Background and aims Familial hypercholesterolemia (FH) is a prevalent genetic disorder causing lifelong elevated LDL-cholesterol and premature cardiovascular disease. After the Dutch national FH testing program ended in 2014, the LEEFH foundation continued testing with an 80% reduction in funding and a leaner model. This study evaluates the first 10 years of FH testing via LEEFH as a model for global FH testing initiatives. Methods Cross-sectional study of retrospective data from the Dutch FH cascade testing program (LEEFH, 2014–2024). Outcomes included the number of individuals tested, diagnostic yield, relatives identified per index patient, temporal trends, and referral patterns. Geographic coverage was assessed by mapping testing data to postal codes and comparing detected cases with estimated FH prevalence. Results 31,487 individuals underwent genetic FH-testing. Annual testing increased from 1,416 in 2014 to 4,356 in 2024, while the annual yield of cascade testing increased from 165 to 541 FH-positive relatives. Diagnostic yield among index patients declined from 20.9% (236/1,128) in 2014 to 10.0% (304/3,044) in 2024 (p<0.001), while yield among relatives remained close to 50% (56.9% to 48.7%, p=0.013). Cascade testing efficiency improved, from 0.69 to 1.78 FH-positive relatives per index case. The proportion of individuals aged <18 years identified through cascade testing was 41.4% in 2014 and 48.1% in 2024 (p=0.138; p for trend=0.006). Conclusion The LEEFH cascade testing program effectively detects new FH cases through family cascade testing, with substantial public health impact. Updated insights into outcomes and efficiency may guide international FH testing efforts.
Although repeated testing of lipoprotein(a) (Lp(a)) is generally not recommended due to the genetically determined nature of concentrations, reports of significant intra-individual variability in serial assessments have challenged the single lifetime measurement framework. Using Lp(a) assessments at baseline, month 12, and month 24 from participants in the REDUCE-IT trial, we identified characteristics that could support repeated testing. Among 386 participants (36.3%) with baseline Lp(a) 50 to <70 mg/dL, 140 (36.3%) had at least one subsequent assessment ≥70mg/dL, whereas among 630 participants with baseline Lp(a) ≥70mg/dL, 133 (21.1%) had at least one subsequent assessment <70 mg/dL. Baseline Lp(a), sex, race, and several other characteristics were related to variability. Consequently, among individuals at high cardiovascular risk with hypertriglyceridemia and controlled LDL-C on statin therapy, considerable variability was observed over 24 months. These findings suggest multiple assessments may be warranted for Lp(a)-related risk stratification and, potentially, eligibility for Lp(a)-targeted treatments, particularly among individuals with relatively high concentrations or certain demographic and clinical characteristics.
Background Elevated plasma concentrations of Lp(a) have been established as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, myocardial infarction, and calcific aortic valve disease. In this paper we performed a systematic review to evaluate the efficacy and safety of emerging Lp(a)-lowering therapies. Methods A systematic search of PubMed, Embase, and ClinicalTrials.gov was conducted to identify clinical trials evaluating targeted Lp(a)-lowering agents. Studies reporting changes in circulating Lp(a) levels and safety outcomes were included. Therapies were categorized based on their mechanism of action, including antisense oligonucleotides, small interfering RNA (siRNA), and small-molecule inhibitors. Results Targeted therapies demonstrated substantial reductions in circulating Lp(a) concentrations across early- and mid-phase clinical trials. Antisense oligonucleotide therapy with pelacarsen reduced Lp(a) levels by up to 80%, while siRNA-based therapies including olpasiran, lepodisiran, and zerlasiran achieved reductions of up to 80–95%. These agents generally demonstrated favorable safety and tolerability profiles, with most reported adverse events being mild and primarily related to injection-site reactions. In addition, muvalaplin, an oral small-molecule inhibitor targeting Lp(a) assembly, has shown promising reductions in Lp(a) levels in early-phase studies. Conclusions Emerging Lp(a)-targeted therapies achieve significant reductions in circulating Lp(a) concentrations and represent a promising strategy for addressing residual cardiovascular risk associated with elevated Lp(a). Ongoing large-scale cardiovascular outcome trials will determine whether pharmacologic lowering of Lp(a) translates into reductions in cardiovascular events.
Background Lipoprotein(a) [Lp(a)] is a genetically mediated, causal risk factor for atherosclerotic cardiovascular disease. We examined Lp(a) changes during and after acute myocardial infarction (AMI), their associations with the LPA genetic risk score (GRS), and within-subject variability in the clinically stable post-AMI period, as well as the efficiency of Lp(a) cascade testing of first-degree relatives. Method Plasma concentrations of Lp(a) were re-measured in 173 patients with AMI and elevated Lp(a) (≥75nmol/L) at outpatient follow-up when clinically stable. Within-subject variability was assessed in 52 patients with ≥2 follow-up Lp(a) measurements. LPA GRS was determined using 41 LPA variants. Forty-four relatives from 23 probands with Lp(a) ≥200 nmol/L at the follow-up visit were tested for Lp(a). Results The median plasma concentrations of Lp(a) increased by 16.5% from 214 (166-276) nmol/L at admission for AMI to 249 (185-323) nmol/L (P<0.001, follow-up:108 days); the two Lp(a) measurements were positively associated (r=0.794, P<0.001); the LPA GRS was only significantly associated with the Lp(a) concentrations at follow-up (P<0.05). The within-subject CV of Lp(a) during follow-up was 11.4%±10.5%. The yield for detecting new cases among relatives was 0.52 (95%CI 0.37-0.67); 4 relatives (17%) with elevated Lp(a) would have been missed from not undertaking testing if Lp(a) concentration at the time of AMI was used for cascade testing. Conclusion Lp(a) levels may be underestimated at the time of AMI. Repeat measurement is required when stable for clinical decision making, including cascade testing of relatives of probands with high Lp(a).
Background Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Objective This study aimed to report real-world outcomes of lomitapide, an LDL receptor-independent microsomal triglyceride transfer protein inhibitor, with follow-up beyond 10 years in an underreported East Asian population. Methods This retrospective study at a tertiary center in Taiwan included genetically confirmed HoFH patients treated with lomitapide since 2013. Clinical characteristics, longitudinal lipid profiles, hepatic transaminases, liver magnetic resonance imaging for hepatic steatosis, carotid ultrasonography for intima-media thickness, and ASCVD events were reviewed through December 2025. Results Six patients with HoFH (mean age, 28.7±18.2 years) were analyzed. After lomitapide initiation, one patient discontinued lomitapide early because of elevated hepatic transaminase. Four patients received lomitapide treatment for more than 10 years (mean follow-up, 140.8±2.9 months). In this long-term cohort, LDL-C decreased from 264.0±97.3 mg/dL at baseline to 141.5±136.9 mg/dL at the last measurement (mean reduction, 55.8±27.3%) and to 54.0±28.6 mg/dL at nadir (maximal reduction, 80.0±6.1%). Three patients (75%) achieved LDL-C <55 mg/dL at nadir. Hepatic transaminase elevations were generally transient without the need of intervention. Imaging assessment demonstrated variable hepatic steatosis and carotid atherosclerosis. No ASCVD events occurred during continued therapy, and no congenital abnormalities were reported following in utero lomitapide exposure. Conclusions Lomitapide provides durable LDL-C reduction beyond a decade with a manageable safety profile, supporting its long-term therapeutic role in East Asian HoFH patients.
Familial dysbetalipoproteinemia (FD) is a rare autosomal recessive inherited dyslipidemia caused by homozygous variants of the ε2 allele in the apolipoprotein E (APOE) gene. Phenotypically, it presents as elevated remnant cholesterol and, in some cases, tuberoeruptive xanthomas - a dermatological manifestation. However, the variable penetrance of ε2ε2-mediated FD complicates early recognition. Patients with FD have a markedly increased risk of premature cardiovascular disease (CVD), making early awareness essential to reduce cardiovascular risk. In this case report, we present an otherwise healthy male aged 38 years with a long history of undiagnosed tuberoeruptive xanthomas despite dermatological assessment. Blood lipids had never been evaluated until the patient presented with concomitant symptomatic triple vessel coronary artery disease. Further genotyping showed the patient was homozygous for APOE (NM_000041.4):c.526C>T p.(Arg176Cys). Early preventive intervention is crucial to reduce the risk of premature CVD in high-risk patients, yet the intervention may be delayed for years because of unawareness of subtle clinical signs of dyslipidemia. The diagnosis of tuberoeruptive xanthomas is an important but rare differential diagnosis to dermatological manifestations. The diagnosis requires specific attention because of its association with FD and the high risk of premature CVD. We recommend screening blood lipids during dermatological investigation. FD associated with the homozygous ε2ε2-genotype shows variable penetrance, and secondary factors may complicate the suspicion of an inherited dyslipidemia.
BACKGROUND:Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease across multiple clinical settings, but its relationship with prevalent cardiovascular disease burden among adults with treated hypertension (HTN) remains incompletely characterized. OBJECTIVE:To evaluate the association between elevated Lp(a) levels and prevalent cardiovascular disease burden among adults with treated HTN after adjustment for contemporaneous office blood pressure (BP) control. METHODS:We performed a predefined cross-sectional subanalysis of the multicenter Argentine Group for the Study of Lp(a) cohort, including adults with treated HTN and available Lp(a) measurements. BP control was defined as office BP ≤130/80 mmHg. Lp(a) was analyzed as a continuous variable using a high-risk threshold of ≥125 nmol/L. Multivariable generalized estimating equation models adjusted for age, sex, diabetes mellitus, smoking status, low-density lipoprotein-cholesterol, statin therapy, and BP control were used to evaluate the association between Lp(a) and prevalent cardiovascular disease burden. RESULTS:Among 2313 patients with treated HTN, higher Lp(a) levels were independently associated with a greater prevalence of cardiovascular disease burden. Each 1-SD increase in log-transformed Lp(a) was associated with higher odds of prevalent cardiovascular disease burden (Odds ratio [OR] 1.24; 95% CI 1.09-1.41; P = .001). Participants with Lp(a) ≥125 nmol/L had significantly higher odds of prevalent cardiovascular disease burden (OR 1.38; 95% CI 1.02-1.88; P = .037). Additional adjustment for body mass index and ethnicity yielded consistent results. No significant interaction was observed between Lp(a) levels and BP control status. CONCLUSION:In adults with treated HTN, elevated Lp(a) was independently associated with prevalent cardiovascular disease burden after adjustment for office BP control and conventional cardiovascular risk factors. These findings support the potential role of Lp(a) assessment in refining cardiovascular risk stratification in treated hypertensive populations.
BACKGROUND:South Asians represent one of the world's largest and fastest-growing ethnic groups and experience a disproportionately high burden of premature atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE:Conventional risk calculators consistently underestimate true risk, largely because of unique metabolic, genetic, and inflammatory factors that accelerate atherosclerosis at younger ages. Coronary computed tomography angiography (CCTA) provides a comprehensive assessment of coronary atherosclerosis and offers an accurate method of detecting subclinical disease in this population. South Asians frequently demonstrate high rates of noncalcified plaque (NCP) despite low calculated risk and even in the presence of a coronary artery calcium score of 0. METHODS:Multiple cohort studies-including Mediators of Atherosclerosis in South Asians Living in America, DIL Wellness and Arterial Health Longitudinal Evaluation, and international registries-show that South Asians exhibit greater total plaque volume, higher proportions of NCP, and more high-risk plaque features compared with other ethnic groups. CCTA enables detailed quantification of plaque burden, characterization of high-risk morphologic features, and assessment of perivascular inflammation through the fat attenuation index. RESULTS:CCTA can better predict adverse cardiovascular events and refine preventive strategies beyond coronary artery calcium scoring. In younger South Asians (age 25-45 years), CCTA can detect early NCP that would otherwise remain undetected by calcium scoring. Integrating CCTA findings into therapeutic algorithms supports more aggressive low-density lipoprotein cholesterol lowering, targeted use of anti-inflammatory therapy, and personalized follow-up based on plaque burden and biology. CONCLUSION:This review summarizes the epidemiology, pathophysiology, and imaging-based risk stratification among South Asians, highlights key data demonstrating CCTA's prognostic value, and proposes a precision-prevention framework that leverages advanced CCTA techniques to address this population's elevated atherosclerotic cardiovascular disease risk.
