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Ageing Research Reviews Jan 2024Familial hypercholesterolemia (FH) is a metabolic condition caused mainly by a mutation in the low-density lipoprotein (LDL) receptor gene (LDLR), which is highly... (Review)
Review
Familial hypercholesterolemia (FH) is a metabolic condition caused mainly by a mutation in the low-density lipoprotein (LDL) receptor gene (LDLR), which is highly prevalent in the population. Besides being an important causative factor of cardiovascular diseases, FH has been considered an early risk factor for Alzheimer's disease. Cognitive and emotional behavioral impairments in LDL receptor knockout (LDLr) mice are associated with neuroinflammation, blood-brain barrier dysfunction, impaired neurogenesis, brain oxidative stress, and mitochondrial dysfunction. Notably, today, LDLr mice, a widely used animal model for studying cardiovascular diseases and atherosclerosis, are also considered an interesting tool for studying dementia. Here, we reviewed the main findings in LDLr mice regarding the relationship between FH and brain dysfunctions and dementia development.
Topics: Humans; Animals; Mice; Hypercholesterolemia; Cardiovascular Diseases; Risk Factors; Hyperlipoproteinemia Type II; Brain; Cognition; Alzheimer Disease; Heart Disease Risk Factors
PubMed: 38056504
DOI: 10.1016/j.arr.2023.102149 -
Current Cardiology Reports Sep 2023Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in the metabolism of LDL receptors and mainly acts in the liver. However, there are... (Review)
Review
PURPOSE OF REVIEW
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in the metabolism of LDL receptors and mainly acts in the liver. However, there are accumulating data that PCSK9 involves in several functions in different organs beyond the liver. Herein we aimed to summarize the effects of PCSK9 in tissues other than the liver.
RECENT FINDINGS
PCSK9 has crucial roles in heart, brain and kidney in addition to the cholesterol metabolism. Targeting PCSK9 for the treatment of hypercholesterolemia is effective in the prevention from cardiovascular diseases and PCSK9 inhibitors are getting to be administered in more cases. Therefore understanding the effects of PCSK9 in other tissues gained importance in the use of PCSK9 inhibitors era. PCSK9 participates in cardiac, renal, and neurologic functions however, current literature reveals that use of PSCSK9 inhibitors have beneficial or neutral effects on these organs. Inhibition of PCSK9 is assigned to be associated with new onset diabetes in experimental studies whereas real world data with PCSK9 inhibitors established no relationship between PCSK9 inhibitors and new onset diabetes. PCSK9 might be used as a target for the treatment of nephrotic syndrome and heart failure in the future.
Topics: Humans; Proprotein Convertase 9; PCSK9 Inhibitors; Hypercholesterolemia; Kidney
PubMed: 37428313
DOI: 10.1007/s11886-023-01918-2 -
Diabetes & Metabolism Journal Nov 2023To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic... (Randomized Controlled Trial)
Randomized Controlled Trial
The Efficacy and Safety of Moderate-Intensity Rosuvastatin with Ezetimibe versus High-Intensity Rosuvastatin in High Atherosclerotic Cardiovascular Disease Risk Patients with Type 2 Diabetes Mellitus: A Randomized, Multicenter, Open, Parallel, Phase 4 Study.
BACKGRUOUND
To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic cardiovascular disease (ASCVD) risk patients with type 2 diabetes mellitus (T2DM).
METHODS
This study was a randomized, multicenter, open, parallel phase 4 study, and enrolled T2DM subjects with an estimated 10-year ASCVD risk ≥7.5%. The primary endpoint was the low-density lipoprotein cholesterol (LDL-C) change rate after 24-week rosuvastatin 10 mg/ezetimibe 10 mg treatment was non-inferior to that of rosuvastatin 20 mg. The achievement proportion of 10-year ASCVD risk <7.5% or comprehensive lipid target (LDL-C <70 mg/dL, non-high-density lipoprotein cholesterol <100 mg/dL, and apolipoprotein B <80 mg/dL) without discontinuation, and several metabolic parameters were explored as secondary endpoints.
RESULTS
A hundred and six participants were assigned to each group. Both groups showed significant reduction in % change of LDL-C from baseline at week 24 (-63.90±6.89 vs. -55.44±6.85, combination vs. monotherapy, p=0.0378; respectively), but the combination treatment was superior to high-intensity monotherapy in LDL-C change (%) from baseline (least square [LS] mean difference, -8.47; 95% confidence interval, -16.44 to -0.49; p=0.0378). The combination treatment showed a higher proportion of achieved comprehensive lipid targets rather than monotherapy (85.36% vs. 62.22% in monotherapy, p=0.015). The ezetimibe combination significantly improved homeostasis model assessment of β-cell function even without A1c changes (LS mean difference, 17.13; p=0.0185).
CONCLUSION
In high ASCVD risk patients with T2DM, the combination of moderate-intensity rosuvastatin and ezetimibe was not only non-inferior but also superior to improving dyslipidemia with additional benefits compared to high-intensity rosuvastatin monotherapy.
Topics: Humans; Rosuvastatin Calcium; Ezetimibe; Cholesterol, LDL; Anticholesteremic Agents; Hypercholesterolemia; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Drug Therapy, Combination; Atherosclerosis
PubMed: 38043782
DOI: 10.4093/dmj.2023.0171 -
Pharmacological Research Aug 2023Familial hypercholesterolaemia (FH) is a common autosomal semi-dominant and highly penetrant disorder of the low-density lipoprotein (LDL) receptor pathway,... (Review)
Review
Familial hypercholesterolaemia (FH) is a common autosomal semi-dominant and highly penetrant disorder of the low-density lipoprotein (LDL) receptor pathway, characterised by lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients with FH are not diagnosed and do not attain recommended LDL-C goals despite maximally tolerated doses of potent statin and ezetimibe. Over the past decade, several cholesterol-lowering therapies such as those targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) or angiopoietin-like 3 (ANGPTL3) with monoclonal antibody or ribonucleic acid (RNA) approaches have been developed that promise to close the treatment gap. The availability of new therapies with complementary modes of action of lipid metabolism has enabled many patients with FH to attain guideline-recommended LDL-C goals. Emerging therapies for FH include liver-directed gene transfer of the LDLR, vaccines targeting key proteins involved in cholesterol metabolism, and CRISPR-based gene editing of PCSK9 and ANGPTL3, but further clinical trials are required. In this review, current and emerging treatment strategies for lowering LDL-C, and ASCVD risk-stratification, as well as implementation strategies for the care of patients with FH are reviewed.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Anticholesteremic Agents; Hyperlipoproteinemia Type II; Cholesterol; Atherosclerosis; Angiopoietin-Like Protein 3
PubMed: 37460004
DOI: 10.1016/j.phrs.2023.106857 -
Lancet (London, England) Jan 2024Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were...
BACKGROUND
Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies.
METHODS
For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia.
FINDINGS
Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified.
INTERPRETATION
Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life.
FUNDING
Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.
Topics: Adult; Child; Humans; Male; Female; Adolescent; Child, Preschool; Cholesterol, LDL; Cross-Sectional Studies; Hypercholesterolemia; Hyperlipoproteinemia Type II; Genetic Testing
PubMed: 38101429
DOI: 10.1016/S0140-6736(23)01842-1 -
Frontiers in Immunology 2023The interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanisms are...
INTRODUCTION
The interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanisms are incompletely understood. Unlike IL-1β, IL-1α is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1α, IL-1β, and NLRP3 for the pathogenesis of atherosclerosis.
METHODS
Atherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (WT) and in Il1a, Nlrp3, and Il1b mice.
RESULTS
PCSK9-Il1a mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between PCSK9-WT, PCSK9-Nlrp3 and PCSK9-Il1b mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g., IL-1β, IL-6) in PCSK9-Il1a as well as in PCSK9-Nlrp3 and PCSK9-Il1b mice. Bone marrow dendritic cells (BMDC) of PCSK9-WT, PCSK9-Nlrp3, and PCSK9-Il1b mice and primary human monocytes showed translocation of IL-1α to the plasma membrane (csIL-1α) upon stimulation with LPS. The translocation of IL-1α to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1α and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1α and IL1R1.
CONCLUSION
The results highlight the importance of IL-1α on the cell surface of circulating leucocytes for the development of atherosclerosis. PCSK9-Il1a mice, but not PCSK9-Nlrp3 or PCSK9-Il1b mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1α to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis.
Topics: Animals; Humans; Mice; Atherosclerosis; Endothelial Cells; Hypercholesterolemia; Inflammasomes; Interleukin-1alpha; Leukocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Proteomics
PubMed: 37701434
DOI: 10.3389/fimmu.2023.1252384 -
Advances in Clinical Chemistry 2024Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and...
Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.
Topics: Humans; Risk Factors; Hyperlipoproteinemia Type II
PubMed: 38514210
DOI: 10.1016/bs.acc.2024.02.004 -
JAMA Cardiology Nov 2023Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD).
OBJECTIVE
To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs.
INTERVENTIONS
All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W.
MAIN OUTCOMES AND MEASURES
Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs).
RESULTS
A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment.
CONCLUSIONS AND RELEVANCE
In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03175367.
Topics: Humans; Female; Middle Aged; Hypercholesterolemia; Cholesterol, LDL; Anticholesteremic Agents; Hyperlipoproteinemia Type II
PubMed: 37703006
DOI: 10.1001/jamacardio.2023.2921 -
Current Atherosclerosis Reports Dec 2023Heterozygous familial hypercholesterolemia (HeFH) is the most common monogenic autosomal dominant disorder. However, the condition is often underdiagnosed and... (Review)
Review
PURPOSE OF REVIEW
Heterozygous familial hypercholesterolemia (HeFH) is the most common monogenic autosomal dominant disorder. However, the condition is often underdiagnosed and undertreated. The objective of this review is to provide an update on the risk stratification in patients with HeFH, incorporating new cardiovascular imaging techniques, various biomarkers, and genetic studies.
RECENT FINDINGS
The diagnosis of HeFH places patients in a high cardiovascular risk category due to the increased incidence of premature atherosclerotic cardiovascular disease. However, the level of risk varies significantly among different individuals with HeFH. Achieving an optimal stratification of cardiovascular risk is crucial for establishing appropriate and accurate treatment and management strategies. Different new tools such as risk scores have emerged in recent years, aiding physicians in assessing the risk stratification for HeFH using imaging, biomarkers, and genetics. This review emphasizes that not all patients with HeFH face the same cardiovascular risk. By utilizing different assessment tools, we can identify those who require more intensive monitoring, follow-up, and treatment.
Topics: Humans; Hyperlipoproteinemia Type II; Genetic Testing; Hypercholesterolemia; Biomarkers; Risk Factors
PubMed: 37921916
DOI: 10.1007/s11883-023-01160-9 -
Current Opinion in Lipidology Dec 2023Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol... (Review)
Review
PURPOSE OF REVIEW
Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.
RECENT FINDINGS
In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1 -/- ), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC.
SUMMARY
Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.
Topics: Humans; Animals; Mice; Cholesterol, HDL; Cholesterol Esters; Cholesterol; Hypercholesterolemia; Atherosclerosis; Cholesterol Ester Transfer Proteins
PubMed: 37732779
DOI: 10.1097/MOL.0000000000000899