Neurohormonal Activation in Scleroderma-Related Pulmonary Arterial Hypertension

描述（由申请方提供）：肺动脉高压（PAH）是一种肺血管系统的进行性疾病，可导致右心衰竭和死亡。虽然靶向PAH肺血管的新疗法改善了特发性PAH（IPAH）患者的生活质量、功能能力和生存率，但这些疗法对硬皮病相关PAH（PAH-SSc）的影响有限。对治疗反应的这些差异的原因尚不清楚。尽管有大量证据支持神经激素功能障碍在左心疾病所致心力衰竭中的核心作用，但很少有人关注其在PAH和右心衰竭的病理生理学中的潜在作用，特别是在PAH-SSc方面。硬皮病患者有潜在的自主神经功能障碍，这可能使他们更快地进行性右心衰竭和死亡的临床过程。此外，与IPAH相比，PAH-SSc中左心疾病的患病率更高，可能会影响神经激素功能。我们假设PAH-SSc的神经激素激活（NHA）解释了与IPAH患者相比，该组患者对治疗反应的差异和生存率降低。因此，我们提出对PAH-SSc和IPAH患者进行一项前瞻性队列研究，以实现三个特定目标（SA）。在SA '#1中，我们将通过1）测量神经激素轴的血清标志物; 2）测量心率变异性;和3）评估右心室活检的NHA基因表达谱来确定IPAH和PAH-SSc之间的NHA是否不同。在SA#2中，我们将确定这两组之间的NHA差异是否可预测住院和死亡风险。在SA#3中，我们将检测与神经激素轴相关的基因的选择单倍型与PAH型（IPAH vs. PAH-SSc）的相关性，以及它们与生存期的关系，这些基因先前显示在左心衰竭中具有临床重要性。完成拟议的研究，沿着补充培训和指导，在一个优秀的和支持性的环境中进行临床研究，将确保主要研究者获得深入的临床研究设计，实施和分析。这些经验将使主要研究者发展成为一个能够追求成功的职业生涯作为一个独立的研究者在学术医学的个人。相关性（见说明书）; PAH相关硬皮病的生存率比IPAH差。这种生存差异的原因尚不清楚，但可能与心脏对压力的过度反应有关。以前对心力衰竭患者的研究表明，心脏对压力的反应决定了疾病的严重程度和生存率，并且可以通过特定的药物进行调整。我们认为与硬皮病相关的PAH中涉及类似的机制，这可能解释了其生存率低，并且可能通过治疗进行修改。 (End摘要）

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right heart failure and death. While new therapies targeting the pulmonary vasculature in PAH have improved quality of life, functional capacity, and survival in patients with idiopathic PAH (IPAH), these therapies have had limited impact in PAH related to scleroderma (PAH-SSc). The reasons for these differences in response to therapy are unclear. Despite a preponderance of evidence supporting a central role of neurohormonal dysfunction in heart failure due to left heart disease, little attention has been paid to its potential role in the pathophysiology of PAH and right heart failure, particularly with respect to PAH-SSc. Patients with scleroderma have underlying autonomic dysfunction which may predispose them to a more rapidly progressive clinical course to right heart failure and death. Further, the higher prevalence of left heart disease in PAH-SSc compared to IPAH may influence neurohormonal function. We hypothesize that neurohormonal activation (NHA) in PAH-SSc explains differences in response to therapy and decreased survival in this group compared to IPAH patients. Therefore, we propose a prospective cohort study of patients with PAH-SSc and IPAH to address three specific aims (SA). In SA'#1, we will define whether NHA differs between IPAH and PAH-SSc by 1) measuring serum markers ofthe neurohormonal axis; 2) measuring heart rate variability; and 3) assessing NHA gene expression profiles of right ventricular biopsies. In SA#2, we will determine whether differences in NHA between these two groups predict hospitalization and risk of death. In SA#3, we will test for association of select haplotypes of genes relevant to the neurohormonal axis, and previously shown to have clinical importance in left heart failure, with PAH-type (IPAH vs. PAH-SSc) and their relationship to survival. Completion ofthe proposed research, along with complementary training and mentorship within an outstanding and supportive environment for clinical research, will ensure that the principal investigator gains in-depth exposure to clinical research design, conduct, and analysis. These experiences will allow the principal investigator to develop into an individual capable of pursuing a successful career as an independent investigator in academic medicine. RELEVANCE (See instructions); Survival in PAH related scleroderma is worse than in IPAH. The reasons for this survival difference are unclear but may be related to an exaggerated response to stress on the heart. Previous studies of patients with heart failure have shown that the response to stress on the heart determines disease severity and survival and may be modified with specific medications. We believe similar mechanisms are involved in PAH related to scleroderma mav explain their poor survival and can potentially be modified bv theraov. (End of Abstract)