Neurohormonal Activation in Scleroderma-Related Pulmonary Arterial Hypertension

描述(申请人提供)：肺动脉高压(PAH)是一种进行性肺血管疾病，可导致右心衰竭和死亡。虽然针对PAH患者肺血管的新疗法改善了特发性PAH患者的生活质量、功能能力和生存率，但这些疗法对与硬皮病相关的PAH(PAH-SSC)的影响有限。对治疗的反应出现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，但对于其在PAH和右心衰竭的病理生理学中的潜在作用，尤其是与PAH-SSC相关的作用，却鲜有人关注。硬皮病患者有潜在的自主神经功能障碍，这可能使他们倾向于更迅速地进展到右心衰竭和死亡的临床过程。此外，与IPAH相比，PAH-SSC患者左心疾病的患病率更高，这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，该组患者对治疗的反应和生存率下降的差异。因此，我们提出了一项针对PAH-SSc和IPAH患者的前瞻性队列研究，以解决三个特定的目标(SA)。在SA‘1中，我们将通过1)测量神经激素轴的血清标记物；2)测量心率变异性；以及3)评估右室活检的NHA基因表达谱，来定义NHA在IPAH和PAH-SSC中的不同之处。在SA#2中，我们将确定这两组之间NHA的差异是否可以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、先前被证明在左心衰竭中具有临床重要性的选定单倍型基因与PAH类型(IPH与PAH-SSC)及其与生存的关系的关联。拟议研究的完成，以及在出色和支持性的临床研究环境中的补充培训和指导，将确保首席研究员深入了解临床研究的设计、实施和分析。这些经验将使首席研究人员能够发展成为能够在学术医学领域追求成功职业生涯的个人。相关性(见说明)；PAH相关硬皮病的存活率比IPAH差。这种存活率差异的原因尚不清楚，但可能与心脏对压力的夸大反应有关。之前对心力衰竭患者的研究表明，对心脏压力的反应决定了疾病的严重性和存活率，并可能被特定的药物改变。我们认为，与硬皮病MAV相关的PAH参与了类似的机制，解释了它们较低的存活率，并有可能通过Ttheraov进行修改。(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)