Vascular Stiffness and Endothelial Cell Function in Intradialytic Hypertension

描述(由申请人提供)：终末期肾病(ESRD)患者的心血管发病率和死亡率比普通人群高。血液透析(HD)患者在血液透析期间血压升高，这是一个具有更大不良后果风险的亚群。透析性高血压(IH)是HD患者住院、心血管和各种原因死亡的另一个独立危险因素，其定义为HD治疗前后的收缩压高于10毫米汞。血管内皮细胞功能障碍(ECD)和动脉僵硬增加在HD患者中普遍存在，可能参与了IH的病理生理过程。 该项目的具体目标是：1)建立与动脉僵硬和IH的关联；2)使用不止一个变量来评估ECD和IH，以证明与ECD和IH的关联；3)研究卡维地洛在废除IH中的作用。 具体目的1：测定25例IH患者和25例非IH HD患者的脉搏波速度(PWV)。动态血压(ABP)也将作为PWV的一个可能的混杂变量在这些受试者中进行测量。 具体目的2：除周中非透析日血流介导的血管扩张和非内皮依赖性血管扩张外，还将测定透析前后内皮素-1和不对称二甲基精氨酸的水平。 具体目标3：在所有基线测量完成后，IH受试者将开始使用卡维地洛。在卡维地洛治疗8周后，包括每天两次50毫克的滴定后4周，将重复AIMS 1和AIMS 2的所有测量。 建立高血压与ECD和动脉僵硬的关联可以促使人们努力探索可能的因果关系。此外，卡维地洛对IH影响的结果可能会在随机对照试验中传播，以确定是否可以改善终点，如心血管疾病或所有原因的死亡率。这一信息的相关性最终可能扩展到更一般的人群，如HD前的慢性肾脏疾病患者或没有肾脏疾病但动脉僵硬或ECD升高的患者。申请者将在项目期间由赞助商和共同赞助商监督。申请者将参与项目的每一个步骤，从招聘到手稿写作。除了获得临床研究技能外，申请者还将学习测量ABP、PWV和FMD的技术。此外，申请者将参加临床科学硕士学位的课程。所有活动的目的都是为了申请者获得临床研究方面的知识和经验，以追求更独立的参与研究事业的水平。 公共卫生相关性：接受血液透析的终末期肾病患者比普通人群患心血管疾病和死亡的风险更高。在血液透析患者中，那些在血液透析过程中血压升高的患者预后不良的风险更高。本研究调查血管健康不良是否与透析期间血压升高有关，以及使用特定的降压药物治疗是否有助于防止这些血压升高。

DESCRIPTION (provided by applicant): Patients with end stage renal disease (ESRD) carry a higher risk for cardiovascular morbidity and mortality than the general population. Hemodialysis (HD) patients whose blood pressure increases during a HD session represent a subpopulation with even greater risk for adverse outcomes. When defined as an increase in systolic blood pressure greater than 10 mmHg from pre to post HD treatment, intradialytic hypertension (IH) is an additional independent risk factor for hospitalization and cardiovascular and all cause mortality in HD patients. Endothelial cell dysfunction (ECD) and increased arterial stiffness both are prevalent in HD patients and may be involved in the pathophysiology of IH. The specific aims of the project are to: 1) establish an association with arterial stiffness and IH; 2) demonstrate an association with ECD and IH using more than one variable to asses for ECD; 3) investigate the effects of carvedilol in abolishing IH. For specific aim 1: Pulse wave velocity (PWV) will be obtained from 25 subjects with IH and 25 control HD subjects without IH. Ambulatory blood pressure (ABP) will also be measured in these subjects as a possible confounding variable for PWV. For specific aim 2: Pre and post HD levels of endothelin-1 and asymmetric dimethyl arginine will be measured in addition to mid week non-HD day flow mediated dilation and endothelium independent vasodilation. For specific aim 3: Subjects with IH will be started on carvedilol after all baseline measurements are taken. After 8 weeks of carvedilol therapy, including 4 weeks after titration up to 50 mg twice daily, all measurements from Aims 1 and 2 will be repeated. Establishing an association of IH with ECD and arterial stiffness can prompt efforts to explore the possible causal relationships. Additionally, results from the effects of carvedilol on IH may propagate randomized, controlled trials to determine if improvements in endpoints such as CV or all cause mortality are attainable. The relevance of this information could eventually be extended to more general populations such as pre-HD chronic kidney disease patients or patients without kidney disease, but with elevated arterial stiffness or ECD. The applicant will be supervised by a sponsor and co-sponsor during the program. The applicant will be involved in every step of the project from recruitment to manuscript writing. In addition to gaining clinical research skills, the applicant will be learning the techniques of measuring ABP, PWV, and FMD. Additionally, the applicant will be enrolled in courses in pursuit of a Masters Degree in Clinical Sciences. All activities are aimed towards the applicant gaining knowledge and experience in clinical research to pursue a more independent level of involvement in a research career. PUBLIC HEALTH RELEVANCE: End stage renal disease patients on hemodialysis are at higher risk for cardiovascular disease and death than the general population. Among hemodialysis patients, those whose blood pressure increases during hemodialysis carry a higher risk for poor outcomes. The present study investigates if poor blood vessel health is related to blood pressure increases during dialysis and whether treatment with a specific blood pressure lowering medication helps prevent these blood pressure elevations.