scholarly journals Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy

2021 ◽  
Author(s):  
Naoto Kuyama ◽  
Yu Kataoka ◽  
Misa Takegami ◽  
Kunihiro Nishimura ◽  
Mariko Harada‐Shiba ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Characteristic Curve ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Area Under The Curve ◽  
Density Lipoprotein ◽  
Multivariable Logistic Regression Analysis ◽  
Percent Reduction ◽  
Artery Disease ◽  
Study Participants

Background Statin‐mediated efficacy of lowering low‐density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine‐protease associated with LDL metabolism, which circulates as mature and furin‐cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin‐naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10‐ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [ P =0.03]), whereas furin‐cleaved level was not (per 10‐ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [ P =0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

Association of apolipoprotein E polymorphism, low-density lipoprotein cholesterol, and coronary artery disease.

1986 ◽  
Vol 32 (5) ◽  
pp. 778-781 ◽  
Author(s):  
H J Lenzen ◽  
G Assmann ◽  
R Buchwalsky ◽  
H Schulte
Keyword(s):  
Myocardial Infarction ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Apolipoprotein E ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Apolipoprotein E Polymorphism ◽  
Artery Disease

Abstract We determined the frequencies of genetic apolipoprotein E isoforms in 570 survivors of myocardial infarction, all with demonstrable coronary heart disease, as compared with 624 healthy persons. In controls, E-4/E-3 heterozygosity was associated with total cholesterol concentrations of 1985 (SD 364) mg/L and low-density lipoprotein (LDL)-cholesterol concentrations of 1306 (SD 332) mg/L. Significantly lower values, 1811 (SD 312) mg/L and 1121 (SD 274) mg/L, respectively, were observed for E-3/E-2 heterozygous persons. In survivors of myocardial infarction, the respective values were significantly higher than in controls, differing between E-4/E-3 and E-3/E-2 heterozygous patients by 233 and 220 mg/L, respectively. Moreover, E-4/E-3 heterozygosity was accompanied by earlier age of myocardial infarction (48.8 +/- 7.4 years) as compared with E-3/E-2 heterozygosity (53.4 +/- 6.9 years) and E-3/E-3 homozygosity (51.2 +/- 7.7 years). Evidently, apolipoprotein E polymorphism can contribute to total and LDL-cholesterol concentrations in serum, thereby affecting risk of coronary heart disease and myocardial infarction.

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1

2019 ◽  
Vol 116 (5) ◽  
pp. 908-915 ◽  
Author(s):  
Zufeng Ding ◽  
Naga Venkata K Pothineni ◽  
Akshay Goel ◽  
Thomas F Lüscher ◽  
Jawahar L Mehta
Keyword(s):  
Inflammatory Cytokines ◽  
Ldl Cholesterol ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Prevention Of Atherosclerosis ◽  
Pro Inflammatory Cytokines

Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

scholarly journals Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia

Cholesterol ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
V. A. Korneva ◽  
T. Yu. Kuznetsova ◽  
T. Yu. Bogoslovskaya ◽  
D. S. Polyakov ◽  
V. B. Vasilyev ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Familial Hypercholesterolaemia ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Gene Mutations ◽  
Density Lipoprotein ◽  
Single Strand Conformation Polymorphism ◽  
Polymorphism Analysis ◽  
Cholesterol Levels

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

Calculated values for low-density lipoprotein cholesterol in the assessment of lipid abnormalities and coronary disease risk

1990 ◽  
Vol 36 (1) ◽  
pp. 36-42 ◽  
Author(s):  
J R McNamara ◽  
J S Cohn ◽  
P W Wilson ◽  
E J Schaefer
Keyword(s):  
Ldl Cholesterol ◽  
Disease Risk ◽  
Direct Method ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Reliable Estimate ◽  
Low Density ◽  
Artery Disease ◽  
Lipid Abnormalities

Abstract Low-density lipoprotein (LDL) cholesterol concentrations are most commonly estimated by the formula LDL cholesterol = total cholesterol - [triglycerides (TG)/5 + high-density lipoprotein cholesterol], although alternative factors such as TG/6 have also been used. Using standardized, automated, enzymatic lipid assays, we analyzed 4797 plasma samples from normal and dyslipidemic adults, to compare LDL cholesterol concentrations obtained after ultracentrifugation with those calculated by several such methods (i.e., TG/4-TG/8). or TG concentrations less than or equal to 0.50 g/L, TG/4 agreed best with the direct assay; for TG of 0.51-2.00 g/L, TG/4.5 was best; and for TG of 2.01-4.00 g/L, TG/5 was best. Differences in estimated values were generally small, however. At TG greater than 4.00 g/L, none of the factors tested allowed a reliable estimate of LDL cholesterol. When TG were less than or equal to 4.00 g/L, 86% of estimated LDL cholesterol values were properly classified according to National Cholesterol Education Program cutpoints when the factor TG/5 was used. We conclude that a convenient direct method for measuring LDL cholesterol is needed but, until one is available, use of the factor TG/5 will assure that most individuals with TG less than or equal to 4.00 g/L, as measured in a standardized laboratory, can be reasonably well classified for risk of coronary artery disease.

scholarly journals Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

2019 ◽  
Vol 116 (22) ◽  
pp. 10937-10942 ◽  
Author(s):  
Wenhai Sui ◽  
Hongshi Li ◽  
Yunlong Yang ◽  
Xu Jing ◽  
Fei Xue ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Atherosclerotic Plaque ◽  
Ldl Cholesterol ◽  
Uncoupling Protein ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cerebrovascular Diseases ◽  
Plaque Development ◽  
Brown Adipose

Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E−/− (ApoE−/−) and low-density lipoprotein (LDL) receptor−/− (Ldlr−/−) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis.

scholarly journals Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 353
Author(s):  
Jesús Martín-Campos ◽  
Sheila Ruiz-Nogales ◽  
Daiana Ibarretxe ◽  
Emilio Ortega ◽  
Elisabet Sánchez-Pujol ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Characteristic Curve ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Single Nucleotide ◽  
Specificity And Sensitivity ◽  
Diagnostic Sensitivity And Specificity ◽  
And Control ◽  
Pathological Variant

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.

scholarly journals ACUTE CORONARY SYNDROME;

2017 ◽  
Vol 24 (12) ◽  
pp. 1818-1822
Author(s):  
Huma Muzaffar ◽  
Shakeel Ahmad ◽  
Naeem Asghar
Keyword(s):  
Acute Coronary Syndrome ◽  
Coronary Artery ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cross Sectional ◽  
Coronary Syndrome ◽  
Study Population ◽  
Artery Disease ◽  
Medical Wards

Objectives: To determine the frequency of raised low density lipoprotein (LDL)cholesterol in patients with acute coronary syndrome. Study Design: Cross sectional study.Setting: Coronary care unit (CCU) and medical wards at Allied Hospital Faisalabad. Durationand Dates: Six months from 01-01-2010 to 30-06-2010. Methods: This was a cross sectionalstudy that included 215 patients fulfilling the criteria of acute coronary syndrome admittingin CCU and medical wards. The demographic details, history and clinical examination of thepatients were recorded and blood samples were collected for the estimation of LDL cholesterol.Statistical Test: Descriptive statistics like mean and standard deviation (S.D) was appliedon age and LDL cholesterol. Gender and type of coronary artery event will be presented aspercentages. Frequency of raised LDL cholesterol was calculated in patients with ACS. Results:In this study population, out 215 patients, 183 (85.1) were found to have raised LDL cholesterollevels. There were 117 (54.4) males and 98 (45.6) females. Mean age was 56.29+- 13.01. Thefrequency of raised level of LDL cholesterol was slightly high in among males. STEMI was mostcommon type of ACS followed by unstable angina and NSTEMI. Conclusions: Frequency ofraised LDL cholesterol was high among the patients with acute coronary syndrome. It supportsthe potential for preventive efforts in persons with high risk of coronary artery disease.

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