Daniel Zambón

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.

Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden ρ2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.

Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic testing for low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB) gene defects is the preferable diagnostic method, but the best phenotype indication to proceed with genetic diagnosis has not been established. The aim of this study was to assess the predictive and accuracy values of standard diagnostic criteria for detecting disease-causing mutations in 825 subjects with clinical FH aged > or =14 years from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations were detected in 459 subjects (55.6%). By logistic regression analysis, familial or personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated with genetic diagnosis (p <0.005, R(2) = 0.41). In subjects without familial or personal histories of TX, the diagnostic criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project, based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity of 71.1%, and accuracy of 71.6%. LDL cholesterol > or =190 mg/dl in subjects with familial or personal histories of TX and > or =220, > or =225, and > or =235 mg/dl in those without such histories aged <30, 30 to 39, and > or =40 years, respectively, showed sensitivity of 91.1%, specificity of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of diagnostic criteria for FH was validated in an independent group of 440 subjects from 6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol cut-off values have the highest value for clinical diagnosis and indication of genetic testing in FH.

Apolipoprotein E polymorphism and gallstones

BACKGROUND & AIMS Apolipoprotein (apo) E is a genetically polymorphic protein influencing lipoprotein metabolism and the risk of both atherosclerosis and Alzheimers disease. As opposed to common apo E3, apo E2 decreases and apo E4 increases hepatic lipoprotein uptake; hence, apo E4 could promote gallstone formation by increasing hepatic and biliary cholesterol concentrations. This study was designed to evaluate whether apo E polymorphism is related to gallstone risk. METHODS apo E phenotype was determined in subjects older than 40 years of age (160 with and 125 without gallstones) and in 61 patients with cholesterol gallstones who underwent cholecystectomy. Bile composition, nucleation time, and gallstone features were analyzed in surgical patients. RESULTS The E4/3 phenotype was enriched in both patients with gallstones and those who underwent cholecystectomy, with significantly (P < 0.006) higher epsilon 4 allele frequencies than in gallstone-free subjects (odds ratio, 2.67 [95% confidence limits, 1.23-5.93] and 3.62 [95% confidence limits, 1.49-8.91], respectively); women, but not men, accounted for these differences. The prevalence of the epsilon 4 allele increased with age in patients with gallstones, whereas the opposite occurred in gallstone-free subjects. Biliary lipid and gallstone cholesterol content tended to increase in the sequence E4 > E3 > E2 in patients who underwent cholecystectomy. CONCLUSIONS Carrying the apo E4 isoform is a genetic risk factor for cholelithiasis in humans, thus adding another adverse effect of apo E polymorphism on health.

Attainment of LDL-Cholesterol Treatment Goals in Patients With Familial Hypercholesterolemia : 5-Year SAFEHEART Registry Follow-Up

BACKGROUND Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. OBJECTIVES We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. METHODS The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). RESULTS The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target <100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals. CONCLUSIONS Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia

The magnitude of serum lipid changes in response to hypolipidemic drugs varies considerably between individuals. These differences may be due to interactions between genetic and environmental factors that effect drug bioavailability or the capacity of the lipid-regulating enzyme and receptor targets to be affected. The apolipoprotein E (apoE) gene locus has been examined in this regard, but reports are conflicting on the effect of its variability on the response to hypolipidemic drugs. We investigated the effect of apoE polymorphism on the serum lipid response to the hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin and the fibric acid derivative gemfibrozil. Lipoprotein changes were assessed after 12 weeks of therapy in 106 patients with primary hypercholesterolemia and combined hyperlipidemia treated with lovastastin and in 63 given gemfibrozil therapy. No significant effect of the apoE phenotypes E3/2, E3/3, or E4/3 on the heterogeneity of lipid responses to either drug was found.

Higher incidence of mild cognitive impairment in familial hypercholesterolemia

OBJECTIVE Hypercholesterolemia is an early risk factor for Alzheimers disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia. METHODS By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment. RESULTS Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P=.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia. CONCLUSION Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.

Frequency of Low-Density Lipoprotein Receptor Gene Mutations in Patients With a Clinical Diagnosis of Familial Combined Hyperlipidemia in a Clinical Setting

OBJECTIVES The purpose of this study was to determine the frequency of mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) genes in consecutive patients with a clinical diagnosis of familial combined hyperlipidemia (FCH) in a nonresearch setting. BACKGROUND The lipid phenotype frequently overlaps in familial hypercholesterolemia (FH) and FCH. Detection of causative mutations in LDLR or APOB provides an unequivocal diagnosis of FH, but such genetic testing has not been systematically performed in FCH. METHODS We used Lipochip (Progenika, Derio, Spain), a microarray that includes 203 causative mutations in LDLR and 4 APOB defects, to investigate 143 unrelated FCH patients. RESULTS Mutations of LDLR were found in 28 patients (overall prevalence, 19.6%). No APOB defects were found. Compared with patients who had a normal LDLR gene, patients with mutations had lower waist circumference (p = 0.02); significantly (p < 0.005) higher total cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apoB; nonsignificantly (p = 0.063) lower triglycerides; and a lower frequency of diabetes mellitus (22% vs. 0%, respectively; p = 0.002). Total cholesterol and apoB levels showed the best receiver-operator characteristics curves in the prediction of LDLR mutations, with areas under the curve (95% CI: of 0.750 (95% confidence interval [CI]: 0.647 to 0.853) and 0.744 (95% CI: 0.636 to 0.851), respectively. Total cholesterol of 335 mg/dl and apoB of 185 mg/dl were the best thresholds for diagnosis of LDLR mutations. CONCLUSIONS Screening for LDLR defects is advisable for patients with a clinical diagnosis of FCH showing high total cholesterol or apoB levels. Diagnostic criteria for FH should not exclude patients whose personal and familial lipid values appear to fit the clinical criteria of FCH.

OriginalesEcografía carotídea en la evaluación de aterosclerosis preclínica. Distribución de valores del grosor íntima-media y frecuencia de placas de ateroma en una cohorte comunitaria españolaCarotid ultrasound in the assessment of preclinical atherosclerosis. Distribution of intima-media thickness values and plaque frequency in a Spanish community cohort☆

BACKGROUND AND OBJECTIVE: High-resolution B-mode ultrasound measurements of carotid intima-media thickness (IMT) and determination of plaque presence are useful to assess preclinical atherosclerosis. Normal IMT values have not been reported in Spanish subjects. Our aim was to define normality data of carotid ultrasound by sex and age. SUBJECTS AND METHODS: We studied 250 healthy, normolipidemic subjects, 125 men and 125 women, with mean age 49 years (range, 20-81). We assessed cardiovascular risk factors and performed ultrasound determination of mean and maximum IMT in the far wall of the common carotid artery, plaque occurrence, and maximum plaque height. RESULTS: Reference values for carotid IMT, expressed as 25th, 50th, and 75th percentiles by sex and 5 age groups, have been obtained. The 50th percentiles of mean IMT ranged from 0.50 to 0.74 mm in men in the age groups 35 years or younger and 65 years or older, respectively. For women, corresponding IMT values ranged from 0.40 to 0.65 mm. IMT was strongly related (p < 0.001) to age, both in men (r = 0.57) and women (r = 0.61). From the regression equations, the estimated yearly increase in IMT was 0.005 mm in men and 0.007 mm in women. More than 50% of men aged 55 years and older, and of women aged 65 years and older, had carotid plaques. CONCLUSIONS: Both IMT and plaque frequency were associated with age in men and women. Carotid IMT values in a Spanish community cohort were lower than those reported for countries with higher cardiovascular risk, such as Northern European countries and the US.BACKGROUND AND OBJECTIVE High-resolution B-mode ultrasound measurements of carotid intima-media thickness (IMT) and determination of plaque presence are useful to assess preclinical atherosclerosis. Normal IMT values have not been reported in Spanish subjects. Our aim was to define normality data of carotid ultrasound by sex and age. SUBJECTS AND METHODS We studied 250 healthy, normolipidemic subjects, 125 men and 125 women, with mean age 49 years (range, 20-81). We assessed cardiovascular risk factors and performed ultrasound determination of mean and maximum IMT in the far wall of the common carotid artery, plaque occurrence, and maximum plaque height. RESULTS Reference values for carotid IMT, expressed as 25th, 50th, and 75th percentiles by sex and 5 age groups, have been obtained. The 50th percentiles of mean IMT ranged from 0.50 to 0.74 mm in men in the age groups 35 years or younger and 65 years or older, respectively. For women, corresponding IMT values ranged from 0.40 to 0.65 mm. IMT was strongly related (p < 0.001) to age, both in men (r = 0.57) and women (r = 0.61). From the regression equations, the estimated yearly increase in IMT was 0.005 mm in men and 0.007 mm in women. More than 50% of men aged 55 years and older, and of women aged 65 years and older, had carotid plaques. CONCLUSIONS Both IMT and plaque frequency were associated with age in men and women. Carotid IMT values in a Spanish community cohort were lower than those reported for countries with higher cardiovascular risk, such as Northern European countries and the US.

Effect of atorvastatin and bezafibrate on plasma levels of C-reactive protein in combined (mixed) hyperlipidemia

C-reactive protein (CRP) is a non-specific but sensitive marker of underlying systemic inflammation. High CRP plasma levels correlate with risk for future cardiovascular events. The present study evaluated the effects of atorvastatin (10-40 mg) and bezafibrate (400 mg) on CRP concentrations after 6 and 12 months of treatment in 103 patients with combined (mixed) hyperlipidemia. The number of cardiovascular risk factors present in a given patient was associated with baseline CRP levels. After 6 months and 1 year, atorvastatin treatment was associated with significant (P<0.001) decreases from baseline of CRP concentrations by 29 and 43%, respectively, while bezafibrate-treated patients showed non-significant reductions of 2.3 and 14.6%, respectively (P=0.056 and 0.005 for the respective differences between the two treatment arms at 6 months and 1 year). The magnitude of change in CRP after 1 year was directly related to baseline CRP levels. Covariance analysis showed that CRP decreases in the atorvastatin group were unrelated to total cholesterol and LDL cholesterol reductions; however, they were directly related to triglyceride changes (r=0.28, P=0.047) and inversely related to HDL cholesterol changes (r=-0.28, P=0.045). A model including baseline CRP values and treatment effect showed that atorvastatin use was a significant predictor of change in CRP levels over time (beta=0.82, P=0.023). These results suggest a potential anti-atherosclerotic additional benefit of atorvastatin in patients at a risk of cardiovascular disease.

The use of Achilles tendon sonography to distinguish familial hypercholesterolemia from other genetic dyslipidemias.

Objective—Achilles tendon (AT) xanthomas, specific for familial hypercholesterolemia (FH), may be clinically undetectable. We assessed the usefulness of AT sonography in the diagnosis of FH. Methods and Results—Sonographic AT characteristics were evaluated in 127 subjects with FH (81 genetically ascertained), 84 familial combined hyperlipidemia, 79 polygenic hypercholesterolemia, and 88 normolipidemic controls. Abnormal echostructure (sonographic xanthoma) was noted only in FH. AT thickness was higher (P<0.001) in FH men and women compared with all of the other groups and, in FH mutation carriers but not in others, correlated positively with low-density lipoprotein cholesterol (r=0.345; P<0.001) and negatively with high-density lipoprotein cholesterol (r=−0.265, P=0.015). Thickness thresholds for the diagnosis of FH with specificity >80%, as were derived from receiver operating curves, were 5.3 and 5.7 mm in men < and >45 years, and 4.8 and 4.9 mm in women < and >50 years, respectively. In FH mutation carriers, sonographic findings increased the clinical diagnosis of xanthomas from 35 (43%) to 55 (68%). Using thresholds in validation sets of 70 genetically identified FH and 54 dyslipidemic non-FH correctly classified 80% and 88%, respectively. Conclusion—Sonographic AT characteristics are normal in non-FH dyslipidemias. Identification of suspected FH by ultrasound using sex- and age-specific AT thickness thresholds is recommended.