Reduced Plasma Low-density Lipoprotein Research Articles

Ursodeoxycholic Acid for Trans Intestinal Cholesterol Excretion Stimulation: A Randomized Placebo Controlled Crossover Study.

The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P=0.002) when compared with placebo. UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

The role of natural products as PCSK9 modulators: A review.

A variety of mechanisms and drugs have been shown to attenuate cardiovascular disease (CVD) onset and/or progression. Recent researchers have identified a potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in modulating lipid metabolism and reducing plasma low density lipoprotein (LDL) levels. PCSK9 is the central protein in the metabolism of LDL cholesterol (LDL-C) owing to its major function in LDL receptor (LDLR) degradation. Due to the close correlation of cardiovascular disease with lipid levels, many in vivo and in vitro investigations are currently underway studying the physiological role of PCSK9. Furthermore, many studies are actively investigating the mechanisms of various compounds that influence lipid associated-disorders and their associated cardiovascular diseases. PCSK9 inhibitors have been shown to have significant impact in the prevention of emerging cardiovascular diseases. Natural products can effectively be used as PCSK9 inhibitors to control lipid levels through various mechanisms. In this review, we evaluate the role of phytochemicals and natural products in the regulation of PCSK9, and their ability to prevent cardiovascular diseases. Moreover, we describe their mechanisms of action, which have not to date been delineated.

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study.

Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships. Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables' (IVs) assumptions. Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy. Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.

Differences among Lactiplantibacillus plantarum strains isolated from different fermented foods in their potential cholesterol-lowering properties

Elevated levels of plasma low-density lipoprotein (LDL) cholesterol have been associated with incident atherosclerotic cardiovascular disease. Animal studies and clinical trials have demonstrated that several Lactiplantibacillus plantarum strains are effective in reducing plasma LDL cholesterol levels. However, it is unclear whether the habitats from which Lactiplantibacillus plantarum strains are isolated have an impact on their potential cholesterol-lowering properties. In this study, 107 Lactiplantibacillus plantarum strains isolated from three habitats (20 isolated from fermented dairy products, 23 from fermented grape must, and 64 from fermented vegetables) were compared for their potential cholesterol-lowering properties on an origin scale. These properties included acid resistance, bile tolerance, surface hydrophobicity, and bile acid deconjugation. The results showed that the fermented dairy products-derived strains were the most bile-tolerant and hydrophobic, the fermented grape must-derived strains were the most effective at hydrolyzing conjugated bile acids, and the fermented vegetables-derived strains were the most acid-resistant. Bile salt hydrolase (BSH) genes were detected in 97.2% of the total strains and 100% of the fermented dairy products-derived strains by standard PCR with agarose gel electrophoresis detection. In the 104 bsh genes-containing strains, 92.3% had detectable BSH activity (n = 96). These BSH-positive strains exhibited a greater substrate preference for glycine-conjugated bile acids than taurine-conjugated bile acids. Overall, the fermented dairy products-derived strains appeared to have greater cholesterol-lowering potential than those isolated from the other two habitats. This study provided valuable information regarding where to obtain Lactiplantibacillus plantarum strains with greater cholesterol-lowering potential.

PCSK9 regulates myofibroblast transformation through the JAK2/STAT3 pathway to regulate fibrosis after myocardial infarction

Cardiac fibrosis is pivotal in the progression of numerous cardiovascular diseases. This phenomenon is hallmarked by an excessive deposition of ECM protein secreted by myofibroblasts, leading to increased myocardial stiffness. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein-converting enzyme family. It has emerged as a viable therapeutic target for reducing plasma low-density lipoprotein cholesterol. However, the exact mechanism via which PCSK9 impacts cardiac fibrosis remains unclear. In the present research, an increase in circulating PCSK9 protein levels was observed in individuals with myocardial infarction and rat models of myocardial infarction. Moreover, the inhibition of circulating PCSK9 in rats was found to reduce post-infarction fibrosis. In vitro experiments further demonstrated that overexpression of PCSK9 or stimulation by extracellular PCSK9 recombinant protein enhanced the transformation of cardiac fibroblasts to myofibroblasts. This process also elevated collagen Ⅰ, and Ⅲ, as well as α-SMA protein levels. However, these effects were countered when co-incubated with the STAT3 inhibitor S3I-201. This study suggests that PCSK9 may function as a novel regulator of myocardial fibrosis, primarily via the JAK2/STAT3 pathway.

Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds.

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.

Advanced progress of the relationship between PCSK9 monoclonal antibodies and hyperglycemic adverse events.

Long-term use of statins had been confirmed to cause an increase in hyperglycemic adverse events (HAEs), whose mechanism has been well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (PCSK9-mAbs), a kind of new lipid-lowering drug, can effectively reduce plasma low-density lipoprotein cholesterol levels in patients with CHD and have been widely used. However, animal experiments, Mendelian randomization studies, clinical researches and Meta-analyses which focused on the relationship between PCSK9-mAbs and HAEs had reached different conclusions, which has attracted great attention from clinicians. The newest FOURIER-OLE randomized controlled trial followed PCSK9-mAbs users for over 8 years, whose results suggested that long-term use of PCSK9-mAbs did not increase the incidence of HAEs. Newest Meta-analyses also indicated that there was no relationship between PCSK9-mAbs and NOD. Meanwhile, genetic polymorphisms and variants related to PCSK9 might have effects on HAEs. According to the results of current studies, there is no significant relationship between PCSK9-mAbs and HAEs. However, longer-term follow-up studies are still needed to confirm it. Although PCSK9 genetic polymorphisms and variants may affect the possible occurrence of HAEs, there is no need to perform relevant genetic testing before applying PCSK9-mAbs.

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol.

Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum. Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.

8(R)-hydroxy-eicosapentaenoic acid (8R-HEPE) induces transcription of cholesterol efflux receptors via activation of liver X receptor in macrophages.

Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease. 8-HEPE from North Pacific krill (Euphausia pacifica) is known to reduce plasma LDL cholesterol levels and increase plasma HDL cholesterol levels in LDL receptor knock-out mice fed a western diet. Moreover, 8-HEPE also reduces the area of aortic atherosclerosis in apoE knock-out mice fed the same diet. In this study, we examined the stereochemical specific activity of 8-HEPE for inducing expression of cholesterol efflux receptors (Abca1 and Abcg1) in J774.1 cells. Our findings show 8R-HEPE induces the expression of Abca1 and Abcg1 via activation of liver X receptor, whereas 8S-HEPE elicits no such activity. These results suggest that 8R-HEPE derived from North Pacific krill may have beneficial effects against dyslipidemia.

Real-World Data on Comparison of Lipid-Lowering Effects between Alirocumab and Evolocumab in Patients with Hypercholesterolemia.

Even though the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, have been approved to reduce plasma low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease in high-risk patients, real-world data showing comparisons of the lipid-lowering effects between alirocumab and evolocumab are scarce because of the low prescription rates of PCSK9 inhibitors in clinical practice. Between Feb 2018 and Sep 2021, 22 patients who received alirocumab and 22 patients who received evolocumab at a tertiary medical center were enrolled. The patients' baseline characteristics, prescribed medications, plasma LDL-C levels, and percentages of reduction in LDL-C were compared between alirocumab users and evolocumab users. The alirocumab users more frequently received ezetimibe treatment (72.7% vs. 40.9%, p = 0.03) and had higher baseline LDL-C (165.6 ± 63.2 mg/dL vs. 130.8 ± 56.3 mg/dL, p = 0.04) compared with the evolocumab users. At 6 months of follow-up, the plasma LDL-C levels in the alirocumab users were similar to those in the evolocumab users (79.3 ± 64.0 mg/dL vs. 63.5 ± 44.1 mg/dL, p = 0.48). Additionally, the percentages of LDL-C reduction following treatment were similar between the alirocumab users and evolocumab users (-47.0% ± 45.0% vs. -49.8 ± 24.9%, p = 0.66). The LDL-C lowering effects of alirocumab are similar to those of evolocumab in clinical practice.

Evaluation of the distribution and excretion of [14C]-inclisiran following single subcutaneous administration in cynomolgus monkeys

Inclisiran is a small interfering RNA molecule that was designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels by inhibiting proprotein convertase subtilisin/kexin type 9 synthesis in the liver. This study aimed to characterize the tissue distribution and excretion of inclisiran after dosing in monkeys.A single 20 mg/kg subcutaneous injection of [14C]-inclisiran was administered to 12 male cynomolgus monkeys. Plasma concentrations and tissue binding parameters for inclisiran were assessed up to 42 days after injection using liquid scintillation of blood samples and tissue homogenates, as well as quantitative whole-body autoradiography.Radioactivity was highest in the liver at all time points from 24 h onward and remained elevated throughout the entire study period. Radioactivity was also detected in the kidneys and bladder wall, returning to low levels by 24 h. The concentration of radioactivity in the liver (402.97 μg equivalent/g) was 15.7-fold higher than in the kidneys (25.70 μg equivalent/g). Very low amounts of radioactivity were detected in all other tissues examined. The highest radioactivity in tissue homogenates was in the liver and kidney pyramid (327 and 351 μg equivalent/g, respectively).This study confirmed the selective uptake of inclisiran by the liver, indicating that the N-acetylgalactosamine linker allows for selective uptake via the asialoglycoprotein receptors expressed on hepatocytes compared with other tissues that lack asialoglycoprotein receptors. The long tissue retention in the liver supports the infrequent, biannual dosing schedule for inclisiran in the clinic and the temporal disconnect between short-term systemic exposure and sustained lowering of LDL-C.

Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that arehighly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drugmetabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

Telemedicine assists in the management of proatherogenic dyslipidemia and postprandial glucose variability in patients with type 2 diabetes mellitus: a cross-sectional study.

ObjectiveCoronary heart disease (CHD) is a prevalent complication of type 2 diabetes mellitus (T2DM). The proatherogenic low-density lipoprotein (LDL) cholesterol is an established risk factor of cardiovascular disease, and evidence also suggests that postprandial plasma glucose (PPG) levels closely delineate CHD mortality in diabetes. The investigators hypothesized that the addition of telehealth consultation to standard antidiabetic therapy may help to reduce postprandial glucose variability and plasma LDL cholesterol levels in patients with T2DM.MethodsThis cross-sectional study enrolled patients with newly diagnosed T2DM who received standard antidiabetic therapy with or without additional telehealth consultation. Participants received blood tests for plasma lipid profile and glucose levels at the diagnosis of diabetes and after 1 month of therapeutic intervention. Laboratory results were compared between treatment groups to determine the efficacy of complementary telehealth consultation.ResultsIn this study, 375 participants were enrolled. The standard treatment group had considerably greater levels of plasma LDL cholesterol than recipients of telehealth consultation (110 mg/dL vs 93.1 mg/dL, P < 0.001). Moreover, patients receiving standard treatment had greater levels of fasting plasma glucose (104 mg/dL vs 98.5 mg/dL, P = 0.027), 2-h PPG (169 mg/dL vs 111 mg/dL, P < 0.001), and postprandial glucose variability (65.4 mg/dL vs 12.8 mg/dL, P < 0.001) than participants under telehealth consultation.ConclusionsTelemedicine in addition to standard antidiabetic therapy helped to reduce plasma LDL cholesterol levels and postprandial glucose variability in patients with newly diagnosed T2DM. Therefore, telehealth consultation is a suitable complement to pharmacologic therapy for diabetic patients to assist in the management of proatherogenic dyslipidemia and postprandial glucose variability.

Intranasal Oxytocin Improves Lean Muscle Mass and Lowers LDL Cholesterol in Older Adults with Sarcopenic Obesity: A Pilot Randomized Controlled Trial

ObjectivesObesity is associated with sarcopenia in older adults, and weight loss can lead to further muscle mass loss. Oxytocin decreases with age, and animal studies suggest that oxytocin administration has trophic effects on skeletal muscle cells and reduces adiposity. We conducted a clinical trial to examine the safety and preliminary efficacy of intranasal oxytocin for older adults with sarcopenic obesity. DesignA double-blind, placebo-controlled randomized controlled trial of intranasal oxytocin (24 IU 4 times per day) for 8 weeks. Setting and ParticipantsTwenty-one older (67.5 ± 5.4 years), obese (30–43 kg/m2), sedentary (<2 strenuous exercise per week) adults with slow gait speed (<1 m/s, proxy measure of sarcopenia) were recruited. MeasuresGeneralized estimating equations were used to evaluate the effect of oxytocin on safety/tolerability of oxytocin administration and whole body muscle and fat mass. ResultsAt baseline, body mass index (BMI) was 36.8 ± 3.6 kg/m2, fat mass 46.09 ± 6.99 kg, lean mass 50.98 ± 11.77 kg, fasting plasma glucose (FPG) 92.0 ± 8.9 mg/dL, hemoglobin A1c (HbA1c) 5.7% ± 0.4%, low density lipoprotein (LDL) 111.3 ± 41.5 mg/dL, high-density lipoprotein (HDL) 47.85 ± 10.96 mg/dL, and triglycerides 140.55 ± 83.50 mg/dL. Oxytocin administration was well tolerated without any significant adverse events. Oxytocin led to a significant increase of 2.25 kg in whole body lean mass compared with placebo (P < .01) with a trend toward decreasing fat mass, and a significantly reduced plasma LDL cholesterol by −19.3 mg/dL (P = .023) compared against placebo. There were no significant changes in BMI, appetite scores, glycemia, plasma HDL, triglycerides, or depressive symptoms. Conclusions and ImplicationsThis proof-of-concept study indicates that oxytocin may be useful for the treatment of sarcopenic obesity in older adults. Oxytocin administration may also provide additional cardiovascular benefits.

Identifying genetic modulators of statin response using subject-derived lymphoblastoid cell lines.

Although statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) have proven effective in reducing plasma low-density lipoprotein levels and risk of cardiovascular disease, their lipid lowering efficacy is highly variable among individuals. Furthermore, statin treatment carries a small but significant risk of adverse effects, most notably myopathy and newonset diabetes. Hence, identification of biomarkers for predicting patients who would most likely benefit from statin treatment without incurring increased risk of adverse effects can have a significant public health impact. In this review, we discuss the rationale for the use of subject-derived lymphoblastoid cell linesin studies of statin pharmacogenomics and describe a variety of approaches we have employed to identify novel genetic markers associated with interindividual variation in statin response.

Plant Stanol Esters Reduce LDL (Low-Density Lipoprotein) Aggregation by Altering LDL Surface Lipids: The BLOOD FLOW Randomized Intervention Study.

Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. Approach and Results: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm, P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index<25 kg/m2. Decreased LDL aggregation susceptibility was associated with decreased proportion of LDL-sphingomyelins and increased proportion of LDL-triacylglycerols. LDL binding to proteoglycans was decreased in the plant stanol ester group, the decrease depending on decreased serum LDL-cholesterol concentration. Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964.

Lifetime risk assessment in cholesterol management among hypertensive patients: observational cross-sectional study based on electronic health record data

BackgroundIn hypertensive patients, reducing plasma low-density lipoprotein cholesterol level (LDL-C) is one of the main interventions for preventing chronic cardiovascular diseases (CVD). However, LDL-C control remains generally insufficient, also in patients with hypertension. We analyzed Electronic Health Record (EHR) data of 7117 hypertensive patients to find the most potential age and sex subgroups in greatest need for improvement in real life dyslipidemia treatment. Taking into account the current discussion on lifetime CVD risk, we focused on the age dependence in LDL-C control.MethodsIn this observational cross-sectional study, based on routine electronic health record (EHR) data, we investigated LDL-C control of hypertensive, non-diabetic patients without renal dysfunction or CVD, aged 30 years or more in Finnish primary care setting.ResultsMore than half (54% of women and 53% of men) of untreated patients did not meet the LDL-C target of < 3 mmol/l and one third (35% of women and 33% of men) of patients did not reach the target even with the lipid-lowering medication (LLM). Furthermore, higher age was strongly associated with better LDL-C control (p < 0.001) and lower LDL-C level (p < 0.001) in individuals with and without LLM. Higher age was also strongly associated with LLM prescription (p < 0.001). In total, about half of the patients were on LLM (53% of women and 51% of men).ConclusionsOur findings indicate that dyslipidemia treatment among Finnish primary care hypertensive patients is generally insufficient, particularly in younger age groups who might benefit the most from CVD risk reduction over time. Clinicians should probably rely more on the lifetime risk of CVD, especially when treating working age hypertensive patients.

Role of PCSK9 in the course of ejection fraction change after ST-segment elevation myocardial infarction: a pilot study.

AimsProprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low‐density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure‐related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging‐derived left ventricular ejection fraction (LVEF) after a first ST‐segment elevation myocardial infarction (STEMI).Methods and resultsWe prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ≥ II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = −0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002).ConclusionsIn patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months.

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia.

Diabetic dyslipidaemia, characterized by quantitative, qualitative and kinetic changes in all major circulating lipids, contributes to the increased cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). A promising therapeutic avenue is the inhibition of the proprotein convertase subtilisin kexin 9 (PCSK9) with human monoclonal antibodies (mAbs) that potently reduce plasma low-density lipoprotein cholesterol (LDL-C) levels on top of statin treatment. The aim of this review is to evaluate the efficacy of PCSK9 inhibitors to lower the residual cardiovascular risk of T2DM patients and to discuss the safety of PCSK9 inhibition in these patients. PCSK9 inhibitors potently lower plasma LDL-C levels in T2DM patients and reduce risk for the development of cardiovascular disease. Anti-PCSK9 mAbs are generally not more or less effective in T2DM patients compared to a general high-risk population. Nevertheless, due to their higher cardiovascular risk, the absolute risk reduction of major cardiovascular events is more significant in T2DM patients. This suggests that treatment of T2DM patients with anti-PCSK9 mAbs could be attractive from a cost-effectiveness perspective. Treatment with anti-PCSK9 mAbs did not result in significant treatment-emergent adverse effects. While genetic studies suggest a potential link between PCSK9 inhibition and glucose homeostasis, anti-PCSK9 mAbs did not worsen glycaemic control in T2DM patients, but their safety should be verified after a longer-term follow-up.

Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice.

Objective- The objective of this study was to determine whether and how activation of farnesoid X receptor (FXR) by obeticholic acid (OCA), a clinical FXR agonist, modulates liver low-density lipoprotein receptor (LDLR) expression under normolipidemic conditions. Approach and Results- Administration of OCA to chow-fed mice increased mRNA and protein levels of LDLR in the liver without affecting the sterol-regulatory element binding protein pathway. Profiling of known LDLR mRNA-binding proteins demonstrated that OCA treatment did not affect expressions of mRNA degradation factors hnRNPD (heterogeneous nuclear ribonucleoprotein D) or ZFP36L1 but increased the expression of Hu antigen R (HuR) an mRNA-stabilizing factor. Furthermore, inducing effects of OCA on LDLR and HuR expression were ablated in Fxr-/- mice. To confirm the post-transcriptional mechanism, we used transgenic mice (albumin-luciferase-untranslated region) that express a human LDLR mRNA 3' untranslated region luciferase reporter gene in the liver. OCA treatment led to significant rises in hepatic bioluminescence signals, Luc-untranslated region chimeric mRNA levels, and endogenous LDLR protein abundance, which were accompanied by elevations of hepatic HuR mRNA and protein levels in OCA-treated transgenic mice. In vitro studies conducted in human primary hepatocytes and HepG2 cells demonstrated that FXR activation by OCA and other agonists elicited the same inducing effect on LDLR expression as in the liver of normolipidemic mice. Furthermore, depletion of HuR in HepG2 cells by short interfering RNA transfection abolished the inducing effect of OCA on LDLR expression. Conclusions- Our study is the first to demonstrate that FXR activation increases LDLR expression in liver tissue by a post-transcriptional regulatory mechanism involving LDLR mRNA-stabilizing factor HuR.