Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment (GEBI)
Genetic, Biochemical and Functional Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment Options
研究概览
详细说明
Impaired blood fat metabolism and chronic inflammation are intertwined as possible causes of atherosclerosis. Lipoprotein (a) (Lp (a)) is a specific subfraction of lipoprotein that is an independent risk factor for coronary heart disease and at the same time predicted residual risk in patients with pre-existing atherosclerosis, regardless of serum LDL-cholesterol concentration. Circulating levels of Lp(a) are mainly genetically determined and varies according to ethnic group. Lp(a) has many functions, which include atherosclerotic, prothrombotic and pro-inflammatory roles. The gene encoding apo (a); LPA, is located on the long arm of chromosome 6 (6q2,6-2,7) and most variants in Lp (a) can be explained by genetic diversity in LPA. To date, the most studied genetic variant is the Kringle-IV type-2 (KIV2) polymorphism, which explains 30-70% of the diversity in Lp (a) in the population. Some KIV2 replicates are associated with smaller isoforms and higher plasma concentrations of Lp (a) which are causally and independently associated with coronary heart disease. Within LPA, the number of KIV2 copies, as well as one nucleotide polymorphism (SNP), rs3798220 and rs10455872, is associated with Lp (a) concentration and coronary heart disease. Recently 'Proprotein convertase subtilisin/kexin type 9' (PCSK9) inhibitors that act through non-specific reduction of Lp(a) are the only drugs that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. The effects of PCSK9 inhibitors are not purely through Lp(a) reduction, but also through LDL cholesterol reduction.
The early stage of the atherosclerosis process is characterized by endothelial cell damage, which results in impaired release and function of nitric oxide (NO) from the endothelium. NO is formed by endothelial NO synthetase (NOS-3) from the amino acid L-arginine, which is most pronounced in the vascular wall and is also most important in the process of atherosclerosis. The NOS-3 gene is located on chromosome 7; in the region 7q35-7q36. Functional polymorphisms are those that alter the expression or activity of NOS-3. Among them, rs2070744, rs3918226 and rs1799983 single nucleotide polymorphisms (SNP) are important. Variations in the expression and activity of NOS-3 genetic polymorphisms at exon 7 of the NOS-3 gene are associated with the incidence of myocardial infarction in very young patients who otherwise have a low atheromatous coronary artery load. Variations in the NOS-3 genes cause diversity in NO bioavailability and are responsible for endothelial dysfunction.
A 6-month observational, prospective, and randomized study will include 70 patients with a first acute coronary syndrome (ACS) (including acute transmural myocardial infarction, nontransmural myocardial infarction or unstable angina pectoris) event before age 55 and Lp (a) levels above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L. With the gradual inclusion ("step-wedge") and randomization of patients, the investigators will also provide a control group that will include 30 patients. The investigators will do anamnesis, targeted clinical examination, take blood samples for laboratory measurements, ultrasound measure endothelium-dependent dilatation of the brachial artery and intima media thickness of carotid arteries, measure pulse wave and calculate carotid artery wall stiffness. Patients will be divided into three groups according to a randomization list. The first group will receive alirocumab, the second group evolocumab, and the third group will be the control group and will be included in the treatment after 6 months. During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard treatment. After 6 months, the investigators will repeat all the mentioned investigations. Patients will be informed about the purpose and course of the study before starting it. All will participate voluntarily, without pressure or inappropriate instigation, which they will confirm by signing.
The investigators hypotheses that in patients with early coronary artery disease Lp (a) and Lp (a) polymorphisms are associated with indicators of inflammation and structural-functional properties of the arterial wall; in patients with early coronary artery disease, PCSK9 inhibitors reduce the value of Lp (a), indicators of inflammation and structural and functional involvement of the arterial wall; in patients with early coronary artery disease, the influence of PCSK9 inhibitors on Lp (a), indicators of inflammation and structural-functional properties of the arterial wall depends on the presence of specific polymorphisms for Lp (a).
研究类型
注册 (预期的)
阶段
- 不适用
联系人和位置
学习地点
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Ljubljana、斯洛文尼亚、1000
- 招聘中
- University Medical Centre Ljubljana-Department of Vascular diseases and dept. of Cardiology
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接触:
- Miran Šebeštjen, prof, PhD
- 电话号码:+38615224811
- 邮箱:miran.sebestjen@kclj.si
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接触:
- Andreja Rehberger Likozar, MD
- 电话号码:+38615228012
- 邮箱:andreja.rehbergerlikozar@kclj.si
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- at least 6 months after acute coronary syndrome,
- up to 55 years at the time of first acute coronary syndrome
- concentration Lp (a) above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L
- optimally treated risk factors for cardiovascular events according to currently valid guidelines.
Exclusion Criteria:
- Age <18 years or > 65 years,
- documented history of myocardial infarction less than 6 months before enrollment
- secondary dyslipidemia,
- severe renal disease (oGFR <30 ml / min),
- moderate to severe liver disease (elevated transaminases above 3 times the norm, elevated bilirubin above 2 times the norm, elevated creatinine kinase above 3 times the norm),
- acute illness 6 weeks before inclusion in the study,
- history of allergic reaction to any ingredient in the drug,
- pregnancy and lactation,
- life expectancy less than 12 months,
- unwillingness to participate or lack of availability for follow-up
学习计划
研究是如何设计的?
设计细节
- 主要用途:治疗
- 分配:随机化
- 介入模型:并行分配
- 屏蔽:无(打开标签)
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的:Alirocumab
The first group of patients will receive 150 mg of alirocumab every two weeks subcutaneously for 6 months
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The first group will receive alirocumab.
Blood samples from all patients will be drawn for laboratory measurements and genetics determination.
Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
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实验性的:Evolocumab
the second group of patients will receive evolocumab 140 mg every two weeks subcutaneously for 6 months
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The second group will receive evolocumab.
Blood samples from all patients will be drawn for laboratory measurements and genetics determination.
Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
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实验性的:Control group
Control group will be included in the treatment after 6 months.
During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard guidelines-based treatment
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The third group will receive only optimal guidelines-based secondary preventive treatment.
Blood samples from all patients will be drawn for laboratory measurements and genetics determination.
Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
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研究衡量的是什么?
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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动脉壁和 Lp (a) 浓度的超声功能和形态学特性
大体时间:基线
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动脉壁的功能和形态特征将与 Lp (a) 浓度相关。
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基线
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Concentration of Lp (a) and SNP in the LPA gene
大体时间:Baseline
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The serum concentration of Lp (a) will correlate with single nucleotide polymorphisms (SNP) in the LPA gene
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Baseline
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The effect of alirocumab or evolocumab on functional and morphological properties of arterial wall after 6 months
大体时间:6 months
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Both drugs will improve functional and morphological properties of arterial wall in with no difference between the drugs.
We expect the improvements in each drug group will be in correlation with the decrease of Lp (a) concentration.
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6 months
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合作者和调查者
调查人员
- 学习椅:Miran Šebeštjen, prof.、University Medical Centre Ljubljana (Slovenia)
- 首席研究员:Andreja Rehberger Likozar, MD、University Medical Centre Ljubljana (Slovenia)
出版物和有用的链接
一般刊物
- Tada H, Takamura M, Kawashiri MA. Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease. J Atheroscler Thromb. 2019 Jul 1;26(7):583-591. doi: 10.5551/jat.RV17034. Epub 2019 Apr 30.
- Machado-Silva W, Alfinito-Kreis R, Carvalho LS, Quinaglia-E-Silva JC, Almeida OL, Brito CJ, Ferreira AP, Cordova C, Sposito AC, Nobrega OT; Brasilia Heart Study Group. Endothelial nitric oxide synthase genotypes modulate peripheral vasodilatory properties after myocardial infarction. Gene. 2015 Sep 1;568(2):165-9. doi: 10.1016/j.gene.2015.05.042. Epub 2015 May 20.
- Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene. 2016 Jan 10;575(2 Pt 3):584-99. doi: 10.1016/j.gene.2015.09.061. Epub 2015 Sep 28.
- Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O'Shaughnessy KM, Brown MJ. A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999 Oct 5;100(14):1515-20. doi: 10.1161/01.cir.100.14.1515.
- Maranhao RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq Bras Cardiol. 2014 Jul;103(1):76-84. doi: 10.5935/abc.20140101.
- Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with elevated and normal Lp(a) concentration. Metabolism. 2019 Jul;96:8-11. doi: 10.1016/j.metabol.2019.04.010. Epub 2019 Apr 14.
- Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016 Apr;57(4):526-37. doi: 10.1194/jlr.R061648. Epub 2015 Dec 4.
- Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692-711. doi: 10.1016/j.jacc.2016.11.042.
- Rehberger Likozar A, Zavrtanik M, Sebestjen M. Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options. Ann Med. 2020 Aug;52(5):162-177. doi: 10.1080/07853890.2020.1775287. Epub 2020 Jun 8.
- Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec 24;361(26):2518-28. doi: 10.1056/NEJMoa0902604.
- Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, Catanese JJ, Buring JE, Devlin JJ, Ridker PM. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009 Apr;203(2):371-6. doi: 10.1016/j.atherosclerosis.2008.07.019. Epub 2008 Jul 26.
- Ober C, Nord AS, Thompson EE, Pan L, Tan Z, Cusanovich D, Sun Y, Nicolae R, Edelstein C, Schneider DH, Billstrand C, Pfaffinger D, Phillips N, Anderson RL, Philips B, Rajagopalan R, Hatsukami TS, Rieder MJ, Heagerty PJ, Nickerson DA, Abney M, Marcovina S, Jarvik GP, Scanu AM, Nicolae DL. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res. 2009 May;50(5):798-806. doi: 10.1194/jlr.M800515-JLR200. Epub 2009 Jan 5.
- Rawther T, Tabet F. Biology, pathophysiology and current therapies that affect lipoprotein (a) levels. J Mol Cell Cardiol. 2019 Jun;131:1-11. doi: 10.1016/j.yjmcc.2019.04.005. Epub 2019 Apr 12.
- BERG K. A NEW SERUM TYPE SYSTEM IN MAN--THE LP SYSTEM. Acta Pathol Microbiol Scand. 1963;59:369-82. doi: 10.1111/j.1699-0463.1963.tb01808.x. No abstract available.
- Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412-23. doi: 10.1001/jama.2009.1063.
- Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR. Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors. Clin Res Cardiol Suppl. 2019 Apr;14(Suppl 1):45-50. doi: 10.1007/s11789-019-00099-z.
- Zigra AM, Rallidis LS, Anastasiou G, Merkouri E, Gialeraki A. eNOS gene variants and the risk of premature myocardial infarction. Dis Markers. 2013;34(6):431-6. doi: 10.3233/DMA-130987.
研究记录日期
研究主要日期
学习开始 (预期的)
初级完成 (预期的)
研究完成 (预期的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- GEBI
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)?
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
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Alirocumab的临床试验
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Population Health Research Institute完全的ST 抬高型心肌梗死 | 血脂异常 | 高胆固醇血症 | 高脂血症 | 急性冠状动脉综合征 | 药物的生理作用加拿大
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Westside Medical Associates of Los AngelesRegeneron Pharmaceuticals; University of Washington未知
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Shanghai Tong Ren HospitalChina Cardiovascular Association招聘中
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Regeneron PharmaceuticalsSanofi终止
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Regeneron PharmaceuticalsSanofi完全的
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Regeneron PharmaceuticalsSanofi完全的
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Regeneron PharmaceuticalsSanofi完全的