Biomarkers of Sudden Death and Progressive Heart Failure

描述（由申请人提供）： 总结/摘要：本申请涉及挑战领域（03）生物标志物发现和验证以及特定挑战主题03-HL-101*：识别和验证血液、血管、心脏和呼吸道功能障碍诊断和治疗反应的临床相关、可量化生物标志物。心力衰竭（HF）仍然是西方国家发病率和死亡率的主要原因，仅在美国就影响超过500万人。HF患者有主要死于心源性猝死（SCD）或进行性泵衰竭的风险。本提案的总体目标是开发转录组学（mRNA和miR）生物标志物，以帮助在一组根据其低LV射血分数被认为具有SCD和HF高风险的患者中鉴定真正具有（a）SCD和（B）HF恶化高风险的患者。诊断为HF的患者预后差，目前用于预测临床病程和评估SCD风险或总体死亡率的方法有限。左心室射血分数<35%的患者致命性心律失常和SCD的一线治疗是使用植入式心律转复除颤器（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;它们需要为每个挽救生命的设备植入10个以上的ICD。器械植入的高成本和手术危害限制了预防性ICD在高风险人群中的使用，而绝大多数SCD发生在低风险患者中。同样，尽管射血分数很低，但一些HF患者会频繁发生心脏失代偿，需要昂贵的住院治疗，而其他患者在随访期间临床上保持稳定。识别心脏失代偿高风险的心力衰竭患者是非常可取的，因为疾病和复杂病例管理计划已证明对这些患者的死亡率，生活质量和住院时间有积极影响。有大量文献表明，炎症过程有助于HF的病理生理学和SCD相关的血管生成。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，因此本提案的目的是开发基于PBMC基因表达谱的转录组学生物标志物，以识别SCD和HF恶化的高风险患者。本研究将利用约翰霍普金斯大学一项成熟的正在进行的前瞻性队列研究的优势：ICD前瞻性观察性研究（PROSE-ICD）是一项对1200例缺血性和非缺血性心肌病（射血分数<35%）患者进行的队列研究，这些患者接受ICD植入术以进行SCD的一级预防。对于所有PROSE-ICD患者，血液样本和广泛的临床和实验室信息是可用的。PROSE-ICD研究中的患者招募正在进行中，从而允许对基因组分类器和新的差异表达转录物进行前瞻性验证。该方案的独特优势如下：1.定期随访（每6个月）的广泛表型HF人群;长期随访数据可用（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稳定化系统（PAXgeneTM）4。MIAME-compliant数据分析5.连续血液样品允许纵向分析以测试基因组分类器随时间的稳定性6。初始血液分子特征将在HF患者的独立队列中验证，因为PROSE-ICD研究的招募正在进行中。每年约翰霍普金斯机构在马里兰州直接产生约100亿美元的经济活动，比2002年产生的70亿美元增加43%，相当于该州经济中每24美元中的一个。2008年，约翰霍普金斯机构提供了45，000个工作岗位，自2002年以来每年创造700个新工作岗位。约翰霍普金斯学院直接和间接地为马里兰州提供了10万多个工作岗位，是该州每29个工作岗位中的一个。仅在巴尔的摩市，约翰·霍普金斯大学就直接和间接支持了60，000个就业岗位，占该市所有就业岗位的16.7%。此应用程序将创建或保留三个工作。 公共卫生相关性：仅在美国就有500多万人患有晚期心脏病，猝死的风险增加。该提案的目标是双重的：提高对易患猝死和进行性心力衰竭的生物学机制的理解，并开发实用的基因表达生物标志物面板，以识别具有最大猝死风险和因心力衰竭再住院的植入心脏起搏器的患者。

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.