Life Course Approach to Familial Hypercholesterolemia.

Should Lipoprotein(a) be Measured in Youth?

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and review efforts. Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease (CVD). The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Recommendations for guideline-directed management and therapy, which encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treatments, are effective only when followed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision-making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities. The ACC/AHA Task Force on Clinical Practice Guidelines strives to ensure that the guideline writing committee both contains requisite expertise and is representative of the broader medical community by selecting experts from a broad array of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. The ACC and AHA have rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found online. Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance “user friendliness.” Guidelines are written and presented in a modular knowledge chunk format, in which each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyperlinked references are provided for each modular knowledge chunk to facilitate quick access and review. More structured guidelines–including word limits (“targets”) and a web guideline supplement for useful but noncritical tables and figures–are 2 such changes. This Preamble is an abbreviated version, with the detailed version available online. The reader is encouraged to consult the full-text guideline(P-1) for additional guidance and details, since the executive summary contains mainly the recommendations.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

High-intensity statins are recommended for all patients with familial hypercholesterolemia (FH) and non-statin lipid lowering therapies (LLTs) are indicated when there is an inadequate response to statins 1, 2 . In the pre-PCSK9 inhibitor (PCSK9i) era only about 40% of FH patients achieved an LDL-C level 3 . Partly based on the need for additional therapeutic options in high-risk FH patients, PCSK9 inhibitors were approved for treatment of heterozygous and homozygous FH in 2015. Nevertheless, emerging anecdotal data suggest that access to non-statin LLTs has been a challenge for FH patients though this has not been systematically evaluated. The FH Optimal Care of the US (FOCUS) study was designed by The FH Foundation to assess current treatment patterns of FH patients, and allowed us to assess rejection rates of PCSK9 inhibitors in those with FH or ASCVD.

Secondary Prevention for Atherosclerotic Cardiovascular Disease: Comparing Recent US and European Guidelines on Dyslipidemia.

The Added Value of Coronary Calcium Score in Predicting Cardiovascular Events in Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is one of the most common genetic disorders characterized by a predominant elevation in plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentration and higher incidence of premature atherosclerotic cardiovascular disease (ASCVD). It has been reported that the long-term coronary artery disease (CAD) and ASCVD risk in the US adults with the FH phenotype are up to approximately five-fold higher than that in the general population.[1] It has also been estimated that there is an important long-term burden of ASCVD in phenotypic but undiagnosed FH patients in the US, with the acceleration of CAD risk by 20–30 years.[1] In recent years, the features of under-diagnosis and under-treatment of FH patients has attained an intensive attention worldwide.[2] This increased risk is age dependent, with the highest relative risk in younger index ages. Notably, several atherosclerosis-related international academic organizations or societies have issued statements or guidelines consequently, which call for the actions to improve the diagnosis and treatment of this unique, treatable disease globally.[3–6] In the Asia Pacific region, FH is estimated to affect at least 15 million people.[7] Among them, China alone may account for more than half of the FH patients as it is the world's most populous country. The general knowledge regarding FH is not very unfamiliar for medical professionals. Premature ASCVD is a great concern in FH patients due to the extremely high plasma LDL-C concentration. If homozygous FH (HoFH) is left untreated, tendon xanthomas may usually be detected.[2] Since the 1950s, FH patients have been divided into heterozygous FH (HeFH) and HoFH, and diagnosing HeFH and HoFH based on the phenotypic features of ASCVD or xanthomas has frequently been difficult without the DNA analysis of FH genes.[3] With the development of genetic testing technology, multiple studies revealed that a severe defect in the ability to bind and internalize LDL particles was caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR).[8] Recent genetic insights indicate that besides LDLR (approximately 75%–95%), mutations in alleles of other genes including apolipoprotein B (ApoB), proprotein convertase subtilin/kexin9 (PCSK9), and LDLR adapter protein 1 (LDLRAP1) may also be a cause in few FH patients, which can result in impaired LDL metabolism, leading to life-long elevations in LDL-C and increased risk for premature ASCVD.[8–10] Currently, it is estimated that this unique disease of abnormal cholesterol metabolism presents in all racial and ethnic groups affecting 1 of 200–500 individuals worldwide and is now increasingly recognized as a global health issue.[5,6] From the perspectives of theory and clinical practice, FH as a major global public health challenge is even more serious in China. First, China is the largest country in the world and accounts for nearly one-fifth (18.84%) of the total 6.7 billion of the world's population. A commonly cited estimation of the frequency of HeFH is 1/500 (0.2%), which was calculated from the FH frequency in survivors of myocardial infarction (MI), of <60 years of age in a single study with some assumptive frequencies, including the prevalence of CAD in the population of the US.[4] However, contemporary data have suggested a higher frequency, highlighting that the burden of the disease is increasing including in the Chinese population.[9,10] According to the recently published 2016 Chinese guidelines for the management of dyslipidemia in adults (2016 revised version), the prevalence of dyslipidemia in Chinese adults reaches as high as 40.4% and covered approximately 160 million individuals.[11] This implies that at least seven millions of Chinese individuals may be classified as HeFH according to the commonly cited overall frequency estimation. Furthermore, a Chinese FH patients’ study with a large sample size from Beijing Fuwai hospital has recently reported that 3.5% of the patients were identified with definite/probable FH phenotype (definite, 1.0% and probable, 2.5%).[9] This study enrolled 8,050 consecutive patients undergoing coronary angiography (CAG) due to angina-like chest pain, and FH was diagnosed made using Dutch Lipid Clinic Network (DLCN) criteria and target exome sequencing in LDLR, ApoB, and PCSK9 genes. Simultaneously, another study by the same researchers showed that in 1843 consecutive patients with myocardial infraction (MI), the prevalence of definite/probable FH was 3.9% (7.1% in patients with premature MI and 0.9% in those with non-premature MI).[10] The authors concluded that the prevalence of FH among Chinese patients with MI or undergoing CAG appeared to be common, particularly among those with premature MI. These data strongly emphasize that FH is not uncommon in China. Therefore, FH should be considered as a condition of high concern, and more efforts are needed for its management. Another challenge is the change in the pattern of lipids during the past several years in China. Although the serum LDL-C concentration and the frequency of CAD may be slightly lower in the Chinese population than those before. With rapid economic growth and lifestyle changes, Chinese populations are experiencing increased cardiovascular risk and cardiovascular disease has become the leading cause of death.[11] A national prospective cohort study performed between 1991 and 2000 reported that 43.8% of deaths in Chinese adults of ≥ 40 years of age were attributable to CAD and stroke.[12] A report from the China National Diabetes and Metabolic Disorders Study (CNDMDS) comprising 46,232 Chinese adults suggests an alarm that levels of total cholesterol (TC) and LDL-C are considerably higher than those previously reported in the general Chinese population.[13] Accordingly, the increasing cholesterol levels have changed the FH phenotype in China, which may be another challenge in its diagnosis. Moreover, early diagnosis as well as effective treatment strategies in affected children with FH are challenges among experts, especially in China due to the single-child policy.[14] Single-child policy which lasted for more than half of a century, resulted in many single-child families. This phenomenon has a high impact on the family in terms of economics burden, psychological stress, healthcare issues, and domestic happiness. Hence, earlier screening of FH individuals including parent-mediated early diagnosis and intervention is important for single-child families.[15] Hence, parent-mediated early diagnosis and treatment for young children are the best strategies for prevention of premature ASCVD and improvement of survival in FH, especially in HoFH patients in the single-child society setting. Furthermore, improving public and healthcare professionals’ awareness of FH is another way for early diagnosis of FH. It is worth emphasizing that Chinese medical professionals should be obliged to actively take part in a global call for FH management.[16] In China, many people are unaware of FH, even among medical professionals who are working in well-known hospitals located in the first line cities. To improve the awareness, knowledge, and perception of FH among practitioners and hospitalized patients, a FH survey was recently performed in multiple cardiovascular centers including Beijing, Shanghai, Guangzhou, Wuhan, and Changchun (unpublished data). Surprisingly, among 345 cardiologists and 1,083 hospitalized patients with CAD, <10% of doctors recognized that an individual with plasma LDL-C >6.5 mmol/L might be considered as a diagnosis of FH (probable), and 3% of them answered that a person whose plasma LDL-C levels are > 8.5 mmol/L should be diagnosed as FH. Although as high as 82% of hospitalized patients vaguely considered that lipid disorders could be genetically inherited, only 0.7% of them learned about FH through consultation of a health website before hospitalization. More importantly, <50% of the investigated patients did not recognize that consistent elevated plasma LDL-C level was a risk factor of CAD. Therefore, a program of FH course for professionals and more propaganda for the population are urgently needed to improve the management of FH in China. Besides early diagnosis, early intervention of FH is crucial for the prevention of CAD. FH represents a major gap in preventive medicine and is clearly a public health problem. Considering the public health challenges that FH poses, gaps in care are currently being addressed by clinicians and researchers worldwide. Treatment of elevated LDL-C concentration in FH involves dietary and lifestyle management and pharmacotherapy. Statins are the mainstay pharmacotherapy and are supported by new evidence. A proportion of patients may need additional therapy with ezetimibe or bile-acid sequestrants. Furthermore, PCSK9 inhibitors are also recommended to treat FH. Without treatment, approximately 50% of men and 30% of women experience an ASCVD-related event by age 50 and 60 years, respectively. Evidence has shown that young adults with 20 years of statin therapy started in childhood had lower rates of both ASCVD-related events (1%) and death (0%) than their affected parent at a comparable age (26% and 7%, respectively), who started statin therapy later in life. According to previous studies,[17,18] 750,000 cases of CAD onset and 10,500 CAD deaths could be prevented if early intervention be employed based on the estimated seven million HeFH patients in China. Hence, early and appropriate intervention is of high importance. In addition, although China has already developed its own diagnostic criteria for FH, which is simpler and more convenient for clinically early diagnosis, more efforts are needed for its popularization and application. During the past several decades, there were scarce studies focusing on FH in China, which were mainly presented as case reports.[19] More recently, a novel modified system of simplified Chinese criteria for FH has been developed.[20] In this criteria, definite FH could be diagnosed in patients who meet any two out of the three items: LDL-C > 4.8 mmol/L, tendon xanthomas, and DNA mutation, which has similar sensitivity and specificity with the Simon Broome (SB) criteria and the Dutch Lipid Clinic Network (DLCN) criteria demonstrated by a large Chinese cohort.[20] However, these novel criteria need to be generalized in Chinese population. Studies in Chinese general population are required to test and confirm these novel FH criteria. Finally, China needs more joint efforts to respond to FH-related global call to arms due to the basic features of developing countries and imbalance in economics. As well-known, there is a great difference of health insurance system and economic growth between urban and rural areas in China, which may influence the early-diagnosis of FH in children and adolescents.[16] Early detection of FH is difficult due to lack of conventional physical examination, especially in vast rural areas of rural China. Universal lipid screening is not conventionally used in some parts of rural area. More efforts are needed for FH screening, early diagnosis, and early treatment, such as establishing a special network and foundation, performing a registry study, and strengthening the publicity.[21] The professionals, society, and even government should pay attention to this issue. Universal lipid screening FH in children between the ages of 9 and 11 years and common genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies to improve the efficacy of early identification and management of FH in China.[1,2] China may bear a heavy health burden as the most populous country in the world.[22,23] Conclusion FH is a common genetic disease characterized by premature ASCVD, which is associated with higher cardiovascular events but is preventable and treatable. With one-sixth of the world's population of individuals who are living with FH residing in China, the time has come to action for FH individuals. The phenotype of FH in China and other Chinese populations is now comparable to that in Western countries and the prevalence of FH in the general population is also similar. However, only a very small proportion of cases has been identified and treated. Although intensive statin treatment or statin plus ezetimibe or PCSK9 inhibitor is recommended for Chinese FH patients, the LDL-C target is often not achieved. Despite a high progress in FH management in China during the last decade, more efforts are needed to improve the current situation of our patients with FH, including engaging healthcare professionals, developing public awareness campaigns, and establishing national FH alliances. Universal lipid screening in children and common or expanded genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies. Finally, optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of FH patients. In summary, although the progress in FH management has been made in China during the past years, greater efforts are still needed in the future. Funding This work was partially supported by the Capital Health Development Fund (201614035), and CAMS Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr Jianjun Li, MD, PhD. Conflict of interest statement The author has no conflict of interest with regard to the content of this manuscript.

PurposeFamilial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH.MethodsAn anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources.ResultsBetween September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0–22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia.Conclusions:The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life.What is Known:• Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD).• The process of atherosclerosis starts in childhood• Pediatricians play an important role in the detection and treatment of children with FH.What is New:• Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment.• FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated low density lipoprotein cholesterol (LDL-C) and dramatically increased risk for premature atherosclerotic cardiovascular disease (ASCVD). FH diagnosis currently requires either the presence of a pathogenic variant in an FH gene, or phenotypic characteristics. However, genetic studies now suggest that FH encompasses four discrete subtypes: 1) presence of a monogenic FH variant, 2) a high LDL-C polygenic score, “polygenic FH,” 3) elevated lipoprotein(a), and 4) LDL-C &gt; 190 mg/dl and a positive family history without an identifiable genetic cause, or true “phenotypic FH.” Here, we screened 134,444 unrelated white British individuals with exome sequences available in the UK Biobank for individuals with FH subtypes. We classified 358 individuals (1 in 376; 0.27%) with a pathogenic variant in their exome sequence as monogenic FH, 2,800 had polygenic FH (1 in 48; 2.1%), 2,246 had elevated lipoprotein (a) (1 in 60; 1.7%), and 3,146 had phenotypic FH (1 in 43; 2.3%). The remaining 125,894 samples without an FH subtype were classified as controls. We stratified the cohort into statin treated and untreated individuals. Those with an FH subtype were 2.8 times more likely to be prescribed a lipid lowering medication at the baseline interview compared to controls. In the statin treated group (n=21,875), those with monogenic FH were at the highest risk for 10-year incident ASCVD. We observed a 2.7 (95% confidence interval (95% CI): 1.6-4.3) fold higher ASCVD risk in monogenic FH compared to controls as measured by the hazard ratio (HR). Those with elevated lipoprotein (a) and phenotypic FH were also at increased risk for ASCVD (HR = 1.5 (95% CI: 1.1-2.1) and HR = 1.6 (95% CI: 1.3-2.1), respectively). In contrast, we do not observe elevated rates of incident ASCVD in those with polygenic FH relative to controls among treated individuals. In the untreated group (n=112,569), the risk of ASCVD in FH subtypes was more pronounced relative to controls. Individuals with elevated lipoprotein (a) were at the highest risk of incident ASCVD (HR = 2.9, 95% CI: 2.4-3.7) among the four subgroups. In conclusion, we observed differences in ASCVD risk among subtypes of FH. These findings demonstrate the importance of considering subtypes in ASCVD risk assessment for patients who present with the FH phenotype.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Early diagnosis and timely treatment can substantially lower the risk of ASCVD. In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. We aimed to evaluate the prognostic impact of cascade screening for FH. Methods: We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1-17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results: During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P &lt; 2.2 х 10 –16 ), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95%CI = 0.22 to 0.60; P = 6.3 х 10 –5 ) when compared with the probands, even after adjusting for those known risk factors. Conclusions: The identification of patients with FH via cascade screening appeared to result in better prognoses.

Funding Acknowledgements Type of funding sources: None. Background The Multi-Ethnic Study of Atherosclerosis demonstrated that coronary artery calcium (CAC) scoring has proven to be an effective tool at guiding lipid lowering therapy in patients with dyslipidaemia who are at risk of atherosclerotic cardiovascular disease (ASCVD) in the setting of a cohort study. The 2019 joint ESC/EAS dyslipidaemia guidelines identify a number of risk modifiers to stratify ASCVD risk from low to very-high including Lipoprotein (a) [Lp(a)] and the identification of familial hypercholesterolaemia (FH) mutations. Purpose 1) To determine whether CAC scoring can improve the risk assessment of ASCVD in a lipid clinic setting and therefore act as a more effective guide for clinicians when implementing lipid lowering therapy. 2) To compare CAC scores in patients grouped by Lp(a) levels and FH mutations. Methods A retrospective cohort analysis of patients attending a specialist lipid clinic from July to December 2021 in a tertiary referral centre. Data was collected in July/August 2022. Patients were divided into two groups, those with a CAC score of 0 and greater than 0. Data collected included patient risk factors and modifiers as described in the 2019 joint ESC/EAS dyslipidaemia guidelines, serum Lp(a) levels and FH mutation status. Statistical analysis with SPSS software applied the Mann-Whitney and Chi Squared test. Results 49.4% patients (n=41) had a CAC score of greater than 0. Of the patients classified as very-high risk, 91.3% (n=21) had a CAC score of greater than 0. For those classified as high risk, 26.5% (n=9) had a CAC score greater than 0. The mean Lp(a) plasma level was 124nmol/L for a CAC score of 0, compared to 249nmol/L for a CAC score of greater than 0 (U=562,p=0.02). 23 patients had FH mutations, of which 47.8% (n=11) had CAC scores of greater than 0 (χ2 = 2.15, p= 0.340). Conclusion This initial analysis describes CAC scores in patients attending a specialist lipid clinic classified by ASCVD risk and risk modifiers. It suggests CAC scores have a role, either additional or confirmatory, in ASCVD risk assessment. Further analysis is required to include additional risk modifiers, expand the cohort and preform a more granular stratification of the group by CAC score.

To discuss recent findings related to epidemiology, diagnosis, natural history, atherosclerotic cardiovascular disease (ASCVD) risk heterogeneity and stratification, and treatment of familial hypercholesterolemia. Familial hypercholesterolemia persists subdiagnosed, inadequately treated and social disparities aggravate this scenario. Molecular diagnosis is recommended but still not widely available and reimbursed, also recent reclassification of genetic variants associated with familial hypercholesterolemia limits its routine use. New familial hypercholesterolemia clinical diagnostic criteria like FAMCAT are being tested and are apparently more accurate than the classical ones. Genetic traits for familial hypercholesterolemia and high lipoprotein(a) concentrations apparently co-exist and are associated with a higher ASVCD risk than each alone. Indeed, ASCVD risk is heterogenous in heterozygous familial hypercholesterolemia and prospective studies show that it is influenced not only by high LDL-C but also by other risk features like smoking, hypertension, or diabetes. Coronary artery calcification might indicate a higher risk familial hypercholesterolemia population that could benefit from further LDL-C lowering with PCSK9 inhibitors. The latter medications may reduce ASCVD risk in familial hypercholesterolemia individuals similarly to their impact on the general population as shown in a randomized prospective development program (SPIRE). Knowledge about familial hypercholesterolemia has improved but there are still many challenges for its optimal management.

Lp(a) (lipoprotein [a]) and coronary artery calcium score (CACS) are independently associated with atherosclerotic cardiovascular disease (ASCVD) risk. This study aimed to investigate sex-specific prognostic differences between Lp(a) and CACS in ASCVD risk. We analyzed 4651 participants from the Multi-Ethnic Study of Atherosclerosis, grouped by sex. Multivariable Cox regression analysis was performed to evaluate the prognostic value of Lp(a) and CACS for ASCVD risk in both sexes. The predictive performance of these factors was compared in men and women. During a median follow-up of 13.84 years, 465 ASCVD events were recorded (272 in men and 193 in women). Multivariable Cox regression analysis revealed that both elevated Lp(a) and CACS were independent predictors of ASCVD risk in both sexes. The C-index analysis demonstrated that CACS provided incremental prognostic value over Lp(a) in men (C-index: 0.732 versus 0.714; P=0.011), but not in women (C-index: 0.776 versus 0.762; P=0.069). Notably, in men with CACS >400, elevated Lp(a) levels (adjusted hazard ratio, 1.822 [95% CI, 1.041-3.189]; P=0.036) were associated with higher ASCVD risk, although no such association was observed in those with CACS ≤400. In women, elevated Lp(a) levels were associated with increased ASCVD risk in those with CACS >100 (adjusted hazard ratio, 1.877 [95% CI, 1.130-3.118]; P=0.015). Although both Lp(a) and CACS independently predict ASCVD risk in both sexes, the predictive value of Lp(a) varies significantly between men and women across different CACS categories. These findings may inform sex-specific strategies for primary prevention of ASCVD.

Introduction: Coronary artery calcium (CAC) scoring is a powerful tool for atherosclerotic cardiovascular disease (ASCVD) risk assessment. Guidelines recommend consideration of CAC scoring in intermediate risk patients, but it’s utility in low and borderline risk patients is less clear. Methods: We used data from 2,894 participants from MESA with low (&lt;5%) or borderline (5-&lt;7.5%) 10-year ASCVD risk defined by the pooled cohort equations (PCE). We evaluated the association between CAC score and coronary heart disease (CHD) and ASCVD risk using multivariable adjusted Cox proportional hazard models. We also evaluated if the addition of CAC to the pooled cohort equations (PCE) improved risk prediction using Harrell’s C-index and net reclassification improvement (NRI). Results/Data: Mean age was 54.1 ± 5.8 years with 66.9% women. Among low-risk individuals, the ASCVD event rate was 3.3% with CAC=0, and 7.8% with CAC&gt;0, and 4.7% vs. 11.4% among borderline-risk individuals. Natural-log transformed CAC score was associated with increased ASCVD risk in low-risk (HR 1.35, 95% CI 1.22-1.50) and borderline-risk (HR 1.29, 95% CI 1.15-1.45) individuals. Similar results were seen for CHD with higher HRs (Table 1). The addition of CAC to the PCE improved the C-index (SE) among low/borderline risk individuals from 0.620 (0.023) to 0.671 (0.024). Continuous NRI was also significant with the addition of CAC to the PCE in low/borderline risk (0.422, 95% CI 0.248-0.611). Greater improvement was seen for CHD (Table 2). Conclusions: The presence of CAC in low and borderline risk individuals is associated with increased ASCVD and CHD risk. The addition of CAC scoring to the PCE improved risk prediction in low and borderline risk individuals, suggesting potential clinical utility in this population.

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