Development of an NIH Consortium for PreclinicAl AssESsment of CARdioprotective Therapies (CAESAR): A Paradigm Shift in Studies of Infarct Size Limitation
Development of an NIH Consortium for PreclinicAl AssESsment of CARdioprotective Therapies (CAESAR): A Paradigm Shift in Studies of Infarct Size Limitation
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DOI：
10.1177/1074248411414155
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发表时间：
2011-09-01
影响因子：
2.6
通讯作者：
Bolli, Roberto
中科院分区：
文献类型：
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作者：
Lefer, David J.;Bolli, Roberto
据估计，每年有935000名美国人患有心肌梗死;因为他们的预后是由梗死的大小决定的，所以减小梗死的大小对于降低发病率和死亡率是至关重要的。40年来，美国国家心脏、肺和血液研究所（NHLBI）在临床前研究中投入了大量资源（至少数亿美元），旨在开发梗死保留疗法，并且已经声称有数百种（如果不是数千种）疗法可以限制临床前模型中的梗死面积。不幸的是，主要由于方法问题，这一巨大的投资并没有产生任何显着的临床应用，目前没有心脏保护疗法可用于临床使用。显然，经过40年的徒劳努力，需要一种新的方法来克服阻碍心脏保护疗法转化的问题。现在是将适用于临床试验的科学严谨性标准应用于心脏保护的临床前研究的时候了。根据2003年6月举行的国家心肺血液研究所（NHLBI）主办的研讨会的建议，并利用NHLBI建立的临床试验网络作为开发研究共享合作基础设施的模式，组织了一个临床前联盟，其运作方式类似于临床试验网络。该基础设施已被命名为CAESAR（心脏病保护治疗临床前评估联盟）。在Roberto Bolli的指导下，4个机构（路易斯维尔大学、约翰霍普金斯大学、埃默里大学和弗吉尼亚医学院）将共同开展设盲、随机和充分把握度的研究，使用严格的设计、剂量-反应分析、最佳统计方法、独立的数据分析核心、独立的统计核心、四唑数据与组织学和血浆生物标志物的验证，和相关动物模型（包括清醒动物和合并症模型）。将在3个种属（麻醉小鼠、清醒家兔和清醒猪）中测试治疗。一个主要目标是确保可重复性;为此，每个物种的每个研究将在两个中心使用相同的协议进行。CAESAR的结构将确保该联盟将成为所有感兴趣的研究者可以使用的真正的公共资源，并且所有拟议的研究将以公平的方式进行评估。将向整个科学界征求研究心脏保护疗法的建议。该联盟将免费提供给所有美国国立卫生研究院（NIH）资助的研究人员。这种独特的基础设施将使严格的临床前评估的有前途的心脏保护疗法，并将服务于整个科学界（在学术界和生物医学行业），从而构成一个公共resources.Consortium临床前评估的心脏保护疗法将是一个重大的范式转变心脏保护。通过筛选有前景的疗法，并确定那些在相关实验模型中真正有效的疗法，从而最有可能对患者有效，CAESAR将大大提高我们将基本发现合理转化为临床应用的能力。本文将总结NHLBI CAESAR联盟的基本原理、结构和运作。
An estimated 935 000 Americans suffer a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For 40 years, the National Heart, Lung, and Blood Institute (NHLBI) has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due largely to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use.Clearly, after 40 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research on cardioprotection, the same standards of scientific rigor that are applied to clinical trials. In compliance with the recommendations of an National Heart, Lung, and Blood Institute (NHLBI)-sponsored workshop held in June 2003 and using the clinical trial networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, a preclinical consortium has been organized that will operate in a manner analogous to a clinical trial network. This infrastructure has been named CAESAR (Consortium for preclinicAl assESsment of cARdioprotective therapies). Under the direction of Roberto Bolli, 4 Institutions (University of Louisville, Johns Hopkins, Emory University, and Medical College of Virginia) will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, dose-response analyses, optimal statistical methods, independent data analysis Cores, an independent statistical Core, verification of tetrazolium data with histology and plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities). Therapies will be tested in 3 species (anesthetized mouse, conscious rabbit, and conscious pig). A major goal is to ensure reproducibility; to this end, each study in each species will be performed in 2 centers using identical protocols.The structure of CAESAR will ensure that the consortium will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. Proposals for studying cardioprotective therapies will be solicited from the entire scientific community. The consortium will be available at no cost to all National Institutes of Health (NIH)-funded investigators. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in the academia and in the biomedical industry), thereby constituting a public resource.Consortium for preclinicAl assESsment of cARdioprotective therapies will be a major paradigm shift in cardioprotection. By screening promising therapies and identifying those that are truly effective in relevant experimental models and, thus, most likely to be effective in patients, CAESAR will dramatically advance our ability to rationally translate basic findings into clinical use. This article will summarize the rationale, structure, and operation of the NHLBI CAESAR Consortium.