C (P=0.0001), and VLDL-C concentrations (P=0.0280) and lower HDL-C concentrations (P=0.0051) in HRG subjects. Similarly, the CG individuals with P1P1 genotype presented high concentrations of total cholesterol and LDL-C compared to other genotypes (P=0. 0001). This study demonstrates the influence of Pvu II polymorphism of the LDLR on serum lipid concentrations of individuals with low and high risk for CAD from Brazil.

Effects of Ava II and Hinc II polymorphisms at the LDL receptor gene on serum lipid levels of Brazilian individuals with high risk for coronary heart disease.

Coronary heart disease (CHD) has presented high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CHD in our country are insufficiently carried out. We have investigated the effects of Ava II (exon 13) and Hinc II (exon 12) polymorphisms at the low-density lipoprotein receptor (LDLR) gene on circulating lipids of 170 white unrelated individuals presenting a lipid profile with high risk for CHD (HRG) and 130 controls (CG) from São Paulo City, Brazil. Ava II and Hinc II polymorphic regions at the LDLR gene were amplified by PCR and analyzed by enzymatic isotyping. The frequency of the genotypes A+A+ (Ava II) and H+H+ (Hinc II) was greater in HRG group compared to that of the controls (32 vs. 16% and 32 vs. 18%, respectively). Moreover, in the HRG group, A+A+ and H+H+ genotypes were associated with high concentrations of total cholesterol and LDL-C in serum (P = 0.0001). Our results indicate that Ava II and Hinc II polymorphisms at the LDLR locus contribute to the variability of total cholesterol and LDL-C levels in HRG individuals. These data suggest that the LDLR polymorphism remains a useful genetic marker for predicting CHD risk.

[Anti-smoking intervention performed by cardiologists during ambulatory care]. / Intervenção sobre tabagismo realizada por cardiologista em rotina ambulatorial.

PURPOSE: The aim of this study was to evaluate the effectiveness of nicotine patches as a strategy to help patients quit smoking in the cardiovascular clinic. METHODS: The population studied was composed of 100 patients (50 women and 50 men). The strategy included medical consultation, Fangerstron escore application and prescription of nicotine patches. Nicotine patches were continuously used for 8 to 12 weeks, with progressive concentration reduction releasing 21, 14, and 7 mg/day. RESULTS: The abstinence rate one year later was 41% confirmed by carbon monoxide exhaled air concentration. CONCLUSION: Nicotine patches are safe, and well tolerated and, for these reasons, should be more frequently prescribed by cardiologists to help patients quit smoking.

First-degree kinship with young coronary artery disease patients markedly increases lipid-level disorders in asymptomatic hypertensives.

BACKGROUND: Association of hypertension and serum lipid disorders has been demonstrated in previous studies. However, there are no investigations about the behaviour of serum lipids in asymptomatic hypertensive individuals who are first degree relatives of young coronary patients. OBJECTIVE: To determine the degree of lipid disorders in Brazilian hypertensive individuals who are first degree relatives of young coronary patients. METHODS: There were four study groups, 2 in each arm of the study: a) 846 subjects without any evidence of heart disease or diabetes who were first degree relatives of patients who underwent coronary artery bypass grafting (CABG) surgery before 55 years-of-age. Of these subjects, 226 individuals were hypertensive (group Hyp F), and 620 were normotensive (group Normo F): b) 910 hospital employees without evidence of cardiovascular disease and family history of coronary artery disease of whom 152 were hypertensive (group Hyp NF), and 758 were normotensive (group Normo NF). Hypertension was defined as blood pressure greater than 140/90 mmHg. The following serum lipid measurements were performed: total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprtein cholesterol (LDLC), and triglycerides. Lipid disorders were defined according to the 2nd Report of the National Cholesterol Education Program (NCEP) (total cholesterol>240 mg/dl; LDLC>160 mg/dl; triglycerides>200 mg/dl). The frequency of lipid disorders in each group was calculated. Subjects were classified according to their body mass index (BMI) as normal, overweight, or obese. The following statistical analyses were performed as indicated: ANOVA (with Tukey's corrections for multiple comparisons), chi-square (x2), and odds ratio (OR). RESULTS: Hyp F subjects had significantly higher total cholesterol, LDLC and triglyceride levels, and significantly lower levels of HDLC than all other groups. There was a higher frequency of lipid disorders in Hyp F subjects than in Hyp NF individuals, with a significant OR of 1.71 (CI 1.26-2.32) and 2.09 (CI 1.48-2.72) for total cholesterol and LDLC respectively. When compared to Normo F subjects, Hyp F individuals had significantly higher risk of having lipid disorders: total cholesterol (OR=8), LDLC (OR=6), and triglycerides (OR=5). There was a higher frequency of obesity among Hyp F patients than in all other groups. The frequency of subjects who were overweight or obese was higher in Hyp F than in Hyp NF subjects. CONCLUSION: Hypertensive patients who were first degree relatives of patients revascularized at a young age had a higher prevalence of lipid disorders, particularly higher total cholesterol and LDLC, than hypertensive individuals without this family history. These individuals may have a greater genetic propensity to develop lipid disorders.

[Lipid profile of subjects undergoing coronary angiography in different Brazilian regions]. / Perfil lipídico de indivíduos submetidos à cinecoronariografia em diferentes regiões do Brasil.

PURPOSE: To analyse the lipid profile and also nonlipid risk factors (RF) in individuals < or = 65 years subjected to coronary angiography in four Brazilian regions. METHODS: We determined in mg/dL plasma glucose, total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) in 260 men and 144 women consecutively subjected to a first coronary angiography in 11 cardiologic centers of 4 Brazilian regions. We also analysed frequencies of hypertension, smoking, diabetes, obesity, sedentary habits and family history. RESULTS: CAD patients exhibited higher mean values of TC, TG and LDL-C and lower of HDL-C and higher frequencies of undesirable values of those variables. CAD women > or = 50 yrs showed higher mean values of TC, HDL-C and LDL-C and higher frequencies of TC > or = 200 and LDL-C > or = 130 mg/dL. CAD men showed higher mean values of TG and lower of HDL-C. Higher mean values of TC were observed in CAD patients from Middle-West. Diabetes and smoking were more frequent in CAD; higher prevalence of diabetes was found in women > or = 50 yrs and of smoking in those < 50 yrs. No differences between CAD and control were observed regarding hypertension, sedentary habits, obesity and family history. CAD from South exhibited higher frequencies of smoking and family history and lower of sedentary habits. CONCLUSION: CAD exhibited differences on the lipid profile and on the prevalence of non lipid risk factor than controls. These differences were not similar in four Brazilian regions. This may reflect different lifestyles from region to region and probably depends on the different socio-economic and educational levels.

Timing of intracranial hemorrhage during extracorporeal life support.

This study was conducted to determine the timing of intracranial hemorrhage (ICH) in patients on extracorporeal life support (ECLS) to improve the use of the head ultrasound in the detection of ICH. A review was conducted of all neonatal ECLS patients at the neonatal intensive care nursery at Kosair Children's Hospital in Louisville, Kentucky, from May, 1985 through November, 1994 to establish a study group of infants in whom an ICH developed while on ECLS. Thirty infants who had an ICH (excluding subarachnoid hemorrhage and infarction) on ECLS were included in the study. Data were collected that included patients demographics, age at initiation of ECLS, duration of ECLS, type of ECLS support (venoarterial or venovenous), oxygenation index and last arterial blood gas before ECLS, hours of ECLS before ICH, and grade of ICH. ICH occurred in 9.9% of the neonatal patients requiring ECLS. These included 8 infants with a Grade I bleed, 1 infant with a Grade II, 4 infants with a Grade III, and 17 infants with a Grade IV. Ten of the 30 patients had sepsis as their primary diagnosis, and these infants were more likely to have an ICH while on ECLS compared to nonseptic infants (p < 0.02). The Kaplan-Meier curve showed that 50% of ICHs occurred in the first 24 hours of ECLS, 75% by 48 hours, and that 85% of ICHs occurred within 72 hours of initiation of bypass. There was no difference in timing of ICH in the septic infants compared to the nonseptic infants. The late occurring bleeds (> 72 hours) were all associated with significant neurologic changes or with multiorgan failure. It is concluded that daily head ultrasounds should be performed during the first 3 days of ECLS because most ICHs (85%) occur in the first 72 hours of cardiopulmonary bypass. In this era of cost containment, subsequent head ultrasounds should be obtained with changes in the infant's neurologic status or with the development of multiorgan failure.

DNA polymorphisms of apolipoprotein B and AI-CII-AIV genes in a Brazilian population: a preliminary report.

Possible associations between coronary heart disease (CHD) and restriction fragment length polymorphisms (RFLPs) in the apo AI-CII-AIV cluster and the apo B gene were investigated in a Brazilian population consisting of 46 patients with CHD and 24 individuals without evidence of CHD. A preliminary genetic analysis of SstI RFLP in the apo AI-CII-AIV cluster showed a significantly higher frequency of the rare SstI allele (S2) in CHD patients as compared with controls. No significant differences were found in the frequencies of PstI RFLP in the apo AI-CII-AIV cluster or XbaI and EcoRI RFLPs in the apo B gene between CHD patients and controls. Moreover, no association was seen between the RFLPs studied and myocardial infarction or plasma cholesterol or triglyceride levels.

DNA polymorphisms of apolipoprotein B and AI-CIII-AIV genes in a Brazilian population: a preliminary report

Possible associations between coronary heart disease (CHD) and restriction fragment length polymorphisms (RFLPs) in the apo AI-CIII-AIV cluster and the apo B gene were investigated in a Brazilian population consisting of 46 patients with CHD and 24 individuals without evidence of CHD. A preliminary genetic analysis of SstI RFLP in the apo AI-CIII-AIV cluster showed a significantly higher frequency of the rare SstI allele (S2) in CHD patients as compared with controls. No significant differences were found in the frequencies of PstI RFLP in the apo AI-CIII-AIV cluster or XbaI and EcoRI RFLPs in the apo B gene between CHD patients and controls. Moreover, no association was seen between the RFLPs studied and myocardial infarction or plasma cholesterol or triglyceride levels.

[Precision and accuracy of blood lipid analyses by a portable device (Cholestech-LDX)]. / Precisão e exatidão das dosagens dos lípides sangüíneos em equipamento portátil (Cholestech-LDX).

PURPOSE: To verify whether precision and accuracy of lipids analyses by a new portable device, Cholestech-lipid desktop analyzer (LDX), were in agreement with the guidelines of the National Cholesterol Education Program (NCEP). METHODS: Serum samples from 45 outpatients were collected for the determination of total Cholesterol (TC), HDL-cholesterol (HDL-C) and triglycerides (TG). These samples were analysed simultaneously by the Cholestech-LDX, and by the automatic enzymatic methods routinely used at the Heart Institute's laboratory. Precision was determined by repeating 20 times the evaluation of the same sample of venous blood. Accuracy was established confronting the values of the lipids variables obtained with Cholestech-LDX against the values determined by the automatic enzymatic routine. RESULTS: Accuracy for TC was 1.60% (NCEP < or = 3%), for HDL-C was -2.74% (NCEP < or = 6%) and for TG was 2.11% (NCEP < or = 5%). Precision for CT was 3.05% (NCEP < or = 3%), for HDL-C was 1.05% (NCEP < or = 6%) and for TG was 2.65% (NCEP < 5%). CONCLUSION: Precision and accuracy of lipids evaluation by the Cholestech-LDX are within the guidelines of the National Cholesterol Education Program. Therefore the cholestech-LDX seems to be a reliable alternative to the conventional biochemical routine, allowing population screenings.

[Coronary risk factors in children of young coronary artery disease patients]. / Fatores de risco para doença arterial coronariana em crianças e adolescentes filhos de coronariopatas jovens.

PURPOSE: To determine whether children and adolescents, whose fathers have established coronary artery disease (CAD), have increased prevalence of coronary risk factors (RF). METHODS: The frequencies of abnormal values of lipid variables, glucose, blood pressure, obesity index (calculated through Newen-Goldstein index), smoking and electrocardiographic alterations (ECG), were assessed in 280 descendents of young revascularized patients (< 55 years). The study population was divided in two groups according to age, respectively GA (2 to 12 years) and GB (12 to 19 years). Eventual influences of age, gender, obesity and smoking on lipid variable were evaluated through variance analysis. RESULTS: Of the study population, 48.2% and 44.6% had total cholesterol (TC) and LDL-C respectively above the desirable values; 21.7% and 26.1% had values similar to adults under increased risk. Triglyceridemia (TG) > 200mg/dl was found in 1.4% of the sample and lower values of HDL-C in 16.8%. Overweight and obesity were observed in 13.1% and 20.0% of the patients and influenced TG levels in GB. Smoking occurred in 10.4%; hypertension in 3 cases and none had abnormal glucose levels or ECG. CONCLUSION: Healthy children of fathers with established CAD, exhibit a high frequency of altered lipid profile and increased body weight. The results suggest the need for early identification of RF in offspring of young CAD patients, thus emphasizing changes in risk profile and improving lifestyle.

Fatores de risco para doença arterial coronariana em crianças e adolescentes filhos de coronariopatia jovens / Coronary risk factors in children of young coronary artery disease patients

Objetivo - verificar a prevalência dos fatores de risco (FR) em crianças e adolescentes filhos de coronariopatas. Métodos - em 280 filhos de coronariopatas jovens (< 55 anos), submetidos à cirurgia de revascularizaçäo miocárdica, foi determinada a frequência de desvios dos valores considerados ideiais para a faixa etária da colesterolemia total-CT, trigliceridemia-TG, HDL-C e LDL-C, glicemia, da pressäo arterial (PA), do peso corpóreo (através do índice de Newen-Goldstein-ING). Foram também verificas as frequências do hábito de fumar, e de alteraçöes eletrocardiográficas. Crianças de 2 a 12 anos formaram o grupo GA e adolescentes de 12 a 19 anos formaram o grupo GB. Eventuais associaçöes entre o FR e a influência dos fatores idade, sexo, peso corpóreo e tabagismo sobre as variáveis lipídicas também foram estudadas. Resultados - no conjunto estudado, 48,2 por cento e 44,6 por cento apresentaram respectivamente valores de CT e LDL-Cacima dos considerados ideais, sendo que 21,7 por cento e 26,1 por eto apresentavam valores indicativos de risco também para adultos. TG acima de 200 mg/dl ocorreur em 1,4 por cento da amostra e valores diminuídos de HDL-C em 16,8 por cento. O sobrepeso e obesidade estiveram presentes, respectivamente, em 13,1 por cento e 20,0 por cento (12,9 por cento e 31,4 por cento em GA e 13,2 por cento e 15,8 por cento em GB) e influenciaram os níveis de TG. Tabagismo ocorreu em 10,4 por cento; houve somente 3 casos de hipertensäo arterial. Näo foram encontradas anormalidades da liemia e nem alteraçöes eletrocardiográficas. Conclusäo - a investigaçäo reitera a necessidade de particular atençäo preventiva nos filhos de coronariopatas jovens, considerando a levada frequência de desvios do metabolismo lipídoco e de aumento do peso corpóreo (sobrepeso e obesidade)

Purpose - To determine whether children and adolescents, whose fathers have established coronary artery disease (CAD), have increased prevalence of coronary rishfactors (RF). Methods - The frequencies of abnormal values of lipid variables, glucose, blood pressure, obesity index (calculated through Newen-Goldstein index), smoking and electrocardiographic alterations (ECG), were assessed in 280 descendents of young revascularized patients (<55 years). The study population was divided in two groups according to age, respectivelly GA (2 to 12 years) and GB (12 to 19 years). Eventual influences ofage, gender, obesity and smoking on lipid variable were evaluated through variance analysis. Results - Of the study population, 48.2% and 44.6% had total cholesterol (TC) and LDL-C respectively above the desirable values; 21.7% and 26.1% had values similar to adults under increased risk. Triglyceridemia (TG) >200mg/dl was found in 1.4% of the sample and lower values of HDL-C in 16.8%. Overweight and obesity were observed in 13.1% and 20.0% of the patients and influenced TG levels in GB. Smoking occurred in 10.4%; hypertension in 3 cases and none had abnormal glucose levels or ECG. Conclusion - Healthy children of fathers with established CAD, exhibit a high freqüency of altered lipid profile and increased body weight. The results suggest the need for early identification of RF in offspring of young CAD patients, thus emphasizing changes in risk profile and improving lifestyle