Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297). METHODS: MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH. RESULTS: Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66-.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74-.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality. CONCLUSIONS: Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Sex differences in the perception of cardiovascular risk in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH), a common genetic condition, is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Recent data indicate an undertreatment of females with FH. OBJECTIVE: To characterize the role of sex in the perception of FH, its associated ASCVD risk and treatment. METHODS: A survey investigating for sex differences in the perception of FH was sent to 1073 patients with FH using a cross sectional study design. RESULTS: A total of 412 patients (51.9 % male) responded to the survey; mean age was 56.2 ± 14.4 years. There was a higher proportion of males with ASCVD than females (41.5 % vs. 16.5 %, respectively, p<0.001). Analyses of the survey responses showed that a majority of both males and females agreed that their risk of ASCVD is higher than healthy individuals of same age (70.8 % vs. 74.7 %, respectively, p = 0.434). Females were more concerned about having high LDL-C levels (67.5 % vs. 56.5 % in males, p = 0.024), especially those in secondary prevention programs. As for treatment of FH, approximately 75 % of both sex groups considered statins to be efficient in reducing the risk of myocardial infarction, but less than half of the females considered statins to be safe (44.8 % vs. 60.0 % in males, p = 0.003). No major sex differences were noted regarding the influence of the doctor in their understanding of FH as a disease. CONCLUSION: Overall, both males and females with FH were well informed about FH, although females were more concerned about having high LDL-C levels and they feared the safety of statins.

Genetic testing for familial hypercholesterolemia in Quebec, Canada: a single-centre retrospective cohort study.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. METHODS: We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the LDLR, APOB and PCSK9 genes, and multiplex ligation-dependent probe amplification of the LDLR gene to detect genetic variants, were performed. RESULTS: Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the LDLR (146 [86.4%]) or APOB (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. INTERPRETATION: Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. Trial registration: ClinicalTrials.gov, no. NCT02009345.

Docetaxel as a Model Compound to Promote HDL (High-Density Lipoprotein) Biogenesis and Reduce Atherosclerosis.

The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.

Biomedical Advances in ABCA1 Transporter: From Bench to Bedside.

ATP-binding cassette transporter A1 (ABCA1) has been identified as the molecular defect in Tangier disease. It is biochemically characterized by absence of high-density lipoprotein cholesterol (HDL-C) in the circulation, resulting in the accumulation of cholesterol in lymphoid tissues. Accumulation of cholesterol in arteries is an underlying cause of atherosclerosis, and HDL-C levels are inversely associated with the presence of atherosclerotic cardiovascular disease (ASCVD). ABCA1 increases HDL-C levels by driving the generation of new HDL particles in cells, and cellular cholesterol is removed in the process of HDL generation. Therefore, pharmacological strategies that promote the HDL biogenic process by increasing ABCA1 expression and activity have been intensively studied to reduce ASCVD. Many ABCA1-upregulating agents have been developed, and some have shown promising effects in pre-clinical studies, but no clinical trials have met success yet. ABCA1 has long been an attractive drug target, but the failed clinical trials have indicated the difficulty of therapeutic upregulation of ABCA1, as well as driving us to: improve our understanding of the ABCA1 regulatory system; to develop more specific and sophisticated strategies to upregulate ABCA1 expression; and to search for novel druggable targets in the ABCA1-dependent HDL biogenic process. In this review, we discuss the beginning, recent advances, challenges and future directions in ABCA1 research aimed at developing ABCA1-directed therapies for ASCVD.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH. Objectives: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time. Methods: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network. Results: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement. Conclusions: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.

Aortic stenosis in homozygous familial hypercholesterolaemia: a paradigm shift over a century.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565). METHODS AND RESULTS: MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted. CONCLUSION: These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

Health-related quality of life in homozygous familial hypercholesterolemia: A systematic review and meta-analysis.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by extreme elevations of low-density lipoprotein cholesterol (LDL-C) and extremely premature atherosclerotic cardiovascular disease. To date, impacts of HoFH and its treatment on the psychosocial wellbeing of patients have been poorly characterized. OBJECTIVES: We performed a systematic review of the association between HoFH and health-related quality of life (HRQL). METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) consensus guidelines. We searched MEDLINE, Embase, The Cochrane Controlled Register of Trials (CENTRAL), Pubmed, Scopus, AfricaWide (via EBSCO), and six trial registries and grey-literature databases from inception to May 2021 for published English-language literature examining HRQL and its determinants in HoFH. Studies were eligible if they included patients with confirmed HoFH and evaluated HRQL using validated tools. We performed a narrative synthesis of qualitative findings from included studies and, where data permitted, random-effects meta-analysis reporting standardized mean differences (SMD) and 95% confidence intervals (CIs). RESULTS: Our review identified seven eligible studies examining HRQL in HoFH participants. Pooling data from two included studies, we found that relative to the general population, HoFH patients demonstrated significantly poorer HRQL in multiple dimensions of the 36-item Short-Form Health Survey (SF-36) with lower scores in physical functioning (SMD -0.37; 95% CI: -0.60, -0.15), role limitations due to physical health (SMD -0.63; 95% CI: -1.24, -0.02), social functioning (SMD -0.61; 95% CI: -1.19, -0.03), bodily pain (SMD -0.24; 95% CI: -0.46, -0.01), and general health (SMD -1.55; 95% CI: -1.80, -1.31). No differences were observed in domains of energy and vitality, mental health and emotional well-being, or role limitations due to emotional problems. Patients suffered high treatment burdens related to lipoprotein apheresis that compromised educational attainment and employment. However, few patients received psychological support in navigating their treatment challenges. No studies evaluated the association of HoFH with incident anxiety, depression, or other psychopathology. CONCLUSIONS: Limited data are available on quality of life for patients with HoFH. The available data suggest that these patients may suffer disease-related impairments in quality of life. Future work should aim to elucidate relationships between HoFH and mental health outcomes and develop interventions to improve quality of life in this population.

Major adverse cardiovascular events in homozygous familial hypercholesterolaemia: a systematic review and meta-analysis.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease and death. Due to its rarity, accurate assessment of cardiovascular outcomes associated with HoFH and how they have changed over time has been challenging. The goal of this study was to assess the prevalence and age-of-onset of major adverse cardiovascular events (MACE) among patients with HoFH. METHODS AND RESULTS: We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Scopus, Africa-Wide, Google Scholar, Open Grey, and various clinical trial registries from inception to February 2020 to identify studies reporting on MACE in HoFH patients. We determined the pooled prevalence and mean age-of-onset of MACE outcomes individually using a random effects inverse variance model. We identified 94 studies that met our eligibility criteria. Myocardial infarction and coronary revascularization were common with a prevalence of 15.1% [95% confidence interval (95% CI) 10.7-20.0] and 28.3% (95% CI 22.5-34.3), respectively. The mean age-of-onset was 24.5 (95% CI 19.2-29.8) years for myocardial infarction and 32.2 (95% CI 26.6-37.8) years for revascularization. Sub-group analyses based on the year of publication revealed significant delays in the onset of MACE outcomes post-1990 compared to pre-1990. Egger's regression suggested possible bias, likely due to small study effects. CONCLUSIONS: Atherosclerotic cardiovascular disease is common among HoFH patients and occurs at a young age. Age-of-onset of myocardial infarction was delayed by more than a decade from pre-1990 to post-1990, likely attributable to widespread use of statins and other therapies, reflecting substantial progress in the management of this rare but severe disorder.

Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.

BACKGROUND: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS: A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS: There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION: The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

Identification of Docetaxel as a Potential Drug to Promote HDL Biogenesis.

Objective: Our recent studies showed that desmocollin 1 (DSC1) binds to apoA-I in order to inhibit apoA-I-mediated high density lipoprotein (HDL) biogenesis in atherosclerotic plaques. To promote HDL biogenesis in the plaque, here we search for small molecules that block apoA-I-DSC1 interactions. Approach and Results: We combined mutational and computational mapping methods to show that amino acid residues 442-539 in the mature DSC1 protein form an apoA-I binding site (AIBS). Using a crystal structure of the AIBS, we carried out virtual screening of 10 million small molecules to estimate their binding affinities to the AIBS, followed by the selection of 51 high-affinity binding molecules as potential inhibitors of apoA-I-DSC1 interactions. Among the 51, the chemotherapy drug docetaxel showed the highest potency in promoting apoA-I-mediated HDL biogenesis in primary human skin fibroblasts with the half-maximal effective concentration of 0.72 nM. In silico docking studies suggest that the taxane ring in docetaxel binds to the AIBS and that the carbon-13 sidechain of the taxane tightens/stabilizes the binding. The HDL biogenic effect of docetaxel was also observed in two predominant cell types in atherosclerosis, macrophages and smooth muscle cells. Importantly, docetaxel promoted HDL biogenesis at concentrations much lower than those required for inducing cytotoxicity. Conclusion: Determination of the AIBS in DSC1 and AIBS structure-based virtual screening allowed us to identify docetaxel as a strong HDL biogenic agent. With the remarkable potency in promoting HDL biogenesis, a chemotherapy drug docetaxel may be repurposed to enhance atheroprotective HDL functions.

Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages.

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1-/-Apoe-/-). After 21 weeks of atherogenic diet, Dj1-/- Apoe-/-mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

New Strategies to Promote Macrophage Cholesterol Efflux.

The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.

Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH. METHODS: This is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec. RESULTS: Mean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment. CONCLUSIONS: Lomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.

The Lifelong Burden of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor gene. It is diagnosed in children or youth who present with extensive tendinous and cutaneous xanthomas and extreme elevation of low-density lipoprotein cholesterol. Untreated, premature coronary artery disease develops in the teenage years or earlier and survival to ages older than 30 years is rare. Herein we describe the clinical course of a patient with homozygous familial hypercholesterolemia treated according to the standards of care and experimental approaches. Despite aggressive therapies, atherosclerosis in all vascular beds progressed, leading to the patient's demise at age 59 years, highlighting the importance of early diagnosis and appropriate follow-up.

Genetic testing for familial hypercholesterolemia: Impact on diagnosis, treatment and cardiovascular risk.

AIMS: Familial hypercholesterolemia (FH) is the most common genetic disorder in medicine, with a prevalence of 1/250. Affected individuals have elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and, more recently, genetic testing. We sought to determine the impact of genetic testing on the: 1) diagnosis of 'definite familial hypercholesterolemia', 2) initiation and adherence of lipid-lowering therapy and 3) risk of ASCVD. METHODS: We performed a systematic review and meta-analysis, pooling odds ratios and 95% confidence intervals for ASCVD from studies comparing risk estimates in individuals harboring FH-causing variants and unaffected individuals. RESULTS: After screening 3304 unique publications, 56 studies were included in the analysis. 1) Genetic testing provided confirmation of FH in 28-80%, over clinical criteria alone, depending on the diagnostic algorithm and the method of analysis. In two large population-based studies comprising 76,751 individuals, an FH-causing variant was identified in only 1.7-2.5% of subjects with an LDL-C > 4.9 mmol/L (190 mg/dL). 2) A confirmed molecular diagnosis increased lipid-lowering therapy adherence (five studies, n = 4181 definite FH). 3) Loss-of-function variant of the LDLR were at a markedly increased risk of myocardial infarction (odds ratio 6.77, 95% confidence interval 4.75-9.66), and patients with a milder (hypomorphic) pathogenic LDLR change had a 4.4-fold increase in risk (odds ratio 4.4, 95% confidence interval 2.34-8.26), compared with controls. CONCLUSION: DNA sequencing confirms the diagnosis of FH but has a poor yield in unselected patients whose sole criterion is an elevated LDL-C. Initiation and adherence to treatment is improved. The risk of ASCVD is 4.4- to 6.8-fold increased in patients with an FH-causing variant compared with controls, depending on the severity of the DNA change.

Prediction of Familial Hypercholesterolemia in Patients at High Atherosclerotic Cardiovascular Disease Risk Using a Recently Validated Algorithm.

BACKGROUND: The prevalence of heterozygous familial hypercholesterolemia (FH) is 1 of 250 in the general population and approximately 1 of 125 in patients with atherosclerotic cardiovascular disease (ASCVD), yet only a minority are diagnosed. The diagnostic criteria for FH rely on a point system using low-density lipoprotein cholesterol (LDL-C), family history, cutaneous manifestations, and molecular diagnosis. The aim of the present study was to determine the prevalence of FH in the Relating Evidence to Achieve Cholesterol Targets (REACT) registry. METHODS: Patients were enrolled as ASCVD (n = 86) or FH (n = 109) and with an LDL-C level > 3.0 mmol/L despite maximally tolerated statin therapy. FH was diagnosed clinically using a validated clinical application integrating an imputation for baseline (untreated) LDL-C levels. RESULTS: There were 109 men and 86 women with a mean age of 63 ± 12 years. Diabetes (29.7%), hypertension (62.1%), smoking (37.9%), and family history of premature ASCVD (59.5%) were common. On-treatment LDL-C was 4.26 ± 0.94 mmol/L. On the basis of the dose and type of statin ± ezetimibe, imputed baseline LDL-C was 7.04 ± 2.90 mmol/L. A diagnosis of probable/definite FH was found in 54.7%, 49.5%, and 61.5% of patients according to the Simon Broome, Dutch Lipid Clinic Network criteria, and the new Canadian FH definition, respectively. Of note, 40% of patients in the ASCVD inclusion subgroup had probable or definite FH. CONCLUSIONS: Our study reveals that a substantial proportion of patients with ASCVD whose LDL-C levels are > 3.0 mmol/L despite maximally tolerated statins have heterozygous FH. Clinicians should consider using the recently described algorithm to assess the possibility of FH in this high-risk population.

CONTEXTE: La prévalence de l'hypercholestérolémie familiale (HF) hétérozygote est de 1 cas sur 250 dans la population générale et d'environ 1 cas sur 125 chez les patients atteints d'une maladie cardiovasculaire athérosclérotique (MCVAS), pourtant on ne la diagnostique que dans une minorité de cas. Les critères diagnostiques de l'HF reposent sur un système de points utilisant comme paramètres le cholestérol à lipoprotéines de faible densité (C-LDL), les antécédents familiaux, les manifestations cutanées et le diagnostic moléculaire. La présente étude visait à déterminer la prévalence de l'HF parmi les patients répertoriés dans le registre REACT (Relating Evidence to Achieve Cholesterol Targets). MÉTHODOLOGIE: Les patients admis à l'étude étaient considérés comme étant atteints d'une MCVAS (n = 86) ou d'une HF (n = 109) et présentaient un taux de C-LDL > 3,0 mmol/l malgré la prise d'un traitement par statine à la dose maximale tolérée. L'HF a été diagnostiquée sur le plan clinique à l'aide d'une application clinique validée incluant une imputation des taux de C-LDL initiaux (en l'absence de traitement). RÉSULTATS: L'étude comptait 86 femmes et 109 hommes âgés en moyenne de 63 ± 12 ans. Le diabète (29,7 %), l'hypertension (62,1 %), le tabagisme (37,9 %) et les antécédents familiaux de MCVAS prématurée (59,5 %) étaient fréquents. Sous traitement, le taux de C-LDL était de 4,26 ± 0,94 mmol/l. D'après la dose et le type de statine ± ézétimibe administrés, le taux de C-LDL imputé au départ était de 7,04 ± 2,90 mmol/l. Un diagnostic d'HF probable ou certaine a été établi respectivement chez 54,7 %, 49,5 % et 61,5 % des patients selon les critères de Simon Broome et du Dutch Lipid Clinic Network, ainsi que la nouvelle définition canadienne de l'HF. Notons que 40 % des patients dans le sous-groupe d'inclusion de la MCVAS présentaient une HF probable ou certaine. CONCLUSIONS: Notre étude révèle qu'une proportion importante de patients atteints de MCVAS dont les taux de C-LDL sont > 3,0 mmol/l malgré la prise de statines à la dose maximale tolérée présentent une HF hétérozygote. Les cliniciens devraient envisager d'utiliser l'algorithme récemment décrit pour évaluer la présence possible d'une HF dans cette population à haut risque.