Diagnosis Of Heterozygous Familial Hypercholesterolemia Research Articles

Abstract 18696: Berberine as a Supplement to Guideline-Based Lipid Management of a Patient With Heterozygous Familial Hypercholesterolemia: A Case Presentation

Description of Case: A 62-year-old female presented for a lipidology consult. Labs revealed total cholesterol >450 mg/dL, Lp(a) 42 mg/dL, and LDL-P 2938. She was not on any lipid lowering therapy. A clinical diagnosis of heterozygous familial hypercholesterolemia (HeFH) was made. She reported occasional chest pain with both cardiac and noncardiac features. She had no personal history of CAD, and her family history revealed a mother and maternal grandfather with CAD in their 50s. A CCTA was performed, which revealed mild-moderate plaque in the ostial left circumflex (25-49%) and a CAC score of 124 (90-95th percentile). She was started on rosuvastatin 10mg daily and alirocumab with reduction of her LDL-C to 247 mg/dL. Given documented CAD, LDL-C <55 mg/dL was targeted. She had intolerable side effects to combination ezetemibe plus bempadoic acid and lomitapide. Evinacumab or LDL pheresis were offered, and the patient preferred to start evinacumab. Alirocumab was stopped. With rosuvastatin plus evinacumab, her LDL-C improved to 198 mg/dL. Berberine 1000mg was added to her regimen and resulted in further reduction of her LDL-C to 117 mg/dL. Discussion: Long used in Traditional Chinese and Ayurvedic medicine, Berberine is an alkaloid found in plants such as barberry and tree turmeric. Berberine suppresses PCSK9 transcription by regulating hepatocyte nuclear factor 1 alpha, a binding site located upstream from the PCSK9 gene promoter. The role of supplements in lipid management remains unknown. We describe a case of HeFH in which berberine yielded an 81 mg/dL absolute reduction (41% relative reduction) in LDL-C when added to guideline-based therapy. In a dedicated integrative lipidology practice, berberine may be an effective supplement to the pharmaceutical management of severe hyperlipidemia.

554 HYPERLIPOPROTEIN(A) AND PREMATURE CORONARY ARTERY DISEASE: A CALL FOR ACTION

Abstract Background and Aims elevated Lipoprotein (a) levels are well recognized as a genetic risk factor for atherothrombotic events. Recently, new therapeutic approaches – such as small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) – have been developed and are under evaluation in phase 3 trials. Evidences from literature suggest the need for screening Lp(a) in premature coronary artery disease. Aim of our study was to evaluate, in a real world scenario: 1) the percentage of premature CAD in whom clinicians choose to screen Lp(a); 2) the prevalence of hyperLp(a) in premature CAD. Methods we retrospectively evaluated data of patients admitted for acute coronary syndrome at Department of Cardiology of Careggi University Hospital, Florence, between 1st January 2018 and 31th July 2022. Inclusion criteria were: age < 50 years for men and < 55 years for women; confirmed diagnosis of acute coronary syndrome with obstructive coronary artery disease at hospital discharge. Results we selected 226 patients (50 F and 176 M; total median age 46 years, F median age 49 years, M median age 45 years). LDL median values at admission were 117.12 mg/dl). Nine out of 226 pts (3.9%) had LDL levels higher than 190 mg/dl, suggesting the possible diagnosis of Heterozygous Familial Hypercholesterolemia (with respect to the expected prevalence in the general population: 1/250 (0.004%). No patient had hepatic or thyroid disease. Sixty-eight out of 226 pts (30%) had triglycerides levels higher than 150 mg/dl; 41/226 (18.1%) with levels higher than 200 mg/dl. As regards Lp(a) levels, a dosage was performed in 93/226 patients (41.2%). We found that lipoprotein dosage was required more frequently in the 2020, 2021 and 2022 years (respectively in the 61%, 49% and 70% of patients) than in the 2018 and 2019 years (respectively in the 27% and 23% of patients) (Figure 1). Among patients in whom lipoprotein was dosed, elevated Lp(a) levels (> 300 mg/L) were documented in 45/93 (48.4%). 15/93 (16.1%) patients had extreme elevated Lp(a) levels (> 700 mg/L) (Figure 2). In two patients we documented both extreme Lp(a) levels and LDL levels higher than 190 mg/dl; in the other patients, elevated Lp(a) levels were the only lipid parameter out of range, and the only risk factor for premature CAD. By comparing these patients with an historical cohort of patients with ACS and age >50 and 55 yrs in men and women respectively, we found at a multivariate analysis adjusted for classical risk factors that both elevated Lp(a) levels (OR:2.1 (95% CI 1.3–4.2), p<0.005) and extreme elevated Lp(a) levels were significantly associated with the risk of premature CAD (OR: 1.8 (95% CI 1.4–3.9); p<0.05). Conclusions these results demonstrated that: 1) it is urgent, from a clinical point of view, to apply screening protocols in premature CAD including Lp(a) dosage; 2) elevated Lp(a) levels, and in particular extreme elevated Lp(a) levels, have an elevated prevalence in a population of premature CAD and are significantly and independently associated with the disease.

REverse cascade screening in the diagnosis of familial hypercholesterolemia

Background and Aims : Early diagnosis of familial hypercholesterolemia (FH) and an effective patient monitoring strategy are extremely promising for reducing the risk of atherosclerosis in the future. Aim of the study. Conduct and analyze the results of reverse cascade screening for the diagnosis of FH.Methods: The study was carried out in the period from December 2018 to August 2021 on the basis of Children's Republican Clinical Hospital, Kazan, City Clinical Hospital No. 7 in Kazan, Kazan State Medical University. Inclusion criteria: age 0-17 years inclusive, diagnosed with "Heterozygous form of familial hypercholesterolemia" in accordance with clinical guidelines according to the criteria of Simon Broome Registry, informed consent for participation in the study of children and / their parents. Exclusion criteria: underlying diseases / conditions, as well as drugs that may cause a secondary increase in LDL cholesterol.Results: During this period, 34 children were identified with a diagnosis of heterozygous FH (mean age 9.1 ± 2.4 years). After further examination of relatives, FH was diagnosed in 35 parents, 17 siblings, 58 relatives of the 2nd line of relationship. The average age of the parents was 37.8 ± 3.3 years. In 21 (60.6%) of them ischemic heart disease was diagnosed, in 19 (55%) atherosclerosis of the brachiocephalic arteries. In addition, 11 (31%) patients required coronary angiography, 3 (8,5%) - coronary artery bypass grafting, 2 (5,7%) - stenting of coronary vessels.Conclusions: The diagnostic result of the cascade screening along the "child-parent" path was 3 new cases of FHC per one child-proband. Background and Aims : Early diagnosis of familial hypercholesterolemia (FH) and an effective patient monitoring strategy are extremely promising for reducing the risk of atherosclerosis in the future. Aim of the study. Conduct and analyze the results of reverse cascade screening for the diagnosis of FH. Methods: The study was carried out in the period from December 2018 to August 2021 on the basis of Children's Republican Clinical Hospital, Kazan, City Clinical Hospital No. 7 in Kazan, Kazan State Medical University. Inclusion criteria: age 0-17 years inclusive, diagnosed with "Heterozygous form of familial hypercholesterolemia" in accordance with clinical guidelines according to the criteria of Simon Broome Registry, informed consent for participation in the study of children and / their parents. Exclusion criteria: underlying diseases / conditions, as well as drugs that may cause a secondary increase in LDL cholesterol. Results: During this period, 34 children were identified with a diagnosis of heterozygous FH (mean age 9.1 ± 2.4 years). After further examination of relatives, FH was diagnosed in 35 parents, 17 siblings, 58 relatives of the 2nd line of relationship. The average age of the parents was 37.8 ± 3.3 years. In 21 (60.6%) of them ischemic heart disease was diagnosed, in 19 (55%) atherosclerosis of the brachiocephalic arteries. In addition, 11 (31%) patients required coronary angiography, 3 (8,5%) - coronary artery bypass grafting, 2 (5,7%) - stenting of coronary vessels. Conclusions: The diagnostic result of the cascade screening along the "child-parent" path was 3 new cases of FHC per one child-proband.

Evaluation of lipid-lowering therapy in patients with definite diagnosis of heterozygous familial hypercholesterolemia in Lodz

Background and Aims : The aim of the study was to analyze a type and efficiency of lipid lowering therapy in patients with definite diagnosis of heFH. We also analyzed LDL corrected with Lp(a) and therapeutic LDL achievement in patients with familial hypercholesterolemia on optimal lipid-lowering therapy.Methods: We conducted retrospective analysis of 20 patients with definite clinical diagnosis of FH (DLCNS>8 score) and very high cardiovascular risk. We analyzed type of lipid lowering therapy (statin, ezetimibe, PCSK9i) baseline and 6 months follow up lipids including total cholesterol, LDL, HDL, non-HDL, Lp(a) and LDL corrected with Lp(a). LDL corrected with Lp(a) was calculated as LDL(corrected) = LDL [mg/dl] – 0,3 x Lp(a)Results: 20 patients enrolled in the study were 15 women and 5 men in mean age 50,65±15. Average baseline lipid parameters were: Total cholesterol: 321±93mg/dl ; LDL cholesterol 252,58±68mg/dl; HDL cholesterol 54,11±16; non-HDL cholesterol 250,14±116mg/dl; Triglycerides 160,55±112mg/dl; Lp(a) 90,34±111; LDL(corrected) 242,47±72mg/dl. All patients had definite diagnosis of familial hypercholesterolemia and mean DLCNS was 14,25±4. All patients had lipid lowering therapy introduced including high intensity statin (atorwastatin 3/20 patients in mean dose 60mg, rosuwastatin 17/20 in mean dose 27,06mg), ezetimibe 19/20 patients in dose 10mg and 14 patients were on PCSK9 inhibitors (6 on ewolocumab and 8 on alirocumab). After 6 months follow-up, mean lipid parameters were: Total cholesterol: 169,2±65mg/dl ; LDL cholesterol 94±50mg/dl; HDL cholesterol 45,64±8; non-HDL cholesterol 102,97±77mg/dl; Triglycerides 167,8±115mg/dl; Lp(a) 70,25±107; LDL(corrected) 87,33±49mg/dl.Conclusions: Despite optimal, intensive lipid-lowering therapy, the achievement of therapeutic LDL in patients with FH is not satisfactory. Background and Aims : The aim of the study was to analyze a type and efficiency of lipid lowering therapy in patients with definite diagnosis of heFH. We also analyzed LDL corrected with Lp(a) and therapeutic LDL achievement in patients with familial hypercholesterolemia on optimal lipid-lowering therapy. Methods: We conducted retrospective analysis of 20 patients with definite clinical diagnosis of FH (DLCNS>8 score) and very high cardiovascular risk. We analyzed type of lipid lowering therapy (statin, ezetimibe, PCSK9i) baseline and 6 months follow up lipids including total cholesterol, LDL, HDL, non-HDL, Lp(a) and LDL corrected with Lp(a). LDL corrected with Lp(a) was calculated as LDL(corrected) = LDL [mg/dl] – 0,3 x Lp(a) Results: 20 patients enrolled in the study were 15 women and 5 men in mean age 50,65±15. Average baseline lipid parameters were: Total cholesterol: 321±93mg/dl ; LDL cholesterol 252,58±68mg/dl; HDL cholesterol 54,11±16; non-HDL cholesterol 250,14±116mg/dl; Triglycerides 160,55±112mg/dl; Lp(a) 90,34±111; LDL(corrected) 242,47±72mg/dl. All patients had definite diagnosis of familial hypercholesterolemia and mean DLCNS was 14,25±4. All patients had lipid lowering therapy introduced including high intensity statin (atorwastatin 3/20 patients in mean dose 60mg, rosuwastatin 17/20 in mean dose 27,06mg), ezetimibe 19/20 patients in dose 10mg and 14 patients were on PCSK9 inhibitors (6 on ewolocumab and 8 on alirocumab). After 6 months follow-up, mean lipid parameters were: Total cholesterol: 169,2±65mg/dl ; LDL cholesterol 94±50mg/dl; HDL cholesterol 45,64±8; non-HDL cholesterol 102,97±77mg/dl; Triglycerides 167,8±115mg/dl; Lp(a) 70,25±107; LDL(corrected) 87,33±49mg/dl. Conclusions: Despite optimal, intensive lipid-lowering therapy, the achievement of therapeutic LDL in patients with FH is not satisfactory.

Familial hypercholesterolemia: cascade screening along the “child–parent” pathway

Familial hypercholesterolemia (FH) is the leading cause of premature cardiovascular disease and the most common disorder of lipid metabolism in childhood. Early diagnosis of FH and an effective patient monitoring strategy are extremely promising for reducing the risk of atherosclerosis in the future.
 Aim. Conduct and analyze the results of cascade screening along the childparent path for the diagnosis of FH.
 Materials and methods. The study was carried out in the period from December 2018 to August 2021 on the basis of Children's Republican Clinical Hospital, City Clinical Hospital No.7 in Kazan, Kazan State Medical University. Inclusion criteria: age 017 years inclusive, diagnosed with Heterozygous form of familial hypercholesterolemia in accordance with clinical guidelines according to the criteria of the Simon Broome Registry, informed consent for participation in the study of children and/or their parents. Exclusion criteria: underlying diseases/conditions, as well as drugs that may cause a secondary increase in low-density lipoprotein cholesterol.
 Results. During this period, 34 children were identified with a diagnosis of heterozygous FH (mean age 8.73.6 years). After further examination of relatives, FH was diagnosed in 33 parents, 15 siblings, 56 relatives of the 2nd line of relationship. The average age of the parents was 384.3 years. In 20 (60.6%) of them ischemic heart disease was diagnosed, in 18 (54.5%) atherosclerosis of the brachiocephalic arteries. In addition, 10 (30%) patients required coronary angiography, 3 (9%) coronary artery bypass grafting, 2 (6%) stenting of coronary vessels.
 Conclusion. The diagnostic result of the cascade screening along the childparent path was 3 new cases of FH per one child-proband.

Prevalence of Cardiovascular Risk Factors and Heterozygous Familial Hypercholesterolemia in Premature Atherosclerotic Patients Presenting with Acute Coronary Syndrome

Background: Heterozygous familial hypercholesterolemia is an autosomal dominant genetic disorder with an estimated prevalence of 1/200 - 1/500 in the general population. Early identification of patient with familial hypercholesterolemia is important, because appropriate treatment may reduce the risk of premature atherosclerosis. Objective: Assessment of the prevalence of different modifiable cardiovascular risk factors and clinical diagnosis of heterozygous familial hypercholesterolemia. Methods: One hundred patients were enrolled, included young patients (males less than 50 years and females less than 60 years old) presented with first attack of acute coronary syndrome either ST elevation myocardial infarction (STEMI), non ST elevation myocardial infarction (NSTEMI) or unstable angina (UA). All patients were subjected to full history taking, general and local examination, Electrocardiogram, transthoracic Echocardiography, laboratory investigations, coronary angiography and Dutch score calculation for familial hyperlipidemias. Results: The mean level of serum cholesterol among studied group was 268.31 ± 59.33, HDL-C was 39.63 ± 7.52, LDL was 192.27 ± 60.61 and TG was 180.10 ± 39.64. With application of Dutch score, 20% of patients diagnosed definite familial hypercholesterolemia with Dutch score > 8. Twenty-six percent of patients diagnosed as probable familial hypercholesterolemia with Dutch score 6 - 8. Thirty-nine percent patients diagnosed as possible familial hypercholesterolemia with Dutch score 3 - 5 and 15% of patients were unlikely familial hypercholesterolemia with Dutch score 3 with significant correlation between Dutch score and age, total cholesterol, LDL-C, serum creatinine. Conclusion: Familial hypercholesterolemia (FH) is one of the most common serious genetic disorders of cholesterol metabolism. The early identification of heterogynous FH patients is crucial to start an effective prevention strategy.

Non-HDL or LDL cholesterol in heterozygous familial hypercholesterolaemia: findings of the Simon Broome Register.

The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

P848Prevalence and Prognosis of Familial Hypercholesterolemia (FH) with Acute Myocardial Infarction (AMI) in China: Chinese Acute Myocardial Infarction (CAMI) Registry

Abstract Background The prevalence and prognosis of familial hypercholesterolemia (FH) with acute myocardial infarction (AMI) in China is unclear. Purpose To invistigate the prevalence and prognosis of familial hypercholesterolemia (FH) with acute myocardial infarction (AMI) in China. Methods In China Acute Myocardial Infarction (CAMI) Registry, 13,002 patients with age 18–80 were consecutively enrolled with first-onset acute myocardial infarction who were naïve to statin before admission from Januanry 1st, 2013 to October 31st, 2014. According to Dutch Lipid Clinical Network Criteria (DLCNC), the patients were divided to heterozygous familial hypercholesterolemia (HeFH) (definite or probable HeFH, possible HeFH) or no HeFH group. All the patients were followed up (average follow-up period, 24 months) and composite major adverse cardiovascular events (ENDPOINT) were recorded which were defined as all-cause death, non-fatal myocardial reinfarction and stroke. Cox regression was performed to analyze the difference of composite endpoint occurrence between HeFH group and no HeFH group. Results The number of the patients in the three groups was as following, 62 in definite or probable HeFH group, 484 in possible HeFH group, 12456 in no HeFH group. The prevalence of HeFH is 4.2% (including 0.47% of definite or probable HeFH, 3.73% of possible FH). The average age of onset of first-time AMI was 54±12,56±12,63±12 years old (p<0.0001) in definite or probable HeFH group, possible HeFH group and no HeFH group, respectively. The percentage of Killip III or above (8.1% vs 4.3% vs 6.3%, p=0.1629), cardiac arrest (1.6% vs 0.6% vs 0.9%, p=0.6990), and TIMI 0–2 grade after primary percutaneous cardiac intervention (PCI) (0% vs 6.8% vs 4.3%, p=0.5866) was not significantly different in definite or probable HeFH group, possible HeFH group and no HeFH group, respectively. After Cox proportional analysis adjusting multiple factors, the rate of composite endpoint during follow-up period was not significantly different (definite or probable HeFH group vs no HeFH group, HR 0. 853, 95% CI 0.381–1.910, p=0.699, possible HeFH group vs no HeFH group, HR1.076, 95% CI 0.795–1.458, p=0.635). The prognosis of FH with AMI in China Conclusions In CAMI Registry, the prevalence of HeFH was 4.2%, the diagnosis of HeFH was not a dependent risk factor for the rate of composite cardiovascular events.

Effect of quantitative and qualitative diet prescription on children behavior after diagnosis of heterozygous familial hypercholesterolemia

BackgroundDiet and healthy modifications in lifestyle represent the first therapeutic approach for early intervention in hypercholesterolemia. We aimed to evaluate the impact of a qualitative dietetic program rather than a quantitative one on metabolic parameters and anxiety level of children affected by heterozygous familial hypercholesterolemia [heFH] and their mothers. MethodsIn a sample of 42 heFH normal weight children (11.4 ± 2.9 years old), we investigated the factors which were associated with children perceived quality of life and with their mothers' anxiety levels after qualitative dietary changes rather than after quantitative ones. ResultsThe administered diets had similar metabolic effects. However, higher Child Behavior Checklist (Behavior Problems subscale) [CBCL] scores were significantly associated with the permanence in quantitative diet, as well as children's higher age, higher Children's Depression Inventory 2 [CDI2] and State–Trait Anxiety Inventory for Children [STAI-CH] score, and with mothers' anxiety at the baseline. ConclusionIn heFH children, an intervention in the diet to improve food choice seems to be associated with a more healthy children behavior rather than a quantitative diet.

Effect of Quantitative and Qualitative Diet Prescription on Children Behavior after a Diagnosis of Heterozygous Familial Hypercholesterolemia

Background: Diet and lifestyle healthy modifications represent the first therapeutic approach of early intervention for hypercholesterolemia. We aimed at evaluating the impact of a qualitative dietetic program rather than a quantitative one on metabolic parameters and anxiety level of children affected by heterozygous familial hypercholesterolemia [hFH] and their mothers. Methods: In a sample of 42 hFH children (11.4±2.9 years old) we investigated which factors were associated with children perceived quality of life and in their mothers' anxiety levels after qualitative dietary changes rather than quantitative ones. Findings: The administered diets had similar metabolic effects. However, higher Child Behavior Checklist (Behavior Problems subscale) [CBCL] scores were significantly associated with the permanence in quantitative diet, as well as children's higher age, higher Children's Depression Inventory 2 (CDI2) and State-Trait Anxiety Inventory for Children (STAI-CH) score, and with mothers' anxiety at the baseline. Interpretation: In hFH children, a diet intervention to improve food choice seems to be associated with a more healthy children behavior rather than a quantitative diet. Funding: No specific funding has been provided for the research. Declaration of Interest: All the authors certify that they have NO affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in the present manuscript. Ethical Approval: Parents signed an informed consent. The study was carried out in accordance with the declaration of Helsinki and approved by the local ethical board.

Drug treatment and adherence of subjects

Background and aimsWe aimed at describing the therapeutic approach in young adult patients diagnosed with heterozygous familial hypercholesterolemia (HeFH) and their adherence and persistence to treatment. MethodsFrom regional administrative databases, individuals aged ≤40 years, who received exemption for HeFH between January 1, 2003 and December 31, 2011, and concomitantly started statin treatment, were identified. Within the first year of treatment, we evaluated therapeutic changes, adherence as MPR (medication possession ratio), persistence as continuous drug coverage without gaps ≥60 days, and influencing factors using log binomial models. ResultsOf 1404 patients, 42.4% were initially treated with a high-efficacy statin. 23.4% of patients showed at least one treatment change. Mean MPR was 68.7% (29.9), and patients showing continued statin use were 47.0%. Therapy modification was significantly associated with a past cardiovascular event (relative risk, RR [95% confidential interval] 2.28 [1.69–3.09]) and at least one lipid test (RR 1.82 [1.31–2.53]). MPR ≥80% was significantly associated with the first statin prescribed (atorvastatin RR 1.28 [1.09–1.51] and rosuvastatin RR 1.21 [1.01–1.44], vs. simvastatin), a past cardiovascular event (RR 1.33 [1.12–1.59]), at least one therapy change (RR 1.28 [1.15–1.43]), at least a lipid test (RR 1.26 [1.07–1.49]). A similar pattern was observed for persistence. ConclusionsThis analysis of young adult HeFH patients showed that therapy change was quite frequent, and probably reflected adjustments according to individual response. Adherence and persistence were inadequate, even in this population at high cardiovascular risk, and they need to be improved through proper patient education and shared treatment decision-making approach.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia

Background and aimsThis multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). MethodsPatients 18–80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. ResultsAt Week 12, treatment with anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: −38.6 to −21.0; p < 0.001) favoring anacetrapib. Anacetrapib also reduced non-HDL-C (23. 6%; p < 0.001), ApoB (14.1%; p < 0.001) and Lp(a) (48.7%; p < 0.001), and increased HDL-C (110.0%; p < 0.001) and ApoA1 (48.2%; p < 0.001) versus placebo. Anacetrapib 100 mg added to ongoing therapy with statin ± other LMT for 12 weeks was generally well-tolerated. There were no differences between the groups in the proportion of patients who discontinued drug due to an adverse event or abnormalities in liver enzymes, creatinine kinase, blood pressure, electrolytes or adjudicated cardiovascular events. ConclusionsIn Japanese patients with HeFH, treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated.(ClinicalTrials.govNCT01824238)

Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study

Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Merck & Co, Inc.

Abstract 17368: The Diagnosis of Heterozygous Familial Hypercholesterolemia: Genotype versus Phenotype

Background: Heterozygous familial hypercholesterolemia (HeFH) is the most common dominantly-inherited disorder in man, affecting between 1:250 and 1:300 persons worldwide and estimates of more than 3 million with HeFH in the USA and Europe alone. Diagnosis is usually made by clinical criteria and confirmed with genetic testing. Despite next-generation gene sequencing, a causative mutation cannot be identified in up to 20% of patients even with a clinical diagnosis of definite HeFH. Given the prevalence, clinical diagnostic criteria are important tools for detection and early treatment of HeFH patients, particularly for clinicians outside of referral centers. Methods: The RUTHERFORD-1 and -2 studies enrolled patients with a clinical and/or genetic diagnosis of HeFH. All consenting patients in this analysis underwent FH genotyping. We compare the accuracy of clinical and genetic diagnosis of HeFH. Results: Of the 416 patients enrolled who consented to genetic testing, 342 (82%) were found to have genetically-confirmed HeFH. Of these patients, 288 (84%) met the Simon Broome criteria for definite and 54 (16%) for probable HeFH; 250 (75%) met the MEDPED clinical criteria for 100%, and 301 (90%) the 80% likelihood for a diagnosis of HeFH (Table). Conclusion: Although the optimal method to diagnose HeFH remains unclear, from these two trials there was close agreement between the two clinical classifications and genetic criteria. There were only a relatively small number of patients in whom genetic testing could not confirm the clinical diagnosis. Clinical criteria offer an inexpensive, low-technology ability for widespread screening in patients suspected of having HeFH. The advantage of genetic testing is that it allows for cascade testing of family members for the identified mutation who may not fulfill clinical criteria for the diagnosis of HeFH and application of family-oriented preventive strategies.

Abstract 9613: Randomized Evaluation of Anacetrapib Lipid-Modifying Therapy in Patients With HeteroZygous Familial HypercholesterolEmia (REALIZE Study)

Introduction: Anacetrapib, a cholesteryl ester transfer protein inhibitor, has been shown to robustly reduce atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), Apo B and raise high-density lipoprotein cholesterol (HDL-C) as well as ApoA1. Hypothesis: This 1-year, Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy and safety profile of anacetrapib added to optimized LDL-C lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH). Methods: Patients with a genotype-confirmed or clinical diagnosis of HeFH, treated with an optimal dose of statin ± other lipid-modifying medication(s) and having an LDL-C ≥100 mg/dL without history of cardiovascular disease or LDL-C ≥70 mg/dL with a history of CVD were randomized in a ratio of 2:1 to anacetrapib 100 mg (n=204) or placebo (n=102) for 52 weeks followed by a 12-week reversal phase. The primary end points were the percent change from baseline in LDL-C (beta-quantification method) and the safety profile of anacetrapib. This trial is registered in ClinicalTrials.gov, #NCT01524289. Results: A total of 306 patients were enrolled at 25 sites in 9 countries. At baseline, most patients were on high-dose statin therapy and &gt;70% also were on ezetimibe. Baseline LDL-C and HDL-C were 129.4 and 53.3 mg/dL, respectively. At Week 52, anacetrapib vs. placebo significantly reduced LDL-C by 39.7% and increased HDL-C by 102.1% (p&lt;0.001 for both). Significant placebo-adjusted reductions in Apo B (24.8%) and increases in Apo A-I (32.9%) also were observed. Significantly more patients in the anacetrapib vs. placebo group achieved LDL-C &lt;100 (82% vs. 18%; p&lt;0.001) and &lt;70 mg/dL (44% vs. 5%; p&lt;0.001). Sustained effects on LDL-C (21.9%; p&lt;0.001) and HDL-C (53.0%; p&lt;0.001) were seen 12-weeks after cessation of anacetrapib therapy. No clinically important between-group differences were seen in the proportions of patients with abnormalities in liver enzymes, CK, blood pressure, electrolytes, adverse experiences and adjudicated CV events. Conclusion: In patients with HeFH, treatment with anacetrapib for 1 year was generally well tolerated and resulted in substantial reductions in LDL-C and increases in HDL-C.

Abstract 19822: Ldlr Splice-Site Mutation (ivs9-1g&gt;A) Identified by Whole-Exome Sequencing in an Extended Family with Myocardial Infarction

Introduction: Large genome-wide association studies have identified a number of chromosomal loci for CAD and MI, which display clear significance yet weak absolute effects for disease manifestation. Combined, these loci explain only a small fraction of the expected heritability. Aim: Here we analyzed a rare extended family with clustering of MI/CAD by means of whole-exome-sequencing (WES) to reveal rare disease-causing variants, which may provide new insights in the cause of the disease. Methods: Primarily, we analyzed three affected cousins of a German MI family with 13 affected and 56 unaffected family members by WES using the Agilent SureSelect 38 Mb Kit. Variants were validated by Sanger re-sequencing. Results and Discussion: We identified 19,870 variants shared by all three sequenced family members. Of these, 17,268 variants were found in dbSNP with a frequency &gt;1%. Of the remaining 2,602 variants, 935 are conserved (46 Way) and again 728 are located outside of regions of segmental duplication. To identify function-altering variants we filtered all variants based on avsift score &gt;0.05 and ,,HIGH“ effect predicted by Annovar and SNPEFF, respectively. Due to the relative large number of potentially disease causing variants, we focused on the variants not known in dbSNP. This approach left three variants. One variant, a single base-pair substitution (G&gt;A) in intron 9 of the LDLR gene, was validated by Sanger re-sequencing. This variant lies in the acceptor splice-site of exon 10 (c.855-1G&gt;A) and leads the loss of exon 10 (loss of 76 AA) in the LDLR domain class B repeat. We sequenced all family members available for genetic analysis and found that the variant co-segregates with MI. Mutation carriers had -on average- elevated LDL cholesterol (LDLC) levels (211 vs 141mg/dL), but with variable plasma levels (116-274mg/dL), such that severe hypercholesterolaemia was not observed in our index patient. Conclusion: Using WES we identified the disease-causing variant for this familial form of MI in the LDLR . Interestingly, highly varying LDLC levels initially impeded the diagnosis of heterozygous familial hypercholesterolaemia. This work clearly show the power of systematic WES approaches for identification of disease causing variants within families.

790 DIABETES: THE MAIN PREDICTOR OF EXTENSIVE CORONARY CALCIFICATION IN STABLE ANGINA?

In a genetically heterogeneous group of 109 patients with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH), the influence of gender, apolipoprotein (apo) E genotype and the type of molecular defect in the LDL-receptor (LDLR) gene on the reduction of plasma LDL-cholesterol levels to treatment with a HMG-CoA reductase inhibitor (simvastatin) were studied. Response was determined as the percentage fall in LDL-cholesterol from untreated levels and as the proportion of patients where levels fell below 4.9 or 4.1 mmol/l. Of the patients, 86 individuals had tendon xanthomata (TX+) and a diagnosis of ‘definite’ FH and these individuals presented with a significantly higher untreated LDL-cholesterol compared to the 23 individuals who did not have xanthomas (TX−) and a diagnosis of ‘probable’ FH (8.14±0.19 vs. 6.81±0.25, P=0.001). Overall, HMG-CoA reductase inhibitor doses of 10, 20 or 40 mg/day resulted in a significant fall of LDL-cholesterol levels of 29, 39 and 49%, but at all doses those with TX had significantly higher levels than those without, and significantly fewer TX+ patients achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l than the TX− group (P<0.05 at each dose). In the TX+ group the response to treatment was of similar magnitude in men and women and in patients with different apoE genotype. In the ‘probable’ FH probands only three mutations were identified (detection rate 13%), one in the LDLR gene and two in the APOB gene, a detection rate significantly lower (P=0.02) than in the ‘definite’ FH probands where 28 mutations were detected (detection rate 37%). In the TX+ patients where no mutation was detected, treatment resulted in a greater proportion achieving LDL-cholesterol levels below 4.9 and 4.1 mmol/l compared to those with any LDLR mutation, this difference was close to statistical significance at the 4.9 mmol/l threshold at 10 mg/day (41 vs. 13%, P=0.058). For the 14 patients with an LDLR mutation that was predicted to be ‘severe’, fewer achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l at each dosage compared to the 16 individuals with ‘mild’ mutations, and this difference was statistically significant at the maximal dosage of 40 mg/day (P=0.018). Thus although characterisation of the molecular defect in FH patients may not be relevant to their immediate clinical management, those with a particular mutation may need more aggressive lipid-lowering treatment to reach LDL-cholesterol levels recommended to reduce the risk of coronary heart disease (CHD).

Effect of LDL-apheresis on plasma lipids, chitotriosidase and anti-oxLDL antibodies in heterozygous familial hypercholes-terolemia

Forty four consecutive subjects aged 29-58 years (21 males and 23 females) with a clinical diagnosis of heterozygous familial hypercholesterolemia periodically treated every 30 days with LDL-apheresis for statin resistance, were enrolled in this study. A lipid profile was obtained immediately before starting LDL-apheresis, a second profile was obtained within four hours after LDL-apheresis. Chit activity and anti-oxLDL levels were determined with appropriate methods in all patients before and after LDL- apheresis. Total cholesterol, LDL-cholesterol, HDL- cholesterol and triglycerides decreased significantly after LDL-apheresis, while the variations of Chit activity and anti-oxLDL were not significant after LDL-apheresis. The correlation between Chit and total cholesterol was negative (r= –0.44 and –0.50 res- pectively) before and after LDL-apheresis as between Chit and LDL-cholesterol (r= –0.45 and –0.55 respectively). Anti-oxLDL concentration before and after LDL-apheresis positively correlated with Chit activity (r= 0.52 and r = 0.63 respectively), negatively with total cholesterol (r= –0.33 and r = –0.35 res- pectively) and with LDL (r = –0.32 and r = –0.21 respectively). We think that removing LDL with LDL-apheresis the anti-oxLDL/oxLDL ratio could increase and the excess of anti-oxLDL could induce macrophage activation through the surface Fc receptors. Alternatively with high levels of LDL- cholesterol, the deposition of foam cells represent the characteristic evolution of atherosclerosis process. Macrophage activation in the heterozygous familial hypercholesterolemia could represent an attempt for re-modeling the vessel wall, reducing the growth of lipid plaques.

Diagnosis of heterozygous familial hypercholesterolaemia in children

Most children with familial hypercholesterolaemia (FH) are diagnosed by raised blood cholesterol levels, but the test lacks sensitivity and specificity. As such children have evidence of vascular dysfunction at an early age, correct identification of affected individuals is important so that treatment can be started. To determine levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in children with genetically proven FH and their unaffected siblings, in order to identify a diagnostic cut-off point if possible. Retrospective case-note survey. We studied the notes of 115 children aged 3-16 years, 69 proven FH and 46 unaffected sibs, 65 boys and 50 girls, from 31 families and 21 different mutations. Data recorded were age, sex, TC, and (when available) LDL-C. The lowest TC level in an affected individual was 4.7 mmol/l and the highest in normal individual was 6.05 mmol/l. This overlap range included 21 children (18% of the total). The corresponding figures for LDL-C were 3.0 and 3.7 mmol/l, which included eight children (8%). TC is not an effective test for differentiating affected and unaffected children with FH. LDL-C is better, but genetic testing remains the method of choice, especially if treatment decisions are to be taken.

Perceived Vulnerability to Heart Disease in Patients with Familial Hypercholesterolemia: A Qualitative Interview Study

Knowledge about the ways patients perceive their vulnerability to disease is important for communication with patients about risk and preventive health measures. This interview study aimed to explore how patients with a diagnosis of heterozygous familial hypercholesterolemia understand and perceive their vulnerability to coronary heart disease. We did a qualitative study of 40 patients with familial hypercholesterolemia who were recruited through a lipid clinic in Norway. We elicited participants' perceptions about their vulnerability to heart disease in semistructured interviews. Data were analyzed by systematic text condensation inspired by Giorgi's phenomenological method. We found that participants negotiated a personal and dynamic sense of vulnerability to coronary heart disease that was grounded in notions of their genetic and inherited risk. Participants developed a sense of their vulnerability in a 2-step process. First, they consulted their family history to assess their genetic and inherited risk, and for many a certain age determined when they could expect to develop symptoms of coronary heart disease. Second, they negotiated a personal sense of vulnerability by comparing themselves with their family members. In these comparisons, they accounted for individual factors, such as sex, cholesterol levels, use of lipid-lowering medications, and lifestyle. Participants' personal sense of vulnerability to heart disease could shift dynamically as a result of changes in situational factors, such as cardiac events in the family, illness experiences, or becoming a parent. Patients with a diagnosis of familial hypercholesterolemia negotiate a personal and dynamic sense of vulnerability to coronary heart disease that is grounded in their understanding of their genetic and inherited risk. Doctors should elicit patients' understanding of their family history and their personal vulnerability to individualize clinical management.