Systemic Endothelial Consequences of Periodontal Disease

描述（由申请人提供）：流行病学研究表明，患有严重牙周病的个体患心血管疾病的风险显著增加。牙周病是牙龈的慢性细菌感染，与复发性菌血症和全身性炎症状态相关，全身性炎症状态可将内皮细胞转化为促动脉粥样硬化表型，伴有炎症因子表达增加和内皮的抗血栓形成、生长抑制和血管扩张特性丧失，包括一氧化氮生物活性降低。在人类受试者中，内皮功能障碍已发展成为公认的早期动脉粥样硬化指标和心血管疾病风险增加的预测因子。我们最近在一项健康人受试者的病例对照研究中证明了严重牙周病和内皮血管功能障碍之间的密切联系。在这项研究中，牙周病也与急性期反应物C反应蛋白（CRP）的血浆水平较高有关。这些结果支持这一假设，即严重的牙周病诱导的全身炎症状态，损害内皮功能，然而，横截面设计留下了开放的可能性，混淆因素解释的结果。我们现在建议在一项随机干预研究中确定牙周病的有效治疗是否能改善内皮功能（目标1）和减少炎症（目标2）。患者将接受全面的牙周治疗，旨在产生牙周健康的状态（刮治和根规划和牙周手术，根据需要进行再治疗）或常规口腔卫生，并将随访24周。该研究将检查治疗前后的内皮依赖性肱动脉血流介导的扩张、炎症和内皮活化的全身标志物（CRP、IL-6、髓过氧化物酶和ICAM-1）以及牙周炎的口腔标志物（PGE 2、髓过氧化物酶和病原体DNA）。与口腔卫生（这将稳定，但不能逆转牙周病）相比，我们假设牙周病的综合治疗将改善内皮依赖性扩张，减少局部和全身炎症。此外，我们认为内皮功能的改善程度与炎症特异性标志物的减少程度有关。这些结果将为牙周病、全身性炎症和内皮功能障碍（公认的心血管风险替代品）之间的因果关系提供更有力的证据。拟议的研究将为牙周病如何导致人类受试者的心血管疾病风险提供新的见解，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Epidemiological studies indicate that individuals with severe periodontal disease have significantly increased risk for cardiovascular disease. Periodontal disease, a chronic bacterial infection of the gums, is associated with recurrent bacteremia and a state of systemic inflammation that may convert endothelial cells to a pro-atherogenic phenotype with increased expression of inflammatory factors and loss of the anti-thrombotic, growth inhibitory, and vasodilator properties of the endothelium, including a decrease in the biological activity of nitric oxide. In human subjects, endothelial dysfunction has evolved into a well accepted indicator of early atherosclerosis and predictor of increased cardiovascular disease risk. We have recently demonstrated a strong association between severe periodontal disease and endothelial vasomotor dysfunction in a case control study of otherwise healthy human subjects. In that study, periodontal disease was also associated with higher plasma levels of the acute phase reactant C-reactive protein (CRP). These results support the hypothesis that severe periodontal disease induces a state of systemic inflammation that impairs endothelial function, however, the cross-sectional design leaves open the possibility that confounding factors explain the results. We now propose to determine whether effective treatment of periodontal disease improves endothelial function (Aim 1) and reduces inflammation (Aim 2) in a randomized intervention study. Patients will receive comprehensive periodontal treatment designed to produce a state of periodontal health (scaling and root planning and periodontal surgery with re-treatment as needed) or routine oral hygiene and will be followed for 24 weeks. The study will examine endothelium-dependent brachial artery flow-mediated dilation, systemic markers of inflammation and endothelial activation (CRP, IL-6, myeloperoxidase, and ICAM-1), and oral markers of periodontitis (PGE2, myeloperoxidase, and pathogen DNA) before and after treatment. Compared to oral hygiene (which will stabilize, but not reverse periodontal disease), we hypothesize that comprehensive treatment of periodontal disease will improve endothelium-dependent dilation and reduce local and systemic inflammation. Further, we suggest that the degree of improvement in endothelial function will relate to the degree of reduction in specific markers of inflammation. Such results would provide much stronger evidence for causal links between periodontal disease, systemic inflammation, and endothelial dysfunction, a recognized surrogate for cardiovascular risk. The proposed studies will provide new insights into how periodontal disease contributes to cardiovascular disease risk in human subjects and may lead to new approaches to therapy.