BACKGROUND: 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., h...BACKGROUND: 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. OBJECTIVE: Additional screening markers are warranted. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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 wit...BACKGROUND: 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. OBJECTIVE: To characterize the clinical demographics of patients with coronary artery disease (CAD) who experienced subsequent ASCVD despite achieving LDL-C <1.4 mmol/L. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
BACKGROUND AND OBJECTIVE: Plaque rupture (PR) is the predominant cause of acute coronary syndrome (ACS). Small dense low-density lipoprotein cholesterol (sd-LDL-C) shows a greater association with cardiovascular event ri...BACKGROUND AND OBJECTIVE: Plaque rupture (PR) is the predominant cause of acute coronary syndrome (ACS). Small dense low-density lipoprotein cholesterol (sd-LDL-C) shows a greater association with cardiovascular event risk than LDL-C. To better understand the contributions of atherogenic lipids and systemic inflammation, we investigated the association of sd-LDL-C and high-sensitivity C-reactive protein (hs-CRP) with PR in patients with ACS. METHODS: We enrolled 315 consecutive patients with ACS who underwent optical coherence tomography-guided emergency percutaneous coronary intervention. Culprit lesions were classified as PR or intact fibrous cap (IFC). The IFC group was further subdivided into plaque erosion (PE) and other IFC. Serum samples were collected before coronary angiography. RESULTS: Among 315 patients (PR: n = 164; IFC: n = 151 [PE: 92, other: 59]), sd-LDL-C was significantly higher in patients with PR than in those with PE and other IFC groups (38.8 vs 31.6 vs 27.6 mg/dL; P = .042), despite similar LDL-C levels. In multivariable logistic regression analysis, continuous hs-CRP was independently associated with PR, whereas continuous sd-LDL-C was not; however, categorical analyses suggested higher odds for PR in the upper quartiles of both markers. Furthermore, the combined high sd-LDL-C/high hs-CRP group (above medians) carried the highest PR risk (OR 3.87, 95% CI 1.99-7.92; P < .001) compared with the low/low group. CONCLUSION: Elevated sd-LDL-C and hs-CRP are independently associated with PR in the culprit lesion. A combined assessment of atherogenic lipids and systemic inflammation may identify individuals with a residual risk for PR beyond LDL-C values.
BACKGROUND: Avocado intake improves blood lipid profiles, but the effect on lipoprotein particles and subclasses is less clear. OBJECTIVE: The aim was to investigate the effect of consuming 1 avocado per day for 26 weeks...BACKGROUND: Avocado intake improves blood lipid profiles, but the effect on lipoprotein particles and subclasses is less clear. OBJECTIVE: The aim was to investigate the effect of consuming 1 avocado per day for 26 weeks on the change in lipoprotein particles and subclasses compared to a habitual diet without supplemental avocados in free-living adults with abdominal obesity. METHODS: This is an ancillary study of the Habitual Diet and Avocado Trial, a multicenter, parallel-arm, 26-week randomized controlled trial. The Avocado-supplemented Diet Group was provided with 1 avocado per day, and the Habitual Diet Group was instructed to follow their habitual diet. Fasting plasma samples collected at baseline and 26 weeks were analyzed for concentrations of lipoprotein particles and subclasses (exploratory outcomes) using nuclear magnetic resonance spectroscopy. Between-group differences in the 26-week change from baseline were evaluated using linear regression, with adjustment for study site. RESULTS: The analytical sample included 786 participants (74% female; aged 51 ± 14 years; body mass index 32.9 ± 5.4 kg/m) with available data (Avocado-supplemented Diet Group: n = 389; Habitual Diet Group: n = 397). The Avocado-supplemented Diet Group had a reduction in total low-density lipoprotein (LDL) particle concentration (mean difference: -49.1 nmol/L; 95% CI: -83.6, -14.5; P = .005) compared to the Habitual Diet Group. No between-group differences were observed for LDL particle size and subclasses, triglyceride-rich lipoprotein particles, high-density lipoprotein particles, or apolipoproteins A or B. CONCLUSION: Incorporating 1 avocado per day into habitual diets for 26 weeks reduced the concentration of atherogenic LDL particles without affecting other lipoprotein particles and subclasses in adults with abdominal obesity.
BACKGROUND: The standard definition of Achilles tendon xanthoma in familial hypercholesterolemia (FH) remains unclear. OBJECTIVE: To examine the optimal cut-off points and diagnostic accuracy of Achilles tendon thickness...BACKGROUND: The standard definition of Achilles tendon xanthoma in familial hypercholesterolemia (FH) remains unclear. OBJECTIVE: To examine the optimal cut-off points and diagnostic accuracy of Achilles tendon thickness measured by radiographs among Thai subjects with FH. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: Approximately 20% of pregnant women have elevated lipid levels. While nonpharmacological therapy suffices for most patients, some require pharmacotherapy. OBJECTIVE: This study analyzed the outcomes of pregna...BACKGROUND: Approximately 20% of pregnant women have elevated lipid levels. While nonpharmacological therapy suffices for most patients, some require pharmacotherapy. OBJECTIVE: This study analyzed the outcomes of pregnancy in women treated with lipid-lowering drugs. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: In many health disparities studies, persons aged 75 and older are underrepresented. Burden of cardiovascular disease (CVD) mortality and morbidity remains high in this age group, with a higher risk to Black i...BACKGROUND: In many health disparities studies, persons aged 75 and older are underrepresented. Burden of cardiovascular disease (CVD) mortality and morbidity remains high in this age group, with a higher risk to Black individuals. Interestingly, at age 85 and older, CVD mortality is higher in White than Black patients. OBJECTIVE: Compared serum lipid patterns in non-Hispanic Black (NHB) and White (NHW) individuals in a national survey of persons aged 75+. METHODS: Data on demographics and serum lipids of NHB and NHW aged 75 and older were examined in the 2007 to March 2020 National Health and Nutrition Examination Survey for 2350 NHW and 496 NHB individuals. Serum triglycerides were measured, and low-density lipoprotein (LDL) was calculated for those examined in the morning (1124 NHW, 223 NHB). Statistical analysis accounted for the complex survey design and sampling weights. RESULTS: Median high-density lipoprotein (HDL) cholesterol levels were higher in Black individuals compared to White individuals and also higher in women than in men. Race remained significantly associated with HDL after multivariable adjustment (P < .01). Median LDL-cholesterol was similar between Black and White individuals and higher in women. Race was not significantly associated with LDL after adjustment. The LDL/HDL ratio was similar in Black and White individuals among women, lower in Black individuals among men, and higher in men than in women. Race was not associated with LDL/HDL in women, but LDL/HDL was higher in NHW than NHB men after adjustment (P = .005). CONCLUSION: This analysis demonstrates that HDL differences persist in older adults, whereas LDL patterns are consistent across races, underscoring the need for age-specific prevention strategies.
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 m...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.
Suresh A, Kodukula SS, Bardach S
… +12 more, Peng AW, Marvel FA, Khandelwal A, Waring A, Clary J, Helm B, Almeida S, Isiadinso I, Razavi AC, Blumenthal RS, Sperling LS, Martin SS
BACKGROUND: 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...BACKGROUND: 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. OBJECTIVE: This review synthesizes evidence from randomized trials, implementation studies, registries, and digital health interventions aimed at closing the FH implementation gap. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: The interaction of elevated lipoprotein(a) [Lp(a)] with local coronary inflammation remains unclear. OBJECTIVE: We investigated whether pericoronary inflammation modulates Lp(a)'s prognostic impact on major a...BACKGROUND: The interaction of elevated lipoprotein(a) [Lp(a)] with local coronary inflammation remains unclear. OBJECTIVE: We investigated whether pericoronary inflammation modulates Lp(a)'s prognostic impact on major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). METHODS: Patients with coronary artery disease undergoing PCI were included with coronary computed tomography angiography within 3 months before coronary angiography. Pericoronary fat attenuation index (FAI) was quantified for pericoronary inflammation evaluation. Four machine learning models with SHapley Additive exPlanations (SHAP) ranked FAI features. Lp(a) was categorized using a 30 mg/dL cut-off per Chinese lipid guidelines. Associations with MACE (all-cause mortality, nonfatal myocardial infarction, unplanned revascularization, and stroke) were assessed via multivariable Cox regression, restricted cubic splines (RCS), and subgroups. RESULTS: Over a median 3-year follow-up, 181 (9.0%) patients experienced MACE. High Lp(a) and elevated FAI independently predicted MACE (hazard ratio [HR] 1.29, 95% CI 1.05-1.76 for high Lp(a); HR 2.06, 95% CI 1.51-2.81 for high FAI-Left anterior descending artery [LAD]). Extreme gradient boosting (area under the curve [AUC] 0.936) ranked FAI-LAD highest (SHAP 1.57). RCS revealed nonlinear associations, with MACE risk escalating sharply above FAI-LAD -77.00 HU. High Lp(a) markedly increased MACE risk in the high FAI-LAD group (HR 2.69, 95% CI 1.75-4.10) but the risk increase was attenuated in the low-FAI-LAD group (HR 1.10, 95% CI 0.65-1.87). Combining Lp(a) and FAI-LAD improved prognostic accuracy (AUC 0.713) over conventional risk factors (AUC 0.599) or either alone (DeLong P < .05). Subgroup analyses showed interactions with age and diabetes (P < .05). CONCLUSION: Lp(a) elevates post-PCI risk mainly in high pericoronary inflammation settings. Integrating Lp(a) and FAI refines risk stratification, supporting targeted Lp(a)-lowering in inflamed subgroups.
Osti N, Musuraca G, Spizzo M
… +21 more, Pattini P, Poli G, Brocco C, Danese E, Marini M, Segala A, Cemin C, Madaffari A, Peruzza F, Mango G, Donini M, Presa F, Grusse M, Van Dreden P, Anesi A, Lippi G, Del Greco M, Castagna A, Friso S, Ferro A, Martinelli N
BACKGROUND: Lipoprotein(a) [Lp(a)] is a causal risk factor for coronary artery disease (CAD), with proposed prothrombotic properties besides proatherogenic effects. However, the association between Lp(a) and coagulation...BACKGROUND: Lipoprotein(a) [Lp(a)] is a causal risk factor for coronary artery disease (CAD), with proposed prothrombotic properties besides proatherogenic effects. However, the association between Lp(a) and coagulation remains controversial so far. OBJECTIVE: This study examined this relationship in subjects with or without angiographically documented CAD. METHODS: Plasma levels of Lp(a) and coagulation biomarkers were assessed in clinically stable subjects undergoing elective coronary angiography. Subjects taking any anticoagulant therapy were excluded. The coagulation panel included coagulant activities of factors II, V, VII, VIII, IX, X, XI, and XII, von Willebrand factor antigen (vWF:Ag), thrombin generation assay (TGA), total tissue factor pathway inhibitor (TFPI), and activated factor VII-antithrombin (FVIIa-AT) complex. Lp(a) threshold values were defined according to the European Atherosclerosis Society consensus statement: normal <30 mg/dL, intermediate 30 to 50 mg/dL, and high >50 mg/dL. RESULTS: Complete laboratory data were available for 383 subjects (males 75.3%; mean age 68.2 ± 9.7 years): 65 subjects had normal coronary arteries, 51 subjects had coronary stenosis <50%, and 267 subjects had coronary stenosis ≥50%. A modest yet significant increase in FV coagulant activity (FV:C) from low to high Lp(a) plasma levels was found and confirmed after adjustment for potential confounding factors. No differences were observed for all the other coagulant activities, vWF:Ag, total TFPI, FVIIa-AT levels, or TGA parameters. CONCLUSION: In this pilot study, no major contribution of Lp(a) plasma levels was observed in modulating coagulation phenotype, as evaluated by multiple biomarkers. High Lp(a) plasma levels were associated with only a mild increase in FV:C.
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 prof...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.
We report a case of normolipidemic lipoprotein glomerulopathy (LPG) associated with the APOE Kyoto variant. A 54-year-old Chinese man was referred for evaluation of persistent low-level proteinuria detected on routine sc...We report a case of normolipidemic lipoprotein glomerulopathy (LPG) associated with the APOE Kyoto variant. A 54-year-old Chinese man was referred for evaluation of persistent low-level proteinuria detected on routine screening, with preserved renal function and no clinical features of nephrotic syndrome. Laboratory evaluation showed proteinuria without overt dyslipidemia. Extensive evaluation excluded secondary causes. Renal biopsy revealed markedly dilated capillary loops filled with characteristic lipoprotein thrombi, consistent with LPG. Subsequent genetic testing identified a heterozygous APOE c.127C>T (p.Arg43Cys) mutation, consistent with the APOE Kyoto variant. Because fasting lipid levels remained within reference ranges, lipid-lowering therapy was not initiated. Angiotensin receptor blockade was associated with a reduction in urine protein-to-creatinine ratio from 0.38 to 0.28 g/g over 2 months. This case broadens the phenotypic spectrum of APOE Kyoto-associated LPG by demonstrating biopsy-proven disease in the setting of largely normal systemic lipid levels.
BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) are linked to lower cardiovascular disease (CVD) risk, potentially via reduced low-grade inflammation (LGI). OBJECTIVE: To examine whether LGI mediates the association...BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) are linked to lower cardiovascular disease (CVD) risk, potentially via reduced low-grade inflammation (LGI). OBJECTIVE: 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. METHODS: Cross-sectional data from The Maastricht Study were analyzed. Fasted n-3 PUFAs were measured with H 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. RESULTS: 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. CONCLUSION: 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.