Comparison of the burden of familial hypercholesterolemia between two cohorts of French Canadians hospitalized 25 years apart for coronary heart disease.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with lifelong elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). Clinical recommendations and treatments have emerged to facilitate the management of FH patients. Their impact on the burden of FH is however not well documented. OBJECTIVE: To compare the burden of FH between patients hospitalized for a CHD event 25 years apart in the French-Canadian founder population. METHODS: Lipid profiles, cardiovascular risk factors, treatments and FH status of 2,029 patients consecutively hospitalized for an acute CHD event between 2017 and 2022 (2022 Cohort) were compared to those of 2,506 patients with angiographically-confirmed CHD who were admitted between 1995 and 1998 (1998 Cohort). RESULTS: At the time of admission, 24.6 % of CHD patients had LDL-C levels >5.0 mmol/L in 1998 compared to 1.4 % in 2022, and FH was diagnosed in 9.6 % of patients in the 1998 cohort compared to 5.5 % in 2022 (p<0.001). FH patients hospitalized for a CHD event were older in 2022 than in 1998 (p <0.001). The prevalence of premature CHD requiring a hospitalization significantly decreased from 1998 to 2022 (64.3% vs. 44.1 %, p<0.001). At the moment of admission, 18.2 % of FH patients had LDL-C concentration <2.0 mmol/L in 2022 vs 0 % in 1998 (p <0.001). CONCLUSIONS: Over 25 years, FH patients tend to be older and contribute to a lower proportion of hospitalizations for CHD in the French-Canadian founder population. Despite significant improvement in diagnosis and treatment, FH management remains however sub-optimal.

Identifying Markers of Cardiovascular Event-Free Survival in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with increased risk of premature atherosclerotic cardiovascular disease (CVD). However, in some cases, FH subjects over 70 years of age have surprisingly never experienced any CVD symptoms throughout their entire lives. The objective of this study consists of identifying biological and environmental markers acting as cardioprotective factors and associated with unexpected survival in FH. Upon age and reported cardiovascular events (CVE) stratification, we identified a total of 458 French-Canadian FH subjects with premature reported CVE, and 1297 young adults as well as 24 elderly subjects (≥70 years) who have never reported CVE requiring hospitalization. Logistic regression models were used to depict cardioprotective markers among FH survivors (≥70 years). Regression analyses of the FH cohort showed that female sex (odds ratio (OR) = 12.92 (4.23-39.46); p < 0.0001), high levels of high-density lipoprotein (HDL)-C (OR = 6.76 (2.43-18.79); p = 0.0002) and elevated concentrations of adiponectin (OR = 71.40 (5.20-980.47); p = 0.001) were significant contributory factors in reducing FH-related CVD risk. Notably, female (OR = 11.45 (1.25-105.98); p = 0.031) and high HDL-C (OR = 9.78 (1.75-54.67); p = 0.009) were shown to be significant covariates associated with survival in FH. Non-smoking (OR = 11.73 (4.36-31.56); p < 0.0001) was also identified as an environmental factor associated with CVE-free survival. Based on this configured model of premature CVE occurrence, these results demonstrated that, beyond LDL-C levels, female sex, high HDL-C, elevated adiponectin and non-smoking are important markers that contribute to a reduced risk of CVD and CVE-free survival in FH.

Association of common gene-smoking interactions with elevated plasma apolipoprotein B concentration.

BACKGROUND: Increased apolipoprotein (apo) B level (hyperapoB) is a strong predictor of cardiovascular disease (CVD), even in patients who achieve recommended LDL-Cholesterol (LDL-C) goals. ApoB level, an important correlate of metabolic syndrome (MetS), is influenced by several gene-environment interactions. Some of them are rare and can explain a large proportion of apoB variance, whereas others more common have variable effects. The aim of this study was to evaluate the association of interaction between smoking and common hyperapoB gene variants (PPARα-L162V, lipoprotein lipase loss-of function mutation, apo e4 allele or apo E2/2 genotype) with plasma apoB concentrations, according to the expression of MetS. METHODS: This study was performed among 1798 subjects. Smoking was defined as non/mild smokers vs. moderate-to-heavy smokers. ApoB levels were determined using nephelometry. Logistic regression models were used to document interactions between smoking habits and the presence of hyperapoB gene variants on the relative odds to exhibit increased plasma apoB concentrations. RESULTS: Around 29% of individuals with a low-risk lipid profile without MetS component had hyperapoB. Smoking and the presence of hyperapoB gene variants tended to be associated with higher plasma apoB levels even in presence of low-LDL-C. There was a significant interaction (P = 0.04) between the presence of ≥1 gene variants and smoking on the risk to exhibit hyperapoB among subjects with low risk profile in primary prevention. CONCLUSIONS: Combination of life habits assessment and some common genes variants may detect a significant proportion of patients with increased apoB levels, and therefore a higher risk of CVD, who could have been initially perceived as low-risk.

Review of the long-term safety of lomitapide: a microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia.

INTRODUCTION: Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening lipid disorder characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) concentrations and premature atherosclerotic cardiovascular disease (CVD). Conventional lipid-lowering agents remain insufficient in managing this disease, which emphasize the unmet medical need for potential therapies capable of lowering LDL-C and decreasing CVD risk in this patient population. AREAS COVERED: Novel LDL receptor (LDLR) independent drugs have been recently approved or are in development for the treatment of HoFH, including lomitapide (Juxtapid®). This oral microsomal triglyceride transfer protein (MTP) inhibitor was approved in 2012 in several countries as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to treat patients with HoFH. This review summarizes key safety and efficacy data of lomitapide from clinical trials and 'real-life' experience. EXPERT OPINION: While lomitapide is an interesting therapy for treating HoFH, long-term safety, as well as cardiovascular outcome data, are yet to be provided. Precision medicine has recently contributed to the development of several agents designed to address the unmet medical need of HoFH. However, combining safety, efficacy, accessibility, and affordability in a single therapy constitutes very challenging individual and societal paradigms in HoFH treatment.

Angiographically-assessed coronary artery disease associates with HDL particle size in women.

UNLABELLED: It has been suggested that a reduced HDL particle size could be another feature of the atherogenic dyslipidemia found among viscerally obese subjects. OBJECTIVE: To investigate, in women, the relationship between HDL particle size and coronary artery disease (CAD). METHODS: Average HDL particle size was measured in a sample of 239 women on whom CAD was assessed by angiography. RESULTS: Overall, women who had CAD were characterized by a deteriorated fasting metabolic risk profile, which was accompanied by smaller HDL particles compared to women without CAD (80.4 ± 2.2 Å vs. 81.5 ± 2.7 Å, p < 0.01). In addition, a reduced HDL particle size was a significant correlate of several features of the atherogenic metabolic profile of abdominal obesity such as increased triglyceride and apolipoprotein B concentrations, decreased HDL cholesterol levels, an elevated cholesterol/HDL cholesterol ratio and hyperinsulinemia and was also associated with an increased waist circumference (0.13≤|r|≤0.21, p < 0.05). Odds ratio of being affected by CAD was increased by 2.5-fold (95% CI: 1.4-4.5; p < 0.01) among women with smaller HDL particles compared to women with larger HDL particles. Finally, women characterized by the presence of the NCEP-ATP III clinical criteria or by hypertriglyceridemic waist were characterized by smaller HDL particles compared to women without these clinical phenotypes (p < 0.05). CONCLUSION: HDL particle size appears to be another relevant feature of a dysmetabolic state which is related to CAD risk in women.

Hypertriglyceridemic waist: a simple clinical phenotype associated with coronary artery disease in women.

The aim of the present study was to compare the ability of the hypertriglyceridemic waist phenotype and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) clinical criteria to predict coronary artery disease (CAD) risk in a sample of women. We studied 254 women among whom the presence/absence of CAD was assessed by angiography. The hypertriglyceridemic waist phenotype was defined as having both a high waist circumference (≥85 cm) and increased fasting triglyceride levels (≥1.5 mmol/L), whereas the presence of at least 3 of the 5 NCEP-ATP III criteria was used as the "reference" screening approach to identify women with the features of the metabolic syndrome. Women with hypertriglyceridemic waist were characterized by higher adiposity indices as well as by a more disturbed fasting metabolic risk profile compared with women without this phenotype. Similar differences were observed when comparing the metabolic profile of women with vs without at least 3 of the NCEP-ATP III clinical criteria. Moreover, differences in the Framingham risk score were essentially similar when women were considered at low or high risk by either hypertriglyceridemic waist or by NCEP-ATP III clinical criteria (P < .0001). Finally, both clinical phenotypes were predictive of CAD (hypertriglyceridemic waist: relative odds ratio, 2.1; 95% confidence interval, 1.1-3.8; P = .02; NCEP-ATP III clinical criteria: relative odds ratio, 2.5; 95% confidence interval, 1.4-4.6; P < .003). These results suggest that hypertriglyceridemic waist is a simple screening tool to identify women with clustering metabolic abnormalities and at increased CAD risk.

Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms. SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies. RESULTS: A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant. CONCLUSIONS: In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms. CLINICAL TRIAL REGISTRATION NUMBER: NCT00367835.

Low plasma adiponectin exacerbates the risk of premature coronary artery disease in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterized by increased risk for premature coronary artery disease (CAD). This risk is exacerbated in the presence of abdominal obesity and insulin resistance. Low adiponectin is part of the clustering of metabolic abnormalities associated with abdominal obesity and insulin resistance. The present study, therefore, aims to examine the relationship between plasma adiponectin and age at CAD diagnosis in FH patients. Plasma adiponectin was measured by ELISA in 568 non-diabetic FH individuals of French-Canadian origin. CAD was defined according to strict clinical criteria. Prior to analyses, patients were grouped according to age and gender-specific tertiles of plasma adiponectin levels. Multivariate Cox proportional hazards regression was used to estimate the association between plasma adiponectin levels and age at diagnosis of CAD. Overall, FH patients in the lowest tertile of plasma adiponectin exhibited CAD at a significantly younger age (hazard ratio=1.73, confidence interval 95%: [1.19-2.53]; p=0.004). These results suggest that low plasma adiponectin is associated with an increased risk of premature CAD over and above the already exaggerated risk seen in FH patients.

Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population.

Susceptibility to coronary heart disease (CHD) has long been known to exhibit familial aggregation, with heritability estimated to be greater than 50%. The French Canadian population of the Saguenay-Lac Saint-Jean region of Quebec, Canada is descended from a founder population that settled this region 300-400 years ago and this may provide increased power to detect genes contributing to complex traits such as CHD. Probands with early-onset CHD, defined by angiographically determined coronary stenosis, and their relatives were recruited from this population (average sibship size of 6.4). Linkage analysis was performed following a genome-wide microsatellite marker scan on 42 families with 284 individuals. Nonparametric linkage (NPL) analysis provided suggestive evidence for a CHD susceptibility locus on chromosome 8 with an NPL score of 3.14 (P=0.001) at D8S1106. Linkage to this locus was verified by fine mapping in an enlarged sample of 50 families with 320 individuals. This analysis provided evidence of linkage at D8S552 (NPL score=3.53, P=0.0003), a marker that maps to the same location as D8S1106. Candidate genes in this region, including macrophage scavenger receptor 1, farnesyl-diphosphate farnesyltransferase 1, fibrinogen-like 1, and GATA-binding protein 4, were resequenced in all coding exons in both affected and unaffected individuals. Association studies with variants in these and five other genes did not identify a disease-associated mutation. In conclusion, a genome-wide scan and additional fine mapping provide evidence for a locus on chromosome 8 that contributes to CHD in a French Canadian population.

Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.

Coronary artery disease (CAD) is a major health concern in both developed and developing countries. With a heritability estimated at ~50%, there is a strong rationale to better define the genetic contribution to CAD. This project involves the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 case and control subjects from the Saguenay Lac St-Jean region of northeastern Quebec, with the use of 1,536 single-nucleotide polymorphisms (SNPs) in 103 candidate genes for CAD. By use of clusters of SNPs to generate multiallelic haplotypes at candidate loci for segregation studies within families, suggestive linkage for high-density lipoprotein (HDL) cholesterol is observed on chromosome 1p36.22. Furthermore, several associations that remain significant after Bonferroni correction are observed with lipoprotein-related traits as well as plasma concentrations of adiponectin. Of note, HDL cholesterol levels are associated with an amino acid substitution (lysine/asparagine) at codon 198 (rs5370) of endothelin-1 (EDN1) in a sex-specific manner, as well as with a SNP (rs2292318) located 7.7 kb upstream of lecithin cholesterol acyl-transferase (LCAT). Whereas the other observed associations are described in the current literature, these two are new. Using an independent validation sample of 806 individuals, we confirm the EDN1 association (P<.005), whereas the LCAT association was nonsignificant (P=.12).

Contribution of abdominal obesity and hypertriglyceridemia to impaired fasting glucose and coronary artery disease.

Multiple logistic regression models were used in a cross-sectional study to determine the relation of fasting glycemia to angiographically assessed coronary artery disease (CAD) in 569 men (aged 18 to 69 years) who were stratified according to fasting blood glucose concentrations (<6.1 mmol/L, and 6.1 to 6.9 mmol/L or 110 to 124 mg/dl), waist circumference (<90 vs >or=90 cm), and fasting triglyceridemia (<2.0 vs >or=2.0 mmol/L or <177 vs >or=177 mg/dl). For this purpose, nondiabetic impaired fasting glucose was defined as from 6.1 to 6.9 mmol/L (110 to 124 mg/dl) compared with 250 normoglycemic controls (fasting glycemia <6.1 mmol/L or <124 mg/dl) without history of CAD. In the absence of "hypertriglyceridemic waist," impaired fasting glucose was not predictive of CAD. However, the risk of CAD was markedly higher among subjects characterized by both the hypertriglyceridemic waist phenotype and the presence of impaired fasting glucose (odds ratio 8.5, 95% confidence intervals 3.5 to 20.4; p <0.05) compared with the normoglycemic group with low waist circumferences and triglyceride levels. Thus, the results of the present study emphasizes the importance of other underlying metabolic abnormalities, such as abdominal obesity and related atherogenic dyslipidemia, in the modulation of the CAD risk associated with hyperglycemia.

A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients.

OBJECTIVE: The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. METHODS: For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45+/-1.18 (S.D.) mmol/l; LDL cholesterol, 5.57+/-1.16 mmol/l; triglycerides (TGs), 1.66+/-0.43 mmol/l) were randomized to either fenofibrate (n=36) or pravastatin (n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2-16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. RESULTS: Whereas significant improvements in the plasma lipoprotein-lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11+/-5.18 A, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size (r=-0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 A) was reduced from 69.4 to 30.6% (P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. CONCLUSION: As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.