Libman-Sacks Endocarditis and NPSLE

描述（由申请人提供）：背景。Libman-Sacks心内膜炎伴植被是系统性红斑狼疮（SLE）中最严重的心脏病。神经精神性SLE （NPSLE）包括中风和短暂性脑缺血。发作与发病率和死亡率增加有关。我们发表的数据表明：1)35%的SLE患者通过经食管超声心动图（TEE）检测到Libman-Sacks或血栓性植被；2) 60%的患者受NPSLE影响。我们对37例SLE患者的初步数据表明：1)27例（73%）患者有NPSLE；2) MRI表现为脑梗死14例（38%）；3) TEE检出瓣膜植被22例（59%），以二尖瓣为主（82%）；4) NPSLE患者脑梗死发生率高于非NPSLE患者（48% vs. 10%, p = 0.056）；5) NPSLE患者的二尖瓣植被比非NPSLE患者更常见（63% vs. 10%, p = 0.008）；最重要的是，6)二尖瓣植被是NPSLE最强的独立预测因子（比值比15.3,95% Cl 1.7 - 139, p = 0.005）。因此，由瓣膜植被引起的血栓栓塞可能是NPSLE的主要原因。假设：瓣膜植被产生大栓塞和微栓塞，阻塞中小脑血管，导致灌注改变，缺血性脑损伤和NPSLE。实验。这是一项前瞻性对照横断面和纵向研究，以确定瓣膜植被作为NPSLE的主要原因的作用。患者将从我们的SLE队列437名受试者中招募。在横断面阶段，31例新发或复发性NPSLE患者，31例无NPSLE患者和20例年龄和性别匹配的对照组将接受：1)TEE检测瓣膜植被；2)经颅多普勒检测微栓子；3)颈动脉双相评估颈动脉内膜-中膜厚度和颈动脉斑块；4)评估SLE和NPSLE的活动性和严重程度；5)神经精神测试；6)通过测定抗磷脂抗体、凝血酶原片段1.2、凝血酶-抗凝血酶III复合物和血小板聚集来评估凝血和血小板活化；7)颅脑MRI、弥散加权成像、灌注加权成像评价脑损伤及脑灌注情况。在48个月的纵向期，1)NPSLE患者处于缓解期；2)新发或复发性NPSLE患者将接受重复的临床、心血管和脑成像评估，以进一步确定植被与微栓子、脑损伤和NPSLE的时间相关性。的意义。这种综合的心血管-脑成像方法提供了一个强大的实验设计，将证明瓣膜植被与微栓子、缺血性脑损伤以及NPSLE的产生之间的因果关系。这些发现将确定：1)心脏栓塞是NPSLE的主要原因；2)瓣膜疾病和NPSLE诊断新策略；3)为未来的选择性抗血栓、抗凝或抗炎治疗试验提供科学依据，以防止瓣膜植被和NPSLE的进展和复发。

DESCRIPTION (provided by applicant): Background. Libman-Sacks endocarditis with vegetations is the most serious heart disease of systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) which includes stroke and transient ischemic .attacks is associated with increased morbidity and mortality. Our published data demonstrate that: 1) Libman-Sacks orthrombotic vegetations are detected by transesophageal echocardiography (TEE) in 35% of SLE patients; and 2) NPSLE affects 60% of patients. Our preliminary data in 37 patients with SLE demonstrate that: 1) 27 patients (73%) had NPSLE; 2) 14 (38%) had cerebral infarcts on MRI; 3) 22 (59%) had valve vegetations detected by TEE, mostly on the mitral valve (82%); 4) cerebral infarcts were more common in patients with than without NPSLE (48% vs. 10%, p = 0.056); 5) mitral valve vegetations were more common in patients with than without NPSLE (63% vs. 10%, p = 0.008); and of most importance, 6) mitral valve vegetations were the strongest independent predictor of NPSLE (odds ratio 15.3, 95% Cl 1.7 - 139, p = 0.005). Thus, thromboembolism from valve vegetations is likely a major cause of NPSLE. Hypothesis: Valve vegetations generate macro- and microemboli that occlude the medium and small cerebral vessels resulting in altered perfusion, ischemic brain injury, and NPSLE. Experimental. This is a prospective controlled cross-sectional and longitudinal study to determine the role of valve vegetations as a major cause of NPSLE. Patients will be recruited from our SLE cohort of 437 subjects. During the cross-sectional phase, 31 subjects with new or recurrent NPSLE, 31 subjects without NPSLE, and 20 age and sex matched controls will undergo: 1) TEE to detect valve vegetations; 2) transcranial Doppler for detection of microemboli; 3) carotid duplex to assess intimal-media thickness and carotid plaques; 4) assessment of SLE and NPSLE activity and severity; 5) neuropsychiatric testing; 6) assessment of coagulation and platelet activation by measurement of antiphospholipid antibodies, prothrombin fragments 1.2, thrombin-antithrombin III complexes, and platelet aggregation; and 7) cranial MRI, diffusion weighted imaging and perfusion weighted imaging for assessment of brain injury and cerebral perfusion. During the longitudinal phase of 48 months, 1) subjects with NPSLE in the remission phase; and 2) subjects with new or recurrent NPSLE will undergo repeat clinical, cardiovascular and cerebral imaging evaluations to further determine a temporal association of vegetations with microemboli, brain injury, and NPSLE. Significance. This integrated cardiovascular-brain imaging approach provides a powerful experimental design that will demonstrate a causal relationship of valve vegetations to the generation of microemboli, ischemic brain injury, arid thus, NPSLE. These findings will establish: 1) cardioembolism as a major cause of NPSLE; 2) new strategies for the diagnosis of valve disease and NPSLE; and 3) the scientific basis for a future trial of selective antithrombotic, anticoagulant, or anti-inflammatory therapy to prevent the progression and recurrence of valve vegetations and NPSLE.