Pulmonary Microvascular Blood Flow and Cor Pulmonale Parvus in Emphysema/COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是全球和美国的第三大死亡原因。超过一半的COPD患者在计算机断层扫描中有肺气肿，这与死亡率增加有关，但COPD的药物治疗只针对呼吸道。多种族动脉粥样硬化(MESA)COPD研究招募了327名参与者来检验肺气肿的内皮假说，该假说认为吸烟相关的肺内皮损伤导致肺气肿。MESA COPD研究证实了其主要目标：磁共振成像(MRI)上的肺微血管血流量(PMBF)大幅减少；COPD和各种严重程度的肺气肿；内皮细胞微粒增加，内皮祖细胞减少；外周血单个核细胞中的基因表达与PMBF密切相关。虽然支持内皮假说，但新发现也可能是由于新描述的异常缺氧性肺血管收缩(HPV)或因换气障碍而残留的HPV。我们还发现COPD和肺气肿患者的右室(RV)容量减少，我们称之为肺心病。试点数据表明，这种情况与普通人群中的全因死亡有关，并可能导致 由于右室僵硬和轻微的呼吸障碍。此次更新是MESA COPD研究的纵向延续，在该研究中，我们旨在使用氧分压、通气量、PMBF和肺气肿的区域性测量方法，以及逆转HPV和治疗恶性通货膨胀的干预措施，以及MRI上的RV功能和静脉血流的创新测量方法，以验证以下假设：肺气肿的特征是独立于HPV和呼吸障碍的PMBF降低；微小肺心病与RV僵硬和胸腔内压力增加有关；以及肺非气肿区域的PMBF减少与五年后肺气肿的局部发展和组织丢失有关。这项建议的创新方面包括使用与临床直接相关的新的MRI成像模式，检查一种新的实体--肺心病，以及对人类肺气肿的血管假说进行纵向测试。这些目标的确认将导致COPD治疗的范式转变，以证明现有的和新的(例如，EPC/干细胞)疗法针对肺气肿的肺血管系统的测试是合理的，提供一个潜在的成像生物标记物，促进此类疗法的早期、短期临床试验，并提出接近和可能治疗肺源性微小肺病的机制。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and in the United States. More than half of COPD patients have emphysema on computed tomography, which is associated with increased mortality, but medical therapies for COPD exclusively target the airways. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 327 participants to test the endothelial hypothesis of emphysema, which posits that smoking-related pulmonary endothelial damage contributes to emphysema. The MESA COPD Study confirmed its primary aims that: pulmonary microvascular blood flow (PMBF) on magnetic resonance imaging (MRI) is substantially reduced COPD and emphysema of all severities; endothelial microparticles are increased and endothelial progenitor cells are reduced; and gene expression in peripheral blood mononuclear cells is strongly linked to PMBF. Although supportive of the endothelial hypothesis, findings also may be due to newly described aberrant hypoxic pulmonary vasoconstriction (HPV) or residual HPV from impaired ventilation. We also found that right ventricular (RV) volumes were reduced in COPD and emphysema, a condition we have termed cor pulmonale parvus. This condition is associated with all-cause mortality in the general population and might result, pilot data suggest, from RV stiffness and subtle ventilatory impairment. The renewal is a longitudinal continuation of the MESA COPD Study in which we aim to use regional measures of oxygen tension, ventilation, PMBF and emphysema, along with interventions to reverse HPV and to treat hyperinflation, and innovative measures of RV function and venous blood flow on MRI to test the hypotheses that: emphysema is characterized by reduced PMBF independent of HPV and ventilatory impairment; cor pulmonale parvus is associated with RV stiffness and increased intrathoracic pressure; and reduced PMBF in non-emphysematous regions of the lung is associated with the local development of emphysema and tissue loss at five years. Innovative aspects of this proposal include the use of novel MRI imaging modalities of direct clinical relevance, examination of a new entity, cor pulmonale parvus, and the longitudinal testing of the vascular hypothesis of emphysema in humans. Confirmation of these aims would create a paradigm shift in COPD treatment to justify the testing of existing and novel (e.g., EPC/stem cell) therapies targeted to the pulmonary vasculature in emphysema, provide a potential imaging biomarker to facilitate early phase, short-term clinical trials of such therapies, and suggest mechanisms to approach and possibly treat cor pulmonale parvus.