Extrapulmonary Microvascular Dysfunction in Pulmonary Arterial Hypertension

肺动脉高压的肺外微血管功能障碍

基本信息

批准号：
9917808
负责人：
ADRIANO TONELLI
金额：
$ 39.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917808
关键词：
Acetylcholine Age American Biological Markers Blood Circulation Blood Platelets Blood Vessels Cardiac Catheterization Procedures Cessation of life Chest Cutaneous Data Defect Diagnostic Disease Epoprostenol Etiology Financial cost Forearm Heart failure Hospitals Hypersensitivity skin testing Investigation Iontophoresis Knowledge Laser-Doppler Flowmetry Lasers Lead Link Lung Methodology Microcirculation Microvascular Dysfunction National Heart, Lung, and Blood Institute Nitric Oxide Nitric Oxide Pathway Nitric Oxide Signaling Pathway Pathway interactions Patients Pharmaceutical Preparations Phenotype Plasma Prediction of Response to Therapy Progressive Disease Prostaglandins I Pulmonary Circulation Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Research Role Selection for Treatments Signal Pathway Skin Societies Soluble Guanylate Cyclase Stimulus Strategic Planning Testing Therapeutic Time Treprostinil Variant Vascular Diseases analog base convict hypertension treatment in vivo in vivo evaluation individual patient individualized medicine inhaled nitric oxide inhibitor/antagonist innovation novel novel strategies patient oriented personalized diagnostics personalized medicine phosphodiesterase V predicting response pressure primary pulmonary hypertension pulmonary arterial hypertension response tool treatment center vasoactive agent vasoconstriction

项目摘要

ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive disease that can lead to right heart failure and death. This devastating disease poses a large financial impact, since medications are expensive and most patients die in a hospital setting. Currently, there are limited biomarkers to help understand the pathobiology of the disease and no mechanistic tools to guide treatment selection. We know little on the interaction between the pulmonary and extrapulmonary vasculatures. Based on our preliminary data, we hypothesize that: (i) the extrapulmonary (cutaneous) microvasculature in IPAH will provide a non-invasive approach of assessing the pulmonary circulation and allow us to test major putative signaling pathways; (ii) defects may manifest at different points along the nitric oxide (NO) and prostacyclin (PGI2) signaling pathways in IPAH patients, and contribute to the extrapulmonary microvascular dysfunction. Aim 1: To study the link between the pulmonary and extrapulmonary circulations and identify the mechanisms involved in the extrapulmonary vascular dysfunction in IPAH. Aim 2: To challenge the extrapulmonary microvasculature in patients with IPAH to predict response to therapy. Our preliminary data, obtained at the time of the diagnostic right heart catheterization, demonstrated a global vascular involvement in IPAH and suggested that the pulmonary and extrapulmonary circulations have a uniform response to vasoactive challenges. We found an association between abnormalities of the NO pathway in plasma and platelets of patients with IPAH and the cutaneous microvascular response to vasoactive agents. The responses to acetylcholine (tests the NO pathway) and treprostinil (tests the PGI2 pathway) iontophoresis predict long-term response to phosphodiesterase-5 inhibitors and PGI2 analogues, respectively. We identified 3 phenotypes of IPAH patients based on the response to vasoactive agents. We propose to test the reactivity of the pulmonary circulation to inhaled NO, the response of the extrapulmonary microvasculature to vasoactive stimuli that challenge the NO and PGI2 pathways, and determine the expression and activity of soluble guanylate cyclase in platelets of IPAH patients. These tests will allow us to phenotype IPAH patients based on the putative mechanisms of the disease; a critical need as expressed in the NHLBI-strategic plan for lung vascular research. The results of this novel proposal will advance the understanding of the pathobiology of IPAH, define the link between the pulmonary and extrapulmonary circulations and predict response to PAH-specific therapies. The in-vivo testing of the NO and PGI2 pathways will help guide PAH treatment based on mechanistic data. It is our conviction that this innovative and non-invasive approach has the potential to revolutionize the way we currently manage and treat this ominous disease.

抽象的肺动脉高压（PAH）是一种进行性疾病，可以导致右心力衰竭和死亡。这种毁灭性疾病会产生巨大的财务影响，因为药物很昂贵，而且大多数患者在医院环境中死亡。目前，生物标志物有限，可以帮助了解该疾病和没有指导治疗选择的机械工具。我们对之间的互动知之甚少肺和肺外血管。根据我们的初步数据，我们假设：（i） IPAH中的肺外（皮肤）微脉管系统将提供一种无创的方法来评估肺循环，使我们能够测试主要的推定信号通路；（ii）缺陷可能表现为一氧化氮（NO）和前列环蛋白（PGI2）信号通路的不同点，以及有助于肺外微血管功能障碍。目标1：研究肺之间的联系和肺外循环，并确定肺外血管所涉及的机制 IPAH功能障碍。目标2：挑战IPAH患者的肺外微脉管系统以预测对治疗的反应。我们在诊断右心导管插入时获得的初步数据证明了一个全球血管参与IPAH，并建议肺和肺外循环具有对血管活性挑战的统一反应。我们发现NO的异常之间存在关联 IPAH患者血浆和血小板的途径以及皮肤微血管反应血管活性剂。对乙酰胆碱的反应（测试NO途径）和Treprostinil（测试PGI2 途径）离子噬菌体预测对磷酸二酯酶5抑制剂和PGI2类似物的长期反应，分别。我们根据对血管活性剂的反应确定了IPAH患者的3种表型。我们建议测试肺循环对吸入NO的反应性，挑战NO和PGI2途径的血管活性刺激的肺外微脉管系统，以及确定IPAH患者血小板中可溶性鸟苷酸环化酶的表达和活性。这些测试将允许我们根据疾病的推定机制表现出IPAH患者；迫切需要在肺血管研究的NHLBI战略计划中表达。这项新建议的结果将提高对IPAH病理生物学的理解，定义肺和肺外循环之间的联系并预测对PAH特异性的反应疗法。 NO和PGI2途径的体内测试将有助于基于PAH治疗机械数据。我们坚信，这种创新和无创的方法有潜力彻底改变了我们目前管理和治疗这种不祥疾病的方式。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Predictors of survival in portopulmonary hypertension: a 20-year experience.

DOI：
10.1097/meg.0000000000002322
发表时间：
2022-04-01
期刊：
European journal of gastroenterology & hepatology
影响因子：
2.1
作者：
Aggarwal M;Li M;Bhardwaj A;Wallace WD;Wang X;Carey WD;Dweik RA;Heresi GA;Tonelli AR
通讯作者：
Tonelli AR

Different efficacy of inhaled and oral medications in pulmonary hypertension.

DOI：
10.1016/j.hrtlng.2017.04.010
发表时间：
2017-07
期刊：
Heart & lung : the journal of critical care
影响因子：
0
作者：
AbuHalimeh BJ;Parambil JG;Tonelli AR
通讯作者：
Tonelli AR

Comparison of volatile organic compound profiles in exhaled breath versus plasma headspace in different diseases.

DOI：
10.1088/1752-7163/ab8866
发表时间：
2020-05-27
期刊：
Journal of breath research
影响因子：
3.8
作者：
Grove D;Miller-Atkins G;Melillo C;Rieder F;Kurada S;Rotroff DM;Tonelli AR;Dweik RA
通讯作者：
Dweik RA

Treatment Barriers in Portopulmonary Hypertension.