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 is 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 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.

Significance of the Wnt signaling pathway in coronary artery atherosclerosis.

Introduction: The progression of coronary atherosclerosis is an active and regulated process. The Wnt signaling pathway is thought to play an active role in the pathogenesis of several cardiovascular diseases; however, a better understanding of this system in atherosclerosis is yet to be unraveled. Methods: In this study, real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting were used to quantify the expression of Wnt3a, Wnt5a, and Wnt5b in the human coronary plaque, and immunohistochemistry was used to identify sites of local expression. To determine the pathologic significance of increased Wnt, human vascular smooth muscle cells (vSMCs) were treated with Wnt3a, Wnt5a, and Wnt5b recombinant proteins and assessed for changes in cell differentiation and function. Results: RT-PCR and Western blotting showed a significant increase in the expression of Wnt3a, Wnt5a, Wnt5b, and their receptors in diseased coronary arteries compared with that in non-diseased coronary arteries. Immunohistochemistry revealed an abundant expression of Wnt3a and Wnt5b in diseased coronary arteries, which contrasted with little or no signals in normal coronary arteries. Immunostaining of Wnt3a and Wnt5b was found largely in inflammatory cells and myointimal cells. The treatment of vSMCs with Wnt3a, Wnt5a, and Wnt5b resulted in increased vSMC differentiation, migration, calcification, oxidative stress, and impaired cholesterol handling. Conclusions: This study demonstrates the upregulation of three important members of canonical and non-canonical Wnt signaling pathways and their receptors in coronary atherosclerosis and shows an important role for these molecules in plaque development through increased cellular remodeling and impaired cholesterol handling.

Meta-Analysis of Randomized Trials: Efficacy and Safety of Colchicine for Secondary Prevention of Cardiovascular Disease.

Background: Colchicine has shown potential cardioprotective effects owing to its broad anti-inflammatory properties. We performed a meta-analysis to assess its safety and efficacy in secondary prevention in patients with established coronary artery disease (CAD). Methods: We searched Ovid Healthstar, MEDLINE, and Embase (inception to May 2022) for randomized controlled trials (RCTs) evaluating the cardiovascular effects of colchicine compared with placebo or usual care in patients with CAD. Study-level data on efficacy and safety outcomes were pooled using the Peto method. The primary outcome was the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Results: A total of 8 RCTs were included with a follow-up duration of ≥1 month, comprising a total of 12,151 patients. Compared with placebo or usual care, colchicine was associated with a significant risk reduction in the primary outcome (odds ratio (OR) 0.70, 95% CI 0.60 to 0.83, P < 0.0001; I2 = 52%). Risks of MI (OR 0.75, 95% CI 0.62 to 0.91, P = 0.003; I2 = 33%), stroke (OR 0.47, 95% CI 0.30 to 0.74, P = 0.001; I2 = 0%), and unplanned coronary revascularization (OR 0.67, 95% CI 0.55 to 0.82, P = 0.0001; I2 = 58%) were all reduced in the colchicine group. Rates of CV and all-cause mortality did not differ between the two groups, but there was an increase in noncardiac deaths with colchicine (OR 1.54, 95% CI 1.10 to 2.15, P = 0.01; I2 = 51%). The occurrence of all other adverse events was similar between the two groups, including GI reactions (OR 1.06, 95% CI 0.94 to 1.20, P = 0.35; I2 = 42%) and infections (OR 1.04, 95% CI 0.84 to 1.28, P = 0.74; I2 = 53%). Conclusions: Colchicine therapy may reduce the risk of future cardiovascular events in patients with established CAD; however, there remains a concern about non-CV mortality. Further trials are underway that will shed light on non-CV mortality and colchicine NCT03048825, and NCT02898610.

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.

Increased FH-Risk-Score and Diabetes Are Cardiovascular Risk Equivalents in Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories. METHODS: This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models. RESULTS: FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P<0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P<0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P<0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P<0.0001). CONCLUSIONS: This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients.

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.

Metabolic syndrome predicts cardiovascular risk and mortality in familial hypercholesterolemia.

BACKGROUND: The association between familial hypercholesterolemia (FH) and premature atherosclerotic cardiovascular disease (ASCVD) is well established. Several risk factors other than the cumulative low-density lipoprotein cholesterol (LDL-C) have been shown to modulate the severity of the phenotype in these patients. However, the effect of the metabolic syndrome (MetS) on ASCVD risk in FH remains to be determined. OBJECTIVES: The objective was to study the association between the presence of MetS and the incidence of different ASCVD endpoints and all-cause mortality. METHODS: This prospective follow up study used data from 5 independent FH cohorts from Europe and North America. We analysed data of 2401 adult heterozygous FH without history of a prior ASCVD event (21,139 person-years of follow-up). Multivariate Cox proportional hazards regression was used to estimate the association between MetS and the incidence of the different endpoints. RESULTS: The prevalence of MetS was 14% in the study population. The presence of MetS was a significant predictor of incident 10-year ASCVD after adjustment for traditional cardiovascular risk factors (HR 2.07, 95% CI 1.34-3.19), as well as of 10-year major adverse cardiovascular event (MACE) (HR 4.59, 95% CI 2.27-9.30), 10-year myocardial infarction (MI) (HR 4.29, 95% CI 1.91-9.63), and 30-year all-cause mortality (HR 4.87, 95% CI 1.99-11.89). CONCLUSION: Our findings suggests that FH patients with MetS, have an increased cardiovascular risk that is independent from LDL-C and other traditional risk factors. Future studies are required to determine the most appropriate strategy to reduce the cardiovascular burden associated with MetS in this population.

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.

Recurrent acute coronary syndrome caused by a primary aortic valve sarcoma: grand rounds and literature review.

Background: Malignant tumours of the aortic valve apparatus are extremely rare and difficult to diagnose. Their proximity to the coronary ostium may cause an acute coronary syndrome (ACS) either by infiltration or by embolization. Case summary: We report a case of primary aortic valve undifferentiated sarcoma causing recurrent episodes of ACS, and we provide a literature review for primary cardiac valve tumours. This case also highlights the need for further evaluation of other causes of ACS in patients with minimal coronary artery disease risk factors and recurrent ACS. Conclusions: The majority of valve tumours are fibroelastomas. Sarcomas are rare and lead to poor outcomes.

Effect of the LDL receptor mutation type on incident major adverse cardiovascular events in familial hypercholesterolaemia.

AIMS: Patients with familial hypercholesterolaemia (FH) are at increased risk of cardiovascular disease (CVD) due to extremely high circulating LDL cholesterol (LDL-C) concentrations. Our objective was to study the effect of the type of LDL receptor (LDLR) mutation on the incidence of major adverse cardiovascular events (MACEs). METHODS AND RESULTS: This was a multinational prospective cohort study, which included patients with heterozygous FH aged 18-65 years, without a prior history of CVD, and carrying a pathogenic or likely pathogenic variant in the LDLR gene. A total of 2131 patients (20 535person-years of follow-up) were included in the study, including 1234 subjects carrying a defective mutation in the LDLR and 897 subjects carrying a null mutation. During the follow-up, a first MACE occurred in 79 cases (6%) in the defective group and in 111 cases (12%) in the null group. The mean baseline LDL-C concentration was 17% higher in the null group than in the defective group (7.90 vs. 6.73 mmoL/L, P < 0.0001). In a Cox regression model corrected for traditional cardiovascular risk factors, the presence of a null mutation was associated with a hazard ratio of 2.09 (1.44-3.05), P = 0.0001. CONCLUSION: Carriers of a null mutation have an independent ∼2-fold increased risk of incident MACE compared with patients carrying a defective mutation. This study highlights the importance of genetic screening in FH in order to improve patient care.

Prevalence and Treatment of Familial Hypercholesterolemia and Severe Hypercholesterolemia in Older Adults in Ontario, Canada.

Background: A simplified Canadian definition was recently developed to enable identification of individuals with familial hypercholesterolemia (FH) and severe hypercholesterolemia in the general population. Our objective was to use a modified version of this new definition to assess contemporary disease prevalence, treatment patterns, and low-density lipoprotein cholesterol (LDL-C) control in Ontario, Canada. Methods: We identified individuals aged 66 to 105 years who were alive as of January 1, 2011, using the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) database, which was created by linking 19 population-based health databases in Ontario. Hypercholesterolemia was identified using LDL-C values. Cholesterol reduction and lipid-lowering treatment were assessed at time of diagnosis and after at least 2 and 5 years' follow-up. Results: Among 922,464 individuals, 2440 (0.26%) met criteria for definite or probable FH, and 72,893 (7.90%) for severe hypercholesterolemia. At diagnosis, mean LDL-C concentration was 9.52 mmol/L for those with definite FH, 5.83 mmol/L for those with probable FH, 5.73 mmol/L for those with severe hypercholesterolemia, and 3.33 mmol/L for all other individuals. After > 5 years, LDL-C concentration remained elevated at 3.58 mmol/L for those with definite FH, 2.72 mmol/L for those with probable FH, and 2.93 mmol/L for those with severe hypercholesteremia. Use of statin therapy was initially high (83% of those with definite FH, 78% of those with probable FH, 62% of those with severe hypercholesterolemia); however, fewer patients remained on statins at follow-up at > 5 years (62% of those with definite FH, 67% of those with probable FH, 58% of those with severe hypercholesterolemia). Conclusions: Among older Ontarians, we estimated that 1 in 378 individuals had FH, and 1 in 13 had severe hypercholesterolemia. Despite being at substantially increased cardiovascular risk, these patients acheived suboptimal LDL-C level control and fewer were on medical therapy at follow-up.

Introduction: Une définition canadienne simplifiée a récemment été élaborée pour permettre la détection des personnes atteintes d'hypercholestérolémie familiale (HF) et d'hypercholestérolémie grave au sein de la population générale. Notre objectif était d'utiliser la version modifiée de cette nouvelle définition pour évaluer la prévalence contemporaine de la maladie, les schémas de traitement et la maîtrise du cholestérol à lipoprotéines de faible densité (cholestérol LDL) en Ontario, au Canada. Méthodes: Nous avons recensé les individus âgés de 66 à 105 ans qui étaient en vie au 1er janvier 2011 à partir de la base de données Cardiovascular Health in Ambulatory Care Research Team (CANHEART), qui a été créée par la liaison de 19 bases de données populationnelles de l'Ontario. L'hypercholestérolémie a été définie par les valeurs du cholestérol LDL. Nous avons évalué la diminution du cholestérol et le traitement hypolipémiant au moment du diagnostic et après au moins les suivis après 2 ans et après 5 ans. Résultats: Parmi les 922 464 personnes, 2 440 (0,26 %) répondaient aux critères de diagnostic définitif ou de diagnostic probable d'HF, et 72 893 (7,90 %), aux critères d'hypocholestérolémie grave. Au diagnostic, les concentrations moyennes de cholestérol LDL étaient de 9,52 mmol/l chez ceux qui avaient un diagnostic définitif d'HF, de 5,83 mmol/l chez ceux qui avaient un diagnostic probable d'HF, de 5,73 mmol/l chez ceux qui avaient un diagnostic d'hypercholestérolémie grave et de 3,33 mmol/l chez toutes les autres personnes. Après > 5 ans, les concentrations de cholestérol LDL étaient demeurées élevées : 3,58 mmol/l chez ceux qui avaient un diagnostic définitif d'HF, 2,72 mmol/l chez ceux qui avaient un diagnostic probable d'HF et 2,93 mmol/l chez ceux qui avaient un diagnostic d'hypercholestérolémie grave. L'utilisation du traitement par statines était initialement élevée (83 % de ceux qui avaient un diagnostic définitif d'HF, 78 % de ceux qui avaient un diagnostic probable d'HF, 62 % de ceux qui avaient un diagnostic d'hypercholestérolémie grave). Toutefois, moins de patients avaient conservé les statines au suivi > 5 ans (62 % de ceux qui avaient un diagnostic définitif d'HF, 67 % de ceux qui avaient un diagnostic probable d'HF, 58 % de ceux qui avaient un diagnostic d'hypercholestérolémie grave). Conclusions: Parmi les Ontariens âgés, nous avons estimé que 1 sur 378 personnes avaient une HF, et que 1 sur 13 avaient une hypercholestérolémie grave. Malgré le fait qu'ils sont exposés à un risque cardiovasculaire substantiellement élevé, ces patients ont atteint une maîtrise sous-optimale du taux de cholestérol LDL et moins d'entre eux étaient sous traitement médical au suivi.

High-Density Lipoprotein and Cardiovascular Disease-Where do We Stand?

Decades of research have shown that high-density lipoprotein cholesterol (HDL-C) levels in humans are associated with atherosclerotic cardiovascular disease (ASCVD). This association is strong and coherent across populations and remains after the elimination of covariates. Animal studies show that increasing HDL particles prevent atherosclerosis, and basic work on the biology of HDL supports a strong biological plausibility for a therapeutic target. This enthusiasm is dampened by Mendelian randomization data showing that HDL-C may not be causal in ASCVD. Furthermore, drugs that increase HDL-C have largely failed to prevent or treat ASCVD.

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.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

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.

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.