BACKGROUND: Despite guideline-directed low-density lipoprotein cholesterol (LDL-C) lowering, substantial residual vascular risk persists after stroke. Triglycerides (TG) and interleukin-6 (IL-6) have each been linked to...BACKGROUND: Despite guideline-directed low-density lipoprotein cholesterol (LDL-C) lowering, substantial residual vascular risk persists after stroke. Triglycerides (TG) and interleukin-6 (IL-6) have each been linked to this risk, yet their joint prognostic effect remains unclear. OBJECTIVE: To evaluate the cumulative prognostic association of baseline TG and IL-6 levels with the risk of recurrent vascular events after stroke. METHODS: We analyzed 962 consecutive patients (mean age, 71.0 years; male, 61.1%) with ischemic stroke or transient ischemic attack enrolled within 1 week of onset in a prospective observational study. TG levels were dichotomized at 150 mg/dL, and IL-6 levels at the median of 4.0 pg/mL. Patients were classified as LL (low TG/low IL-6), HL (high TG/low IL-6), LH (low TG/high IL-6), and HH (high TG/high IL-6) groups. The primary endpoint was 1-year major adverse cardiovascular events (MACE), defined as recurrent stroke, acute coronary syndrome, or vascular death. RESULTS: Both TG ≥ 150 mg/dL and IL-6 ≥ 4.0 pg/mL were independently associated with an increased risk of MACE. Annual MACE rates increased across the 4 categories: 8.0%, 17.5%, 15.7%, and 23.8% in the LL, HL, LH, and HH groups, respectively (log-rank P = .001). Compared with LL, both HL (hazard ratio [HR], 2.12; 95% CI 1.18-3.80) and LH (HR, 1.71; 95% CI 1.05-2.77) had significantly higher risk, with HH showing the highest risk (HR, 2.43; 95% CI 1.40-4.23). Notably, this cumulative association remained consistent in patients with atherothrombotic stroke, those receiving statin therapy, and those with LDL-C levels <100 mg/dL or <70 mg/dL. CONCLUSION: Stratification by TG and IL-6 levels revealed a cumulative increase in MACE risk after stroke, with the highest risk in patients with a dual burden of hypertriglyceridemia and systemic inflammation.
BACKGROUND: Obesity is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). While lowering low-density lipoprotein cholesterol (LDL-C) reduces ASCVD, it remains unclear whether patients with obesity ex...BACKGROUND: Obesity is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). While lowering low-density lipoprotein cholesterol (LDL-C) reduces ASCVD, it remains unclear whether patients with obesity exhibit distinct plaque responses to LDL-C control. OBJECTIVE: The current study sought to compare disease progression under achieving LDL-C <1.8 mmol/L in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) with and without obesity. METHODS: This prespecified sub-analysis of the OPTIMAL randomized trial (jRCT1052180152; UMIN000036721) evaluated 78 statin-treated patients with T2DM and CAD who underwent serial intravascular ultrasound imaging. Change in percent atheroma volume (PAV) was compared in those with obesity (body mass index [BMI] ≥ 25 kg/m, n = 31) and without (BMI <25 kg/m, n = 47) stratified by achievement of LDL-C<1.8 mmol/l at 48 weeks. RESULTS: LDL-C<1.8 mmol/L was attained in 41.9% with obesity and 57.4% without (P = .18). In participants without obesity, achieving LDL-C<1.8 mmol/L was not associated with significant change in PAV (-0.5 ± 0.4 vs -0.3 ± 0.4%, P = .74) or regression frequency (59.3 vs 62.0%, P = .85). In contrast, patients with obesity achieving LDL-C<1.8 mmol/L more often received high-intensity statins and demonstrated significant PAV regression (-0.9 ± 0.3 vs 0.4 ± 0.2%, P = .006) and greater regression frequency (79.6 vs 25.2%, P = .01). CONCLUSION: A greater regression of coronary atheroma following LDL-C<1.8 mmol/L was observed in obese patients. Future dedicated study is warranted to further elucidate atheroma regression in response to LDL-C control in obese and nonobese patients.
BACKGROUND: National epidemiologic data are needed to inform country-specific healthcare policies for prevention and new developing treatments. OBJECTIVE: We aimed to analyze Greek epidemiologic data in clinically releva...BACKGROUND: National epidemiologic data are needed to inform country-specific healthcare policies for prevention and new developing treatments. OBJECTIVE: We aimed to analyze Greek epidemiologic data in clinically relevant special populations for targeted treatments and to evaluate the utility of lipoprotein(a) [Lp(a)] as a risk enhancer METHODS: Two independent cohorts were included in this analysis: (1) consecutively recruited patients assessed in a tertiary outpatients' lipid clinic (Athens Angiometabolic cohort [AAC], n = 1106) with available peripheral vascular markers, and (2) sample of the Greek general population (ATTICA study [AS], n = 2682) with available 20-year follow-up data for atherosclerotic cardiovascular disease (ASCVD) events. RESULTS: Increased Lp(a) was found in 8.3% of the AS (≥50 mg/dL) and in 18.9% of the AAC (≥125 nmol/L) (16.0% without ASCVD and 22.1% with ASCVD, P = .006). Elevated Lp(a) levels were associated with increased carotid, coronary artery, and lower extremity atherosclerosis (P < .05 for all). Both the European Atherosclerosis Society (EAS) recommendations (net reclassification index [NRI]: 0.170) and a derived sex-specific inflation factor for HellenicSCOREII+ (NRI: 0.176) were efficient in incorporating Lp(a) as a risk enhancer over HellenicSCOREII+ for 20-year major adverse cardiovascular events. For 10-year cardiovascular death, only the EAS consensus provided significant reclassification. Finally, Lp(a) conferred increased eligibility for more aggressive primary prevention measures both by EAS recommendations (23.6% in AAC/13.6% in AS) and by sex-specific inflation factors (25.6% in AAC/22.3% in AS). CONCLUSION: Elevated Lp(a) levels were observed in 8.3% of the general population cohort and up to 23.9% in participants with ASCVD from the lipid clinic cohort, highlighting a risk gradient across ASCVD categories. Incorporating Lp(a) as a risk enhancer improves ASCVD risk reclassification beyond the validated HellenicSCOREII+.
BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premat...BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes. METHODS: This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes. RESULTS: Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis. CONCLUSION: This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.
BACKGROUND: The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. OBJECTIVE: To examine the associations between lipid traits and CRC risk us...BACKGROUND: The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. OBJECTIVE: To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. METHODS: In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. RESULTS: Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. CONCLUSION: Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings.
In the recent ApoA-I Event Reducing in Ischemic Syndromes II trial, a plasma-derived apolipoprotein A-I (apoA-I) infusion (CSL112) demonstrated no significant reduction in major cardiovascular events in the overall postm...In the recent ApoA-I Event Reducing in Ischemic Syndromes II trial, a plasma-derived apolipoprotein A-I (apoA-I) infusion (CSL112) demonstrated no significant reduction in major cardiovascular events in the overall postmyocardial infarction population. However, exploratory analyses revealed benefits in subgroups with both elevated low-density lipoprotein cholesterol (LDL-C) and systemic inflammation, suggesting that biologic context may be critical to therapeutic efficacy. Building on these trial findings, we highlight that the efficacy of CSL112 may depend on the coexistence of elevated LDL-C and systemic inflammation. We integrate ATP-binding cassette transporter A1 (ABCA1) biology with subgroup trial findings to propose a precision-stratification framework for future apoA-I infusion trials. We focus on the interaction of lipid burden and inflammation on ABCA1 transporter function, the impact of statin-induced transporter downregulation, and strategies for patient selection, including ex vivo efflux assays and molecular transporter profiling, and the therapeutic promise of combination therapies (apoA-I infusion with liver X receptor agonists) in patients with impaired transporter function.
Sikora Kessler A, Vera-Llonch M, Karwatowska-Prokopczuk E
… +9 more, Alexander VJ, Ann Q, Mejia Herrera C, Paparrodopoulos S, Xia S, Stroes ESG, Baum SJ, Tsimikas S, Balance Investigators
BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with extreme hypertriglyceridemia and high risk of acute pancreatitis. Olezarsen-an antisense oligonucleotide targeting hepatic ap...BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with extreme hypertriglyceridemia and high risk of acute pancreatitis. Olezarsen-an antisense oligonucleotide targeting hepatic apolipoprotein C3 (APOC3) messenger RNA-reduces triglycerides and may decrease pancreatitis risk. Olezarsen 80 mg once monthly is approved in the United States as an adjunct to diet to reduce triglycerides in adults with FCS. OBJECTIVE: To assess the effect of olezarsen on all-cause healthcare resource utilization (HCRU) and overall experience of patients with genetically identified FCS enrolled in the Balance trial (NCT04568434). METHODS: Prespecified exploratory endpoints included yearly all-cause hospitalization, total inpatient days, and emergency room visits for patients treated with olezarsen (80 or 50 mg) vs placebo, as well as Patient Global Impression of Change (PGIC). Ad hoc outcomes included length of hospital stay, intensive care unit (ICU) admissions, reasons for HCRU, and all-cause HCRU according to patients' history of acute pancreatitis and for individual olezarsen doses vs placebo. RESULTS: Treatment with olezarsen vs placebo for 1 year was associated with an 84% reduction in all-cause hospitalizations (mean rate ratio [95% CI], 0.16 [0.05, 0.50]), 6.3 fewer total inpatient days (95% CI, -11.09, -1.53), better PGIC scores, shorter length of stay, and numerically fewer ICU admissions. Acute pancreatitis was the most frequent cause of hospitalization. Reduction in all-cause inpatient service utilization was consistent for individual dose groups and in patients with a history of acute pancreatitis. CONCLUSION: In the Balance study, olezarsen reduced all-cause inpatient service utilization and improved the experience of patients with FCS.
Gómez-Coronado D, Rodríguez-Jiménez C, Villar P
… +10 more, Fernández-Suárez ME, Eble JA, de la Peña G, Martínez-Botas J, Acebes-Huerta A, Prieto-Cazorla P, Villa-Fajardo M, Lasunción MA, Rodríguez-Nóvoa S, Gutiérrez L
BACKGROUND: ATP-binding cassette A1 (ABCA1) is a membrane-associated cholesterol efflux pump that is crucial for high-density lipoprotein (HDL) biogenesis and cellular cholesterol homeostasis. Pathogenic variants in the...BACKGROUND: ATP-binding cassette A1 (ABCA1) is a membrane-associated cholesterol efflux pump that is crucial for high-density lipoprotein (HDL) biogenesis and cellular cholesterol homeostasis. Pathogenic variants in the ABCA1 gene cause Tangier disease (TD), a rare autosomal recessive disorder characterized by nearly absent HDL in plasma and cholesteryl ester accumulation in tissue macrophages. Clinical manifestations vary among patients with TD, including splenomegaly, thrombocytopenia, and cardiovascular disease (CVD), with no clear association with specific ABCA1 pathogenic variants. Thrombocytopenia is attributed to hypersplenism-mediated platelet clearance; however, there is controversy regarding platelet production and function in TD. OBJECTIVE: To identify and functionally characterize the suspected alteration in ABCA1, and to study platelet production and function in a Spanish family with HDL deficiency and thrombocytopenia. METHODS: Lipid and apolipoprotein profile analyses, next-generation/Sanger sequencing, in vitro ABCA1 expression and cholesterol efflux assays, primary megakaryocyte differentiation cultures, and platelet functional studies were performed. RESULTS: We identified a novel variant, ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16), which results in a truncated protein with defective apolipoprotein AI-dependent cholesterol efflux. Mild to severe thrombocytopenia and splenomegaly were observed in homozygous carriers; however, there was no clinical history of CVD. Platelet degranulation was overtly normal, although a distinct aggregation profile was observed in ABCA1:p.(Ile1103Serfs*16) carriers. Impaired megakaryocyte differentiation associated with aberrant accumulation of neutral lipids in megakaryocytes was observed in primary cell cultures from homozygous carriers. CONCLUSION: The ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16) variant causes TD. Our findings suggest that thrombocytopenia in TD is not merely due to platelet clearance but also a consequence of ineffective megakaryopoiesis due to ABCA1 dysfunction.
BACKGROUND: Omega-3 polyunsaturated fatty acid (PUFA) administration has been associated with a reduced risk of developing cardiovascular diseases. Some studies have explored the potential effect of omega-3 PUFA on lipop...BACKGROUND: Omega-3 polyunsaturated fatty acid (PUFA) administration has been associated with a reduced risk of developing cardiovascular diseases. Some studies have explored the potential effect of omega-3 PUFA on lipoprotein-associated phospholipase A2 (Lp-PLA2) levels with conflicting results; while some have shown no effect, others have found reduced levels of Lp-PLA2 with omega-3 supplementation. This meta-analysis of randomized controlled trials aims to clarify the impact of omega-3 supplementation on Lp-PLA2 mass and activity. SOURCES OF MATERIAL: The Medical Subject Headings (MeSH) terms and keywords were searched in Web of Science, PubMed, Scopus, Google Scholar, and ClinicalTrials.gov databases. The random- or fixed-effects model and the generic inverse variance weighting method were applied for quantitative data. The influence of each study on the overall effect size was determined using the leave-one-out method. ABSTRACT OF FINDINGS: The meta-analysis of 16 randomized controlled trials showed a significant reduction in Lp-PLA2 mass with omega-3 intervention (weighted mean difference [WMD]: -24.05 ng/mL, 95% CI: -27.63, -20.47, P < .0001) but no significant changes in Lp-PLA2 activity (WMD: -8.54 nmol/mL/min, 95% CI: -27.25, 10.18, P = .37). A subgroup analysis by type of omega-3 supplementation revealed that either icosapent ethyl (WMD: -32.67 ng/mL, 95% CI: -34.36, -30.98, P < .00001) or other omega-3 formulations (WMD: -17.05 ng/mL, 95% CI: -22.93, -11.18, P < .00001) significantly decreased the Lp-PLA2 mass. CONCLUSION: Omega-3 supplementation significantly reduces circulating levels of Lp-PLA2 mass without affecting its activity.
OBJECTIVES: Patients with muscular dystrophies are at increased cardiometabolic risk due to reduced mobility, increased adiposity, glucose intolerance, and dyslipidemia. While statins remain the cornerstone of cardiovasc...OBJECTIVES: Patients with muscular dystrophies are at increased cardiometabolic risk due to reduced mobility, increased adiposity, glucose intolerance, and dyslipidemia. While statins remain the cornerstone of cardiovascular disease prevention in the general population, their use in muscular dystrophies is complicated by the presence of underlying muscle symptoms, which can be difficult to distinguish from statin-associated myopathy. This overlap contributes to heightened concerns about statin tolerance and may impair long-term adherence. The emergence of nonstatin lipid-lowering therapies presents an important opportunity to revisit the conventional "statin-first" approach. Therefore, we sought to highlight the under-recognized issue of atherosclerotic cardiovascular disease (ASCVD) prevention in patients with muscular dystrophy, and explore alternative lipid-lowering strategies beyond statins, given the unique challenges in this population. METHODS: We conducted a comprehensive review of the existing literature on dyslipidemia and ASCVD risk in muscular dystrophies, evaluated current management guidelines, and shared our institutional experience by presenting the largest known case series of patients with muscular dystrophies treated with nonstatin lipid-lowering therapies. RESULTS: Statin use in muscular dystrophy is complicated by the difficulty in distinguishing baseline muscle symptoms from statin-associated myopathy, leading to concerns about tolerance and adherence. Our case series demonstrates that nonstatin therapies are a viable and well-tolerated alternative in this population. CONCLUSIONS: There is a critical need to expand the focus of cardiovascular care in muscular dystrophy to include ASCVD prevention. Nonstatin therapies represent a promising and practical option for managing dyslipidemia in patients with muscular dystrophy. Tailored approaches are needed to balance cardiovascular risk reduction with the unique neuromuscular challenges in this population.
Lipodystrophic syndromes are a heterogeneous group of disorders characterized by a lack of fatty tissue or abnormal fat accumulation outside of the body's typical fat distribution areas. Partial lipodystrophy most common...Lipodystrophic syndromes are a heterogeneous group of disorders characterized by a lack of fatty tissue or abnormal fat accumulation outside of the body's typical fat distribution areas. Partial lipodystrophy most commonly manifests in childhood or young adulthood, and is classified into 6 primary subtypes, along with other rare categories. Lipodystrophy subtype 4 is associated with severe insulin resistance and unique traits, including severe hyperlipidemia, progressive liver disease, and arterial hypertension. Here we present the case of a 30-year-old woman with alarming hypertriglyceridemia, newly diagnosed diabetes mellitus, and severe hypertension. A complex differential diagnostic procedure yielded the diagnosis of familial partial lipodystrophy subtype 4. Initial treatment with plasmapheresis effectively reduced her triglyceride values but failed due to lack of intravenous access. Recurrent severe hypertriglyceridemia and normal leptin levels prompted the use of volanesorsen therapy, which is primarily indicated for treatment of hypertriglyceridemia in familial chylomicronemia syndrome. Volanesorsen proved very effective in this case.