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Journal of Cardiovascular Development... Apr 2024This study aims to explore the relationship of the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein (HDL-C) ratio with glycated hemoglobin (HbA1c),...
This study aims to explore the relationship of the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein (HDL-C) ratio with glycated hemoglobin (HbA1c), renal dysfunction, coronary heart disease (CHD) and cardiac structure and function in elderly patients with hypercholesterolemia. : A total of 1129 hospitalized Chinese elderly (aged ≥ 65 years) with hypercholesterolemia were collected retrospectively. The patients were divided into low (<2.63), moderate (≥2.63 to <3.33) and high (≥3.33) LDL-C/HDL-C ratio groups according to the tertiles of LDL-C/HDL-C. : Regression analysis of the LDL-C/HDL-C ratio with metabolic and echocardiographic parameters revealed that a high LDL-C/HDL-C ratio (≥3.33) was associated independently with male gender, elevated HbA1c, decreased estimated glomerular filtration rate (eGFR), prevalent CHD and left ventricular dilatation (all < 0.05). : A high LDL-C/HDL-C ratio was associated with male gender, increased HbA1c, decreased eGFR, CHD and enlarged left ventricle in elderly with hypercholesterolemia.
PubMed: 38786962
DOI: 10.3390/jcdd11050140 -
Cells May 2024PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's...
PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified "protein X". The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be "protein X" candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of PCSK9's functions through interactions of HFE and HLA-C.
Topics: Humans; Receptors, LDL; Proprotein Convertase 9; Protein Transport; Hemochromatosis Protein; HLA-C Antigens; Lysosomes; HEK293 Cells; Protein Binding
PubMed: 38786080
DOI: 10.3390/cells13100857 -
European Heart Journal Open May 2024Over several decades, the approach to treating dyslipidaemias during pregnancy remains essentially unchanged. The lack of advancement in this field is mostly related to... (Review)
Review
Over several decades, the approach to treating dyslipidaemias during pregnancy remains essentially unchanged. The lack of advancement in this field is mostly related to the fact that we lack clinical trials of pregnant patients both with available as well as new therapies. While there are numerous novel therapies developed for non-pregnant patients, there are still many limitations in dyslipidaemia treatment during pregnancy. Besides pharmacotherapy and careful clinical assessment, the initiation of behavioural modifications as well as pre-conception management is very important. Among the various lipid-lowering medications, bile acid sequestrants are the only ones officially approved for treating dyslipidaemia in pregnancy. Ezetimibe and fenofibrate can be considered if their benefits outweigh potential risks. Statins are still considered contraindicated, primarily due to animal studies and human case reports. However, recent systematic reviews and meta-analyses as well as data on familial hypercholesterolaemia (FH) in pregnant patients have indicated that their use may not be harmful and could even be beneficial in certain selected cases. This is especially relevant for pregnant patients at very high cardiovascular risk, such as those who have already experienced an acute cardiovascular event or have homozygous or severe forms of heterozygous FH. In these cases, the decision to continue therapy during pregnancy should weigh the potential risks of discontinuation. Bempedoic acid, olezarsen, evinacumab, evolocumab and alirocumab, and inclisiran are options to consider just before and after pregnancy is completed. In conclusion, decisions regarding lipid-lowering therapy for pregnant patients should be personalized. Despite the challenges in designing and conducting studies in pregnant women, there is a strong need to establish the safety and efficacy of dyslipidaemia treatment during pregnancy.
PubMed: 38784103
DOI: 10.1093/ehjopen/oeae032 -
Frontiers in Neuroscience 2024Evaluating the correlation between serum potassium and Parkinson's disease (PD) in US adults.
BACKGROUND
Evaluating the correlation between serum potassium and Parkinson's disease (PD) in US adults.
METHODS
A cross-sectional study was conducted on 20,495 adults aged 40 years or older using NHANES data from 2005 to 2020. The study utilized one-way logistic regression and multifactorial logistic regression to examine the correlation between serum potassium levels and PD. Additionally, a smoothed curve fitting approach was employed to assess the concentration-response relationship between serum potassium and PD. Stratified analyses were carried out to investigate potential interactions between serum potassium levels and PD with variables such as age, sex, race, marital status, education, BMI, smoking and medical conditions like coronary, stroke, diabetes, hypertension, and hypercholesterolemia.
RESULTS
In this study, a total of 20,495 participants, comprising 403 PD and 20,092 non-PD individuals, were included. After adjusted for covariates, multivariable logistic regression revealed that high serum potassium level was an independent risk factor for PD (OR:1.86, 95% CI:1.45 ~ 2.39, < 0.01).The linear association between serum potassium and PD was described using fitted smoothing curves. Age, sex, race, education, marital, BMI, coronary, stroke, diabetes, hypertension and hypercholesterolemia were not significantly correlated with this positive connection, according to subgroup analysis and interaction testing (P for interaction >0.05).
CONCLUSION
Serum potassium levels are elevated in patients with Parkinson's disease compared to non-PD patients. Additional prospective studies are required to explore the significance of serum potassium levels in individuals with Parkinson's disease.
PubMed: 38784091
DOI: 10.3389/fnins.2024.1387266 -
Scientific Reports May 2024Statins, the drugs used for the treatment of hypercholesterolemia, have come into the spotlight not only as chemoadjuvants, but also as potential stem cell modulators in...
Statins, the drugs used for the treatment of hypercholesterolemia, have come into the spotlight not only as chemoadjuvants, but also as potential stem cell modulators in the context of regenerative therapy. In our study, we compared the in vitro effects of all clinically used statins on the viability of human pancreatic cancer (MiaPaCa-2) cells, non-cancerous human embryonic kidney (HEK 293) cells and adipose-derived mesenchymal stem cells (ADMSC). Additionally, the effect of statins on viability of MiaPaCa-2 and ADMSC cells spheroids was tested. Furthermore, we performed a microarray analysis on ADMSCs treated with individual statins (12 μM) and compared the importance of the effects of statins on gene expression between stem cells and pancreatic cancer cells. Concentrations of statins that significantly affected cancer cells viability (< 40 μM) did not affect stem cells viability after 24 h. Moreover, statins that didn´t affect viability of cancer cells grown in a monolayer, induce the disintegration of cancer cell spheroids. The effect of statins on gene expression was significantly less pronounced in stem cells compared to pancreatic cancer cells. In conclusion, the low efficacy of statins on non-tumor and stem cells at concentrations sufficient for cancer cells growth inhibition, support their applicability in chemoadjuvant tumor therapy.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pancreatic Neoplasms; Cell Survival; Mesenchymal Stem Cells; Cell Line, Tumor; Spheroids, Cellular; HEK293 Cells
PubMed: 38782983
DOI: 10.1038/s41598-024-62615-w -
Arteriosclerosis, Thrombosis, and... Jul 2024Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by...
BACKGROUND
Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH.
METHODS
We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease.
RESULTS
Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant.
CONCLUSIONS
Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.
Topics: Humans; Hyperlipoproteinemia Type II; Female; Male; Middle Aged; Multifactorial Inheritance; Cholesterol, LDL; Phenotype; Registries; Genetic Predisposition to Disease; Coronary Artery Disease; Risk Assessment; Genome-Wide Association Study; Lipoprotein(a); Adult; Aged; Canada; United Kingdom; Severity of Illness Index; Risk Factors; Case-Control Studies; Biomarkers; Incidence
PubMed: 38779854
DOI: 10.1161/ATVBAHA.123.320287 -
International Journal of Medical... 2024Hyperlipidemia is notorious for causing coronary artery disease (CAD). IL-18 is a proinflammtory cytokine that contributes to the pathogenesis of CAD. Previous reports...
Hyperlipidemia is notorious for causing coronary artery disease (CAD). IL-18 is a proinflammtory cytokine that contributes to the pathogenesis of CAD. Previous reports have revealed that genetic polymorphism of IL-18 is associated with its expression level as well as the susceptibility to CAD. In the present study, we aim to investigate the relationship between IL-18 single nucleotide polymorphisms (SNPs) and hyperlipidemia in the Han Chinese population in Taiwan. A total of 580 participants older than 30 were recruited from the community. We collected the demographics, self-reported disease histories, and lifestyles. We also assessed the levels of lipid profiles including total cholesterol (CHOL), triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Two SNPs, rs3882891C/A (intron 5) and rs1946518A/C (promoter -607) of IL-18 were elucidated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Our results revealed that rs3882891 AA was associated with lower risk of hypercholesterolemia, higher CHOL and LDL-C in subjects (p=0.003, p=0.000 and p=0.005 separately), and rs1946518 CC was associated with hypercholesterolemia, higher CHOL and LDL-C as well (p=0.021, p=0.003 and p=0.001 separately) Furthermore, both SNPs were associated with IL-18 expression level, which was examined by Genotype-Tissue Expression (GTEx) Portal (p=0.042 and 0.016 separately). Finally, the haplotype of IL-18 was subsequently arranged in the order of rs3882891 and rs1946518. The result revealed that the AC haplotype of 2 IL-18 SNPs was also associated with lower risk of hypercholesterolemia, lower levels of CHOL and LDL-C (p=0.01, p=0.001 and 0.003). The current study is the first to report the association between IL-18 SNPs and hyperlipidemia in the Chinese Han population.
Topics: Humans; Interleukin-18; Polymorphism, Single Nucleotide; Male; Middle Aged; Female; Hyperlipidemias; Genetic Predisposition to Disease; Adult; Taiwan; Asian People; Aged; Haplotypes; Coronary Artery Disease; Cholesterol, LDL; Genetic Association Studies
PubMed: 38774744
DOI: 10.7150/ijms.90341 -
JVS-vascular Science 2024The extent of collateral artery enlargement determines the risk of limb loss due to peripheral arterial disease. Hypercholesterolemia impairs collateral artery...
Hypercholesterolemia impairs collateral artery enlargement by ten-eleven translocation 1-dependent hematopoietic stem cell autonomous mechanism in a murine model of limb ischemia.
OBJECTIVE
The extent of collateral artery enlargement determines the risk of limb loss due to peripheral arterial disease. Hypercholesterolemia impairs collateral artery enlargement, but the underlying mechanism remains poorly characterized. This study tests the hypothesis that hypercholesterolemia impairs collateral artery enlargement through a ten-eleven translocation 1 (Tet1)-dependent hematopoietic stem cell (HSC)-autonomous mechanism that increases their differentiation into proinflammatory Ly6C monocytes and restricts their conversion into proangiogenic Ly6C monocytes.
METHODS
To test our hypothesis, we induced limb ischemia and generated chimeric mouse models by transplanting HSCs from either wild-type (WT) mice or hypercholesterolemic mice into lethally irradiated WT recipient mice.
RESULTS
We found that the lethally irradiated WT recipient mice reconstituted with HSCs from hypercholesterolemic mice displayed lower blood flow recovery and collateral artery enlargement that was nearly identical to that observed in hypercholesterolemic mice, despite the absence of hypercholesterolemia and consistent with an HSC-autonomous mechanism. We showed that hypercholesterolemia impairs collateral artery enlargement by a Tet1-dependent mechanism that increases HSC differentiation toward proinflammatory Ly6C monocytes and restricts the conversion of Ly6C monocytes into proangiogenic Ly6C monocytes. Moreover, Tet1 epigenetically reprograms monocyte gene expression within the HSCs. Restoration of Tet1 expression in HSCs of hypercholesterolemic mice restores WT collateral artery enlargement and blood flow recovery after induction of hindlimb ischemia.
CONCLUSIONS
These results show that hypercholesterolemia impairs collateral artery enlargement by a novel Tet1-dependent HSC-autonomous mechanism that epigenetically reprograms monocyte gene expression within the HSCs.
PubMed: 38774713
DOI: 10.1016/j.jvssci.2024.100203 -
JACC. Case Reports Jun 2024We present a young boy with a diagnosis of homozygous familial hypercholesterolemia who presented with statin and ezetimibe resistance. The patient received lipoprotein...
We present a young boy with a diagnosis of homozygous familial hypercholesterolemia who presented with statin and ezetimibe resistance. The patient received lipoprotein apheresis at 6 years of age. His low-density lipoprotein cholesterol levels significantly were reduced by adding lomitapide and evinacumab, and his carotid plaque started to regress.
PubMed: 38774638
DOI: 10.1016/j.jaccas.2024.102367 -
Social Science & Medicine (1982) Jun 2024Familial Hypercholesterolemia (FH) is an inherited disorder leading to increased risk of premature atherosclerotic cardiovascular disease. This risk can be ameliorated... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Familial Hypercholesterolemia (FH) is an inherited disorder leading to increased risk of premature atherosclerotic cardiovascular disease. This risk can be ameliorated through adherence to pharmacological treatment and salient lifestyle behaviors (e.g., physical activity participation, healthy eating). Identifying theory-based, modifiable determinants of these behaviors may inform behavioral interventions promoting participation in FH self-management behaviors. We aimed to identify the belief-based social cognition constructs uniquely associated with intentions to perform, and actual participation in, FH self-management behaviors in the extant research.
METHOD
A systematic database search identified studies (k = 9, N = 1394) reporting relations between social cognition theory constructs and intention toward, or actual participation in, self-management behaviors in FH patients. As no studies examining prospectively-measured behaviors were identified, we tested relations among social cognition constructs, intentions, and past FH-self-management behavior using random effects multi-level meta-analysis and meta-analytic structural equation modelling.
RESULTS
We found non-zero averaged correlations among the key social cognition constructs (attitudes, norms, risk perceptions, self-efficacy), intentions, and past behavior. A meta-analytic structural equation model indicated non-zero averaged direct effects of attitudes, norms, self-efficacy, and past behavior on FH self-management behavioral intentions. There were also non-zero averaged indirect effects of past behavior on intentions mediated by the social cognition constructs.
CONCLUSION
Findings provide evidence to support the proposed model and highlight the importance of personal, normative, and capacity related beliefs and past experience as unique correlates of intentions to perform FH self-management behaviors. The model may signal potential constructs that could be targeted in behavioral interventions to promote participation in FH self-management behaviors.
Topics: Humans; Self-Management; Hyperlipoproteinemia Type II; Social Cognition; Health Behavior; Intention; Self Efficacy
PubMed: 38759387
DOI: 10.1016/j.socscimed.2024.116968