Contribution of APOE Genetic Variants to Dyslipidemia.

BACKGROUND: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. METHODS: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. RESULTS: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. CONCLUSIONS: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE. However, more investigation is required to elucidate the significance of rarer variants of apoE.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors.

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

Current causes of death in familial hypercholesterolemia.

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.

APOE Genotypes Modulate Inflammation Independently of Their Effect on Lipid Metabolism.

The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.

Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia.

BACKGROUND AND AIMS: Cardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins. METHODS AND RESULTS: Among primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included. LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects. CONCLUSION: According to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.

Effect of bergamot on lipid profile in humans: A systematic review.

Dyslipidemia is a well-established modifiable cardiovascular risk. Although statins can reduce LDLc by 50-60%, less than 20% of patients with high risk of CVD achieve LDL targets. The aim of this systematic review is to evaluate the effect of the nutraceutical, bergamot (Citrus bergamia), on lipid parameters in humans. PubMed, Embase, Cochrane Library, and Google Scholar databases were searched for interventional and observational studies investigating the effect of bergamot on lipid profile in humans. This systematic review retrieved a total of 442 studies of which 12 articles fulfilled the eligibility criteria and were included in the qualitative synthesis. Based on data, 75% of studies showed a significant decrease in total cholesterol, triglycerides and LDLc. The decrease in total cholesterol varied from 12.3% to 31.3%, from 7.6% to 40.8% in LDLc and from 11.5% to 39.5% in triglycerides. Eight trials reported HDLc increase after intervention with bergamot. Overall, a dose-dependent and possible synergistic effect when administering with statins can be deducted from these trials. It is essential to point out that studies had heterogeneous designs and scientific quality of studies was quite limited. Promising findings reveal an alternative therapeutic option in dyslipidemia management with bergamot supplementation, especially in subjects with statins intolerance.

Three Dimensional Carotid and Femoral Ultrasound is not Superior to Two Dimensional Ultrasound as a Predictor of Coronary Atherosclerosis Among Men With Intermediate Cardiovascular Risk.

BACKGROUND: Current cardiovascular disease (CVD) risk stratification scales, drawn up from traditional risk factors, have important limitations. The detection of subclinical atherosclerosis, by a non-invasive technique such as peripheral arteries ultrasound (US) may improve cardiovascular risk (CVR) stratification, especially in intermediate risk population. Our aim was to compare the predictive power of atherosclerotic plaques detected in carotid and femoral arteries by 2-dimensional (2D) vs. 3-dimensional (3D) US for positive coronary artery calcium score (CACS), used as a proxy for CVD, in a middle-aged sample with intermediate 10-year CVR (7.5-20%). METHODS: To detect atherosclerotic plaques by 2D vs. 3D US scan of carotid and femoral arteries and comparison of their association with CACS obtained by computed tomography (CT) of subjects with intermediate CVR belonging to the Aragon Workers' Health Study. RESULTS: 120 men were included, with a 10.4% average 10 years CVR. Forty-one (34.2%) participants had CACS ≥ 1. 90 participants (75%) had at least one plaque detected by 2D scan while 85 participants (70.8%) had at least a plaque detected by 3D US. Conventional CVR estimates c-statistic for CACS was .590. Although the variables most predicted of CACS ≥ 1 were those measured by 3D US (total plaque volume and mean of plaque density, c-statistics: .743 and .750 respectively), their predictive capacity was not statistically significantly different from the number of territories with plaque, measured either by 2D and 3D US (c-statistics .728 to .740 respectively). CONCLUSION: Subclinical atherosclerosis measured by 2D and 3D US were better predictors of CACS ≥ 1 than CVR estimated by conventional guidelines. In our sample, 3D US did not show any significant advantages with respect to 2D US for the prediction of coronary atherosclerosis.

Comparative efficacy between atorvastatin and rosuvastatin in the prevention of cardiovascular disease recurrence.

BACKGROUND: There is no randomized clinical trials with recurrence of atherosclerotic cardiovascular disease (ASCVD) as a major outcome with rosuvastatin. In order to analyze potential differences in the clinical response to atorvastatin and rosuvastatin in secondary ASCVD prevention, we have analyzed the clinical evolution of those subjects of the Dyslipemia Registry of the Spanish Society of Arteriosclerosis (SEA) who at the time of inclusion in the Registry had already suffered an ASCVD. METHODS: This observational, retrospective, multicenter, national study was designed to determine potential differences between the use of atorvastatin and rosuvastatin in the ASCVD recurrence. Three different follow-up start-times were performed: time of inclusion in the registry; time of first event if this occurred after 2005, and time of first event without date restriction. RESULTS: Baseline characteristics were similar between treatment groups. Among atorvastatin or rosuvastatin users, 89 recurrences of ASCVD were recorded (21.9%), of which 85.4% were coronary. At the inclusion of the subject in the registry, 345 participants had not suffered a recurrence yet. These 345 subjects accumulated 1050 person-years in a mean follow-up of 3 years. Event rates were 2.73 (95% CI: 1.63, 4.25) cases/100 person-years and 2.34 (95% CI: 1.17, 4.10) cases/100 person-years in the atorvastatin and rosuvastatin groups, respectively. There were no statistically significant differences between the two groups independently of the follow-up start-time. CONCLUSIONS: This study does not find differences between high doses of rosuvastatin and atorvastatin in the recurrence of ASCVD, and supports their use as clinically equivalent in secondary prevention of ASCVD.

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed. METHODS: Clinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (n = 63) and without (n = 40) TX. Student-t test o Mann-Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal-Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied. RESULTS: Patients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (P = 0.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, ß-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (p = 0.002, 0.012, 0.020, 0.045 and 0.040, respectively). CONCLUSIONS: Our results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX.

Factors associated with the presence of tendon xanthomas in familial hypercholesterolemia.

INTRODUCTION AND OBJECTIVES: Tendon xanthomas (TX) are lipid deposits highly specific to familial hypercholesterolemia (FH). However, there is significant variability in their presentation among FH patients, primarily due to largely unknown causes. Lipoprotein(a) is a well-established independent risk factor for atherosclerotic cardiovascular disease in the general population as well as in FH. Given the wide variability of lipoprotein(a) among FH individuals and the likelihood that TX may result from a proatherogenic and proinflammatory condition, the objective of this study was to analyze the size of TX in the Achilles tendons of FH participants and the variables associated with their presence, including lipoprotein(a) concentration. METHODS: A cross-sectional study was conducted on 377 participants with a molecular diagnosis of heterozygous FH. Achilles tendon maximum thickness (ATMT) was measured using ultrasonography with standardized equipment and procedures. Demographic variables and lipid profiles were collected. A multivariate linear regression model using a log-Gaussian approach was used to predict TX size. Classical cardiovascular risk factors and lipoprotein(a) were included as explanatory variables. RESULTS: The mean low-density lipoprotein cholesterol level was 277mg/dL without lipid-lowering treatment, and the median ATMT was 5.50mm. We demonstrated that age, sex, low-density lipoprotein cholesterol, and lipoprotein(a) were independently associated with ATMT. However, these 4 variables did not account for most the interindividual variability observed (R2=0.205). CONCLUSIONS: TX, a characteristic hallmark of FH, exhibit heterogeneity in their presentation. Interindividual variability can partially be explained by age, male sex, low-density lipoprotein cholesterol, and lipoprotein(a) but these factors account for only 20% of this heterogeneity.

Influence of triglyceride concentration in lipoprotein (a) as a function of dyslipidemia. / Influencia de la concentración de triglicéridos en la lipoproteína(a) en función de la dislipidemia.

BACKGROUND: Recently, an inverse relationship between the blood concentration of lipoprotein(a) (Lp(a)) and triglycerides (TG) has been demonstrated. The larger the VLDL particle size, the greater the presence of VLDL rich in apoliprotein E and in subjects with the apoE2/E2 genotype, the lower Lp(a) concentration. The mechanism of this inverse association is unknown. The objective of this analysis was to evaluate the Lp(a)-TG association in patients treated at the lipid units included in the registry of the Spanish Society of Atherosclerosis (SEA) by comparing the different dyslipidemias. PATIENTS AND METHODS: Five thousand two hundred and seventy-five subjects ≥18 years of age registered in the registry before March 31, 2023, with Lp(a) concentration data and complete lipid profile information without treatment were included. RESULTS: The mean age was 53.0 ± 14.0 years, with 48% women. The 9.5% of subjects (n = 502) had diabetes and the 22.4% (n = 1184) were obese. The median TG level was 130 mg/dL (IQR 88.0-210) and Lp(a) 55.0 nmol/L (IQR 17.9-156). Lp(a) concentration showed a negative association with TG concentration when TG values exceeded 300 mg/dL. Subjects with TG > 1000 mg/dL showed the lowest level of Lp(a), 17.9 nmol/L, and subjects with TG < 300 mg/dL had a mean Lp(a) concentration of 60.1 nmol/L. In subjects without diabetes or obesity, the inverse association of Lp(a)-TG was especially important (p < 0.001). The median Lp(a) was 58.3 nmol/L in those with TG < 300 mg/dL and 22.0 nmol/L if TG > 1000 mg/dL. No association was found between TG and Lp(a) in subjects with diabetes and obesity, nor in subjects with familial hypercholesterolemia. In subjects with multifactorial combined hyperlipemia with TG < 300 mg/dL, Lp(a) was 64.6 nmol/L; in the range of 300-399 mg/dL of TG, Lp(a) decreased to 38. 8 nmol/L, and up to 22.3 nmol/L when TG > 1000 mg/dL. CONCLUSIONS: Our results show an inverse Lp(a)-TG relationship in TG concentrations > 300 mg/dL in subjects without diabetes, obesity and without familial hypercholesterolemia. Our results suggest that, in those hypertriglyceridemias due to hepatic overproduction of VLDL, the formation of Lp(a) is reduced, unlike those in which the peripheral catabolism of TG-rich lipoproteins is reduced.

Low-Quality Carbohydrate Intake Is Associated With a Higher Prevalence of Metabolic Syndrome: The AWHS Study.

CONTEXT: The relationship between carbohydrate quality intake and metabolic syndrome (MetS) is of growing interest. OBJECTIVE: We aimed to assess the association between the adherence to a dietary carbohydrate quality index (CQI) with the occurrence of MetS in a Spanish cohort of working adults. METHODS: A cross-sectional study was conducted of 2316 middle-aged men, aged 50.9 (SD 3.9) years, with no previous cardiovascular disease, and pertaining to the Aragon Workers' Health Study (AWHS) cohort. Diet was collected with a 136-item semiquantitative food-frequency questionnaire. The CQI (range 4-15) was based on: dietary fiber intake, a low glycemic index, the ratio of whole grains/total grains, and the ratio of solid carbohydrates/total carbohydrates. The higher the CQI, the healthier the diet. MetS was defined by using the harmonized National Cholesterol Education Programme-Adult Treatment Panel III (NCEP-ATP III) definition. The associations across 3-point categories of the CQI and the presence of MetS were examined using logistic regression. RESULTS: An inverse and significant association between the CQI and MetS was found. Fully adjusted odds ratios (ORs) for MetS risk among participants in the 10- to 12-point category (second highest CQI category) was 0.64 (95% CI, 0.45-0.94), and in the 13- to 15-point category (highest category) was 0.52 (95% CI, 0.30-0.88), when compared with the 4- to 6-point category (lowest category). Participants with 10 to 12 and 13 to 15 points on the CQI showed a lower risk of hypertriglyceridemia: OR 0.61 (95% CI, 0.46-0.81), and 0.48 (95% CI, 0.32-0.71) respectively. CONCLUSION: Among middle-aged men, a higher adherence to a high-quality carbohydrate diet is associated with a lower prevalence of MetS. Triglyceridemia is the MetS component that contributed the most to this reduced risk.

An elevated parametric thyroid feedback quantile-based index is associated with atrial fibrillation.

Introduction: 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. Materials and methods: 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. Results: 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). Conclusions: 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.

Impact of conducting a genetic study on the management of familial hypercholesterolemia.

BACKGROUND: Clinically diagnosed familial hypercholesterolemia (FH) may require a genetic test (GT) to confirm diagnosis. GT availability/accessibility is resource-dependent and usually restricted to specialized clinics. While GT has a diagnostic value, it has not yet defined its impact on long-term management and prognosis of FH. OBJECTIVE: The aim was to identify the clinical characteristics associated with the request for a GT in suspected heterozygous FH. METHODS: Retrospective study including adult patients with clinically suspected to be FH. Positive GT (GT+) was defined as having a pathogenic/likely pathogenic variant. Patients were stratified based on whether they had a genetic study conducted, and among those with a genetic study, according to those who did or did not have a GT+. RESULTS: From 4854 patients included, 3090 were performed a GT (GT+: 2113). Median follow-up: 6.2 years. A younger age, FH-related physical signs, premature coronary disease, higher low-density lipoprotein cholesterol (LDLc) and lower body mass index and triglycerides, associated higher odds of being conducted a genetic study. These patients had higher baseline LDLc (252 mg/dL vs. 211 mg/dL among clinically diagnosed patients) and experienced larger reductions over the follow-up (157.7 mg/dL vs. 113.5 mg/dL, respectively). A similar pattern was observed among patients with GT+ (vs. negative GT). LDLc target attainment was low but increased to 66-95% when a triple combination with statin/ezetimibe/proprotein convertase subtilisin kexin type 9-inhibitor was used. Cardiovascular events occurred in 3.2% and 3.1% of patients who conducted/not conducted a genetic study. Patients conducted a genetic analysis and those with GT+ tended to present the events earlier. CONCLUSIONS: Genetic study, vs. having a clinical-only diagnosis, impacts the management of FH. Cardiovascular prognosis was similar in both groups, perhaps as a result of the more intensive management of patients with a genetic study.

Dyslipidemia treatment strategies in primary and secondary prevention. Dyslipemia Registry of the Spanish Arteriosclerosis Society. / Estrategias de tratamiento de las dislipemias en prevención primaria y secundaria. Registro de la Sociedad Española de Arteriosclerosis.

INTRODUCTION: Clinical studies show that patients with high cardiovascular risk are still far from reaching the therapeutic objectives, especially of the levels of LDL cholesterol. If the management of these patients in specialized units differs from other scenarios is known. PATIENTS AND METHODS: 61 certified Lipid Units were selected in the Registry of Dyslipemias of the Spanish Arteriosclerosis Society for the collection of study data. The study included 3958 subjects >18 years of age who met the criteria for hypercholesterolemia (LDL cholesterol ≥160 mg/dL or non-HDL cholesterol ≥190 mg/dL) without familial hypercholesterolemia. A total 1,665 subjects were studied with a mean follow-up time of 4.2 years. RESULTS AND CONCLUSIONS: A total of 42 subjects had a cardiovascular event since their inclusion in the Registry, which represents 0.6%. There were no differences in the treatment used at follow-up, but 50% of the patients did not reach the therapeutic goals at the visit end of follow-up. An increase in the potency of the lipid-lowering treatment was observed, including PCSK9 inhibitors use in 16.7% of subjects with recurrences.

Association of Cholesterol and Oxysterols in Adipose Tissue With Obesity and Metabolic Syndrome Traits.

OBJECTIVE: Adipose tissue stores a substantial amount of body cholesterol in humans. Obesity is associated with decreased concentrations of serum cholesterol. During weight gain, adipose tissue dysfunction might be one of the causes of metabolic syndrome. The aim of this study is to evaluate cholesterol storage and oxidized metabolites in adipose tissue and their relationship with metabolic clinical characteristics. METHODS: Concentrations of cholesterol and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) in subcutaneous and visceral adipose tissue were determined by high-performance liquid chromatography with tandem mass spectrometry in 19 adult women with body mass index between 23 and 40 kg/m2 from the FAT expandability (FATe) study. Tissue concentration values were correlated with biochemical and clinical characteristics using nonparametric statistics. RESULTS: Insulin correlated directly with 24S-hydroxycholesterol in both adipose tissues and with 27-hydroxycholesterol in visceral tissue. Leptin correlated directly with 24S-hydroxycholesterol in subcutaneous adipose tissue. Tissue cholesterol correlated directly with 27-hydroxycholesterol in both adipose tissues and with 24S-hydroxycholesterol in visceral tissue, where cholesterol correlation with 24S-hydroxycholesterol was higher than with 27-hydroxycholesterol. In addition, some tendencies were observed: serum high-density lipoprotein cholesterol tended to be inversely correlated with visceral adipose tissue cholesterol; high-sensitivity C-reactive protein tended to be correlated directly with subcutaneous adipose 24S-hydroxycholesterol and inversely with visceral 27-hydroxycholesterol. CONCLUSIONS: Adipose tissue oxysterols are associated with blood insulin and insulin resistance. Tissue cholesterol correlated more with 27-hydroxycholesterol in subcutaneous adipose tissue and with 24S-hydroxycholesterol in visceral adipose tissue. Levels of adipose 24S-hydroxycholesterol seem to be correlated with some metabolic syndrome symptoms and inflammation while adipose 27-hydroxycholesterol could represent some protection against them.

Triglyceride Metabolism Modifies Lipoprotein(a) Plasma Concentration.

BACKGROUND: Lipoprotein(a) (Lp(a)) is a significant cardiovascular risk factor. Knowing the mechanisms that regulate its concentration can facilitate the development of Lp(a)-lowering drugs. This study analyzes the relationship between triglycerides (TGs) and Lp(a) concentrations, cross-sectionally and longitudinally, and the influence of the number and composition of TG-rich lipoproteins, and the APOE genotype. METHODS: Data from Aragon Workers Health Study (AWHS) (n = 5467), National Health and Nutrition Examination Survey III phase 2 (n = 3860), and Hospital Universitario Miguel Servet (HUMS) (n = 2079) were used for cross-sectional TG and Lp(a) relationship. Lp(a) intrasubject variation was studied in AWHS participants and HUMS patients with repeated measurements. TG-rich lipoproteins were quantified by nuclear magnetic resonance in a subsample from AWHS. Apolipoproteins B and E were quantified by Luminex in very low-density lipoprotein (VLDL) isolated by ultracentrifugation, from HUMS samples. APOE genotyping was carried in AWHS and HUMS participants. Regression models adjusted for age and sex were used to study the association. RESULTS: The 3 studies showed an inverse relationship between TG and Lp(a). Increased VLDL number, size, and TG content were associated with significantly lower Lp(a). There was an inverse association between the apoE concentration in VLDL and Lp(a). No significant association was observed for apolipoprotein (apo)B. Subjects carrying the apoE2/E2 genotype had significantly lower levels of Lp(a). CONCLUSION: Our results show an inverse relationship Lp(a)-TG. Subjects with larger VLDL size have lower Lp(a), and lower values of Lp(a) were present in patients with apoE-rich VLDL and apoE2/E2 subjects. Our results suggest that bigger VLDLs and VLDLs enriched in apoE are inversely involved in Lp(a) plasma concentration.

Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH. METHODS: We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers' Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort. RESULTS: Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type-2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain. CONCLUSIONS: Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc.

Nursing workload. Calculation of cardiovascular risk and therapeutic objectives. / Carga de enfermedad. Cálculo del riesgo cardiovascular y objetivos terapéuticos.

Therapeutic intervention should be determined by the risk of developing atheromatous cardiovascular disease (CVD). The higher the risk, the more intense the action should be. This is the reason for the stratification of patient risk. In primary prevention, the two main guidelines used, the American Heart Association and the American College of Cardiology (ACC/AHA) use the Pooled cohort equations (PCE) and the guidelines of the European societies use the SCORE tables. The PCE calculates the risk of fatal and non-fatal CVD, and the SCORE calculates risk of fatal CVD only. In young people, it is useful to consider the lifetime risk calculation. The Spanish Society of Arteriosclerosis (SEA) recommends the SCORE system in Spain. SCORE and PCE calculate the risk for people up to 70 and 75 years of age. Prediction and potentials are available for 80 years of age and above, with the data available being much more scarce. Risk stratification in secondary prevention may be useful to identify the subgroup of patients who may benefit from more intensive treatment. Imaging tests, especially coronary calcium scans and vascular ultrasound, can help to better the profile risk. European guidelines identify LDL cholesterol as a therapeutic target. They recommend initiating treatment with statins, and increasing dose and potency until targets are achieved, and then to treatment with potent statins at a maximum tolerated dose, and ezetimibe if targets are not achieved. As a third step, PCSK9 inhibitors are indicated. They set very ambitious targets, as low as 40 mg/dL in those subjects with recurrences before two years of CVD despite high-intensity statin therapy, and below 55 mg/dL for all very high-risk subjects.

Cataract Surgery in Elderly Subjects with Heterozygous Familial Hypercholesterolemia in Prolonged Treatment with Statins.

BACKGROUND: Cataracts are the main cause of blindness and represent one fifth of visual problems worldwide. It is still unknown whether prolonged statin treatment favors the development of cataracts. We aimed to ascertain the prevalence of cataract surgery in elderly subjects with genetically diagnosed heterozygous familial hypercholesterolemia (HeFH) receiving statin treatment for ≥5 years, and compare this with controls. METHODS: This is an observational, multicenter, case-control study from five lipid clinics in Spain. We collected data with the following inclusion criteria: age ≥65 years, LDL cholesterol levels ≥220 mg/dL without lipid-lowering drugs, a pathogenic mutation in a candidate gene for HeFH (LDLR, APOB, or PCSK9) and statin treatment for ≥5 years. Controls were selected from relatives of HeFH patients without hypercholesterolemia. Linear and logistic regressions based on generalized linear models and generalized estimating equations (GEE) were used. Cataract surgery was used as a proxy for cataract development. RESULTS: We analyzed 205 subjects, 112 HeFH, and 93 controls, with a mean age of 71.8 (6.5) and 70.0 (7.3) years, respectively. HeFH subjects presented no difference in clinical characteristics, including smoking, hypertension, and type 2 diabetes mellitus, compared with controls. The mean duration of lipid-lowering treatment in HeFH was 22.5 (8.7) years. Cataract surgery prevalence was not significantly different between cases and controls. The presence of cataracts was associated neither with LDLc nor with the length of the statin therapy. CONCLUSION: In the present study, HeFH was not a risk factor for cataract surgery and prolonged statin treatment did not favor it either. These findings suggest that statin treatment is not related with cataracts.