Neurohormonal Activation in Scleroderma-Related Pulmonary Arterial Hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种进行性肺血管疾病，可导致右心衰和死亡。虽然针对肺血管系统的PAH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。这些治疗反应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引起的心力衰竭中起核心作用，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，这可能使他们更容易迅速进展到右心衰和死亡的临床过程。此外，与IPAH相比，PAH-SSc患者左心疾病的患病率较高可能会影响神经激素功能。我们假设PAH-SSc中的神经激素激活（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的降低。因此，我们建议对PAH-SSc和IPAH患者进行前瞻性队列研究，以解决三个具体目标（SA）。在SA'#1中，我们将通过1)测量神经激素轴的血清标志物来确定NHA在IPAH和PAH-SSc之间是否存在差异；2)测量心率变异性；3)评估右心室活检NHA基因表达谱。在SA#2中，我们将确定这两组之间NHA的差异是否预测住院和死亡风险。在SA#3中，我们将测试与神经激素轴相关的基因选择单倍型的关联，这些基因在左心衰中具有临床重要性，与pah型（IPAH vs. PAH-SSc）及其与生存的关系。在临床研究的优秀和支持性环境中完成拟议的研究，以及补充培训和指导，将确保首席研究员获得深入的临床研究设计，实施和分析。这些经历将使首席研究员发展成为一个有能力在学术医学领域追求成功的独立研究者的个人。相关性（见说明书）；PAH相关硬皮病患者的生存率比IPAH患者差。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。先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，并可能通过特定药物加以改变。我们相信与硬皮病相关的多环芳烃存在类似的机制，这可能解释了硬皮病患者生存率低的原因，并可能通过治疗得到改善。（摘要结束）

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)