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...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.
BACKGROUND: Lipoprotein(a) [Lp(a)] is recommended for atherosclerotic cardiovascular disease (ASCVD) risk assessment and is targeted by new drugs in development. However, the association of Lp(a) with ASCVD was identifie...BACKGROUND: Lipoprotein(a) [Lp(a)] is recommended for atherosclerotic cardiovascular disease (ASCVD) risk assessment and is targeted by new drugs in development. However, the association of Lp(a) with ASCVD was identified from epidemiologic studies that typically used plasma samples. OBJECTIVE: To determine the agreement between serum- and plasma-based Lp(a) measurements. METHODS: We measured Lp(a) in both EDTA plasma and serum using the same validated, isoform-insensitive assay in 100 Atherosclerosis Risk in Communities participants equally distributed across age, sex, race, and Lp(a) levels (0 to >200 nmol/L). We assessed correlation (Spearman), mean differences, and bias (Deming regression). RESULTS: The correlation between serum and plasma was excellent (Spearman's r = 0.99). Deming regression yielded a slope of 1.05 (95% CI 1.03, 1.08) and an intercept of 0.26 nmol/L (95% CI -1.97, +2.41). Bland-Altman analysis identified no statistically significant mean difference (serum minus plasma: +7.7 nmol/L [95% CI -16.7, +32.0]). CONCLUSION: We demonstrated excellent agreement between serum and plasma Lp(a), supporting the use of either specimen for Lp(a) measurement and pooling data from both sources.
BACKGROUND: Sex-specific mechanisms in atherosclerosis have been suggested, with low-density lipoprotein cholesterol (LDL-C) playing a less prominent role in predicting cardiovascular risk in women than in men. OBJECTIVE...BACKGROUND: Sex-specific mechanisms in atherosclerosis have been suggested, with low-density lipoprotein cholesterol (LDL-C) playing a less prominent role in predicting cardiovascular risk in women than in men. OBJECTIVE: The aim of this study was to assess sex-specific differences in the association between LDL-C levels and plaque morphology. METHODS: In this multicenter observational study, 325 patients with coronary artery disease underwent optical coherence tomography (OCT) before percutaneous coronary intervention. The plaque morphology at target lesions was assessed using OCT. RESULTS: Among the participants, 263 were men, and 62 were women. Patients were stratified into the following LDL-C tertiles: low (<72 mg/dL), moderate (72-97 mg/dL), and high (≥98 mg/dL). In men, higher LDL-C levels correlated with an increased prevalence of lipid-rich plaques, macrophage infiltration, cholesterol crystals, and multilayered plaque. The LDL-C levels were also associated with a maximal layer arc (low vs moderate vs high LDL-C levels: 0 vs 131 vs 169) and a greater maximal lipid arc (low vs moderate vs high LDL-C levels: 160 vs 214 vs 252). In contrast, no corresponding associations were observed in women. CONCLUSION: LDL-C levels were associated with plaque vulnerability in men, particularly lipid accumulation and layered plaque formation, but not in women, underscoring sex-specific differences in lipid-driven coronary pathology.
BACKGROUND: An elevated level of lipoprotein(a) (Lp[a]) is a genetically-determined cardiovascular risk factor. A size polymorphism in its apolipoprotein(a) (apo[a]) component, expressed as kringle (K) 4 repeat numbers,...BACKGROUND: An elevated level of lipoprotein(a) (Lp[a]) is a genetically-determined cardiovascular risk factor. A size polymorphism in its apolipoprotein(a) (apo[a]) component, expressed as kringle (K) 4 repeat numbers, is a major contributor to variability in levels. While chronic kidney disease (CKD) increases Lp(a) levels, less is known about its effect on Lp(a) molecular properties. OBJECTIVE: To assess and compare Lp(a) lipidomic properties in patients with CKD and controls. METHODS: We assessed and compared Lp(a)-lipidomic properties in 54 nondiabetic, nondialysis patients with CKD and 39 controls. CKD was defined by an estimated glomerular filtration rate of <60 mL/min/1.73 m. RESULTS: The mean age of the cohort was 63 years, 48% were women, and 77% were of European descent. Lp(a)-bound oxidized phospholipids (Lp[a]-OxPL) concentrations were higher in patients with CKD vs controls (median [IQR] 2.7 [0.5; 7.4] vs 1.2 [0.5; 3.4] U/L, P = .031), in particular for the medium (23-27 K repeats) apo(a) size range (P = .002). Among Lp(a)-OxPL subspecies, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine relative abundance was significantly higher in patients with CKD compared to controls (21% vs 16%, P = .0004). Of the 437 individual lipid species in Lp(a), 146 species primarily representing diacylglycerols (P = .009), acylcarnitines (P = .003), and triacylglycerols (P = .005) showed significantly higher abundance in patients with CKD vs controls. This pattern remained unchanged after adjusting for differences in Lp(a) levels, indicating an impact of the CKD condition on Lp(a) lipidomic properties. CONCLUSION: Among individuals without diabetes, kidney impairment was characterized by higher Lp(a)-OxPL concentrations and proinflammatory Lp(a)-lipidomic properties. Mechanisms underlying these changes and relevance to cardiovascular risk warrant further investigations.
BACKGROUND: 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 fa...BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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 enabl...BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: Bempedoic acid (BA) lowers low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP), but prior meta-analyses pooled heterogeneous timepoints and effect metrics, limiting pr...BACKGROUND: Bempedoic acid (BA) lowers low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP), but prior meta-analyses pooled heterogeneous timepoints and effect metrics, limiting precision and clinical interpretability. We conducted a harmonized meta-analysis using prespecified 12-week windows to generate consistent, clinically applicable estimates of BA's lipid and anti-inflammatory effects. OBJECTIVE: To quantify the lipid-lowering and anti-inflammatory effects of BA using harmonized placebo-corrected percentage change estimates at prespecified 12-week timepoints and to evaluate whether treatment effects differ according to statin intolerance, background lipid-lowering therapy, or ezetimibe co-administration. METHODS: PubMed, Scopus, and ClinicalTrials.gov were searched through November 2025 for randomized trials comparing BA monotherapy or fixed-dose BA-ezetimibe versus placebo. The primary endpoint was placebo-corrected percentage (PC%) change in LDL-C at 12 weeks; PC% change in hs-CRP was secondary. Multi-arm trials were pre-combined using inverse-variance weighting. Random-effects models used restricted maximum likelihood with Hartung-Knapp confidence intervals (CI), and prediction intervals (PI) were reported. Prespecified meta-regression evaluated diabetes prevalence, statin intolerance, background lipid-lowering therapy (LLT), ezetimibe co-administration, and timepoint. RESULTS: Fourteen trials were included. BA monotherapy lowered LDL-C by -20.3 percentage points (pp) (95% CI -23.2 to -17.4), with consistent effects on background statin therapy (-18.3 pp; 95% CI -20.0 to -16.6). Statin-intolerant cohorts showed numerically larger LDL-C reductions (~25 pp), without statistically significant effect modification. Diabetes prevalence was not associated with differential LDL-C response in meta-regression. Fixed-dose BA-ezetimibe achieved a total -39.0 pp LDL-C reduction (95% CI -48.7 to -29.3); the pooled difference between monotherapy and fixed-dose combination estimates suggests an approximate 18 pp incremental reduction associated with ezetimibe co-administration. BA reduced hs-CRP by -23.1% (95% CI -32.7% to -13.6%), without augmentation by ezetimibe. CONCLUSION: Across randomized trials, BA provides predictable LDL-C lowering that is consistent across LLT backgrounds and diabetes prevalence. Ezetimibe substantially augments LDL-C reduction but does not enhance hs-CRP lowering. These findings are consistent with an intrinsic anti-inflammatory effect of BA, although causality independent of LDL-C reduction cannot be definitively established from study-level data. These results refine BA's role within stepwise lipid-lowering strategies for patients who remain above LDL-C targets despite standard therapy.
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,...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.
BACKGROUND: 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) w...BACKGROUND: 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. SOURCES OF MATERIAL: We review evidence that highlights gaps in lipid management for patients with PAD, and how these may be addressed by leveraging implementation science. ABSTRACT OF FINDINGS: 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. CONCLUSION: 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.
BACKGROUND: 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 dyslipidem...BACKGROUND: 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. OBJECTIVE: To determine the prevalence and associated factors of dyslipidemia and hyperglycemia among adult people living with HIV on ART. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
One in 10 individuals 65 years and older has dementia. The most common form is Alzheimer's disease, followed by vascular dementia. There are myriad shared risk factors between brain health and cardiovascular health, incl...One in 10 individuals 65 years and older has dementia. The most common form is Alzheimer's disease, followed by vascular dementia. There are myriad shared risk factors between brain health and cardiovascular health, including modifiable risk factors such as high cholesterol, diabetes, hypertension, obesity, and physical inactivity. Important nonmodifiable dementia risk factors include increasing age and the apolipoprotein E4 allele, which negatively alters brain cholesterol handling and the integrity of the blood-brain barrier. This Journal of Clinical Lipidology Roundtable presents a conversation between Drs Anum Saeed, James Trippi, Priya Palta, Kellyann Niotis, and Kevin C. Maki, who discussed the heart-brain connection in health and disease, including the epidemiology of dementia, lipids, and other shared risk factors between heart and brain health, and the lipid biology related to neurodegeneration with an emphasis on apolipoprotein E alleles. They also discussed the role of cognitive testing, biomarkers, including blood biomarkers, metabolomics, and brain imaging measurements, as well as the available evidence-based strategies to reduce risk and ongoing investigations of potential future therapies. Their conversation emphasized the importance of early prevention to decrease cardiovascular and dementia risks. Prevention is not just the best strategy to reduce the risk of dementia, but is virtually the only strategy available to clinicians at this time.
BACKGROUND: The relationship between circulating lipid profiles and lesion-level plaque lipid burden in humans remains incompletely defined. OBJECTIVE: We investigated the association between lipid profiles and plaque li...BACKGROUND: The relationship between circulating lipid profiles and lesion-level plaque lipid burden in humans remains incompletely defined. OBJECTIVE: We investigated the association between lipid profiles and plaque lipid burden assessed by near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS), with stratification according to statin exposure. METHODS: We analyzed 410 patients undergoing NIRS-IVUS-guided percutaneous coronary intervention. Associations between lipid profiles (total cholesterol, low-density lipoprotein cholesterol [LDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and triglycerides) and lesion-level plaque lipid burden, quantified by the maximum lipid core burden index within 4 mm (LCBI), were assessed using correlation analyses, multivariable linear regression, and logistic regression for lipid-rich plaque (defined as LCBI ≥324.7). RESULTS: Circulating atherogenic lipoproteins, including LDL-C and non-HDL-C, were associated with plaque lipid burden in the overall cohort, with more pronounced and independent associations observed in statin-naïve patients (eg, LDL-C: β = 2.02 [1.24-2.81]). These lipid parameters were also independent predictors of lipid-rich plaque in statin-naïve individuals (eg, LDL-C per 10 mg/dL: odds ratio = 1.28 [1.15-1.42]). In contrast, no significant associations were observed in statin-treated patients. CONCLUSION: In statin-naïve patients, circulating atherogenic lipoproteins are associated with lesion-level plaque lipid burden, supporting a direct biological link between circulating lipid levels and local plaque lipid characteristics. This coupling is attenuated following statin exposure, suggesting that pharmacologic lipid lowering modifies the relationship between circulating lipid levels and plaque lipid biology.
BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are common, underdiagnosed monogenic dyslipidemias that significantly increase cardiovascular risk. OBJECTIVE: We investigated whether st...BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are common, underdiagnosed monogenic dyslipidemias that significantly increase cardiovascular risk. OBJECTIVE: 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. METHODS: We analyzed 378 lipid clinic patients receiving Lp(a) screening and FH genetic testing with multinomial logistic regression. RESULTS: 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. CONCLUSIONS: 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.