Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: a family study.

Epidemiological and clinical studies have shown that a low plasma high­density lipoprotein cholesterol (HDL-C) level is a strong predictor of cardiovascular disease (CVD). Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the formation, maturation and function of HDL. Therefore impaired LCAT function may enhance atherosclerosis because of defective cholesterol transport. In this study, we examined a 34-year old LCAT­deficient patient and eight first-degree family members. There was a strong family history for CVD and type 2 diabetes mellitus (DM2). The proband was found homozygous for a previously reported LCAT gene mutation (Thr37Met). A sister and two sons of the proband were heterozygous for the same mutation. The proband had DM2 and showed severe multivessel coronary artery disease, corneal opacification and extremely low HDL-C levels. Large HDL particles were absent while small HDL particles were increased. The HDL of the patient had a reduced ability to promote cell cholesterol efflux, and the low­density lipoproteins (LDL) were more susceptible to oxidation. Among his family members, two heterozygotes and one non-carrier had early carotid or coronary atherosclerosis. In conclusion, as the increased LDL oxidability and structural and functional abnormalities of HDL particles have been reported in patients with obesity and diabetes, the results suggested that the adverse coronary risk profile, and not being LCAT deficient, may be responsible for the CVD found in our proband, and for the early atherosclerosis observed in the two heterozygotes and in the wild­type family members.

Association of fatty liver with cardiovascular risk factors and subclinical atherosclerosis in a Mexican population.

INTRODUCTION: Individuals with fatty liver (FL) have an increased risk of coronary artery disease (CAD) probably due to its association with cardiometabolic risk factors (CMRF). OBJECTIVE: To know the prevalence of FL and analyze its association with CMRF and subclinical atherosclerosis, in a sample of Mexican Mestizo population. MATERIAL AND METHODS: This study included 846 subjects from the Genetic of Atherosclerosis Disease (GEA) study (53 ± 9 years, 50.7% women) without diabetes and no personal or family history of premature CAD. Blood samples were taken for measurements of lipids profile, uric acid, and insulin. The presence of FL was identified by computed tomography. Carotid intima media thickness (CIMT) was measured by B mode ultrasound, using the > 75 percentile as cutoff value to define subclinical atherosclerosis. RESULTS: The general prevalence of FL was 32.4%. In men, FL was associated with hyperuricemia, whereas in women, hyperuricemia, low level of high density lipoprotein cholesterol, and metabolic syndrome were the factors associated with this hepatic alteration. In women, FL was associated with a 66% higher probability of having high CIMT, independently of age, hypertension, dyslipidemia, and waist circumference, but not of HOMA-IR. CONCLUSIONS: In women, FL was associated with the presence of subclinical atherosclerosis independently of traditional CMRF. Our study suggests that, in women, insulin resistance could be a mediator of metabolic abnormalities and of subclinical atherosclerosis.

Cholesterol efflux and metabolic abnormalities associated with low high-density-lipoprotein-cholesterol and high triglycerides in statin-treated coronary men with low-density lipoprotein-cholesterol <70 mg/dl.

In 69 statin-treated male coronary patients with low-density lipoprotein cholesterol at goal levels (<70 mg/dl), the investigators tested whether low high-density lipoprotein (HDL) cholesterol (<40 mg/dl) and high triglyceride (>150 mg/dl) are associated with dysfunctional HDL particles and abnormal insulin, adiponectin, C-reactive protein serum levels. Thirty-four patients with low HDL cholesterol and high triglyceride (dyslipidemia) and 35 patients with low-density lipoprotein cholesterol, HDL cholesterol, and triglyceride at target levels (normolipidemia) were studied. Twenty healthy men were also studied. High-sensitivity C-reactive protein was measured using immunonephelometry, insulin using a radioimmunometric assay, and total adiponectin by enzyme-linked immunosorbent assay. Cell cholesterol efflux to serum and total isolated HDL was assayed using rat hepatoma Fu5AH cells for scavenger receptor class B type 1-mediated efflux. Compared to the normolipidemia and healthy groups, and after adjustment for age and waist circumference, patients with dyslipidemia showed higher fasting insulin (14, 9.9, and 8.5 µU/ml, respectively), homeostasis model assessment of insulin resistance values (3.4, 2.3, and 1.8, respectively), lower adiponectin concentrations (5.1, 8.1, and 11 µg/ml, respectively), and reduced cholesterol efflux to serum (14%, 15%, and 19%, respectively) and to HDL fractions (4.4%, 4.6%, and 5.6%, respectively) (p <0.05 for all variables). Multivariate analysis showed that adiponectin and apolipoprotein A1 accounted for 10.7% and 3.9%, respectively, of the variance in cholesterol efflux. In conclusion, the decreased cholesterol efflux and metabolic abnormalities found in the dyslipidemia group may contribute to the residual risk observed in the large statin trials and the higher morbidity and mortality in statin-treated coronary patients with low HDL cholesterol even when attaining low-density lipoprotein cholesterol <70 mg/dl.

Abnormal high-density lipoproteins in overweight adolescents with atherogenic dyslipidemia.

OBJECTIVE: This study aimed to evaluate high-density lipoprotein functionality and the cardiovascular risk factor profile in the overweight pediatric population. We hypothesized that overweight adolescents with low high-density lipoprotein cholesterol and elevated triglyceride plasma levels have metabolic abnormalities and dysfunctional high-density lipoprotein particles, similar to those reported in adults. PATIENTS AND METHODS: Overweight adolescents with (group 1 [n = 21]) and without (group 2 [n = 36]) atherogenic dyslipidemia (high-density lipoprotein cholesterol: ≤ 40 mg/dL and triglycerides: ≥ 150 mg/dL) and normal-weight normolipidemic subjects, as a reference (group 3 [n = 36]), were included. The cardiovascular risk factor profile (lipids, lipoproteins, high-sensitivity C-reactive protein, and insulin), high-density lipoprotein subclass distribution, composition, and cholesterol efflux capacity were studied. RESULTS: Group 1 adolescents showed abnormalities in high-density lipoprotein subclass distribution and high-density lipoprotein chemical composition, as well as a significantly lower capacity to promote cholesterol efflux (14.8 ± 2.8, 16.5 ± 3.8, 20.4 ± 3.5, for groups 1, 2 and 3, respectively). High-density lipoprotein(2a) (R(2) = 0.212, ß = 0.472, P < .0001) and the Tanner score (R(2) = 0.054, ß = -0.253, P = .02) were the independent predictors of cholesterol efflux. Group 1 also showed a higher degree of cardiovascular abnormalities (an adverse lipoprotein profile, greater insulin resistance and systemic inflammation; and lower low-density lipoprotein size) than group 2, even after BMI and Tanner score adjustment. CONCLUSIONS: This study suggests that atherogenic dyslipidemia identifies overweight adolescents with quantitative, qualitative, and functional high-density lipoprotein abnormalities. Atherogenic dyslipidemia seems to be a marker of an increased risk for developing cardiovascular disease and indicates that those adolescents should be a target of aggressive prevention programs and lipid management guidelines.

[High and low density lipoprotein abnormalities in coronary patients with LDL-C at target and uncontrolled HDL-C and triglycerides]. / Alteraciones de las lipoproteínas de alta y baja densidad en pacientes coronarios con C-LDL en meta pero C-HDL y triglicéridos anormales.

OBJECTIVE: To investigate the high density lipoprotein (HDL) subclasses distribution and chemical composition, as well as low density lipoprotein (LDL) size and LDL oxidation, in coronary male patients treated with statins, that had LDL-cholesterol levels at target (< 100 mg/dL), but whose HDL-cholesterol (< 40 mg/dL) and triglycerides (TG > or = 150 mg/dL) levels were abnormal. The control group was formed by statin treated coronary male patients with LDL-C below 100 mg/dL and normal HDL-C and TG levels. MATERIAL AND METHODS: HDL subclasses and LDL size were determined by gradient gel electrophoresis. LDL susceptibility to oxidation was determined by measuring lag phase duration, after adding the oxidant agent. RESULTS: Compared with the control group (n = 35), patients with low HDL-C + high TG (n = 34) showed significantly lower proportions of large HDL and higher proportions of small HDL particles. In addition, these patients had abnormal HDL composition, smaller LDL size, and higher LDL susceptibility to oxidation (p < 0.05 for all). CONCLUSIONS: Coronary patients with optimal LDL-C levels on statin therapy but with low HDL-C and high TG, have HDL and LDL abnormalities that have been shown to be associated with a higher risk of new coronary events.

High-density lipoprotein subclasses distribution and composition in Mexican adolescents with low HDL cholesterol and/or high triglyceride concentrations, and its association with insulin and C-reactive protein.

We tested whether low high-density lipoprotein cholesterol (HDL-C) and/or high triglycerides are associated to abnormal HDL subclasses distribution and composition, and their relationships with fasting insulin and C-reactive protein (CRP). Four groups of adolescents were studied: group 1 (HDL-C< or =35 mg/dl+TG> or =150 mg/dl; n=16); group 2 (isolated HDL-C< or =35 mg/dl; n=31); group 3 (isolated TG> or =150 mg/dl; n=20); and group 4 (CT<200 mg/dl, HDL-C>35 mg/dl, LDL-C<130 mg/dl, and TG<150 mg/dl; n=39). Tanner score-adjusted proportions of large subspecies (HDL(2b), HDL(2a)) were lower, and small (HDL(3b), HDL(3c)) were higher in groups 1, 2 and 3 than in group 4. As a result, HDL particle size in the three dyslipidemic groups was smaller than in group 4 (p<0.001). HDL CE, FC, PL, and apo AI percent contents were lower, whereas HDL TG percent content was higher in groups 1, 2 and 3 compared to group 4. CRP median values were also significantly higher in the three groups with dyslipidemia than in normolipidemic subjects (group 4). Fasting Insulin concentration and HOMA-IR were significantly higher in group 1 than in the other three groups. In stepwise multivariate analysis HDL subclass distribution and composition were independently associated only with HDL-C and waist circumference. As reported in adults, adolescents with low HDL-C and/or high TG have abnormalities in HDL subclasses distribution and lipid composition, which may render their HDL dysfunctional. In addition, these subjects have high CRP and insulin levels suggesting the presence of chronic low-grade inflammation.

Alteraciones de las lipoproteínas de alta y baja densidad en pacientes coronarios con C-LDL en meta pero C-HDL y triglicéridos anormales / High and low density lipoprotein abnormalities in coronary patients with LDL-C at target and uncontrolled HDL-C and triglycerides

OBJECTIVE: To investigate the high density lipoprotein (HDL) subclasses distribution and chemical composition, as well as low density lipoprotein (LDL) size and LDL oxidation, in coronary male patients treated with statins, that had LDL-cholesterol levels at target (< 100 mg/dL), but whose HDL-cholesterol (< 40 mg/dL) and triglycerides (TG > or = 150 mg/dL) levels were abnormal. The control group was formed by statin treated coronary male patients with LDL-C below 100 mg/dL and normal HDL-C and TG levels. MATERIAL AND METHODS: HDL subclasses and LDL size were determined by gradient gel electrophoresis. LDL susceptibility to oxidation was determined by measuring lag phase duration, after adding the oxidant agent. RESULTS: Compared with the control group (n = 35), patients with low HDL-C + high TG (n = 34) showed significantly lower proportions of large HDL and higher proportions of small HDL particles. In addition, these patients had abnormal HDL composition, smaller LDL size, and higher LDL susceptibility to oxidation (p < 0.05 for all). CONCLUSIONS: Coronary patients with optimal LDL-C levels on statin therapy but with low HDL-C and high TG, have HDL and LDL abnormalities that have been shown to be associated with a higher risk of new coronary events.

Lipid and lipoprotein profiles and prevalence of dyslipidemia in Mexican adolescents.

The objective of the study was to determine the prevalence of different forms of dyslipidemia in an urban population of Mexican adolescents. A cross-sectional study was conducted in 1846 students from 8 randomly selected public junior high schools in Mexico City. Anthropometry, blood pressure, and 12-hour fasting lipids and lipoproteins were measured. We studied 770 male and 1076 female adolescents (13.2 +/- 1 years). The most prevalent dyslipidemia was low high-density lipoprotein cholesterol (HDL-C) (<35 mg/dL) either combined with other abnormalities (17.5% for male and 12.9% for female subjects, P < .001) or isolated (13.5% and 9.6% for male and female subjects, respectively, P < .001). Obese subjects showed the highest prevalence of low HDL-C (47.2% for male and 34.4% for female subjects) and of high total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) (19.4%, 27.8%, and 36.1%, respectively, for male subjects; 9.8%, 13.1%, and 24.6%, respectively, for female subjects). Multiple regression analysis showed that waist circumference was negatively associated with HDL-C and positively associated with LDL-C and TG levels, whereas Tanner stages were negatively associated but sex was positively associated with total cholesterol, LDL-C, and TG concentrations. As in Mexican adults, low HDL-C and high TG levels were the most prevalent dyslipidemias. Increased blood lipids over long periods suggest that, as adults, these adolescents will be facing a higher risk for atherosclerosis.

Abnormal HDL subclasses distribution in overweight children with insulin resistance or type 2 diabetes mellitus.

BACKGROUND: Small HDL particles have emerged as significant predictors of incident type 2 diabetes mellitus (T2DM) in adults with impaired glucose tolerance (IGT). However, no previous study has investigated HDL size in pediatric subjects with these clinical conditions. METHODS: We studied the HDL size distribution by native polyacrilamide gradient gel electrophoresis in 106 overweight children, 47 with T2DM, 43 with normal glucose tolerance (NGT), 16 with IGT, and 39 healthy weight controls. RESULTS: Diabetic children had significantly lower proportions of HDL2b and HDL2a, and higher proportions of HDL3b and HDL3c than the other 3 groups. Overweight subjects showed HDL size distributions similar to those of controls. However, insulin-resistant children had lower proportions of HDL2b, and HDL2a, and higher proportions of HDL3b when compared with the insulin-sensitive overweight subjects. Multiple linear regression analyses showed that homeostasis model assessment correlated inversely with HDL2b and HDL2a, and directly with HDL3b, while BMI was independently associated only with HDL3a. CONCLUSIONS: This study showed that HDL size distribution was shifted toward smaller particles in T2DM pediatric patients and in overweight children with insulin resistance, independent of their glucose tolerance status. Insulin resistance was the main factor associated with these HDL size abnormalities. This parameter could be useful as an early risk marker of incident diabetes and, probably, of coronary heart disease.

[Treatment of the patient with ideal LDL cholesterol]. / Tratamiento del paciente con colesterol de LDL ideal.

Coronary heart disease (CHD) is the leading cause of death worldwide. Low-density lipoprotein-cholesterol (LDL-C) reduction is the corner-stone in both primary and secondary cardiovascular prevention. Use of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (statins) has proved to reduce LDL-C levels and major coronary event risks. The benefit on cardiovascular risk reduction is greater as LDL-C lowering is greater. Cardiovascular risk remains unacceptably high, even in patients with on-target LDL-C. This paper presents a review of alternatives for both approach and therapy in patients with on-target LDL-C.