The 2026 American College of Cardiology (ACC)/American Heart Association (AHA)/Multisociety Guideline on the Management of Dyslipidemia (2026 Guideline) replaces the 2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol. The 2026 Guideline expands the section on the management of hypertriglyceridemia (HTG) and acknowledges that triglyceride (TG)-rich lipoproteins contribute to atherosclerotic cardiovascular disease (ASCVD) risk. The 2026 Guideline emphasizes lifestyle interventions as the foundation of HTG management and recommends risk-based pharmacologic interventions for prevention of both ASCVD and pancreatitis. Nutritional interventions, preferably provided as medical nutrition therapy by registered dietitian nutritionists (RDNs), should be individualized based on underlying causes and degree of TG elevation. Referral rates to RDNs have been historically low, in part due to lack of awareness by providers and patients, and in part due to lack of RDN availability and lack of payer coverage. The 2026 Guideline emphasizes the importance of RDN involvement in care, especially for complex patients. Pharmacologic management requires initial and ongoing assessment of risk of ASCVD and pancreatitis, as well as modifications in therapy as appropriate. When TGs are ≥500 mg/dL, and especially ≥1000 mg/dL, preventing pancreatitis is the primary concern. Patients should be reassessed for ASCVD risk once TGs are reduced. Shared decision-making is critical to these discussions of lifestyle and pharmacologic interventions. Implementation of these recommendations necessitates clinician and patient education, as well as improvements in access and coverage for RDN involvement and combination pharmacotherapy, to enhance care of patients with HTG and reduce their risks of ASCVD and pancreatitis.
Familial chylomicronemia syndrome (FCS) (OMIM #238600) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and chylomicronemia due to profound reduction of lipoprotein lipase (LPL). Here, we report 2 unrelated cases of FCS caused by novel homozygous variants in the LPL gene, expanding the known mutational spectrum of this condition. The first case involved a 43-year-old man with longstanding severe hypertriglyceridemia and recurrent acute pancreatitis. Genetic analysis revealed a novel homozygous frameshift variant, c.1172_1173insTCCACAAATAAGA (p.Leu392ProfsTer25), in the LPL gene predicted to result in loss of function. The second case was a female infant presenting with extreme neonatal hypertriglyceridemia, in whom a homozygous missense variant, c.296T>C (p.Leu99Pro), in the LPL gene was identified. Both variants were absent from population databases and identified as novel candidate variants. These cases underscore that phenotypic variability in FCS, ranging from severe neonatal presentation to adult-onset recurrent pancreatitis, is shaped by both the type of the variant and the functional domain involved. Our findings underscore the significance of domain-specific interpretation in genotype-phenotype correlations and identify novel candidate variants for future functional validation.
n-3 polyunsaturated fatty acids (PUFAs) are linked to lower cardiovascular disease (CVD) risk, potentially via reduced low-grade inflammation (LGI). To examine whether LGI mediates the association of n-3 PUFAs with (pre)clinical CVD, and whether LGI and endothelial dysfunction (ED) mediate the associations with clinical CVD. Cross-sectional data from The Maastricht Study were analyzed. Fasted n-3 PUFAs were measured with 1H nuclear magnetic resonance (NMR; n = 3193, 50.8% men, 60 ± 8 years; EDTA plasma) and gas chromatography (GC; n = 1032, 49.6% men, 60 ± 8 years; serum). LGI was defined as the z-score of 6 plasma biomarkers. Preclinical markers of CVD comprised: ED, ankle-brachial index, carotid intima-media thickness, and carotid-femoral pulse wave velocity. CVD was self-reported as coronary heart disease, cerebrovascular disease, or peripheral artery disease. Mediations with n-3 PUFAs (exposures), LGI (mediator), and (pre)clinical CVD (outcomes), and sequential mediations with LGI and ED (mediators) and CVD (outcome) were performed. A total of 522 participants reported CVD. In the NMR subset, n-3 PUFAs were inversely associated with CVD and ED. n-3 PUFAs were inversely associated with LGI (β: -0.09 [-0.12, -0.05]), while LGI was positively associated with ED (β: 0.58 [0.55, 0.61]) and CVD (OR: 1.15 [1.03, 1.28]). LGI mediated the associations with CVD (<5%) and ED (54.4%). LGI and ED mediated small but significant proportions of the associations with CVD (<5%). Similar, although nonsignificant, results were observed in the GC subset. Biomarker-based LGI mediated substantial parts of the associations with ED, while together they mediated a small proportion of the associations between n-3 PUFAs and CVD. Further studies are warranted to identify the metabolic pathways via which n-3 PUFAs influence CVD, and the role of LGI in early stages of CVD.
Lipoprotein glomerulopathy (LPG) is a rare disease affecting the kidney, clinically characterized by type III hyperlipoproteinemia, mutated apolipoprotein E (ApoE), the presence of glomerular lipoprotein thrombi, proteinuria in the nephrotic range, and progression toward chronic kidney disease (CKD). Evaluate the role of lipoprotein apheresis (LA) as rescue therapy in LPG. Since 2011, we have identified 6 unrelated patients living in the same geographical area of Central Italy (Tuscany Region) who share the same rare ApoE mutation. Four patients, due to nephrotic syndrome associated with biopsy-proven LPG, underwent LA. LA was able to stabilize renal function even for years in three of these subjects: of note, a better prognosis was reported when less impairment of renal function was present.LA was associated with a significant decrease of the number of plasmatic extracellular vesicles (EV) released from activated and/or damaged cells. In vitro studies showed that EV isolated from plasma of LPG patients induced human glomerular endothelial cell and podocyte alterations potentially responsible for the development of nephrotic syndrome and tissue injury. In conclusion, we demonstrated, in unrelated LPG patients with LPG carrying the same ApoE mutation, a protective role of LA on proteinuria and progression toward CKD. This LA-associated protective effect may be at least in part related to the modulation of biologically active EVs in patients' plasma.
The standard definition of Achilles tendon xanthoma in familial hypercholesterolemia (FH) remains unclear. To examine the optimal cut-off points and diagnostic accuracy of Achilles tendon thickness measured by radiographs among Thai subjects with FH. Achilles tendon thickness in the anteroposterior dimension was determined using plain radiographs of lateral ankles in 80 subjects with genetically confirmed FH, 57 non-FH subjects with elevated low-density lipoprotein-cholesterol (LDL-C) ≥130 mg/dL, and 54 control subjects (LDL-C <130 mg/dL). The optimal cut-off values, sensitivity, specificity, and diagnostic accuracy for FH diagnosis were examined. The diagnostic performance of Achilles tendon measurements obtained from radiographs, skinfold calipers, and ultrasound was compared in a subset of 16 subjects from each group. The Achilles tendon was significantly thicker in the FH group compared with the non-FH and the control groups (median values [IQR] were 11.5 [8.0-14.5] mm vs 5.9 [5.4-6.5] mm and 6.4 [5.5-7.5] mm, respectively, P < .001). The optimal cut-off values determined by receiver operating characteristic analysis were 7.95 mm for men and 7.25 mm for women, with sensitivity, specificity, and accuracy of 92%, 85%, and 88% for men, and 91%, 88%, and 89% for women, respectively. In the subgroup of subjects, tendon thickness measured by radiographs or ultrasound demonstrated higher sensitivity, specificity, and accuracy than tendon width measured by ultrasound or calipers. The Achilles tendon thickness values of 7.95 mm in men and 7.25 mm in women could be useful for identifying tendon xanthomas for the diagnosis of FH in the Thai population.
The European Society of Cardiology guideline recommends lowering low-density lipoprotein cholesterol (LDL-C) to <1.4 mmol/L for the prevention of atherosclerotic cardiovascular disease (ASCVD) in patients with very high-risk. However, despite favorable LDL-C control, atherosclerosis still continues to progress, which eventually causes cardiovascular events. To characterize the clinical demographics of patients with coronary artery disease (CAD) who experienced subsequent ASCVD despite achieving LDL-C <1.4 mmol/L. The current study retrospectively analyzed 780 patients with CAD who achieved LDL-C <1.4 mmol/L after percutaneous coronary intervention. Clinical characteristics were compared between patients with and without major adverse cardiovascular events (MACE) (=cardiac death, nonfatal MI, and clinically driven coronary revascularization at nonculprit segments). During the observational period (median = 1632 days), MACE occurred in 6.2% (=48/780) of the study population. Patients experiencing MACE were more likely to exhibit polyvascular disease (PVD) (72.9% vs 17.3%, P < .001). Statins and high-intensity statins were frequently used in both groups (statin = 94.8%, P = .218; high-intensity statin = 73.3%, P = .198), whereas patients with MACE were less likely to receive ezetimibe (45.8% vs 63.2%, P = .023). Consequently, a lower proportion of on-treatment LDL-C <1.0 mmol/L was observed in those with MACE (16.7% vs 33.2%, P = .018). On multivariate analysis, PVD (hazard ratio [HR] = 10.74, 95% CI = 5.65-20.39, P < .001) and on-treatment LDL-C <1.0 mmol/L (HR = 0.37, 95% CI = 0.17-0.81, P = .010) were independently associated with MACE. In patients with PVD (n = 162), on-treatment LDL-C <1.0 mmol/L was associated with a lower frequency of MACE (HR = 0.36, 95% CI = 0.14-0.87, P = .024). Ongoing cardiovascular risks existed despite achieving LDL-C <1.4 mmol/L. Given the association of on-treatment LDL-C <1.0 mmol/L with a reduced risk of MACE, a further lower LDL-C goal may be considered to prevent recurrence of ASCVD in patients with CAD.
Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are common, underdiagnosed monogenic dyslipidemias that significantly increase cardiovascular risk. We investigated whether standard clinical risk factors-low-density lipoprotein cholesterol (LDL-C), family history, and personal history of premature atherosclerotic cardiovascular disease (pASCVD)-can accurately distinguish these conditions. We analyzed 378 lipid clinic patients receiving Lp(a) screening and FH genetic testing with multinomial logistic regression. we found that while higher LDL-C and younger age were associated with FH, personal/family histories of pASCVD failed to differentiate between FH, elevated Lp(a), or dual diagnoses. Genetic testing for FH and Lp(a) measurement revealed that 22.5% had FH, 35.7% had elevated Lp(a), and 12.7% had both. Despite statistical associations, predicted probabilities for each diagnosis overlapped considerably, and clinical risk factors commonly used in FH clinical diagnostic criteria would insufficiently distinguish these genetic disorders. Results demonstrate that clinical risk factors and scoring systems cannot reliably substitute diagnostic FH genetic testing and Lp(a) measurement-essential for accurate diagnosis and management for these high-risk disorders.
Approximately 20% of pregnant women have elevated lipid levels. While nonpharmacological therapy suffices for most patients, some require pharmacotherapy. This study analyzed the outcomes of pregnancy in women treated with lipid-lowering drugs. Nationwide data on all births and abortions in the Czech Republic (2011-2023) were obtained from the National Registry of Reproductive Health and the National Registry of Reimbursable Health Services. Women with preexisting lipid disorders who were prescribed any lipid-lowering drug from select Anatomical Therapeutic Chemical groups (C10A, C10B) within 1 year before pregnancy, and women with treatment initiation during pregnancy, were included in the analysis. Univariate logistic regression was performed to calculate the odds ratios (ORs) for adverse outcomes. Among 1,342,432 deliveries, 1100 women were treated with lipid-lowering drugs during pregnancy. Statin treatment had increased odds of cesarean section (OR 1.68-1.96), preterm delivery (OR 1.42-2.58), and low birth weight (OR 1.23-2.16). Atorvastatin and rosuvastatin were comparably safe, but simvastatin had higher odds of complications. Treatment with cholestyramine was associated with higher odds of cesarean section (OR 2.45), preterm delivery (OR 4.78), and low birth weight (OR 3.16) compared to fenofibrate or statins. No detrimental effect on neonatal hypoxia was observed. The fixed combination of atorvastatin and amlodipine was limited in use but associated with a higher risk of adverse outcomes. Atorvastatin and rosuvastatin had a relatively low risk of adverse maternal and fetal outcomes, comparable to fibrates. Cholestyramine and the fixed combination of statin and amlodipine were associated with increased risk.
Familial hypercholesterolemia (FH) is characterized by a lifelong elevation of low-density lipoprotein cholesterol (LDL-C), conferring an increased risk of premature atherosclerotic disease and its associated burden of morbidity and mortality. Autosomal recessive hypercholesterolemia (ARH) is a rare form of homozygous FH (HoFH) and is a distinct subset caused by mutations in the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene. We present a 29-year-old South Asian male who visited the lipid clinic with a markedly elevated, untreated LDL-C level of 557 mg/dL. Clinical and genetic evaluation identified a homozygous pathogenic splice donor variant in the LDLRAP1 (c.344+1G>A), confirming the diagnosis of ARH. On examination, a grade III/VI systolic ejection murmur was appreciated, prompting further investigation that confirmed mild aortic stenosis. Achieving adequate LDL-C control for this patient required stepwise escalation of the lipid-lowering therapy comprising high-intensity statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitor, bempedoic acid, and ultimately evinacumab. This case draws attention to the importance of appropriately diagnosing and treating individuals with ARH and initiating combination lipid-lowering therapy, including specialty medications indicated for this diagnosis, to effectively treat this disorder, as well as the importance of screening for valvular heart disease in this population.
While low levels of LDL-cholesterol can be atheroprotective, homozygous Class I familial hypobetalipoproteinemia (Ho-Class I FHBL) and heterozygous Class I FHBL (He-Class I FHBL) due to APOB variants (i.e., heterozygous FHBL1 (HeFHBL1)) have serious complications due to genetic defects in the chylomicron/VLDL secretion pathway. However, Ho-Class I FHBL with milder phenotypes and HeFHBL1 are often underdiagnosed due to overlapping lipid profiles with other forms of hypobetalipoproteinemia. Additional screening markers are warranted. We established a prospective HBL cohort and performed detailed genotype-phenotype analyses to identify biomarkers associated with Class I FHBL. For further exploration, we systematically reviewed cases with Class I FHBL. In our lipid genome cohort (n = 440), whole-exome sequencing of 18 consecutive cases of HBL (LDL-C <30 mg/dL) identified 7 novel pathogenic variants in 7 cases of Class I FHBL. Genotype-phenotype analyses revealed that plasma vitamin K1 is the strongest independent predictor of Class I FHBL. The vitamin K1 levels in HeFHBL1 were significantly reduced by approximately 50% compared to controls, reflecting the half-normal lipoprotein secretion. Systematic review analyses (n = 472) revealed that vitamin K1 is the only fat-soluble vitamin that is significantly decreased not only in Ho-Class I FHBL but also in HeFHBL1. Plasma vitamin K1 may serve as a sensitive screening marker of fat malabsorption, facilitating the genetic diagnosis of Class I FHBL, enabling early management of its complications, such as fat malabsorption, fat-soluble vitamin deficiency, potential vitamin K deficiency, and steatotic liver disease.
Cardiovascular diseases are the leading cause of mortality globally, requiring early and accurate detection through tools like electrocardiography. While artificial intelligence models have emerged to provide reproducible analysis of electrocardiogram printouts, their clinical deployment is hindered by a lack of transparency and sensitivity to real-world image variations such as discolorations, handwriting, or paper wrinkles. This study introduces an explainable artificial intelligence framework designed to quantify the stability of deep learning models and identify vulnerabilities in their behavior under controlled image perturbations. We utilized a large-scale dataset of electrocardiogram printouts synthesized from the PTB-XL benchmark, creating both clean and contaminated versions featuring various image-level manipulations. Four deep learning architectures, including EfficientNet and InceptionNet, were trained and evaluated using different activation functions. The stability of these models was assessed using local interpretable model-agnostic explanations. We employed intersection over union metrics to measure the consistency of explanations across perturbations and extracted radiomic-like image features to quantitatively analyze the characteristics of the generated explanations. Our experiments demonstrate that models trained on augmented datasets generalize better to perturbed data, with the best-performing model achieving an area under the receiver operating characteristic curve of 0.894 on the contaminated test set. Stability analysis showed that models trained on data containing perturbations achieved the highest average intersection over union of 0.399, indicating a more consistent focus on diagnostic features. Furthermore, radiomic-like features enabled the precise identification of the underlying deep learning model with an accuracy of up to 98%. The proposed framework enables a comprehensive visual and quantitative evaluation of artificial intelligence stability in cardiovascular disease detection. By identifying how specific image manipulations affect model reliability, this approach can guide the development of more robust algorithms and targeted data augmentation strategies. To ensure full reproducibility and foster cross-domain collaboration, our tools and datasets are available at https://github.com/smile-research/xai-ecg.
Optimizing health-related quality of life (HRQoL) is a goal of preventive and therapeutic cardiovascular care worldwide, yet sex disparities in HRQoL remain insufficiently explored at a population level. The objective of this study was to examine sex differences in HRQoL in relation to secondary prevention in patients with CHD across all six World Health Organization regions. Cross-sectional analysis of the INTERASPIRE study of adults hospitalized in the preceding six to 24 months with CHD who underwent standardized interview and examination across 14 countries. Endpoints were HRQoL (EQ-5D-5L; HeartQoL), and an INTERASPIRE-Guideline Target Score (GTS); a 10-point assessment of achieving secondary prevention lifestyle, risk factor, and therapeutic targets. Analyses were adjusted for age and country-level clustering. A total of 4546 patients (21.1% women) were interviewed. Compared to men, women had lower HRQoL across all assessments (p < 0.001) e.g., mean HeartQoL global score 2.1 vs 2.6; EQ-5D-5L self-care 17.8% vs 9.2%, and usual activities 39.1% vs 22.4%. Positive correlations (p < 0.001) were identified between HRQoL and INTERASPIRE-GTS. Female sex was independently associated with poor HRQoL (p < 0.001), either expressed by EQ-5D-5L index score or the HeartQoL overall and subscale scores. Female sex was independently associated with poorer HRQoL in patients with CHD. Higher HRQoL was associated with ability to achieve secondary prevention guideline targets. Routine integration of HRQoL assessment into secondary prevention programs can inform individualized clinical care and assist in reducing sex-based disparities in cardiovascular outcomes.
The use of highly active antiretroviral therapy (ART) has significantly reduced morbidity and mortality associated with HIV infection and AIDS. However, a cluster of metabolic derangements, such as dyslipidemia and hyperglycemia, is increasing among patients on ART. To determine the prevalence and associated factors of dyslipidemia and hyperglycemia among adult people living with HIV on ART. A hospital-based cross-sectional study was conducted from November 20, 2023, to January 30, 2024, at Asella Referral and Teaching Hospital, South-East Ethiopia. Sociodemographic, anthropometric, and clinical data were collected. Serum glucose and lipid profiles were measured using the Cobas C 311 Clinical Chemistry Analyzer. Data were entered in EpiData version 3 and analyzed by STATA version 17.0. A total of 388 patients with HIV on ART were enrolled. The overall prevalence of dyslipidemia and hyperglycemia were 72.7% (95% CI: 68.0%-76.9%) and 16.2% (95% CI: 12.9%-20.3%), respectively. Older age (≥54 years) and raw meat consumption were associated with dyslipidemia and hyperglycemia, respectively, while chewing khat was associated with a reduced likelihood of hyperglycemia. Dyslipidemia and hyperglycemia are prevalent in patients with HIV on ART, highlighting the need for regular monitoring and lipid-lowering treatments, especially for older and raw meat consumers.
Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol from birth and increased risk of premature atherosclerotic cardiovascular disease. Early initiation of lipid-lowering therapies improves outcomes, and advances in genetic testing, electronic health record (EHR)-based algorithms, and cascade screening have strengthened identification. Despite these advances, FH remains underdiagnosed and undertreated, reflecting an "implementation gap" between patient identification and initiation of therapy. This review synthesizes evidence from randomized trials, implementation studies, registries, and digital health interventions aimed at closing the FH implementation gap. Strategies were organized across patient, clinician, and health system levels, including EHR-integrated clinical decision support systems, multidisciplinary lipid clinics, automatic referral systems, shared decision-making tools, mobile health applications, population dashboards, risk registries, and emerging machine learning approaches to enhance clinician adoption of new strategies. Evidence supports several effective strategies to close the FH care gap. EHR-integrated clinical decision support and multidisciplinary lipid clinics consistently improve lipid testing, prescribing, and treatment initiation, though real-world adoption remains low. Patient-facing digital tools enhance education and adherence but require further validation of long-term outcomes. Emerging approaches using artificial intelligence may strengthen case detection and workflow integration. Evidence suggests that no single intervention is sufficient to close the FH care gap. Effective implementation requires a combination of approaches, such as multidisciplinary clinics and clinician decision support, with digital and patient engagement tools. Integrating these strategies within routine practice will be essential to reducing preventable morbidity and mortality in FH.
Sitosterolemia is a rare autosomal recessive disorder caused by pathogenic variants in ABCG5 or ABCG8, leading to plant sterol buildup and variable low-density lipoprotein cholesterol levels. Its symptoms often mimic familial hypercholesterolemia (FH), making diagnosis difficult since standard lipid panels do not measure plant sterols. We aimed to estimate the genetic burden of sitosterolemia in Qatar using pathogenic ABCG5/ABCG8 variants METHODS: We interrogated the ABCG5/ABCG8 variation in 14,060 Qatar Genome Program participants linked to Qatar Biobank phenotypes. Variants were annotated using ClinVar and gnomADv4.1 and classified according to American College of Medical Genetics and Genomics criteria. The carrier frequency was estimated in 5385 unrelated Qataris, incorporating a recessive disease burden model that accounted for inbreeding. We observed 7 pathogenic/likely pathogenic variants (3 in ABCG5; 4 in ABCG8) and identified 4 novel predicted loss‑of‑function variants in ABCG8. Estimated carrier frequencies were ∼1:215 (ABCG5) and ∼1:192 (ABCG8), yielding a combined ∼1:102 and an overall disease burden of ∼1:7509 in Qatar, markedly exceeding gnomAD estimates (∼1:251 carrier frequency; ∼1:383,744 disease burden). Several variants had homozygous individuals with abnormal lipid profiles and self‑reported hypercholesterolemia, suggestive of a potential FH-like phenotype. ABCG5/ABCG8 variants are enriched in Qatar relative to global datasets, consistent with population structure and consanguinity. Given the phenotypic overlap with FH but distinct therapeutic implications (notably superior response to ezetimibe and dietary sterol restriction), we propose integrating ABCG5/ABCG8 into dyslipidemia diagnostic workflows, especially in FH clinics, pediatrics, and ancestry-informed screening programs in the Middle-East and North Africa (MENA) region. These data highlight the potential value of plant-sterol testing and ABCG5/ABCG8 screening to reduce misdiagnosis, guide treatment, and enable cascade testing.
Dysbetalipoproteinemia is classically associated with the Apolipoprotein E (APOE) ε2/ε2 genotype. However, rare variants may lead to atypical presentations with dominant inheritance patterns and distinct biochemical profiles. We report a 65-year-old woman with persistent mixed dyslipidemia and intolerance to multiple lipid-lowering therapies. Despite correction of secondary causes, including subclinical hypothyroidism, lipid abnormalities persisted. Advanced lipid testing revealed elevated apolipoprotein B and lipid ratios consistent with remnant lipoprotein accumulation. Density-gradient ultracentrifugation demonstrated cholesterol-enriched very-low-density lipoprotein (VLDL) particles with an increased cholesterol content of VLDL (VLDL-C)/triglyceride ratio (0.38), supporting the diagnosis of dysbetalipoproteinemia. Genetic analysis identified a heterozygous p.(Arg154Ser) variant in the APOE gene, while the APOE genotype was ε3/ε3. Treatment with a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor led to significant lipid improvement. This case highlights a nonclassical form of dysbetalipoproteinemia associated with a rare APOE variant in the absence of the ε2/ε2 genotype and illustrates a pragmatic, stepwise diagnostic approach integrating accessible biomarkers with specialized testing.
Familial chylomicronemia syndrome (FCS) is a rare genetic form of primary hypertriglyceridemia with an increased risk of acute pancreatitis (AP). Apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran, provide therapeutic approaches to reduce triglycerides in patients with FCS. To compare the efficacy and safety of olezarsen (Balance) with plozasiran (PALISADE) in FCS. An anchored matching-adjusted indirect comparison was conducted. Outcome analyses included only the approved dosages of study therapies, while the AP analysis also pooled high- and low-dose regimens. Analyses showed no statistically significant differences in 52-week efficacy or safety. Mean differences (olezarsen vs plozasiran) in triglycerides and apoC-III reduction were -15.5% (95% CI: -76.2, 45.2) and -8.4% (95% CI: -69.7, 53.0). Relative risks of AP, treatment-emergent, and serious adverse events were 0.70 (95% CI: 0.07, 6.66), 0.81 (95% CI: 0.58, 1.13), and 0.50 (95% CI: 0.10, 2.58). Overall, there was no evidence of differences in efficacy or safety between olezarsen and plozasiran in the treatment of patients with FCS.
Lower extremity peripheral arterial disease (PAD) is a prevalent manifestation of systemic atherosclerosis associated with significant morbidity, mortality, and economic burden. Lipid-lowering therapy (LLT) with high-intensity statins and nonstatin therapies is a cornerstone of guideline-directed management to reduce the risk of major adverse limb and cardiovascular events. Despite robust evidence and clear guideline re--ations, the utilization of LLT in patients with PAD remains suboptimal. We review evidence that highlights gaps in lipid management for patients with PAD, and how these may be addressed by leveraging implementation science. A large proportion of patients with PAD do not receive re--ed LLT and subsequently do not achieve low-density lipoprotein cholesterol (LDL-C) goals. These patients are at risk of major adverse cardiovascular and limb events, including preventable amputations. Health inequities can further exacerbate the underutilization of LLT. While there is a paucity of studies specifically evaluating the effectiveness of implementation strategies for lipid management in patients with PAD, we propose approaches that are grounded in evidence from broader populations with other forms of atherosclerotic cardiovascular disease. There is a clear and urgent need for better implementation strategies to ensure optimal care is provided to patients with PAD, regardless of race, ethnicity, or socioeconomic status. Addressing the underutilization of guideline-re--ed LLT in PAD requires multifaceted approaches considering healthcare systems, clinicians, and patients' needs. By ensuring that all patients with PAD receive appropriate LLT to achieve guideline-directed LDL-C goals, we can hope to substantially improve their cardiovascular outcomes and quality of life.
Despite optimal lipoprotein cholesterol control, patients with chronic coronary syndrome (CCS) exhibit substantial residual cardiovascular risk. Lipoprotein(a) (Lp[a]) is an independent cardiovascular risk factor, primarily determined by genetic variation within the LPA gene. To evaluate the association between the LPA polymorphisms rs10455872 and rs3798220, plasma Lp(a) concentrations-including extreme phenotypes-and clinical and coronary anatomical characteristics in patients with CCS. A total of 390 patients with CCS undergoing genetic evaluation for suspected inherited dyslipidemia were included. Lp(a) concentrations were measured using standardized assays, and the LPA polymorphisms rs10455872 and rs3798220 were genotyped. Associations with Lp(a) levels, clinical events, and coronary anatomical complexity were assessed using linear, logistic, ordinal, and negative binomial regression models. Both polymorphisms were robustly and independently associated with higher Lp(a) concentrations under dominant and additive genetic models (P < .001). The combined LPA genetic burden explained approximately 28% of the variability in Lp(a) levels. Extreme Lp(a) phenotypes were significantly more frequent among risk allele carriers. However, neither Lp(a) levels, extreme phenotypes, nor LPA genetic burden were independently associated with coronary events, multivessel disease, or coronary anatomical complexity (number of stents) after multivariable adjustment. Negative binomial models incorporating disease duration confirmed the lack of association with recurrent ischemic events. In patients with CCS, common LPA gene variants strongly determine plasma Lp(a) concentrations, including extreme phenotypes, but are not associated with the anatomical extent of coronary artery disease. These findings suggest that Lp(a) plays a predominant role in early disease stages rather than in established coronary anatomy.
Familial hypercholesterolemia (FH) is a genetic condition that significantly increases the risk of coronary artery disease if left unmanaged. Although FH remains underdiagnosed globally, early detection enables timely therapy and reduces cardiovascular risk. Traditional FH criteria, such as the Dutch Lipid Clinic Network and Simon Broome diagnostic criteria, rely on clinical data often missing in real-world practice. Artificial intelligence (AI) offers potential to improve FH case identification. To review recent advances in simplified FH screening criteria, summarize applications of AI models in FH detection, compare model performance, and evaluate limitations and advantages. A literature search was conducted to identify peer-reviewed studies on AI in FH screening, diagnosis, or management. The search used Medical Subject Headings and free-text terms for FH and AI technologies. Titles and abstracts were reviewed, and full texts were assessed if potentially eligible. Machine learning models generally outperform simplified criteria. Logistic regression models remain the most commonly used and are valued for interpretability. Performance comparisons between models are limited by differences in cohort characteristics. Predictive variables commonly used by models include established examples such as family history, lipid profiles, demographics, and prescription records. AI models that leverage electronic health record (EHR) data can outperform traditional criteria, uncover missed cases, and complement cascade screening. Challenges include external validation, workflow integration, and model transparency. To ensure clinical utility, further work is needed to standardize comparison metrics, broaden applicability, increase interpretability, and address EHR integration complexities.