Arterial Function and Atherosclerosis in Patients With JAK2 V167F Positive Essential Thrombocythemia
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 82
- 主要终点
- Carotid Artery Stiffness (Expressed by Beta-stiffness Index ) in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period (From Baseline to Year 4).
研究概览
简要总结
The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. All subjects will be examined twice. The first visit already took place between the years 2014 - 2015 and the second visit will take place between 2018-2019. All participants will have signed their informed consent before entering the study. Each visit will consist of completing a structured questionnaire (on personal and family medical history, risk factors for CVD and medication), physical examination, donating a blood sample for laboratory tests and undergoing carotid ultrasound and coronary calcium measurement oft the extent of coronary artery calcification. At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood.
详细描述
- Patients and control subjects
Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. There were 124 JAK2 positive ET patients, among those 61 did not have a personal history of clinically manifest atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke). 40 patients (14 male and 26 female) with JAK2 V617F positive ET without clinically apparent cardiovascular disease signed the informed consent and were enrolled in the study in 2014 - 2015 for the first examination and 36 (12 male and 24 female) of them are expected to participate also in 2018-19.
The control group is selected among healthy employees of the University Medical Centre Ljubljana and their relatives. It is matched with the patient group for age and sex distribution and classical risk factors for cardiovascular disease. 42 individuals (16 male and 26 female) participated in the first examination and at least 38 (14 male and 24 female) subjects are expected to paticipate in the second examination. 2. Baseline measurements
Each participant will complete a questionnaire about family history of cardiovascular diseases, personal medical history, smoking status and medications. A physical examination will be performed, including measurements of height, weight, waist circumference, systolic and diastolic blood pressure. Blood will be sampled for laboratory analysis of complete blood cell count, electrolytes, serum lipids, liver function tests, urea, creatinine, and inflammatory markers.
The 10-year risk of coronary heart disease (CHD) and general cardiovascular disease (CVD) will be calculated using the Framingham risk equation. 3. JAK2 V617F/G1849T allele burden
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •patients with JAK2 V617F positive essential thrombocythemia
- •age-and sex-matched apparently healthy control subjects
排除标准
- •personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke)
- •chronic kidney disease stage 3 and above
- •known cancer
- •chronic inflammatory disease
- •autoimmune disease
- •pregnancy
结局指标
主要结局
Carotid Artery Stiffness (Expressed by Beta-stiffness Index ) in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period (From Baseline to Year 4).
时间窗: From Baseline (in 2014-2015) to Year 4 (in 2018-2019)
4-year change carotid artery in Beta-stiffness Index measured in JAK2 V617F positive ET patients in comparison to healthy control subjects. All measurements were performed by echo-tracking ultrasound of the common carotid artery. Echo-tracking of the common carotid artery wall was used to assess arterial stiffness expressed by the β-stiffness index. Measurement swere done at the common carotid artery 2 cm proximal to the bulb on both sides. The β-stiffness index was calculated as: β = ln (P_max / P_min) / \[(D_max - D_min / D_min)\] (P_max = the systolic blood pressure, P_min = the diastolic pressure; D_max = the maximum arterial diameter and D_min = the minimal arterial diameter). In the adult population, the values of β range from 4 - 10 and increase with age. A larger value of β means increased arterial stiffness, i.e., a worse outcome.
Change of Coronary Calcium Burden in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.
时间窗: From Baseline (in 2014-2015) to Year 4 (in 2018-2019)
Change in the Agatston coronary artery calcium score in a 4 year observation period. Agatston score denotes the number of coronary artery calcifications weighted for the intensity of calcification. Grading of coronary artery disease (CAD) based od Agatston score goes as follows: no CAD = score 0, minimal CAD = score 1-10, mild CAD = score 11-100, moderate CAD = score 101-400, svere CAD = score \> 400.
Carotid Artery Stiffness (Expressed by the Pulse Wave Velocity) in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period (From Baseline to Year 4).
时间窗: From Baseline (in 2014-2015) to Year 4 (in 2018-2019)
4-year change in carotid artery pulse wave velocity (PWV) measured in JAK2 V617F positive ET patients in comparison to healthy control subjects. All measurements were performed by echo-tracking ultrasound of the common carotid artery. Measurements were done at the common carotid artery 2 cm proximal to the bulb on both sides. PWV was calculated from the beta stiffness index (β, for description see above), as follows: PWV = √ ((β x P_min) / 2ρ)); ρ = 1050 kg/m³. PWV increases with arterial stiffness, a larger value means a worse outcome. PWV in adults ranges from 3 m/s to 12 m/s; values are strongly age dependent.
Change of Digital Endothelial Function, Expressed as Reactive Hyperemia Index and Augmentation Index (AI), in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.
时间窗: From Baseline (in 2014-2015) to Year 4 (in 2018-2019)
4-year change in Reactive Hyperemia Index (RHI) and 4-year change Augmentation Index (AI). RHI was calculated by the formula: RHI = (A/B) / (C/D) where A is the post-occlusion pulse wave amplitude (PWA) of the occluded hand, B the baseline PWA of the occluded hand, C the post-occlusion PWA of the contralateral hand, and D the baseline PWA of the contralateral hand. A higher RHI means better endothelial function (= good outcome). RHI in patients ranges from1-3. Arbitrarily, normal RHI is defined as =\> 1.67, and abnormal RHI as RHI =\< 1.66. The AI was determined from the shape of the arterial pulse wave by the EndoPAT 2000 software which distinguished between the primary pulse wave (P1) and the reflected pulse wave (P2) by the formula: AI = ((P2-P1)/P1) x 100. The results were normalized to a heart rate of 75/min. A higher AI means greater arterial stiffness (= bad outcome). AI \>0.4 is abnormal.
The JAK2 V617F Mutation Burden in Patients With JAK2 V617F Positive ET.
时间窗: At baseline (in 2014- 2015) and at the second visit (in 2018-2019)
Change in JAK2 V617F mutation burden in the 4-year observation period. Ipsogen JAK2 MutaQuant Kit, Qiagen (USA) was used for the detection of JAK2 V617F mutation and quantification of its burden in genomic DNA, which was extracted from granulocytes in peripheral blood. Real-time quantitative polymerase chain reaction (qPCR) was used with double-dye oligonucleotide hydrolysis principle. The JAK2 V617F burden was defined as the percentage of JAK2 V617F mutated alleles in total genomic DNA.
Change of Carotid Artery Plaque Score in JAK2 V617F Positive ET Patients in Comparison to Healthy Control Subjects in a 4-year Period.
时间窗: From Baseline (in 2014-2015) to Year 4 (in 2018-2019)
Change in carotid plaque score (i.e., the number of carotid artery segments with detected plaques, reported on a scale from 0-6) in a 4 year observation period. A carotid plaque score 0 means that the common carotid, internal carotid and exteranal carotid artery on both sides are free from plaques. A score of 6 means that the common carotid, internal carotid and external carotid artery on both sides have plaques detected by ultrasound.
次要结局
未报告次要终点
研究者
Ales Blinc
Ales Blinc, MD, PhD, Head, Dept of Vascular Diseases
University Medical Centre Ljubljana