Premature Atherosclerotic Cardiovascular Disease Research Articles

Familial Hypercholesterolemia and Lipoprotein(a): A Gordian Knot in Cardiovascular Prevention.

Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000-400,000 for the homozygous and ~1:200-300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk.

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease

BackgroundGenetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD. ObjectivesWe determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD. MethodsWe examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD. ResultsFor risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD. ConclusionsLipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

Assessment of the Effective Management of Patients With Severe Primary Hypercholesterolemia Under Care in Family Medicine Clinics at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Background Atherosclerotic cardiovascular disease (ASCVD) is the primary cause of death in Saudi Arabia. Hypercholesterolemia is a prevalent risk factor that can lead to ASCVD. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines have provided recommendations for managing severe primary hypercholesterolemia, defined as medically well adults 21-75 years of age with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL (≥4.9 mmol/L). Underutilization of the guideline recommendations has led to concern and the need for further review. This study aims to review the management of severe primary hypercholesterolemia in the Family Medicine and Polyclinics at King Faisal Specialist Hospital and Research Centre (KFSH&RC) in Riyadh, Saudi Arabia. Methodology In this retrospective cohort study, data were obtained from electronic medical records of patients aged 21-75 years who received care in the Family Medicine and Polyclinics at KFSH&RC in Riyadh with LDL-C≥190 (≥4.9 mmol/L). The data collected included demographics, body mass index (BMI), LDL-C blood level, and lipid-lowering medications prescribed. We measured the prevalence of hypercholesterolemia, reviewed if appropriate statin therapy was prescribed as per the ACC/AHA guidelines, and determined if treated patients with severe primary hypercholesterolemia achieved LDL-C ≤100 mg/dL (≤2.6 mmol/L) from January 1, 2015, until June 30, 2020. Results The prevalence of hypercholesterolemia was 7.4%. The sample size studied included 195 patients. The majority of patients were aged 40-59 years and were either overweight or obese. Treatment with a moderate-intensity statin was observed in 46.4% of patients, and 45.4% of patients were not prescribed a statin. The LDL-C ≤100 mg/dL (≤2.6 mmol/L) was not achieved in 88.3% of patients. Conclusions Despite guidelines, the majority of patients with severe primary hypercholesterolemia are inadequately managed. High-risk patients need to be diagnosed appropriately so that they receive proper treatment to prevent ASCVD. We encourage adherence to established guidelines in the management of severe primary hypercholesterolemia to prevent premature ASCVD.

Evolocumab treatment reduces carotid intima-media thickness in paediatric patients with heterozygous familial hypercholesterolaemia

Abstract Background Familial hypercholesterolemia (FH) is characterised by high plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Previous studies show that carotid intima-media thickness (cIMT) is increased in children with FH, an indicator of early ASCVD. Add-on treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab, substantially reduced atherosclerotic lipid levels in children with heterozygous FH (HeFH) and was safe and well tolerated. The effect of evolocumab on cIMT in paediatric patients (pts) has not been investigated. Purpose To investigate the effect of evolocumab treatment on cIMT progression in paediatric pts with HeFH. Methods HAUSER-RCT was a multicenter, randomised, placebo-controlled study in which paediatric FH pts (ages 10–17 years) received monthly subcutaneous injections of evolocumab 420 mg or placebo. Of 157 pts, 150 continued to an open-label extension study (HAUSER-OLE) during which all received up to 80 weeks of monthly evolocumab 420 mg on top of stable background statin therapy. cIMT was measured by B-mode ultrasound scanning at baseline, week 24 of the RCT, and weeks 24, 48, and 80 of the OLE. cIMT was measured on anterior, lateral, and posterior imaging angles of the right and left common carotid artery. Mean thickness at each visit and mean changes from baseline were summarised by treatment received during the RCT and artery location. In addition, the largest measurements (anterior, lateral, or posterior) from a patient's left and right carotid artery were averaged to calculate a summary score. Results Mean baseline cIMT summary score was 0.568 mm (SD=0.06) for 46 placebo pts and 0.586 mm (SD=0.06) for 82 evolocumab pts. During the RCT, 37 placebo pts had a mean increase of 0.006 mm (SD=0.05) from baseline to week 24; in contrast, 76 evolocumab pts had a mean decrease of 0.003 mm (SD=0.05). Although this treatment group difference was not statistically significant (P=0.403), the pattern of increased cIMT for placebo and decreased cIMT for evolocumab was consistent across artery locations (Table). During the OLE, for pts who initially received placebo, mean cIMT summary score decreased by 0.019 mm (SD=0.04, n=34) from baseline to week 80 (P=0.007) (Figure). Pts who received evolocumab in both the RCT and OLE showed continued improvement during the OLE; at week 80, mean cIMT summary score decreased by 0.012 mm (SD=0.05, n=59) from baseline (P=0.067). For all pts at week 80 (n=128), the mean decrease in LDL-C from baseline was 35.3% (SD=28.0). Conclusions Open-label evolocumab treatment for up to 80 weeks led to reductions in mean cIMT. In this small sample of pts with FH, the data suggest that the addition of PCSK9 inhibition to background lipid-lowering therapy has the potential to reduce the risk of ASCVD progression and future cardiovascular events in this vulnerable paediatric population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen, Inc.

GENETIC TESTING FOR FAMILIAL HYPERCHOLESTEROLEMIA IN THE PROVINCE OF QUÉBEC: A SINGLE CENTER RETROSPECTIVE COHORT STUDY

Familial Hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated LDL-C. Although early diagnosis and treatment of FH can normalize life expectancy, less than 15% of cases are diagnosed. The role of genetic testing, compared with clinical definitions remains contentious.

SEX DISPARITIES IN TREATMENT AND CLINICAL OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

SEX DISPARITIES IN TREATMENT AND CLINICAL OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA IN CANADA

Homozygous familial hypercholesterolemia (HoFH) is life-threatening orphan disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients often present with extensive xanthomas and marked premature atherosclerotic cardiovascular disease (ASCVD) before the age of 20. Prior to the advent of statins and extracorporeal LDL filtration techniques, survival beyond 30 years of age was unusual. Treatment with lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy, reducing the risk of ASCVD to background population rates.

PCSK9 inhibition in children with familial hypercholesterolaemia

Heterozygous familial hypercholesterolaemia is the most prevalent monogenic dyslipidaemia, affecting approximately 1 in 300 people worldwide.1 If left untreated, elevated LDL cholesterol concentrations in heterozygous familial hypercholesterolaemia are associated with a more than ten-fold increased risk of premature atherosclerotic cardiovascular disease.1 For children and adolescents with heterozygous familial hypercholesterolaemia, clinical guidelines recommend early intervention with lifestyle modification and statin drugs, with increasingly assertive targets for LDL cholesterol.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

Major adverse cardiovascular events in homozygous familial hypercholesterolemia: A systematic review and meta-analysis

Background and Aims : Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease (ASCVD) 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.

Novel pathogenic variants of the LDLR gene identified in putative FH subjects

Background and Aims : Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism causing elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. FH is typically caused by deleterious variants of LDLR, APOB or PCSK9 genes and its prevalence is of about 1:300 in the general population. Aim of this study was the genetic characterization of suspected FH patients.

Registry data indicate higher risk of eating disorders in individuals with familial hypercholesterolemia compared with age and sex matched controls

Background and Aims : Events of illness, loss of family members and maintaining a restrictive diet are some of many risk factors for developing an eating disorder. Familial hypercholesterolemia (FH) is a hereditary condition that predisposes for premature atherosclerotic cardiovascular disease and death. Consequently, medical and dietary treatment are initiated from childhood. The aim of this study was to examine whether having FH is associated with a risk of developing an eating disorder.

Treatment gaps in paediatric patients with homozygous familial hypercholesterolaemia

Background and Aims : Patients with Homozygous Familial Hypercholesterolaemia (HoFH) require intensive combination lipid lowering therapy (LLT) from diagnosis to avoid premature atherosclerotic cardiovascular disease (ASCVD). However, not all LLT are licensed for use in children and adolescents. We aimed to compare use of LLT in children, adolescents and adults with HoFH.

Predictive factors of statin initiation during childhood in a cohort of 245 child-parent pairs with Familial Hypercholesterolemia: Importance of genetic diagnosis

Background and Aims : Children with heterozygous familial hypercholesterolemia (HeFH) are undertreated despite international guidelines advocating for early statin initiation during childhood; dramatically increasing their risk of premature atherosclerotic cardiovascular disease (ASCVD).The objective of the study was to identify childhood and parental factors associated with statin early initiation in HeFH children to promote early treatment.

A Danish nationwide study of individuals suspected of FH referred from general practice to lipid clinics: Clinical characteristics, plasma lipoprotein(a) and final diagnosis

Background and Aims : Familial hypercholesterolemia (FH) is an inherited condition characterized by severely elevated plasma levels of low-density lipoprotein (LDL) cholesterol believed to occur in approximately 1:250 subjects. FH is associated with a very high risk of premature atherosclerotic cardiovascular disease. Unfortunately, less than 20% of the affected are currently diagnosed in Denmark, which represents a health challenge here and in most other (Western) countries. The aims of the study were to describe important clinical characteristics and examine the proportion of verified FH diagnoses among adult subjects referred from General Practice to Danish Lipid Clinics on suspicion of FH. Also we aimed to investigate the importance of plasma lipoprotein(a) levels for a diagnosis of FH.Methods: All subjects referred from General Practice to one of the 15 Danish Lipid Clinics between September 2020 and November 2021 will be included. More than 1.200 individuals are expected to be recruited into the study and informed consent will be obtained from the subjects. Referrals for suspicion of FH were based on pre-specified criteria including LDL cholesterol levels > 5.0 mmol/l (> 4.0 mmol/l in subjects < 40 years) or premature cardiovascular disease. Secondary dyslipidaemias were excluded before admittance. Individuals were interviewed for personal and familial cardiovascular disease, diet, lifestyle, treatment and examined for cholesterol deposits. Individuals were classified according to the Dutch Lipid Clinic Network Score for FH.Results: Main results will be available in April 2022 and will be presented at the Congress.Conclusions: Will be presented when the results are available. Background and Aims : Familial hypercholesterolemia (FH) is an inherited condition characterized by severely elevated plasma levels of low-density lipoprotein (LDL) cholesterol believed to occur in approximately 1:250 subjects. FH is associated with a very high risk of premature atherosclerotic cardiovascular disease. Unfortunately, less than 20% of the affected are currently diagnosed in Denmark, which represents a health challenge here and in most other (Western) countries. The aims of the study were to describe important clinical characteristics and examine the proportion of verified FH diagnoses among adult subjects referred from General Practice to Danish Lipid Clinics on suspicion of FH. Also we aimed to investigate the importance of plasma lipoprotein(a) levels for a diagnosis of FH. Methods: All subjects referred from General Practice to one of the 15 Danish Lipid Clinics between September 2020 and November 2021 will be included. More than 1.200 individuals are expected to be recruited into the study and informed consent will be obtained from the subjects. Referrals for suspicion of FH were based on pre-specified criteria including LDL cholesterol levels > 5.0 mmol/l (> 4.0 mmol/l in subjects < 40 years) or premature cardiovascular disease. Secondary dyslipidaemias were excluded before admittance. Individuals were interviewed for personal and familial cardiovascular disease, diet, lifestyle, treatment and examined for cholesterol deposits. Individuals were classified according to the Dutch Lipid Clinic Network Score for FH. Results: Main results will be available in April 2022 and will be presented at the Congress. Conclusions: Will be presented when the results are available.

Diabetes status and risk of premature atherosclerotic cardiovascular disease: A study from approximately 1 million young adults

Background and Aims : Risk of premature atherosclerotic cardiovascular disease (ASCVD) attributable to diabetes is poorly understood. We evaluated the impact of diabetes on future risk of ASCVD in young men and women.

Association between lipoprotein(a) concentrations and atherosclerotic cardiovascular disease risk in patients with familial hypercholesterolemia: An analysis from the hellas-fh

Background and Aims : Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH.Methods: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels.Results: A total of 541 adult patients (249 males) with heterozygous FH (HeFH) were included (mean age 48.5±15.0 years at registration, 40.8±15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of CVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p=0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5%, 13.4% and 19.8%, respectively (p=0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3%, 12.2% and 16.1%, respectively; p=0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles.Conclusions: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with HeFH. Background and Aims : Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH. Methods: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels. Results: A total of 541 adult patients (249 males) with heterozygous FH (HeFH) were included (mean age 48.5±15.0 years at registration, 40.8±15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of CVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p=0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5%, 13.4% and 19.8%, respectively (p=0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3%, 12.2% and 16.1%, respectively; p=0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles. Conclusions: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with HeFH.

Lipoprotein(a) in Cardiovascular Diseases: Insight From a Bibliometric Study.

Lipoprotein(a) [Lp(a)] is a complex polymorphic lipoprotein comprised of a low-density lipoprotein particle with one molecule of apolipoprotein B100 and an additional apolipoprotein(a) connected through a disulfide bond. The serum concentration is mostly genetically determined and only modestly influenced by diet and other lifestyle modifications. In recent years it has garnered increasing attention due to its causal role in pre-mature atherosclerotic cardiovascular disease and calcific aortic valve stenosis, while novel effective therapeutic options are emerging [apolipoprotein(a) antisense oligonucleotides and ribonucleic acid interference therapy]. Bibliometric descriptive analysis and mapping of the research literature were made using Scopus built-in services. We focused on the distribution of documents, literature production dynamics, most prolific source titles, institutions, and countries. Additionally, we identified historical and influential papers using Reference Publication Year Spectrography (RPYS) and the CRExplorer software. An analysis of author keywords showed that Lp(a) was most intensively studied regarding inflammation, atherosclerosis, cardiovascular risk assessment, treatment options, and hormonal changes in post-menopausal women. The results provide a comprehensive view of the current Lp(a)-related literature with a specific interest in its role in calcific aortic valve stenosis and potential emerging pharmacological interventions. It will help the reader understand broader aspects of Lp(a) research and its translation into clinical practice.

*Lipoprotein X hyperlipidemia and Its Complications in a Patient with Primary Sclerosing Cholangitis

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis We reviewed a case of a young man referred for management of severe hypercholesterolemia and bilateral palpebral xanthelasma. This is intended to highlight key features in diagnosis and management of severe hypercholesterolemia due to LpX from biliary obstructive disease. Objective/Purpose To review clinical management of severe hypercholesterolemia due to LpX. Methods Clinical management at tertiary care lipid program. Results A 22-year-old slim male with history of Wilson's disease, Crohn's disease, and primary sclerosing cholangitis (PSC) was referred for management of severe hypercholesterolemia and progressive symmetric palpebral xanthelasmas. There is no family history of severe hypercholesterolemia or premature atherosclerotic cardiovascular disease (ASCVD), nor were any other secondary causes identified. He was successfully treated with cholestyramine for pruritis which resulted in marked total cholesterol reduction and increased triglyceride (TG) level. Conclusions Very severe hypercholesterolemia with total cholesterol levels >500 mg/dL is a rare condition. Levels this high are typically associated with homozygous familial hypercholesterolemia (FH) due to an increased level of atherogenic LDL cholesterol (LDL-C). However, other causes need to be considered in the right clinical context, such as lipoprotein fraction lipoprotein X (LpX) in an individual with obstructive biliary disease. LpX is a consequence of ``spillover'' of hepatic free cholesterol (FC)/phospholipid complexes in disc- shaped lipoproteins which do not contain apoB. Consequently, there is wide discordance between apoB and the calculated LDL-C and high serum FC levels. The diagnosis is typically made in the right clinical context without FC measurement since this test is not commercially available. Hypercholesterolemia due to LpX is not associated with increased ASCVD risk, but its presence can be a marker of the severity of liver disease and cause other medical complications including hyperviscosity syndrome, pulmonary embolism and cholesteroloma.Our patient's marked increase in total cholesterol without severe increase in apoB suggested progression of PSC and prompted referral back to his primary Hepatology team. Additional cholesterol-lowering pharmacotherapy is not indicated for hypercholesterolemia due to LpX without hyperviscosity. Nothing to disclose.

A Clinically Validated Genetic Screening for Familial Hypercholesterolemia in Quebec

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Familial Hypercholesterolemia (FH) is the most common genetic disorder in humans with an estimated prevalence of 1/311. In geographic regions with founder effect mutations, such as the province of Quebec, Canada, prevalence is as high as 1/80. FH is associated with premature atherosclerotic cardiovascular disease (ASCVD) caused by elevated low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and therapy of FH can normalize life expectancy, less than 15% of cases are diagnosed. Cascade screening and genetic testing aim to improve diagnosis, treatment, and outcomes in FH. Objective/Purpose Determine the impact of unbiased genetic testing in re-classification of patients with a clinical diagnosis of FH in Quebec, in comparison with the existing genetic panel offered by Quebec's Ministry of Health and Social Services (Ministere de la Sante et des Services Sociaux (MSSS)). Methods A retrospective cohort study was conducted on patients seen in the Preventive Cardiology/Lipid Clinic of the McGill University Health Center (MUHC) at the Royal Victoria Hospital in Montreal, Quebec, Canada, between September 2017 to September 2021. The MUHC Preventive Cardiology/Lipid clinic is one of the 19 academic FH Canada Registry participating sites. Here, we report a single-center experience with the only clinically validated molecular genetic screening for FH (CLIA compliant) in Canada. We performed next-generation sequencing of the LDLR, APOB, and PCSK9 genes and multiplex ligation-dependent probe amplification (MLPA) of the LDLR gene to detect genetic mutations and copy number variants. All mutations were reviewed by a geneticist and cross-referenced in ClinVar. Results Between 2018-2021, we examined 369 FH cases (57% males, 43% females) based on the Canadian FH definition clinical criteria. For index patients, mean age at diagnosis was 40+/- 16 years, while 30+/-16 years was for cascade screening patients. Baseline (untreated) LDL-C was 6.5+/-2.0 mmol/L. In 224 patients who underwent genetic testing, a pathogenic mutation was identified in 167 (75%) individuals, in keeping with ∼20% of FH patients with a polygenic form. A majority of affected patients had mutations in the LDLR (87%) or APOB (13%) genes. Interestingly, the genetic panel offered by Quebec's Health Ministry, which includes 10 common mutations in French Canadians, only accounted for 46% of identified mutations. Even in patients self-describing as French Canadians, more than 20% did not have a common mutation. We subsequently examined the impact of genetic testing in re-classification of patients' FH diagnosis. Interestingly, genetic screening identified a genetic variant in 26% of patients initially classified as 'severe hypercholesterolemia' and allowed for 85 (75%) of patients initially diagnosed as 'probable FH' to be re-classified as 'definite FH'. Conclusions Genetic testing in patients suspected of having FH provides diagnostic certainty and permits re-classification of individuals with a diagnosis of 'severe hypercholesterolemia' or 'probable FH' according to current definitions. Furthermore, the limited genetic panel offered by the province of Quebec, focusing on common French-Canadian mutations, provides incomplete data in the majority of cases. We therefore propose that most patients with a presumptive diagnosis of FH undergo an unbiased genetic analysis. This allows for increased identification of FH patients and can help reduce burden of ASCVD and death in Canadians with FH. Furthermore, this study has important implications on cascade screening, public health policies and reimbursement of drugs such as PCSK9 inhibitors. Nothing to disclose.