Background Familial hypercholesterolemia (FH), the most frequent hereditary cause of premature coronary heart disease (CHD), is underdiagnosed and insufficiently treated. Objectives The objectives of ...the study were to estimate the prevalence of the FH phenotype (FH-P) and to describe its clinical characteristics in a Mediterranean population. Methods Data were obtained from the Catalan primary care system's clinical records database (Catalan acronym: SIDIAP). Patients aged >7 years with at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2,554,644) were included. Heterozygous FH-P and homozygous FH-P were defined by untreated low-density lipoprotein cholesterol plasma concentrations. The presence of cardiovascular diseases and risk factors was defined by coded medical records from primary care and hospital discharge databases. Results The age- and sex-standardized prevalence of heterozygous FH-P and homozygous FH-P were 1/192 individuals and 1/425,774 individuals, respectively. In the group aged 8 to 18 years, 0.46% (95% confidence interval: 0.41–0.52) had FH-P; overall prevalence was 0.58% (95% confidence interval: 0.58–0.60). Among patients with FH-P aged >18 years, cardiovascular disease prevalence was 3.5 times higher than in general population, and CHD prevalence in those aged 35 to 59 years was 4.5 times higher than in those without FH-P. Lipid-lowering therapy was lacking in 13.5% of patients with FH-P, and only 31.6% of men and 22.7 of women were receiving high or very high-intensity lipid-lowering therapy. Conclusion Prevalence of FH-P was higher than expected, but underdiagnosed and suboptimally treated, especially in women. Moreover, treatment started late considering the high CHD incidence associated with this condition.
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.
Patients with RA are at a higher risk of developing CV diseases than the general population. The precise mechanisms are still unknown. We evaluated the associations between 8 plasma growth factors ...(GFs) (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, and VEGFd) and subclinical arteriosclerosis in RA patients.
A total of 199 patients with RA treated at the Hospital Universitari Sant Joan de Reus (Spain) between 2011 and 2015 were included in this cross-sectional study. Carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV) were measured. GFs were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2 (Bio-Rad). Multivariate models and partial least square discriminant analysis (PLS-DA) were used for analysis (RStudio, version 4.0.1).
Multivariate models showed that angiopoietin-2 was associated with cPP and PWV in the overall cohort (OR = 1.53 and β = 0.20, respectively). VEGFc (β = 0.29), VEGFa (β = 0.26) and HB-EGF (β = 0.22) were also associated with PWV. VEGFa (OR = 2.36), VEGFd (OR = 2.29), EGF (OR = 2.62), PLGF (OR = 2.54), and HB-EGF (OR = 2.24) were associated with cPP in men. According to PLS-DA, GFs were able to distinguish between patients with and without cPP in the overall cohort, male cohort, and female cohort. In women, angiopoietin-2 was associated with PWV (β = 0.18).
The selected GFs were closely related to atherosclerosis in patients with RA and are potential predictors of CV disease in patients with RA.
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In the statin era, the incidence of atherosclerotic cardiovascular diseases (ASCVD) in patients with familial hypercholesterolemia (FH) has not been updated. We aimed to determine the incidence of ...ASCVD in patients with FH-phenotype (FH-P) and to compare it with that of normal low-density lipoprotein cholesterol (LDL-C) patients. We performed a retrospective cohort study using the Database of the Catalan primary care system, including ≥18-year-old patients with an LDL-C measurement. From 1,589,264 patients available before 2009, 12,823 fulfilled FH-P criteria and 514,176 patients were normolipidemic (LDL-C < 115 mg/dL). In primary prevention, patients with FH-P had incidences of ASCVD and coronary heart disease (CHD) of 14.9/1000 and 5.8/1000 person-years, respectively, compared to 7.1/1000 and 2.1/1000 person-years in the normolipidemic group. FH-P showed hazard ratio (HR) of 7.1 and 16.7 for ASCVD and CHD, respectively, in patients younger than 35 years. In secondary prevention, patients with FH-P had incidences of ASCVD and CHD of 89.7/1000 and 34.5/1000 person-years, respectively, compared to 90.9/1000 and 28.2/1000 person-years in the normolipidemic group (HR in patients younger than 35 years: 2.4 and 6.0). In the statin era, FH-P remains associated with high cardiovascular risk, compared with the normolipidemic population. This excess of risk is markedly high in young individuals.
Obesity and adipose tissue have been closely related to a poor cancer prognosis, especially in prostate and breast cancer patients. The ability of transferring lipids from the adipose tissue to the ...tumor cells is actively linked to tumor progression. However, different types of breast tumor seem to use these lipids in different ways and metabolize them in different pathways. In this study we have tracked by mass spectrometry how palmitic acid from the adipocytes is released to media being later incorporated in different breast cancer cell lines (MDA-MB-231, SKBR3, BT474, MCF-7 and its resistant MCF-7 EPIR and MCF-7 TAXR). We have observed that different lines metabolize the palmitic acid in a different way and use their carbons in the synthesis of different new lipid families. Furthermore, we have observed that the lipid synthesis pattern varied according to the cell line. Surprisingly, the metabolic pattern of the resistant cells was more related to the TNBC cell line compared to their sensitive cell line MCF-7. These results allow us to determine a specific lipid pattern in different cell lines that later might be used in breast cancer diagnosis and to find a better treatment according to the cancer molecular type.
Assessment of individual cardiovascular risk, distinguishing primary and secondary prevention, would improve the clinical management of the population with familial hypercholesterolemia. We aimed to ...develop and validate two risk functions to predict incident and recurrent atherosclerotic cardiovascular disease (ASCVD) in a primary care-based population with familial hypercholesterolemia phenotype (FHP), and to compare their predictive capacity with that of the SpAnish Familial hypErcHolEsterolemiA cohoRT (SAFEHEART) risk equation (SAFEHEART-RE).
Data from the Catalan primary care system database (SIDIAP) of patients ≥18 years old with FHP in 2006–2013 were used to develop and validate two risk functions to predict incident and recurrent ASCVD. A validation dataset was also used to compare the model predictive capacity to that of SAFEHEART-RE.
The new model (SIDIAP-FHP) included age, diabetes, smoking, sex (male), hypertension, and baseline low-density lipoprotein cholesterol in the primary prevention cohort and age, diabetes, smoking, and disease characteristics (progressive, recent, polyvascular, or included myocardial infarction) in the secondary prevention cohort.
The models demonstrated a fair fit: C-Statistic: 0.71 (95%CI:0.68–0.75) in primary prevention and 0.65 (95%CI:0.60–0.70) in secondary prevention (higher than that of SAFEHEART-RE: 0.64 95%CI:0.60–0.68 and 0.55 95%CI:0.51–0.59, respectively; both p < 0.01). The Brier scores obtained with the SIDIAP-FHP score were significantly lower than that obtained with SAFEHEART-RE in both the primary and secondary prevention cohorts.
The SIDIAP-FHP score provides accurate ASCVD risk estimates for primary and secondary prevention in the FHP population, with better predictive capacity than that of SAFEHEART-RE in this general population, especially in persons with previous ASCVD.
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•Familial hypercholesterolemia phenotype entails high risk of atherosclerotic events.•A patient-tailored assessment of risk may help achieve optimal treatment.•The SIDIAP-FHP score is useful in general population or primary care settings.•Clinicians may use the SIDIAP-FHP to prioritize referrals to lipids-clinic specialists.
Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene and characterized by high low-density ...lipoprotein-cholesterol (LDL-C) levels, which often are associated with low HDL-C levels (2). ...our findings in patients with FH, together with those found in hypercholesterolemic pigs (3), indicate that high LDL particle concentration is linked to dysfunctional HDL particles characterized by their altered remodeling and an impaired capacity to promote cholesterol removal from macrophages. The Student’s unpaired t-test was used to compare differences between groups.ac-LDL = acetylated low-density lipoprotein; apo = apolipoprotein; cAMP = cyclic adenosine monophosphate; CETP = cholesteryl ester transfer protein; FH = familial hypercholesterolemia; HDL = high-density lipoprotein; LCAT = lecithin-cholesterol acyltransferase; LDL = low-density lipoprotein; PLTP = phospholipid transfer protein.
Abstract
Aims
The retrospective NEPTUNO study evaluated the effectiveness of the Centro Nacional de Investigaciones Cardiovasculares (CNIC)-polypill (including acetylsalicylic acid, ramipril, and ...atorvastatin) vs. other therapeutic approaches in secondary prevention for cardiovascular (CV) disease. In this substudy, the focus was on the subgroup of patients with ischaemic heart disease (IHD).
Methods and results
Patients on four strategies: CNIC-polypill, its monocomponents as loose medications, equipotent medications, and other therapies. The primary endpoint was the incidence of recurrent major adverse CV events (MACEs) after 2 years. After matching, 1080 patients were included in each cohort. The CNIC-polypill cohort had a significantly lower incidence of recurrent MACE compared with monocomponents, equipotent drugs, and other therapies cohorts (16.1 vs. 24, 24.4, and 24.3%, respectively; P < 0.001). The hazard ratios (HRs) for recurrent MACE were higher in monocomponents (HR = 1.12; P = 0.042), equipotent drugs (HR = 1.14; P = 0.031), and other therapies cohorts (HR = 1.17; P = 0.016) compared with the CNIC-polypill, with a number needed to treat of 12 patients to prevent a MACE. The CNIC-polypill demonstrated a greater reduction in LDL cholesterol (LDL-c; −56.1 vs. −43.6, −33.3, and −33.2% in the monocomponents, equipotent drugs, and other therapies, respectively; P < 0.001) and systolic blood pressure (−13.7 vs. −11.5, −10.6, and −9.1% in the CNIC-polypill, monocomponents, equipotent drugs, and other therapies, respectively; P < 0.001) compared with other cohorts. The CNIC-polypill intervention was less costly and more effective than any other therapeutic option, with €2317–€2407 cost savings per event prevented.
Conclusion
In IHD, the CNIC-polypill exemplifies a guideline-recommended secondary prevention treatment linked to better outcomes and cost saving compared with other therapeutic options.
Graphical Abstract
Graphical Abstract
While the impact of very low concentrations of low–density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low ...LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL-LDL receptor (LDLR) activity reveal no safety issues. Patients achieving extremely low LDL levels in the IMPROVE-IT and FOURIER, and the PROFICIO and ODYSSEY programs seem not to have an increased prevalence of adverse effects. The main concern regarding extremely low LDL-C plasma concentrations is the adequacy of the supply of cholesterol, and other molecules, to peripheral tissues. However, LDL proteomic and kinetic studies reaffirm that LDL is the final product of endogenous lipoprotein metabolism. Four of 5 LDL particles are cleared through the LDL-LDLR pathway in the liver. Given that mammalian cells have no enzymatic systems to degrade cholesterol, the LDL-LDLR pathway is the main mechanism for removal of cholesterol from the body. Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that extremely low LDL-C levels due to increased LDLR activity may be a surrogate of adequate LDL-LDLR pathway function.
•Many patients on proprotein convertase subtilisin/kexin type 9 inhibitors achieve extremely low low-density lipoprotein cholesterol (LDL-C) levels.•Extremely low LDL-C levels are associated with even less cardiovascular risk.•Extremely low LDL-C concentrations cause no clinically relevant side effects.•Low LDL-C levels due to higher clearance are a marker of adequate LDL–LDLreceptor function.
The U.S. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults recommendations (1) have had a huge impact on the treatment of ...hypercholesterolemia around the world and have had a decisive influence on all recommendations worldwide. ...the recommendations were based on lowering low-density lipoprotein cholesterol (LDL-C) as the treatment goal.
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