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 ≥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 ≥190 mg/dl in subjects with familial or personal histories of TX and ≥220, ≥225, and ≥235 mg/dl in those without such histories aged <30, 30 to 39, and ≥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.
The aim of our study was to investigate a large cohort of overweight subjects consuming a homogeneous diet to identify the genetic factors associated with weight loss that could be used as predictive ...markers in weight loss interventions. We retrospectively recruited subjects (N = 788) aged over 18 years with a Body Mass Index (BMI) between 25 and 40 kg/m
who were treated at our lipid unit for at least one year from 2008 to 2016, and we also recruited a control group (168 patients) with normal BMIs. All participants received counselling from a nutritionist that included healthy diet and physical activity recommendations. We genotyped 25 single nucleotide variants (SNVs) in 25 genes that were previously associated with obesity and calculated genetic scores that were derived from 25 SNVs. The risk allele in CADM2 showed a higher frequency in overweight and obese subjects than in controls (p = 0.007). The mean follow-up duration was 5.58 ± 2.68 years. Subjects with lower genetic scores showed greater weight loss during the follow-up period. The genetic score was the variable that best explained the variations in weight from the baseline. The genetic score explained 2.4% of weight change variance at one year and 1.6% of weight change variance at the end of the follow-up period after adjusting for baseline weight, sex, age and years of follow-up.
Abstract
Background
Familial hypercholesterolemia (FH) is a codominant autosomal disease characterized by high low-density lipoprotein cholesterol (LDLc) and a high risk of premature cardiovascular ...disease (CVD). The molecular bases have been well defined, and effective lipid lowering is possible. This analysis aimed to study the current major causes of death of genetically defined heterozygous familial hypercholesterolemia (heFH).
Methods
A case‒control study was designed to analyse life-long mortality in a group of heFH and control families. Data from first-degree family members of cases and controls (nonconsanguineous cohabitants), including deceased relatives, were collected from a questionnaire and review of medical records. Mortality was compared among heFH patients, nonheFH patients, and nonconsanguineous family members.
Results
A total of 813 family members were analysed, 26.4% of whom were deceased. Among the deceased, the mean age of death was 69.3 years in heFH individuals, 73.5 years in nonheFH individuals, and 73.2 years in nonconsanguineous individuals, without significant differences. CVD was the cause of death in 59.7% of heFH individuals, 37.7% of nonheFH individuals, and 37.4% of nonconsanguineous individuals (
P
= 0.012). These differences were greater after restricting the analyses to parents. The hazard ratio of dying from CVD was 2.85 times higher (95% CI, (1.73–4.69) in heFH individuals than in individuals in the other two groups (non-FH and nonconsanguineous), who did not differ in their risk.
Conclusions
CVD mortality in heFH individuals is lower and occurs later than that described in the last century but is still higher than that in non-FH individuals. This improved prognosis of CVD risk is not associated with changes in non-CVD mortality.
Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present ...study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486-0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.
Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and ...increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.
Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol with co-dominant transmission and high risk of cardiovascular disease (CVD), although with high ...variability among subjects. Currently, CVD stratification tools for heterozygous FH (HeFH) are not available. A definition of severe HeFH has been recently proposed by the International Atherosclerosis Society (IAS), but it has not been validated. Our study aims to see clinical characteristics and prevalence of CVD in subjects defined as severe HeFH by IAS criteria. Probable or definite HeFH introduced in the Dyslipidemia Registry of Spanish Arteriosclerosis Society were analyzed by the IAS criteria. Univariate and multivariate analysis was used to assess the association of CVD with the IAS criteria. About 1,732 HeFH cases were analyzed. Severe HeFH had higher prevalence of familial history of CVD, personal history of tendon xanthomas, LDL cholesterol, and CVD than nonsevere HeFH. A total of 656 (77.1%) and 441 (50.1%) of men and women, respectively, fulfilled the IAS criteria of severe HeFH. In the univariate analysis, subjects defined as severe HeFH showed odds ratio 3.016 (95% CI 3.136 to 4.257, p <0.001) for CVD. However, when traditional risk factors were included in the multivariate analysis, only the presence of cholesterol >400 mg/dl had a statistically significant association with CVD odds ratio 8.76 (95% CI 3.90 to 19.69, p <0.001). In conclusion, the IAS definition of severe HeFH is not significantly associated with CVD when adjusted for classic risk factors. Risk stratification in HeFH is an important issue, but the proposed criteria do not seem to solve this problem.
Abstract Objective Hypercholesterolemia is an early risk factor for Alzheimer's 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.
Non-cholesterol sterols have been used as markers of cholesterol intestinal absorption and hepatic synthesis, leading to a better understanding of cholesterol homeostasis in humans. This review ...discusses the main noncholesterol sterols that are clinically useful, different methods to quantify the factors associated with blood concentration, and the potential role of non-cholesterol sterols in the diagnosis and treatment of different types of dyslipidemia. The main indication is the use of non-cholesterol sterols for the diagnosis of rare diseases associated with defects in cholesterol synthesis or anomalies in the absorption and/or elimination of phytosterols. However, other potential uses, including the diagnosis of certain hypercholesterolemias and the individualization of lipid-lowering therapies, are promising as they could help treat a wider population.
Background and Aims
Many addictive substances, such as tobacco and alcohol, influence atherosclerosis development. Whether or not tobacco's pro‐atherosclerotic effect is influenced by alcohol ...consumption is unknown. We aimed to estimate the impact of alcohol intake on the presence of subclinical atherosclerosis in femoral arteries in smoking and non‐smoking middle‐aged men.
Design, Setting and Participants
Cross‐sectional analysis of a subset of the Aragon Workers Health Study (AWHS), comprising 2099 men with mean age 50.9 years without previous cardiovascular disease.
Measurements
The presence of plaques in femoral arteries was assessed by high‐resolution sonography. Self‐reported alcohol consumption over the previous year was measured with a food frequency questionnaire. The sample was divided into four groups according to their daily grams of alcohol consumption ≤ 1 (abstainers), ≥ 2 to < 30, ≥ 30 to < 60 and ≥ 60 g/day. Participants were divided on ever‐smoking (current and former) versus never‐smoking strata in the main analysis.
Findings
We did not find a significant association between the different levels of alcohol intake and the likelihood of developing femoral artery atherosclerosis in never‐smokers. Ever‐smoking was positively associated with femoral atherosclerosis overall odds ratio (OR) = 3.00; 95% confidence interval (CI) = 2.40, 3.74; P < 0.001 and within each level of alcohol consumption. Atherosclerosis was lower in ever‐smokers who consumed 2 g/day or more but less than 30 g/day with respect to those ever‐smokers who were abstainers (OR = 0.70; 95% CI = 0.49, 0.99; P < 0.05). However, among these ever‐smokers, atherosclerosis prevalence was still higher than among never‐smokers who consumed alcohol in the same amount (2 g/day or more but less than 30 g/day) (OR = 2.73; 95% CI = 2.07, 3.61; P < 0.001).
Conclusions
Among middle‐aged men, moderate alcohol consumption appears to be associated with lower prevalence of femoral artery subclinical atherosclerosis compared with alcohol abstinence only in ever‐smokers.
Atrial fibrillation is associated with hyperthyroidism. Within the euthyroid range, it is also associated with high thyroxine (fT4), but not with thyrotropin (TSH). We aim to describe differences in ...thyroid regulation, measured by the Parametric Thyroid Feedback Quantile-Based Index (PTFQI), between patients with atrial fibrillation and the general population.
Thyroid parameters (PTFQI, TSH, and fT4) of a sample of 84 euthyroid subjects with atrial fibrillation (cases) were compared to a reference sample of euthyroid healthcare patients (controls). We calculated age and sex adjusted ORs for atrial fibrillation across tertiles of these parameters. Also, within cases, we studied thyroid parameters association with clinical characteristics of the atrial fibrillation.
After adjusting for age and sex, fT4 and PTFQI were higher in subjects with atrial fibrillation when compared to the general sample (p<0.01 and p=0.01, respectively). Atrial fibrillation ORs of the third versus the first PTFQI tertile was 1.88(95%CI 1.07,3.42), and there was a gradient across tertiles (p trend=0.02). Among atrial fibrillation patients, we observed that higher PTFQI was associated with sleep apnea/hypopnea syndrome (OSAS) (p=0.03), higher fT4 was associated with the presence of an arrhythmogenic trigger (p=0.02) and with heart failure (p<0.01), and higher TSH was also associated with OSAS (p<0.01).
Euthyroid subjects with atrial fibrillation have an elevation of the pituitary TSH-inhibition threshold, measured by PTFQI, with respect to the general population. Within atrial fibrillation patients, high PTFQI was associated with OSAS, and high fT4 with heart failure. These results hint of the existence of a relationship between thyroid regulation and atrial fibrillation.
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