Biomarkers of Sudden Death and Progressive Heart Failure

描述(由申请人提供)： 摘要/摘要：本申请涉及挑战领域(03)生物标记物的发现和验证以及具体的挑战主题03-HL-101*：识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标记物。心力衰竭仍然是西方国家发病率和死亡率的主要原因，仅在美国就有500多万人受到影响。心力衰竭患者有主要死于心脏性猝死(SCD)或进行性泵衰竭的风险。这项建议的总体目标是开发转录(mRNA和miR)生物标记物，以帮助识别真正处于(A)SCD和(B)心力衰竭恶化风险的患者，这些患者被认为是SCD和HF的高风险患者，因为他们的左心室射血分数较低。被诊断为心力衰竭的患者预后很差，目前用于预测临床病程和评估SCD风险或总死亡率的方法有限。对于左心室射血分数<35%的致命性心律失常和SCD患者的一线治疗是使用植入型心律转复除颤器(ICD)。然而，这一策略反映了当前对SCD理解的主要局限性，因为现有的风险分层算法(主要基于射血分数)既不敏感也不特异；它们要求为每个挽救生命的装置植入10个以上的ICD。装置植入的高成本和程序风险限制了预防性ICD的使用，仅限于高危人群，而绝大多数SCD发生在低风险患者中。同样，尽管射血分数相对较低，但一些心衰患者出现频繁的心脏失代偿发作，需要昂贵的住院治疗，而另一些患者在随访期间临床上保持稳定。确定心力衰竭患者具有心脏失代偿的高风险是非常可取的，因为疾病和复杂的病例管理计划已经证明对这些患者的死亡率、生活质量和住院时间有积极作用。有大量的文献表明，炎症过程对心力衰竭的病理生理和与SCD相关的心律失常的发生都有贡献。由于外周血单个核细胞(PBMC)在免疫和炎症中起着至关重要的作用，本研究的目的是开发一种基于PBMC基因表达谱的转录生物标志物，以识别SCD和恶化的HF的高危患者。这项研究将利用约翰·霍普金斯大学正在进行的一项成熟的前瞻性队列研究的优势：ICD的前瞻性观察研究(PROSE-ICD)是一项针对1200名缺血性和非缺血性心肌病患者的队列研究，这些患者接受了ICD植入术以一级预防SCD。对于所有散文型ICD患者，都可以获得血液样本和广泛的临床和实验室信息。患者在散文-ICD研究中的登记正在进行中，从而允许对基因组分类器和新的差异表达转录本进行前瞻性验证。这一建议的独特优势是：1.广泛表型的HF人群，定期随访(每6个月一次)；可获得长期随访数据(长达5年)2.血液样本可立即用于分析3.严格的研究设计和标准化包括FDA批准的全血采集和RNA稳定系统(PAXgene TM)4.符合MIAME的数据分析5.系列血液样本允许进行纵向分析，以测试基因组分类器随时间推移的稳定性6.初始血液分子签名将在HF患者的独立队列中得到验证，因为每年都在进行加入散文-ICD研究，约翰霍普金斯大学的机构在马里兰州直接创造了约100亿美元的经济活动，比2002年的70亿美元增长了43%，相当于今天该州经济每24美元中就有1美元。2008年，约翰霍普金斯大学提供了4.5万个工作岗位，自2002年以来，每年创造700个新工作岗位。约翰霍普金斯大学的机构直接和间接地支持了马里兰州10万多个工作岗位，该州每29个工作岗位中就有一个。仅在巴尔的摩市，约翰斯·霍普金斯就直接和间接支持了60,000个工作岗位，占整个城市就业人数的16.7%。此应用程序将创建或保留三个工作岗位。 与公共卫生相关：仅在美国就有500多万人患有晚期心脏病，猝死的风险增加。这项建议的目标有两个：加强对易导致猝死和进行性心力衰竭的生物学机制的了解，并开发一种实用的基因表达生物标记物小组，以确定植入除颤器的患者具有最大的猝死和心力衰竭再住院风险。

DESCRIPTION (provided by applicant): Summary/Abstract: This application addresses Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101*: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Heart failure (HF) remains a leading cause of morbidity and mortality in Western countries, affecting more than 5 million people in the United States alone. HF patients are at risk of dying primarily of sudden cardiac death (SCD) or progressive pump failure. The overall goals of this proposal are to develop transcriptomic (mRNA and miR) biomarkers to aid identification of patients that are truly at high risk of (a) SCD and (b) worsening HF among a group of patients that is considered to be at a high risk for SCD and HF based on their low LV ejection fraction. The prognosis of patients diagnosed with HF is poor and current methods used to predict the clinical course and assess risk of SCD or overall mortality are limited. The frontline management of lethal arrhythmias and SCD in patients with a left ventricular ejection fraction <35% is the use of the implantable cardioverter defibrillator (ICD). However, this strategy reflects major limitations in the current understanding of SCD, as existing risk-stratification algorithms (based largely on ejection fraction) are neither sensitive nor specific; they require implantation of more than 10 ICDs for every device that saves a life. The high cost and procedural hazards of device implantation limit the use of prophylactic ICDs to high-risk populations, while the overwhelming majority of SCDs occur in lower- risk patients. Likewise, despite comparably low ejection fractions, some HF patients develop frequent episodes of cardiac decompensation that require costly hospitalizations, while others remain clinically stable during follow-up. Identifying heart failure patients at high-risk of cardiac decompensation is highly desirable, as disease and complex case management programs have demonstrated positive effects on mortality, quality of life, and length of hospitalization in these patients. There is an extensive body of literature to suggest that inflammatory processes contribute to both the pathophysiology of HF and arrhythmogenesis associated with SCD. As peripheral blood mononuclear cells (PBMC) have crucial roles in immunity and inflammation, the objectives of this proposal are to develop a transcriptomic biomarker based on gene expression profiling of PBMC in order to identify patients at high risk for SCD and worsening HF. This study will leverage the strengths of a well-established ongoing prospective cohort study based at the Johns Hopkins University: The PRospective Observational Study of ICD (PROSE-ICD) is a cohort study of 1200 patients with ischemic and non-ischemic cardiomyopathy (ejection fraction <35%) undergoing ICD implantation for primary prevention of SCD. For all PROSE-ICD patients, blood samples and extensive clinical and laboratory information are available. Enrollment of patients in the PROSE-ICD study is ongoing, thus allowing for prospective validation of genomic classifiers and novel differentially expressed transcripts. The unique strengths of this proposal are as follows: 1. Extensively phenotyped HF population with regular follow-up (every 6 months); long-term follow- up data are available (up to 5 years) 2. Blood samples are immediately available for analysis 3. Rigorous study design and standardization includes an FDA-approved system for whole blood collection and RNA stabilization (PAXgeneTM) 4. MIAME-compliant data analysis 5. Serial blood samples permit longitudinal analysis to test stability of genomic classifiers over time 6. Initial blood molecular signatures will be validated in independent cohorts of HF patients, as enrollment into the PROSE-ICD study is ongoing Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly, Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create or retain three jobs. PUBLIC HEALTH RELEVANCE: More than 5 million people in the United States alone have advanced heart disease with an increased risk of dying suddenly. The objectives of this proposal are two-fold: to enhance understanding of the biological mechanisms that predispose to sudden death and progressive heart failure and to develop a practical gene expression biomarker panel to identify patients with implanted defibrillators at greatest risk of sudden death and rehospitalizations for heart failure.