PCSK9 Levels Research Articles

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Lipid regulation of protocatechualdehyde and hydroxysafflor yellow A via AMPK/SREBP2/PCSK9/LDLR signaling pathway in hyperlipidemic zebrafish

The consumption of a high-cholesterol diet is known to cause hyperlipidemia, which is one of the main risk factors for cardiovascular disease. Protocatechualdehyde (PCA) and hydroxysafflor yellow A (HSYA) are the active components of Salvia miltiorrhiza and safflower, respectively. However, their exact mechanism is still unclear. The aim of this study is to investigate its effects on lipid deposition and liver damage in hyperlipidemic zebrafish and its mechanism of anti-hyperlipidemia. The results showed that the use of PCA and HSYA alone and in combination can improve lipid deposition, slow behavior, abnormal blood flow and liver tissue damage, and the combined use is more effective. Further RT-qPCR results showed that PCA + HSYA can regulate the mRNA levels of PPAR-γ, SREBP2, SREBP1, HMGCR, PCSK9, mTOR, C/EBPα, LDLR, AMPK, HNF-1α and FoxO3a. The PCA + HSYA significantly improves lipid deposition and abnormal liver function in hyperlipidemic zebrafish larvae, which may be related to the AMPK/SREBP2/PCSK9/LDLR signaling pathway.

Investigating the association of the effect of genetically proxied PCSK9i with mood disorders using cis-pQTLs: A drug-target Mendelian randomization study.

PCSK9-inhibitors (PCSK9i) are new drugs recently approved to lower LDL-cholesterol levels. However, due to the lack of long-term clinical data, the potential adverse effects of long-term use are still unknown. The PCSK9 genetic locus has been recently implicated in mood disorders and hence we wanted to assess if the effect of PCSK9i that block the PCSK9 protein can lead to an increase in the incidence of mood disorders. We used genetically-reduced PCSK9 protein levels (pQTLs) in plasma, serum, cerebrospinal fluid as a proxy for the effect of PCSK9i. We performed Mendelian randomization analyses using PCSK9 levels as exposure and mood disorder traits major depressive disorder, mood instability, and neuroticism score as outcomes. We find no association of PCSK9 levels with mood disorder traits in serum, plasma, and cerebrospinal fluid. We can conclude that genetically proxied on-target effect of pharmacological PCSK9 inhibition is unlikely to contribute to mood disorders.

Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes.

The loss-of-function of the proprotein convertase subtilisin-kexin type 9 (Pcsk9) gene has been associated with significant reductions in plasma serum low-density lipoprotein cholesterol (LDL-C) levels. Both CRISPR/Cas9 and CRISPR-based editor-mediated Pcsk9 inactivation have successfully lowered plasma LDL-C and PCSK9 levels in preclinical models. Despite the promising preclinical results, these studies did not report how vehicle-mediated CRISPR delivery inactivating Pcsk9 affected low-density lipoprotein receptor recycling in vitro or ex vivo. Extracellular vesicles (EVs) have shown promise as a biocompatible delivery vehicle, and CRISPR/Cas9 ribonucleoprotein (RNP) has been demonstrated to mediate safe genome editing. Therefore, we investigated EV-mediated RNP targeting of the Pcsk9 gene ex vivo in primary mouse hepatocytes. We engineered EVs with the rapamycin-interacting heterodimer FK506-binding protein (FKBP12) to contain its binding partner, the T82L mutant FKBP12-rapamycin binding (FRB) domain, fused to the Cas9 protein. By integrating the vesicular stomatitis virus glycoprotein on the EV membrane, the engineered Cas9 EVs were used for intracellular CRISPR/Cas9 RNPdelivery, achieving genome editing with an efficacy of ±28.1% in Cas9 stoplight reporter cells. Administration of Cas9 EVs in mouse hepatocytes successfully inactivated the Pcsk9 gene, leading to a reduction in Pcsk9 mRNA and increased uptake of the low-density lipoprotein receptor and LDL-C. These readouts can be used in future experiments to assess the efficacy of vehicle-mediated delivery of genome editing technologies targeting Pcsk9. The ex vivo data could be a step towards reducing animal testing and serve as a precursor to future in vivo studies for EV-mediated CRISPR/Cas9 RNP delivery targeting Pcsk9.

VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients.

VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients.

Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus

Background and aimsProprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs.ResultsCirculating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p < 0.001]. Circulating PCSK9 levels positively correlated with CHD severity (diseased vessels: r = 0.35, p < 0.001; Gensini score: r = 0.46, p < 0.001). Elevated PCSK9 levels are an independent risk factor for CHD risk and severity (CHD group vs. non–CHD group: OR = 2.829, 95% CI: 1.771–4.520, p < 0.001; three vessel disease group vs. one vessel disease group: OR = 4.800, 95% CI: 2.387–9.652, p < 0.001; high GS group vs. low GS group: OR = 5.534, 95% CI: 2.733–11.208, p < 0.001). Through a six-year follow-up and multivariate Cox regression analysis, elevated circulating PCSK9 levels were found to be independently associated with MACEs in all participants (HR: 3.416, 5% CI: 2.485–4.697, p < 0.001; adjusted HR: 2.780, 95% CI: 1.930–4.004, p < 0.001).ConclusionsSerum PCSK9 levels were positively correlated with multi-vessel CHD and Gensini score. Elevated circulating PCSK9 levels are an independent risk factor for CHD and increased incidence of MACEs in T2DM.

PCSK9 polymorphism rs505151 is associated with the risk of NAFLD in Iranian participants: A case-control study

BackgroundGain-of-function mutations in the PCSK9 gene lead to elevated serum lipid profile levels, including low-density lipoprotein (LDL), which increases the risk of cardiovascular diseases. This study aims to investigate the relationship between selected PCSK9 gene polymorphisms and serum levels of PCSK9 enzyme in patients with non-alcoholic fatty liver disease (NAFLD) in Kurdistan province, Iran. Methods110 NAFLD patients and 50 healthy controls underwent biochemical assays to determine lipid profile levels, while genotyping for PCSK9 gene polymorphisms was done via RFLP-PCR and Sanger sequencing. Serum levels of PCSK9 were measured using an ELISA kit. ResultsSerum PCSK9 levels were not significantly different between NAFLD patients and healthy controls. The rs778796405 and rs28362201 polymorphisms had no mutant nucleotides. The rs505151 polymorphism had a frequency of 17.2 % in NAFLD patients and 10 % in controls, with no significant difference (P > 0.05). The G allele of rs505151 was associated with higher levels of LDL, ALT, cholesterol, and BMI, and the AG genotype was associated with the severity of liver steatosis in female patients. However, the AG genotype had no significant effect on NAFLD incidence. ConclusionsThe G allele of the rs505151 polymorphism in the PCSK9 gene may represent a genetic risk factor for developing fatty liver disease, with potential implications for the pathogenesis of lipid-related disorders.

Abscence of high lipoprotein(a) levels is and independent predictor of acute myocardial infarction without coronary lesions

Abstract Ministry of Science. The pathophysiological mechanisms underlying Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA) are still under debate. Lipoprotein (a) [Lp(a)] has proinflammatory and prothrombotic actions and has been involved in the pathogenesis of atherosclerosis. However, no previous studies have linked Lp(a) levels with the probability of developing MINOCA. Moreover, the relationship between MINOCA and the plasma levels of other proatherogenic and proinflammatory molecules such as Interleukin-18 (IL18) and proprotein convertase subtilisin/kexin type 9 has not been studied. We conducted a prospective, multicenter study involving 1042 patients with acute myocardial infarction (AMI). Seventy-six patients had no significant coronary lesions. All patients underwent plasma analysis on admission. MINOCA patients were younger (57 (47–68) vs. 61 (52–72) years; p = 0.010), more frequently female (44.7% vs. 21.0%; p &amp;lt; 0.001), and had lower rates of diabetes and of Lp(a) &amp;gt; 60 mg/dL (9.2% vs. 19.8%; p = 0.037) than those with coronary lesions; moreover, High Density Lipoprotein cholesterol (HDL-c) levels were higher in MINOCA patients. The absence of Lp(a) &amp;gt; 60 mg/dL and of diabetes were independent predictors of MINOCA, as well as female sex, high HDL-c levels, and younger age. IL-18 and PCSK9 levels were not predictors of MINOCA. During a follow-up of 5.23 (2.89, 7.37) years, the independent predictors of the primary outcome (acute ischemic events or death) in the whole sample were Lp(a) &amp;gt; 60 mg/dL, older age, low estimated Glomerular Filtration rate (eGFR), hypertension, previous heart failure (HF), coronary artery bypass graft, use of insulin, and no therapy with acetylsalicylic acid. In conclusion, in AMI patients, the absence of high Lp(a) levels, as well high HDL-c levels, were independent predictors of the inexistence of coronary artery disease. High Lp (a) levels were also an independent predictor of ischemic events or death.

Sirtuin-1 directly binds and deacetylates hepatic PCSK9 to inhibit low-density lipoprotein receptor degradation

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is causally involved in atherosclerotic cardiovascular disease (ASCVD). We have previously shown that pharmacological activation of Sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, reduces plasma LDL-C levels by decreasing PCSK9 and increasing hepatic LDLR expression, thus exerts atheroprotective effects in mice; however, the mechanism of SIRT1 action remains elusive. Purpose We found diminished levels of circulating SIRT1 in atherosclerotic mice compared to wild-type healthy controls. We hypothesized that this decrease in SIRT1 levels may promote dysregulated lipid metabolism and ASCVD in humans. Herein, we aimed to restore the reduced systemic Sirtuin-1 plasma levels in ASCVD by injecting recombinant murine Sirtuin-1 (rmSIRT1) in atherosclerotic mice. Methods Twelve-week-old apolipoprotein E-deficient (ApoE-/-) male mice fed a high-cholesterol diet (1.25% w/w) were randomized to receive rmSIRT1 (n=6; 0.3mg/kg BW i.p.) or vehicle treatment (n=6) every third day over 4-weeks. Mice were euthanized and organs were harvested to study lipid metabolism and ASCVD progression. Human hepatocytes (Huh7) cells were used to perform radioactive assays to study cellular uptake of radioiodinated LDL, surface plasmon resonance to study binding and site-directed mutagenesis to dissect the underlying molecular mechanism exerted by circulating SIRT1. Results Boosting circulating SIRT1 levels increased hepatic LDLR expression, reduced plasma LDL-C levels and progression of plaques in ApoE-/- mice (Figure 1). rmSIRT1 treatment did not change hepatic expression of total PCSK9 but increased its deacetylated status. Mechanistically, rmSIRT1 directly bound to hepatic PCSK9 and deacetylated PCSK9 at 3 sites: Lys243, Lys421 and Lys506 as shown by Surface Plasmon Resonance and mass spectrometry, respectively. In vitro mutagenesis to triple deacetylation mimetic (3KR) in hepatocytes (Huh7 cells) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL through LDLR in Huh7cells. Finally, plasma levels of SIRT1 and PCSK9 were assessed at baseline in patients with acute coronary syndromes (ACS) where plasma SIRT1 showed an inverse correlation with PCSK9 and conferred a reduced risk of major adverse cardiovascular events. Conclusion SIRT1 directly binds PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-C clearance by hepatic LDLR upregulation. Increased circulating SIRT1 exerts atheroprotective effects and is associated with improved prognosis in patients with ACS.Figure 1

Olive extract enriched with hydroxytyrosol improves cardiac and vascular function in patients with stable coronary artery disease: a double-blind, placebo-controlled trial

Abstract Aims We investigated the effect of olive extract enriched with hydroxytyrosol, on vascular and myocardial function markers in patients with stable coronary artery disease (SCAD). Methods In a prospective, cross-over, double-blind, placebo-controlled, clinical trial, 30 patients with stable CAD were randomly assigned to an oral supplement containing olive oil extract enriched with hydroxytyrosol (OOHT) or placebo for one month and then were crossed over to the alternate treatment (placebo or OOHT for one more month). We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), b) flow-mediated dilation (FMD), c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography d) Pulse Wave Velocity (PWV) e) oxidative/nitrosative stress and inflammatory biomarkers and blood lipids at baseline and after one month treatment. Results Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.81±0.35 vs 1.77±0.40 μm p=0.04 3.71±2.12 vs 6.51±2.31%, p&amp;lt;0.001;2.37±0.40 vs 2.45±0.41, p=0.030 and 11.03±1.81 vs 11.78±2.34 m/sec, p=0.002), while there was no effect after placebo (p&amp;gt;0.05). Compared to baseline, treatment with OOHT reduced malondialdehyde (MDA) a marker of lipid peroxidation (2.10±1.37 vs 1.69±0.83 mmol/lt, p=0.045), oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p&amp;lt;0.05) in contrast to placebo. There was a parallel improvement of E’ of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p&amp;lt;0.05) but not after placebo. Conclusions Olive extract enriched with hydroxytyrosol improves endothelial and arterial function likely by reducing oxidative and inflammatory burden leading to improved LV diastolic function after one month of treatment in patients with stable CAD.

Epigenetic regulation of PCSK9 expression by statins

Abstract Background Statins are lipid-lowering drugs widely used to reduce the risk of cardiovascular diseases. Although they inhibit HMG-CoA, statins are known to induce the expression of PCSK9, a key regulator of plasma LDL-cholesterol. However, the underlying epigenetic mechanisms remain unknown. Objective This study aimed at investigating the histone modification-mediate epigenetic regulation of PCSK9 and the underlying mechanisms during statin treatment. Methods Using immunoblotting, qPCR, and immunofluorescence techniques we assessed various histone modifications and expression levels of PCSK9 and other cholesterol-regulating candidates upon statin treatment. Further, 4-6 weeks old C57BL/6 mice were subjected to high-fat diet in combination with atorvastatin for 10 weeks. We then performed ChIP-qPCR to evaluate the fold enrichment of targeted histone marks at the gene promoter regions of PCSK9 and SREBP. Results Atorvastatin and cholesterol-treated HepG2 cells were reported to have an increased transcript and protein expression of PCSK9. Further, screening of different histone methylation and acetylation marks under atorvastatin treatment revealed significant enrichment in the levels of the activating H3K4me3 and H3K9ac marks. ChIP-qPCR analysis suggested significantly higher enrichment of H3K4me3 and H3K9ac at the gene promoter region of PCSK9 and SREBP2 (Figure 1&amp;2). In vitro pharmacological intervention against these histone modifications not only significantly lowered their activation but also attenuated statin-induced PCSK9 expression. Conclusion Together, these findings suggest that statins modulate the expression of PCSK9 by regulating H3K4me3 and H3K9ac levels at the PCSK9 gene promoter. Inhibition of these activating histone modifications repressed statin-dependent PCSK9 expression. Thus, targeting chromatin remodeling may help negate the adverse effects of statin treatment, primarily of increasing PCSK9 during hypercholesterolemia.

Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.

E670G PCSK9 polymorphism in HeFH & CAD with diabetes: is the bridge to personalized therapy within reach?

To assess the distribution of PCSK9 E670G genetic polymorphism and PCSK9 levels in patients with Coronary Artery Disease (CAD) and Heterozygous Familial Hypercholesterolemia (HeFH), based on the presence of type 2 Diabetes Mellitus (T2DM). The study included 201 patients with chronic CAD, including those with HeFH (n=57, group I) and without it (n=144, group II). DLCN was used to diagnose HeFH. The PCSK9 E670G (rs505151) polymorphism was genetically typed using the PCR-RFLP procedure. In both the patient and control groups, the genotype frequency matched the Hardy-Weinberg equilibrium distribution (P>0.05). There were twice more G alleles in group I (13, 11.4%) than in group II (17, 6.0%), and thrice more (1, 3.0%) than in the healthy control group; nevertheless, these differences weren't statistically significant. Simultaneously, PCSK9 levels were higher in HeFH patients (P<0.05) compared to non-HeFH patients not taking statins (n=63). T2DM was equally represented in groups I and II (31.6% vs. 33.3%). But carriers of AG+GG genotypes in group I had a higher chance of having a history of T2DM (RR 4.18; 95%CI 2.19-8.0; P<0.001), myocardial infarction (RR 1.79; 95%CI 1.18-2.73; P<0.05), and revascularization (RR 12.6; 95%CI 4.06-38.8; P<0.01), than AA carriers. T2DM was also more common among G allele carriers (RR 1.85; 95% CI 1.11-3.06; P<0.05) in patients with non-HeFH. T2DM in patients with CAD, both with HeFH and non-HeFH, in the Uzbek population was significantly more often associated with the presence of the "gain-of-function" G allele of the PCSK9 E670G genetic polymorphism.

Elevated circulating PCSK9 level is associated with 28-day mortality in patients with sepsis: a prospective cohort study

ObjectivesPro-protein convertase subtilisin/kexin 9 (PCSK9) decreases the clearance of the pathogenic lipids, supporting the potential role of PCSK9 in the prognosis of sepsis.MethodsIn this prospective cohort study, patients with sepsis were consecutively recruited from 1 to 2020 to 30 September 2021 at the First People’s Hospital of Huaihua, China. All the eligible patients were categorized into low-PCSK9 and high-PCSK9 groups, based on their PCSK9 levels at admission. Time-dependent receiver operating characteristic curves and Cox proportional hazards regression were used to evaluate the association between PCSK9 level and 28-day mortality of sepsis.ResultsOf the 203 enrolled patients, 56 (27.59%) died during the 28-day follow-up. The PCSK9 level was positively related to the C-reactive protein level. The cut-off point of PCSK9 levels for 28-day mortality risk was 370 ng/ml. Through comparison between high-PCSK9 (> 370 ng/ml) with low-PCSK9 (≤ 370 ng/ml) groups, the adjusted HR for mortality was 2.56 (95% CI: 1.25–5.23, p = 0.01).ConclusionsThe 28-day mortality of sepsis increased significantly as the baseline circulating PCSK9 level exceeded 370 ng/ml, indicating circulating PCSK9 levels may be a potential biomarker to predict the prognosis of sepsis.

Exploring PCSK9 Genetic Impact on Lipoprotein(a) via Dual Approaches: Association and Mendelian Randomization.

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

Evolocumab prevents atrial fibrillation in rheumatoid arthritis rats through restraint of PCSK9 induced atrial remodeling

IntroductionProprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in the pathogenesis and progression of autoimmune disease. Patients with rheumatoid arthritis (RA) are at high risk of developing atrial fibrillation (AF), while whether PCSK9 is involved in the onset of AF among RA patients remains unclear. ObjectivesTo explore the role of PCSK9 in the occurrence of AF in RA patients and decipher the underlying mechanism. MethodsWe established a rat model of collagen-induced arthritis (CIA) by immunization with type II collagen in Freund’s incomplete adjuvant. Atrial electrophysiological test was used to evaluate AF susceptibility. We performed a clinical study to examine the correlation between PCSK9 level and AF, which recruited healthy control, RA patients and RA patients complicated with AF. Evolocumab (a monoclonal antibody of PCSK9) is administered via intraperitoneal injection in CIA rats to assess the role of PCSK9 in RA-related AF. LPS-RS (LPS inhibitor), clodronate liposomes (depletion of macrophages), and cell co-culture model were used to dissect the mechanism underlying PCSK9 promotes AF. ResultsAF inducibility and duration were higher in CIA rats, accompanied by elevated plasma and atrial PCSK9. Interestingly, compared with healthy control subjects, patients with RA showed an increase in PCSK9, and the PCSK9 is much higher in RA patients complicated with AF. The level of PCSK9 was independently associated with AF risk in RA patients. In the in vivo experiment, evolocumab reduced AF susceptibility, and ameliorated atrial structural remodeling of CIA rats. Mechanistically, augmented LPS in CIA rats led to an increase in PCSK9, which exacerbated fibrosis of cardiac fibroblasts and apoptosis of cardiac myocytes by enhancement of M1 macrophages polarization and inflammation, thereby contributing to AF. ConclusionThis study suggests that elevated PCSK9 causes atrial structural remodeling by enhancement of M1 macrophages polarization in atria, and evolocumab can effectively protects CIA rats from AF.

A case of hypocholesterolemia under research

Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband’s clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.

Correlation between Plasma PCSK9 and Blood Lipids in Patients with Newly Diagnosed Primary Nephrotic Syndrome

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a major post-transcriptional regulator of low-density lipoprotein receptor degradation. Recently, PCSK9 was shown to be overexpressed by liver cells in rats with proteinuria. However, the levels of PCSK9 in newly diagnosed primary nephrotic syndrome (PNS) patients and correlations involving PCSK9 and blood lipids are not clearly understood. Aim of the Work The aim of this study is to assess the association between plasma pcsk 9 and blood lipids in patients with newly diagnosed primary nephrotic syndrome Patients and Methods This was a case control study in Ain Shams University hospital for 4 months on 50 patients, 35 control. Results in our study elevated plasma PCSK9 levels had a positive linear correlation with elevated serum TC (p value &amp;lt;0.001) and LDL-C (p value &amp;lt;0.001), triglycerides (p value 0.003), HDL (p value 0.012), VLDL(p value 0.001) A comparison of plasma PCSK9 levels of MCD, MN And primary focal segmental patients showed that they were not significantly different (p value 0.954). In our study, we found that the plasma levels of pcsk9 were significantly higher than in healthy controls 314.580 ± 73.835 ng/ml vs 253.429 ±36.666, and this difference was statistically significant P-value &amp;lt;0.001. In our study plasma PCSK9 levels in patients with PNS had no linear correlation with the amount of proteinuria per 24 h, p value 0.070 or with albumin p value 0.549 and there was no statistical difference between the the two groups of proteinuria (3.5-8 (g)/24 h vs &amp;gt; 8 (g)/24 h) p value 0.378. Conclusion Plasma PCSK9 levels in newly diagnosed primary nephrotic patients were markedly increased and positively correlated with total cholesterol, VLDL, LDL, HDL. suggesting that PCSK9 may emerge as a novel therapeutic target in nephrotic syndrome associated hypercholesterolemia

Effect of repeatedly applied cold water immersion on subclinical atherosclerosis, inflammation, fat accumulation and lipid profile parameters of volunteers.

Significant acute cardiovascular, metabolic, and endocrine changes have been traced to short-lasting cold water immersion (CWI); however, the long-term impact of recurrent CWI on atherogenesis, lipid parameters, and fat distribution has not yet been studied. The goal of this study was to investigate the alleged protective effect. A total of 35 healthy volunteers were monitored for a period of 5 months during which the CWI was performed under standardized conditions (three times per week for 7-10 min, without neoprene equipment). Volunteers with measured weight or muscle mass increases of more than 5% were ineligible. An analogous control group (N = 30) was included. At the onset and completion of the study, blood samples were obtained, and clinical assessments took place. PCSK9 and hsCRP levels were measured together with other lipid-related and non-lipid-related indicators. Carotid intima-media thickness test (cIMT) and echo-tracking for the identification of arterial stiffness (PWV, AI, and β) were used to identify early vascular alterations. Hepatorenal index (HRI) calculations served to quantify liver steatosis, while changes in subcutaneous and visceral fat thickness were used to quantify fat distribution. The given protocol was successfully completed by 28volunteers. Long-term repeated CWI resulted in asignificant decline in cIMT (p = 0.0001), AI (p = 0.0002), Beta (p = 0.0001), and PWV (p = 0.0001). PCSK9 (p = 0.01) and hsCRP (p = 0.01) showed asignificant decrease when compared to initial values. In comparison to the starting values, liver fat accumulation decreased by 11% on average (HRI p = 0.001). LDL, TC, TG, and VLDL levels all significantly decreased as well. We suggest that repeated CWI may have beneficial impact on lipid, non-lipid, and lipid-related indices, as well as atherogenesis and liver fat storage.

Gender-affirming hormone therapy decreases d-dimer but worsens insulin sensitivity in transgender women.

Gender-affirming hormonal therapies (GAHT) and HIV increase cardiovascular risk for transgender women (TW), yet there is a paucity of data quantifying cardiometabolic changes following GAHT initiation, particularly among TW with HIV. The Féminas study enrolled TW from October 2016 to March 2017 in Lima, Peru. Participants reported sexual activity that was high risk for HIV acquisition or transmission. All were tested for HIV/ sexually transmitted infection and were given access to GAHT (oestradiol valerate and spironolactone), HIV pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) for 12 months. Biomarker measurement was done on stored serum, whereas fasting glucose and lipids were measured in real time. In all, 170 TW (32 with HIV, 138 without HIV) had median age 27 years and 70% prior GAHT use. At baseline, PCSK9, sCD14, sCD163, IL-6, sTNFRI/II, CRP and EN-RAGE levels were significantly higher in TW with HIV than in TW without HIV. High-density lipoprotein and total cholesterol were lower and insulin and glucose parameters were similar. All TW with HIV started ART, but only five achieved virological suppression at any time. No TW without HIV initiated PrEP. Over 6 months, all participants initiated GAHT and had worsening insulin, glucose and HOMA-IR. Large d-dimer decreases also occurred. Similar changes occurred in TW with and without HIV. In this unique cohort of TW, GAHT decreased d-dimer but worsened insulin sensitivity. Because PrEP uptake and ART adherence were very low, observed effects are primarily attributed to GAHT use. Further study is needed to better understand cardiometabolic changes in TW by HIV serostatus.