Journal of clinical lipidology最新文献

Background: To examine associations between metabolic syndrome (MetS), its components, and MetS subgroups based on the absence or presence of hypertension (HTN) and diabetes mellitus (DM), with incident myocardial infarction (MI).

Methods: Among 7824 Tehran Lipid and Glucose Study participants (mean age 46.9 years; 44.9% men) without baseline cardiovascular disease, multivariable Cox models and restricted cubic spline analyses assessed the associations of MetS, its subgroups, and components with incident MI.

Results: Of the 7824 participants included, 4092 (52.3%) were free of MetS. Among participants with MetS, 1847 (49.5%) had neither DM nor HTN, 1217 (32.6%) had HTN only (DM-/HTN+), 330 (8.8%) had DM only (DM+/HTN-), and 338 (9.1%) had both DM and HTN (DM+/HTN+). During a median follow-up of 19.9 years, 252 MI events occurred. Compared with MetS-free individuals, the adjusted hazard ratio (HR) of MetS for incident MI was 2.04 (95% CI: 1.54-2.70). HRs were 1.41 (1.00-1.99) for MetS (DM-/HTN-), 2.06 (1.44-2.95) for MetS (DM-/HTN+), 3.40 (2.15-5.38) for MetS (DM+/HTN-), and 5.09 (3.33-7.81) for MetS (DM+/HTN+) subgroups. Individuals with MetS but without the elevated glucose component or HTN were still at increased risk of MI. Using the American College of Cardiology/American Heart Association definition of HTN did not alter the findings. All MetS components showed significant associations with MI. After adjustment for the other MetS components, elevated waist circumference (HR: 1.47, 95% CI: 1.09-1.98) and elevated blood pressure (1.50; 1.14-1.98) components were associated with higher risk of MI.

Conclusion: MetS in the absence of HTN and DM conferred a greater risk of MI.

Background: A large evidence base supports lipid lowering to reduce atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. Despite guideline-recommended lipid-lowering therapies (LLT), gender-based disparities in lipid management persist, with women less likely to be treated aggressively and achieve optimal low-density lipoprotein cholesterol (LDL-C) levels.

Objective: We aimed to investigate whether provider gender impacted lipid treatment gaps.

Methods: We conducted a retrospective chart review of 364,021 adults within a large health system who underwent lipid testing between 2022 and 2023. Demographic, clinical, and prescribing data were abstracted from electronic health records. Optimal LDL-C was defined based on ASCVD risk.

Results: Women had higher mean LDL-C (108 vs 102 mg/dL, P < .0001) and were less likely to achieve an LDL-C of <100 mg/dL (41% vs 47%, P < .0001) compared to men. Among those with ASCVD, only 31% of women vs 47% of men achieved an LDL-C <70 mg/dL (P < .0001). Women were less likely to be prescribed statins (26% vs 33%, P < .0001) in the overall population and high-intensity statins (23% vs 31%, P < .0001) in the ASCVD population than men. No prescribing difference was noted between male and female providers across specialties.

Conclusion: Women with or at risk for ASCVD experience lower rates of LLT prescription and LDL-C goal attainment compared to men. These disparities underscore the need for targeted interventions to improve LDL-C goal attainment in women.

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: Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with a markedly increased risk of cardiovascular disease (CVD) that is not fully explained by traditional risk factors. Lipoprotein(a) [Lp(a)], a genetically determined lipoprotein with proatherogenic, prothrombotic, and proinflammatory properties, has emerged as a potential contributor to this excess cardiovascular burden. Growing evidence suggests that Lp(a) may represent a mechanistic link between chronic inflammation, immune dysregulation, and accelerated atherosclerosis in RA.

Sources of material: This narrative review synthesizes evidence from observational studies, mechanistic research, genetic analyses, biomarker investigations, and emerging therapeutic trials examining Lp(a) in RA. Relevant literature was identified through comprehensive searches of major biomedical databases, with emphasis on studies addressing pathophysiology, cardiovascular outcomes, disease activity, and treatment effects on Lp(a).

Abstract of findings: RA patients frequently exhibit elevated Lp(a) levels, particularly in the presence of active systemic inflammation. Lp(a) contributes to vascular injury through enhanced arterial wall retention, carriage of oxidized phospholipids, endothelial activation, and impaired fibrinolysis. Clinical studies associate elevated Lp(a) with subclinical atherosclerosis, arterial stiffness, and increased cardiovascular events in RA, independent of conventional lipid parameters. Inflammatory cytokines, particularly interleukin-6 (IL-6), appear to modulate Lp(a) metabolism, providing a biological rationale for the Lp(a)-lowering effects observed with IL-6 receptor blockade. Advances in standardized assays, genetic insights into LPA polymorphisms, and novel RNA-based therapies have revitalized interest in Lp(a) as both a biomarker and therapeutic target in RA.

Conclusion: Lp(a) occupies a critical intersection between inflammation and atherosclerosis in RA. Incorporating Lp(a) into cardiovascular risk stratification and exploring targeted therapies may enable more precise, integrated management of cardiovascular risk in RA patients, warranting dedicated prospective studies.

Background: Lipoprotein(a) (Lp[a]), is a significant risk factor for cardiovascular disease, yet is infrequently measured.

Objective: A qualitative investigation was designed to better understand the barriers and facilitators to Lp(a) testing.

Methods: Focus groups were held with clinicians (n = 26) and at-risk individuals (n = 24). Transcripts were thematically analyzed, guided by the Integrated Screening Action Model (I-SAM). Consistent with the I-SAM, barriers and facilitators of Lp(a) measurement were categorized as motivational, capability, and opportunity factors.

Results: Facilitators identified included perceived clinical utility, emotional reassurance associated with a newfound understanding of prior events, the ability to use Lp(a) knowledge to better prepare for the future, as well as active requests for testing. Barriers identified included a lack of perceived clinical utility and the potential to cause emotional distress with results, uncertainty and knowledge limitations around Lp(a), cost-related concerns, low expectations for testing, and clinician reluctance to test.

Conclusions: This analysis highlights that Lp(a) testing decisions are multifactorial, providing multiple opportunities for intervention and improvement. Strategies to convey how Lp(a) measurement can inform risk assessment and treatment approaches may be foundational to encouraging more widespread testing.

Background: Heart transplantation represents an increasingly utilized procedure for end-stage heart failure patients.

Current evidence: Cardiac allograft vasculopathy (CAV) is a post-transplant complication of pathological vasculature remodeling and remains an important cause for long-term graft failure and mortality. Current preventive strategies for CAV include optimization of vascular risk factors and pharmacotherapy with statins and immunosuppressants.

Conclusion: Despite demonstrated post-transplant mortality benefit and reduction in CAV with statins, the role of other pharmacotherapies on CAV reduction through LDL-C lowering remains less established. This review explores established evidence as well as evolving pathways for LDL-C lowering strategies to prevent CAV.

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.

Background: Rare variants in SCARB1, which encodes the high-density lipoprotein (HDL) receptor scavenger receptor class B type 1 (SR-B1), are hypothesized to drive unexplained extreme levels of plasma HDL cholesterol (HDL-C).

Objective: We sequenced and phenotypically correlated SCARB1 by analyzing individuals with extreme HDL-C levels and characterizing the functional consequences of rare identified variants.

Methods: SCARB1 was Sanger-sequenced in 96 unrelated participants with extreme HDL-C levels. Clinical, biochemical, and anthropometric data were compared between groups. Bioinformatic tools were used to predict the functional impact of all detected variants. Familial analyses of predicted damaging in silico or not previously described variants was assessed, and HDL uptake was quantified by flow cytometry in HEK293 cells expressing rare SCARB1 variants showing a suggestive pattern of familial segregation.

Results: Compared with the high-HDL-C group, low-HDL-C subjects exhibited lower low-density lipoprotein cholesterol and total cholesterol but higher triglycerides, higher body mass index, and a greater frequency of atherosclerotic cardiovascular disease events. Twenty-five SCARB1 variants were identified; 4 of them, c.-177G>T, p.(Thr118Ser), c.843-982G>A and p.(Thr378Met), were predicted to be deleterious. The missense changes p.(Thr118Ser) and p.(Thr378Met) showed a suggestive pattern of segregation with high HDL-C in available pedigrees. Cells expressing p.(Thr378Met) SCARB1 variant showed a reduction in HDL uptake vs wild-type.

Conclusion: Rare predicted damaging in silico variant in SCARB1, p.(Thr378Met), impairs SR-B1-mediated HDL uptake and associates with high HDL-C levels, highlighting SCARB1 as a candidate gene for genetic screening in dyslipidemic patients.

Background: Patients experiencing premature cardiovascular events (males: <55 years; females: <65 years) represent a high-risk subgroup within the atherosclerotic cardiovascular disease (ASCVD) population. Elevated lipoprotein(a) (Lp[a]) is an independent, genetic, causal risk factor for ASCVD. Lp(a) distribution among patients with premature ASCVD is poorly characterized.

Objective: This study aimed to describe Lp(a) distribution and baseline characteristics in a large real-world sample of patients with premature ASCVD.

Methods: We identified 17,594 patients with premature ASCVD who had Lp(a) values from US Medicare, Medicaid, and commercial plans between January 2016-September 2022.

Results: Mean age (SD) was 50.9 (10.1) years, most patients were female (68.9%), and half (52.2%) were not prescribed lipid-lowering therapy. Lp(a) levels ≥125, ≥175, and ≥225 nmol/L occurred in 26.8%, 18.8%, and 11.5%, respectively. Black patients had higher median (Q1-Q3) Lp(a) levels (111.0 [51.1-206.0] nmol/L) than Asian (35.0 [14.4-100.0] nmol/L), Hispanic (31.0 [10.9-95.0] nmol/L), or White patients (31.0 [10.7-110] nmol/L).

Conclusion: In one of the largest studies in the US investigating Lp(a) distribution in premature ASCVD, we found over a quarter of patients had elevated Lp(a) (≥125 nmol/L).

Background: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary atherosclerosis. Functional aspects of high-density lipoprotein (HDL), including cholesterol transfer capacity, may contribute to cardiovascular risk heterogeneity in FH.

Objective: To investigate whether cholesterol transfer to HDL and other HDL-related parameters are associated with coronary artery disease (CAD) in patients with heterozygous FH (HeFH).

Methods: Fifty-three genetically confirmed FH patients (mean age: 49.2 years; 73.6% female) were included. Twenty-seven had plaques, while 26 had no vessel abnormalities as determined by coronary computed tomography angiography. The transfer of both unesterified and esterified cholesterol (UC and EC) to HDL, as well as HDL antioxidant capacity, particle size, and subfractions, plasma concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON-1) activity were assessed.

Results: Family history of premature CAD (P < .028) and tendinous xanthomas (P = .014) were more frequent in those with plaques. No differences were found in apolipoprotein (apo) B, LDL-C, LDL-C year score, lipoprotein(a), non-HDL-C, apo A-I, HDL-C, HDL subfractions, or triglycerides. Transfer of lipids to HDL and antioxidant capacity did not differ between the groups. LCAT concentrations and PON-1 activity were also similar. In contrast, CETP concentration was higher in those with plaques (P < .008). However, only family history of early CAD (odds ratio [OR]: 4.12, 95% CI, 1.23-13.80, P = .022) and xanthomas (OR: 3.65, 95% CI, 1.06-12.60, P = .040) were independently associated with plaques.

Conclusion: Among patients with HeFH, no HDL-related parameter was independently associated with subclinical CAD.