Dyslipidemia is a major contributor in initiation, development and progression of atherosclerotic cardiovascular disease (ASCVD). Most lipid guidelines are from Europe and America and centered on the ...reduction of atherogenic lipids levels through lifestyle intervention and pharmacotherapy. Recently, the 2017 Taiwan lipid guidelines for high risk patients was published to facilitate the control of dyslipidemia in patients that are highly susceptible to ASCVD, including patients with preexisting ASCVD, diabetes, chronic kidney disease and familial hypercholesterolemia. Most recommendations outlined in the 2017 Taiwan lipid guidelines for high risk patients are in concordance with those of Western guidelines. However, based on evidence from the studies originating from Asia and local expert opinions, there are some recommendations different from the other guidelines. The purpose of the current review is to compare the similarities and differences between the perspectives of the 2017 Taiwan lipid guidelines for high risk patients and other Western guidelines in individuals at high risk of ASCVD. The definitions of high risk groups and treatment goals defined to achieve ASCVD risk reduction are specifically compared.
Heme oxygenase is a rate-limiting enzyme in heme degradation, leading to the generation of free iron, biliverdin, and carbon monoxide. Induction of heme oxygenase-1 is implicated in the antioxidant ...defense mechanism and can modulate vascular function. To test the association of microsatellite polymorphism in the promoter region of human HO-1 gene with the risk of coronary artery disease (CAD) in type 2 diabetic patients, we examined the allele frequencies of (GT) (n) repeats in HO-1 gene in 474 patients with CAD and in 322 controls. A transient-transfection assay with HO-1 promoter/luciferase fusion constructs carrying various lengths of (GT) (n) repeats was performed to explore the regulatory effect of (GT) (n) repeats on HO-1 gene expression in cultured rat aortic smooth muscle cells. Serum thiobarbituric acid-reactive substances (TBARs), a measure of lipid peroxidation, was significantly higher in subjects carrying the L/L genotype (> or =32 repeats). Among type 2 diabetic subjects, the frequencies of the L alleles and proportion of genotypes with L alleles were significantly higher in those with CAD than in those without CAD. The adjusted odds ratio for CAD in type 2 diabetic patients with L alleles was 4.7 (95% confidence interval, 1.9-12.0, P=0.001). Transfection experiments in aortic smooth muscle cells revealed that HO-1 promoter/luciferase fusion constructs containing longer (GT) (n) repeats exhibited lower transcriptional activity. These results imply that the length polymorphism in the HO-1 gene promoter modulate the transcription of the gene in vascular cells. Type 2 diabetics carrying longer (GT) (n) repeats might have higher oxidative stress and increased susceptibility to the development of CAD.
Abstract Background Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified ...in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. Methods and results We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes – LDL receptor ( LDLR ), apolipoprotein B ( APOB ), and proprotein convertase subtilisin/kexin type 9 gene ( PCSK9 ) – and 290 known insertion/deletion mutations on LDLR . We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis. Conclusions The high-throughput FH resequencing array detects LDLR , APOB , and PCSK9 with high efficiency and accuracy and identifies disease-causing mutations. Thus, it facilitates large-scale screening of the heterogeneous FH populations.
ASCVD /CVD Risk Reduction
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels. Currently, ...few treatments effectively lower LDL-C levels in pediatric patients with HoFH. Here, we report the efficacy and safety of evinacumab, a monoclonal antibody inhibitor of angiopoietin-like 3, in pediatric patients with HoFH.
This is a three-part, open-label study (NCT04233918); Part B results are reported here. Part B enrolled 14 patients with HoFH 5–11 years old with LDL-C >130 mg/dL on optimized lipid-lowering therapy, including apheresis and lomitapide. All patients received intravenous evinacumab 15 mg/kg every 4 weeks.
All 14 patients completed Part B. Evinacumab treatment reduced mean (standard deviation) LDL-C from 263.7 (91.0) mg/dL at baseline to 131.8 (109.8) mg/dL at Week 24, with a mean (standard error SE) percent reduction of −48.3% (10.4%). Mean (SE) reductions in apolipoprotein B (−41.3% 9.0%), non-high-density lipoprotein cholesterol (−48.9% 9.8%), and total cholesterol (−49.1% 8.1%) were also observed. Furthermore, percent LDL-C reduction observed at Week 24 from baseline based on the baseline LDL-C values or the presence of lomitapide treatment are presented in a Table. Additionally, the percent change from baseline in Lp(a) at Week 24 according to baseline apheresis status (Yes vs No) was similar: −43.7% (1.6%) versus −32.7% (1.4%), respectively. Treatment-emergent adverse events (TEAEs) occurred in 10 (71.4%) patients; no deaths or treatment discontinuations due to TEAEs were reported.
Evinacumab substantially reduced LDL-C levels and other key atherogenic lipid parameters in pediatric patients with HoFH additive to any pre-existing treatment (including apheresis and lomitapide). Evinacumab was generally well-tolerated.
Green tea intake has been shown to improve endurance capacity in animal studies, but whether it has a similar effect on humans remains unclear. A randomized, double-blinded, parallel-controlled study ...was conducted to evaluate the short-term effect of STA-2, a pharmaceutical preparation of green tea polyphenols, in patients with effort-induced angina and documented positive exercise tolerance test.
A total of 79 patients recruited from three medical centers were randomly assigned to receive 2 STA-2 250 mg capsules, each containing 100 mg green tea polyphenols, three times daily, or placebo for six weeks after two consecutive symptom-limited treadmill exercise tests to ascertain the reproducibility of exercise tolerance.
There was no difference in total exercise tolerance time from baseline to Week 6 between two groups (p = 0.639). There were also no observed improvements in subgroup analyses stratified by age, gender, and BMI categories. However, a significant reduction in low-density lipoprotein levels was shown in patients in the STA-2 group (-8.99 ± 19.18 mg/dL) versus the placebo group (0.57 ± 19.77 mg/dL), p = 0.037, with greater benefits in patients not taking antihyperlipidemic drugs (STA-2: -9.10 ± 19.96 mg/dL vs. placebo: 4.42 ± 15.08 mg/dL, p = 0.037).
STA-2 treatment for 6 weeks did not increase exercise time as measured on a treadmill. However, this study also indicated that STA-2 treatment could have potential beneficial effects on LDL-cholesterol concentrations.
FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitouslyexpressed and interacts with proteins in several intracellular signal transduction ...systems.Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-β(TGF-β) superfamily in vitro, the function of FKBP12 in TGF-β superfamily signalling iscontroversial. FKBP12 also physicallyinteracts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor(RyR1),. In contrast, the cardiacryanodine receptor, RyR2, appears to bind selectively theFKBP12 homologue, FKBP12.6 (9, 10). To define the functions of FKBP12 in vivo, we generated mutantmice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle buthave severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of leftventricular myocardium,. About 9% of themutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable forTGF-β-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodinereceptors.
Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure ＞20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance ...(PVR) ＞ 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.
The cholesterol-reducing drug atorvastatin is widely used in hyperlipidemic patients and it is crucial to consider its potential myotoxic effect when adjusting the prescription for patients. The aim ...of this study was to establish a simple high-performance liquid chromatography method that would be applicable for the quantitative determination of high serum atorvastatin concentrations in patients for the assessment of myalgia. The average recovery of atorvastatin from the extraction using ethyl acetate was 85.1%. The extract was dried, re-dissolved in methanol, and subjected to chromatographic separation using a reverse-phase C18 analytical column and a mobile phase consisting of 61.3% methanol in 0.05 M sodium phosphate buffer at pH 3.5. The concentration of atorvastatin was quantitatively determined by measuring the absorbance at 247 nm and β-naphthoflavone was used as an internal standard. The lower limits of detection and quantification of atorvastatin were 1.2 ng/mL and 3.0 ng/mL, respectively. There was a good linear relationship (r = 0.999) of the peak area and atorvastatin within a concentration range of 3.0–150 ng/mL in human serum. Among 61 lipid-controlling patients with detectable serum atorvastatin concentrations, 7 patients had myalgia and their serum concentrations were not significantly greater than those in patients without myalgia.
Tranilast, an antiallergic medication, is a very promising inhibitor of restenosis after balloon angioplasty. Tranilast can prevent the proliferation and migration of smooth muscle cells by ...activating the gene expression of p21, a strong cyclin/cyclin‐dependent kinase (CDK) inhibitor, and by arresting cell growth at the G0/G1 phase.
The signaling pathway of Tranilast in regulating p21 is to our best interest and is elucidated in the present study. The major emphasis was weighted on exploring the regulatory effects of Tranilast on promoter activity of p21.
By serial deletion analysis, the sequence between −74 and −83 bp of the p21 promoter, previously identified as the transforming growth factor‐β (TGF‐β)‐response element, was found sufficient, where as most of the promoter region 5′ to −111 bp was found unnecessary for the transcriptional activation of p21 by both TGF‐β1 and Tranilast.
Tranilast was also found to induce phosphorylation of Smad2 (a cytoplasmic signaling molecule essential for mediating TGF‐β signal transduction). Transfection of ΔkTβRII, a truncated form of TGF‐β type II receptor known to exert a dominant‐negative effect on TGF‐β signaling, was found to suppress the signaling of both Tranilast and TGF‐β1 to a similar extent.
These results suggested that induction of p21 by Tranilast might be closely related to TGF‐β signal transduction pathway.
British Journal of Pharmacology (2006) 147, 117–124. doi:10.1038/sj.bjp.0706460
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