Atherosclerosis Society Research Articles

Impact of the severe familial hypercholesterolemia status on atherosclerotic risks

Abstract Backgrounds Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. Purpose This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Methods Data of patients with FH (N = 1,050, male = 490) who were admitted to our university hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1,000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Results Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P < 0.001). The event rates per 1,000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1,000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Conclusions Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Impact of changes of Achilles tendon thickening on cardiovascular events among patients with familial hypercholesterolemia

Abstract Backgrounds Achilles tendon thickening (ATT) can be regressed through LDL-lowering in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) determined the threshold of ATT as ≥8.0 mm in male and ≥7.5 mm in female. Purpose We aimed to determine clinical impact of changes of ATT in development of major adverse cardiovascular events (MACE). Methods Patients with clinically diagnosed FH (N=1,273, male/female=614/659) with ATT data using X-ray were assessed. We divided the patients into 4 groups (group 1: patients without ATT from baseline to their follow-up, group 2: patients without ATT at baseline, but developed ATT at follow-up, group 3: patients with ATT at baseline, but regressed at follow-up, group 4: patients with ATT from baseline to their follow-up). Cox proportional hazards models were used to assess factors associated with MACE, including cardiovascular death and any coronary events. Results The median follow-up period was 10.9 years. During the follow-up period, 142 MACEs were observed, and median ATT was regressed from 7.8 to 7.6 mm. We found that there was more significant positive correlation between cholesterol-year score and ATT among patients with and without MACE (p <0.001; Spearman’s r=0.33, and p <0.001; Spearman’s r=0.35, respectively). Under these circumstances, changes of ATT were significantly associated with the occurrence of MACE (hazard ratio (HR): 2.73; 95% confidence interval (CI): 1.33–4.13; p<0.001, HR: 2.18; 95% CI: 1.08–3.28; p<0.001, HR: 6.34; 95% CI: 3.10–9.58; p<0.001, in group 2, group 3, and group 4, respectively when group 1 was considered as reference). Conclusion Assessments of ATT condition represent diagnostic values and risk stratification information among patients with FH.

Intraindividual variability in lipoprotein(a): the value of a repeat measure for reclassifying individuals at intermediate-risk

Abstract Background Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease and outcomes. Levels are predominantly genetically determined and repeat measurements are traditionally considered unlikely to be useful. However, the temporal variation of Lp(a) is not well characterized and it is unclear whether a single measure of Lp(a) is sufficient to assess cardiovascular risk in all individuals. Purpose To determine the intraindividual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. Methods This retrospective cohort study analyzed initial and repeated Lp(a) measures obtained using the same laboratory assay from 609 individuals in the Nashville Biosciences database accessed through the American Heart Association Precision Medicine Platform. Categorical variables are presented as counts (%) and compared using Fisher’s exact test. Continuous variables are presented as mean ± standard deviation or median (Q1-Q3), tested for normality using the Shapiro-Wilk test, and compared using parametric and nonparametric tests where appropriate. The Spearman’s Rank correlation coefficient was used to assess the relationship between two variables. The significance level was set at p<0.05. Results Median age was 52.5 (37.1-62.8) years, 45% were women, 80.3% were White patients, 13.3% were Black patients, 1.6% were Asian patients, and 4.8% were other/unknown patients. In terms of relevant comorbidities, 41% had ischemic heart disease, 24.1% had chronic kidney disease, and 13.5% had liver disease. The median time between the two Lp(a) measures was 1.07 (0.5-2.1) years. Our analysis shows a significant difference between the paired Lp(a) values (p<0.05), with 38.1% [95% CI 34.2%-42%] changing by ≥10mg/dL, and 40.5% [95%CI 36.6%-44.3%] changing by >25%. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r=0.59, p<0.01). The proportions of individuals with variability are similar in those who were never on the potentially Lp(a)-altering agents (statin, niacin, or PCSK9 inhibitor drugs) (n=91), with 32% [95%CI 22.4%-41.6%] changing by ≥10mg/dL, and 34% [95%CI 24.3%-43.7%] changing by >25%. While over 90% of those whose values were initially in the EAS low-risk and high-risk categories remained in those categories, 53% of those in the intermediate "grey-zone" category transitioned to either the low (20%)- or the high (33%)- risk category (Figure). Conclusion(s) Temporal-related changes in Lp(a) variability were present in many individuals and should be included in calculating the expected effect sizes in future studies targeting Lp(a). A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate "grey-zone" category.

Serum Lipoprotein(a) Levels and Their Association with Atherosclerotic Cardiovascular Disease in Japan.

To investigate the distribution of lipoprotein(a) (Lp(a)) and its association with atherosclerotic cardiovascular disease (ASCVD) in Japanese patients at high risk for ASCVD using a health insurance database. Between July 2013 and June 2021, patients eligible for ASCVD prevention according to the 2017 Japan Atherosclerosis Society (JAS) guidelines with documented Lp(a) test results were extracted from the Medical Data Vision claims database and divided into three groups: primary prevention high-risk (Group I), secondary prevention (Group II) and secondary prevention high-risk (Group III). Data on lipid levels, cardiovascular morbidity risk factors and lipid-lowering treatments were extracted. Of 700,580 patients with documented low-density lipoprotein cholesterol (LDL-C), 2,967 (0.42%) were tested for Lp(a). In 2,170 eligible patients, the median [interquartile range] serum concentration of Lp(a) was 13.9 [7.5-24.6] mg/dL, with 151 patients (7.0%) above the recommended risk threshold of ≥ 50 mg/dL. Lp(a) levels increased with risk across all prevention groups. Being in the highest Lp(a) quintile (Q5) was associated with an increased frequency of ASCVD (28.9% versus 18.9% in the lowest quintile (Q1) for unstable angina; 18.7% versus 10.1% for myocardial infarction; 27.9% versus 17.0% for ischemic stroke). In the secondary prevention groups, the proportion of patients meeting an LDL-C target of ＜70 mg/dL decreased from 30.2% in Q1 to 19.0% in Q5 for Group II and from 32.9% to 16.3% for Group III. Despite a high prevalence of Lp(a) ≥ 50mg/dL in Japanese patients at high risk for ASCVD, it found that the Lp(a) testing rate was very low.

Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia (APH-19): results from the efficacy phase of an open-label, multicentre, phase 3 study

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder characterised by extremely high concentrations of LDL cholesterol, leading to early-onset atherosclerosis. Lomitapide is an orally administered microsomal triglyceride transfer protein (MTP) inhibitor that effectively lowers LDL cholesterol and is approved for adults with HoFH. We aimed to investigate the efficacy and safety of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy. APH-19 is an open-label, single-arm, phase 3 trial performed at 12 study centres in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. A 6-week run-in period was followed by a 24-week efficacy phase and an 80-week safety phase. Patients aged 5-17 years, on stable lipid-lowering therapy, with HoFH diagnosed using the criteria from the 2014 European Atherosclerosis Society Consensus Panel on HoFH were titrated to maximum tolerated doses of oral lomitapide, starting at 2 mg (patients aged 5-15 years) or 5 mg (patients aged 16-17 years). The primary endpoint was the percentage change from baseline to week 24 in LDL cholesterol, which was assessed in patients who had received at least one dose of lomitapide, and who had a baseline and at least one post-baseline measurement. The secondary outcomes were the percentage change from baseline at week 24 in total cholesterol, non-HDL cholesterol, VLDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04681170. Between Dec 20, 2020, and Oct 16, 2022, 43 patients were included and treated (24 [56%] were female and 19 [44%] were male, and median age was 10·7 years [7·0-14·0]). Mean change from baseline in LDL cholesterol at week 24 was -53·5% (95% CI -61·6 to -45·4, p<0·0001). Mean percentage reductions were observed at week 24 for non-HDL cholesterol (-53·9%, 95% CI -61·7 to -46·1, p<0·0001), total cholesterol (-50·0%, 95% CI -57·6 to -42·4, p<0·0001), VLDL cholesterol (-50·2%, -59·1 to -41·2, p<0·0001), apolipoprotein B (-52·4%, -60·3 to -44·5, p<0·0001), triglycerides was -49·9% (-58·8 to -41·0, p<0·0001), and lipoprotein(a) (-11·3%, -32·9 to 10·3 [in 21 patients with measurements in mg/dL]; -23·6%, -38·2 to -9·0 [in 22 patients with measurements in nmol/L]; p=0·0070 combined). Adverse events were mostly mild, and gastrointestinal and hepatic in nature. Adverse events of special interest were reported for five (12%) patients (gastrointestinal in two patients and hepatic in three). One serious treatment-emergent adverse event was reported (also classed as an adverse event of special interest): an increase in hepatic enzymes, resulting in two dose interruptions, two dose reductions, and a repeated dose escalation. Lomitapide provided a significant, clinically meaningful LDL cholesterol reduction and has the potential to be an efficient, LDL receptor-independent option for paediatric patients with HoFH. Amryt Pharmaceuticals.

Relationship Between Smoking and Lipid Profile in Four Primary Health Care Units: A Research Study.

Introduction Smoking is the most preventable cause of cardiovascular disease (CVD).Dyslipidemia is also an important risk factor for CVD. Yet, research has provided contradicting findings regarding the association between smoking and blood lipids. This study aims to assess the relationship between smoking and dyslipidemia, as well as compliance with the previously established treatment target. Materials and methods This was a cross-sectional study. Apparently, healthy users aged 40 or over, were from four primary health care units (PHCU) in Portugal. The inclusion criteria were: age between 40 and 69 and active enrollment in one of the four PHCU. The exclusion criteria were: background of atherosclerotic disease, heart failure, chronic kidney disease, diabetes mellitus, and a history of acute myocardial infarction; no record of lipid profile or triglyceride value of more than 400 mg/dL.Cardiovascular risk levels were determined using the Systematic Coronary Risk Evaluation (SCORE) 2 risk. The low-density lipoprotein cholesterol (LDL-c) target was considered the recommendation by the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) 2019. Results From an initial population of 16,939 patients, 12,076 apparently healthy patients were included.The difference between cholesterol values is statistically significant, with total cholesterol, LDL-c, and triglyceride values tending to be higher in the smoking group and the high-density lipoprotein cholesterol (HDL-c) value tending to be higher in the non-smoking group. Regarding the LDL target, there is also a statistically significant difference between smokers and non-smokers. Discussion Smoking and dyslipidemia are two isolated cardiovascular risk factors. Their association has been questioned. This study demonstrated that there is an association between smoking and the lipid profile, but also with the LDL target. However, there are some biases that must be considered, and which do not allow for generalization. Conclusions This study concludes that smoking negatively influences the lipid profile, with lipids being found less frequently on target. However, more studies are needed in this area, particularly studying other relevant factors such as body mass index.

Intra-individual variability in lipoprotein(a): the value of a repeat measure for reclassifying individuals at intermediate risk.

Lipoprotein(a) [Lp(a)] levels are predominantly genetically determined and repeat measurements are generally considered unlikely to be clinically useful. However, the temporal variation of Lp(a) is not well characterized. Our aim was to determine the intra-individual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. This retrospective cohort study analysed initial and repeated serum Lp(a) levels measured using the same methodology from 609 individuals in the Nashville Biosciences database, a de-identified electronic medical records database. Baseline and follow-up paired values were significantly different (P < 0.05), with an absolute change of ≥10 mg/dL in 38.1% [95% CI 34.2-42%] and a >25% change in 40.5% [95% CI 36.6-44.3%] of individuals. Although the categories of those whose values were in the EAS low-risk and high-risk categories did not change, 53% of those in the intermediate 'grey-zone' category transitioned to either the low-risk (20%) or high-risk (33%) category. Black individuals exhibited greater variability than White individuals and women exhibited greater variability than men. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r = 0.59, P < 0.01). Temporal-related changes in Lp(a) variability were present in many individuals. A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate 'grey-zone' category. Lp(a) variability should be included in calculating the expected effect sizes in future clinical research studies targeting Lp(a).

Primary Prevention of Coronary and Other Cardiovascular Diseases: A Focused Review.

In 2022, the Japan Atherosclerosis Society (JAS) updated its prevention guidelines, the "Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022" (JAS2022GL), expanding its scope from coronary artery disease (CAD) to atherosclerotic cardiovascular diseases (ASCVDs), including atherothrombotic stroke. The following year, the Japanese Circulation Society (JCS) updated its guidelines for primary prevention entitled "JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease" (JCS2023GL). Since those publications, scientific advancements in relevant fields have continued. This review article outlines the current recommendations provided by the guidelines, provides background information supporting these recommendations, introduces scientific findings subsequent to prior publications, and discusses future directions on select topics for the primary prevention of CVD. The topics covered in this review are traditional risk factors, including dyslipidemia and hypertension, the application of comprehensive risk stratification or risk scoring systems, patient-specific topics, salt and alcohol, and environmental factors. These topics were deliberate and selected by the authors, who were involved in the compilation of either or both JAS2022GL and JCS2023GL. This review not only emphasizes the pivotal role of continuously updated guidelines in shaping clinical practice but also stresses the urgent need for ongoing research to bridge existing knowledge and practice gaps.

Highlights of the 92nd European Atherosclerosis Society (EAS) Congress, May 26-29, 2024, Lyon, France

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Improved Efficiency of the Clinical Diagnostic Criteria for Familial Hypercholesterolemia in Children: A Comparison of the Japan Atherosclerosis Society Guidelines of 2017 and 2022.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467. The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

The Role of Reverse Cascade Screening in Children with Familial Hypercholesterolemia: A Literature Review and Analysis.

Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevation of severely elevated plasma low-density lipoprotein cholesterol. Atherosclerotic cardiovascular disease (ASCVD) risk accelerates after age 20. Early diagnosis allows for treatment of children with FH and creates an opportunity to identify affected relatives through reverse cascade screening (RCS). Historically, cascade screening has had little impact on identifying individuals with FH. Universal cholesterol screening (UCS) to identify youth with FH, beginning at 9-11 years-of-age, is currently recommended in the U.S. The European Atherosclerosis Society has called for UCS worldwide, emphasizing the need for educational programs to increase awareness amongst healthcare professions. Underdiagnoses and undertreatment of FH remain high. Improved rates of UCS and a systematic approach to RCS are needed. The absence of a coordinated RCS program limits the benefits of UCS. Further research is needed to identify barriers to cholesterol screening in youth.

OPA1 affects lipid metabolism and atherosclerosis progression

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): European Atherosclerosis Society Introduction Mitochondria are involved in cellular metabolism, energy generation, calcium homeostasis, sterol and bile acids (BAs) production. Mitochondria continuously undergo biogenesis, fusion, fission and mitophagy, maintaining a continuous balance between all forms. Purpose On these premises, we test the impact of OPA1, an inner mitochondria membrane fusion protein, on mitochondrial tethering on lipid metabolism in the liver and the atherosclerotic plaque. Methods OPA1HepKO and OPA1 TG on LDLR KO background were fed with a Western-type diet (WTD) respectively for 12 weeks. Inverse calorimetry, GTT, and LipidToleranceTest (LTT) were performed. Paraffin-embedded tissues were used for histological analysis, frozen tissues were used for OMICs analysis. VSMCs were isolated and cultured with VLDL (50 µg/ml). Results While OPA1HepKO mice display altered systemic metabolism with reduced body weight and reduced circulating lipid levels OPA1 overexpression on LDLR KO background showed significantly high cholesterol levels. OPA1 deficiency impair hepatic bile acid conjugation with significant accumulation of primary unconjugated bile acids in the liver. On the contrary OPA1 overexpression leads to a reduction of unconjugated bile acids and higher percentage of conjugated bile acids. OPA1 reduction leads to a reduced atherosclerotic plaque while, on the contrary, its overexpression doesn’t affect atherosclerosis despite an increase in circulating lipid and lipoprotein levels. OPA1 overexpression is therefore promoting plaque stabilization with VSMCs that are less prone to change their metabolism to synthetic. Conclusion Hepatic Opa1 deficiency alters bile acids production and therefore circulating lipid profile with a consequent reduction in atherosclerotic plaque formation. OPA1 overexpression in the aorta affects plaque stability despite the highest levels of circulating lipids.

#1212 Trends in real-world lipid lowering therapy use among adult patients with chronic kidney disease: 5-year single center experience in the Philippines

Abstract Background and Aims Patients with chronic kidney disease (CKD) carry an extremely high burden for atherosclerotic cardiovascular disease (ASCVD), which worsens as CKD progresses. Several international guidelines, including the 2013 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, have recommended the use of lipid-lowering therapy (LLT) in this high-risk population. To evaluate the implementation of these recommendations in real-world practice, we assessed patterns of dyslipidemia management among patients with CKD. Specific objectives include describing the prevalence and intensity of LLT prescription [stratified by estimated glomerular filtration rate (GFR) and whether requiring renal replacement therapy or not] as well as adherence to guideline recommendations on LLT use. Method We conducted a single-center, cross-sectional study covering the period of January 2019 to December 2023. A review of inpatient and outpatient medical records of the Department of Medicine, University of the Philippine—Philippine General Hospital was done. Eligible patients were at least 18 years of age, and diagnosed with CKD. Exclusion criteria included having a concomitant diagnosis of Acute Kidney Injury, and being pregnant or breastfeeding at any point in the study period. Sociodemographic, clinical, and laboratory data were based off the latest entry in each patient's medical record. No clinical data were collected beyond those that were available on the records. Classification of statin intensity was based on the 2019 American Heart Association/American College of Cardiology Guidelines on the Management of Blood Cholesterol as well as the 2020 Philippine Clinical Practice Guidelines on the Management of Dyslipidemia. All analyses were descriptive and done using STATA 18. Categorical variables were summarized as frequencies and percentages. Continuous variables were reported as measures of central tendency [i.e. mean (SD) or median (IQR), as appropriate]. Results Of the 3845 patients included in the study, 2922 (76%) were prescribed LLT. The most common LLT were statins (92%), followed by statin/ezetimibe combinations (6%), then statin/fibrate combinations (2%). None were prescribed PCKS9 inhibitors, niacin, omega-3 fatty acids, or bile acid sequestrants. Among non-dialytic patients, the distribution of LLT use was as follows: a) eGFR ≥ 60 ml/min/1.73 m2: 40% (173/431) b) eGFR 30-60 ml/min/1.73 m2: 76% (1198/1576) c) eGFR &amp;lt;30 ml/min/1.73 m2: 84% (1551/1838). Among dialytic patients, 68% (601/884) were already on LLT prior to initiation of dialysis while 35% (283/884) were started on LLT after dialysis initiation. Notably, 89% (786/884) of these dialytic patients were still on moderate-to-high-intensity statin doses. Based on recommendations from the 2013 KDIGO guidelines, only 78% (2610/3334) of eligible patients were prescribed on LLT, while 61% (312/511) of ineligible patients were prescribed on LLT. Similar rates of adherence were seen to other international guideline recommendations on the management of dyslipidemia in CKD (e.g. 2018 American Heart Association/American College of Cardiology Guideline on the Management of Blood Cholesterol, 2019 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidaemias, 2020 Clinical Practice Guidelines for the management of dyslipidemia in the Philippines). Conclusion Real-world LLT use among CKD patients remains high, even at lower eGFRs. More importantly, a large proportion of patients remain under- and over-treated, highlighting significant gaps between guideline recommendations and real-world clinical practice. Further investigation regarding the underlying reasons for these practice variations is necessary to improve quality of care, and safely reduce the burden of dyslipidemia and ASCVD among CKD patients.

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors.

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

Simplified Criteria for Identification of Familial Hypercholesterolemia in Children: Application in Real Life.

The diagnosis of familial hypercholesterolemia (FH) in children is primarily based on main criteria including low-density lipoprotein cholesterol (LDL-C) levels, increased in the proband and relatives, and its inheritance. Two other relevant parameters are symptoms, rarely occurring in children, as rare are the FH homozygous patients, and the mutation detection of related genes. The latter allows the final diagnosis, although it is not commonly available. Moreover, the application of diagnostic scores, useful in adults, is poorly applied in children. The aim of this study was to compare the reliability of criteria here applied with different scores, apart from genetic analysis, for FH diagnosis. The latter was then confirmed by genetic analysis. n. 180 hypercholesterolemic children (age 10.2 ± 4.6 years) showing LDL-C levels ≥95th percentile (age- and sex-related), the dominant inheritance pattern of hypercholesterolemia (including LDL-C ≥95th percentile in one parent), were considered potentially affected by FH and included in the study. The molecular analysis of the LDLR, APOB and PCSK9 genes was applied to verify the diagnostic accuracy. Biochemical and family history data were also retrospectively categorized according to European Atherosclerosis Society (EAS), Simon Broome Register (SBR), Pediatric group of the Italian LIPIGEN (LIPIGEN-FH-PED) and Dutch Lipid Clinic Network (DLCN) criteria. Detailed kindred biochemical and clinical assessments were extended to three generations. The lipid profile was detected by standard laboratory kits, and gene analysis was performed by traditional sequencing or Next-Generation Sequencing (NGS). Among 180 hypercholesterolemic subjects, FH suspected based on the above criteria, 164/180 had the diagnosis confirmed, showing causative mutations. The mutation detection rate (MDR) was 91.1%. The scoring criteria proposed by the EAS, SBR and LIPIGEN-FH-PED (resulting in high probable, possible-defined and probable-defined, respectively) showed high sensitivity (~90%), low specificity (~6%) and high MDR (~91%). It is noteworthy that their application, as a discriminant for the execution of the molecular investigation, would lead to a loss of 9.1%, 9.8% and 9.1%, respectively, of FH-affected patients, as confirmed by the genetic analysis. DLCN criteria, for which LDL-C cut-offs are not specific for childhood, would lead to a loss of 53% of patients with mutations. In the pediatric population, the combination of LDL-C ≥95th percentile in the proband and the dominant inheritance pattern of hypercholesterolemia, with LDL-C ≥95th percentile in one parent, is a simple, useful and effective diagnostic criterion, showing high MDR. This pattern is crucial for early FH diagnosis. EAS, SBR and LIPIGEN-FH-PED criteria can underestimate the real number of patients with gene mutations and cannot be considered strictly discriminant for the execution of molecular analysis.

Frequency and determinants of lipid management target achievement in primary prevention of cardiovascular disease in type 2 diabetes.

This study aimed to clarify the real-world status of lipid management in outpatients with type 2 diabetes (T2DM) following the 2022 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases. It also aimed to evaluate characteristics associated with the failure to achieve management targets. In this post-hoc analysis of a multicenter, cross-sectional study, we included Japanese outpatients with T2DM undergoing primary prevention of atherosclerotic cardiovascular diseases (ASCVD) who provided fasting blood samples. The frequency and determinants of achieving low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) targets were assessed. Among 223 participants with a mean age of 67 and mean HbA1c of 7.1%, 61 had no history of peripheral arterial disease, microvascular complications, or smoking. Out of the 223 participants, 64.1% (95% CI: 57.6-70.1%) achieved the LDL-C target. In multivariate logistic regression analysis, being female (odds ratio [OR] 3.139, P = 0.0011), having diabetic nephropathy (OR 2.868, P = 0.0021), smoking (OR 2.292, P = 0.0281), and non-use of statins (OR 4.857, P < 0.0001) were independently associated with non-achievement. For non-HDL-C, 65.6% (95% CI: 58.1%-70.6%) of patients met the target. Having diabetic neuropathy (OR 2.428, P = 0.0054), smoking (OR 2.008, P = 0.0478), and non-use of statins (OR 2.277, P = 0.0112) were identified as factors associated with non-achievement. Low achievement rate of revised lipid management targets for ASCVD primary prevention in T2DM was unveiled. Assessing comorbidities, encouraging smoking cessation, and prioritizing statin use are considered.

Application of implementation science for improving the utilization of an international clinical practice guidance on familial hypercholesterolemia

The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones. Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy. Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target). A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target). We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice.

Serum Lipoprotein(a) and Angiographic Severity of Coronary Artery Disease in Asian Indians

Abstract Background: With the renewed interest in lipoprotein a (Lp(a)) shown by the European Atherosclerosis Society in relation to cardiovascular disease occurrence worldwide and especially in the South Asian population, its estimation once in a lifetime has been recommended (1–3). However, the role of this proatherogenic Lp(a) in regulating the severity of angiographic lesions in coronary artery disease (CAD) is poorly understood. This study aimed to correlate the serum Lp(a) level with angiographic lesion severity in subjects with CAD. Subjects and Methods: In this cross-sectional study, a total of 100 adult patients (mean age: 52.56 [±12.84] years, 84 [84%] males) with angiographically confirmed CAD were enrolled in a tertiary care hospital in Eastern India and their serum Lp(a) levels were estimated (by immunoassay method) and correlated with the SYNTAX score groups (&lt;22, 22–33, and &gt;33) and extent of disease – single-vessel disease (SVD), double-vessel disease (DVD), or triple-vessel disease (TVD). Results: Mean serum Lp(a) was elevated in the more severe disease group with SYNTAX &gt;33 (88.79 mg/dl) than in lesser severity disease groups of SYNTAX 22-33 (57.07 mg/dl) and SYNTAX &lt;22 (35.13 mg/dl), and this trend was found to be significant by analysis of variance (ANOVA) (P &lt; 0.001). Mean levels of Lp(a) were lower in patients with SVD (33.15 mg/dl) and DVD (33.93 mg/dl) than in those with the TVD group (77.71 mg/dl), and this trend was found to be significant by ANOVA (P &lt; 0.001). Conclusion: Serum Lp(a) values had a high significant positive correlation with the angiographic severity (higher SYNTAX score and Multivessel CAD) in patients of CAD in this study. Lp(a) is a known risk factor for CAD in South Asians and statins do not appear to decrease their levels; further, our study compounds the problem by correlating its level with increasing severity of CAD. This study therefore asserts the importance of the estimation of Lp(a) in South Asian individuals and proposes larger studies to confirm its correlation with the severity of CAD.