The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR) A New Paradigm for Rigorous, Accurate, and Reproducible Evaluation of Putative Infarct-Sparing Interventions in Mice, Rabbits, and Pigs
The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR) A New Paradigm for Rigorous, Accurate, and Reproducible Evaluation of Putative Infarct-Sparing Interventions in Mice, Rabbits, and Pigs
复制标题
DOI：
10.1161/circresaha.116.305462
复制
发表时间：
2015-02-13
影响因子：
20.1
通讯作者：
Bolli, Roberto
中科院分区：
文献类型：
--
作者：
Jones, Steven P.;Tang, Xian-Liang;Bolli, Roberto
基本原理：尽管40年的努力和大量的财政投资，心脏保护领域未能提供一个单一的药物，有效地减少患者的心肌梗死面积。一个主要原因是临床前研究的严谨性和可重复性不足。目的：建立一个多中心、随机、对照、类似临床试验的基础设施，对心脏保护疗法进行严格和可重复的临床前评价。方法和结果：在国家心脏、肺和血液研究所的支持下，我们建立了心脏保护治疗临床前评估联盟（CAESAR），基于随机化、研究者设盲、先验样本量确定和排除标准、适当的统计分析和重现性评估的原则。为了验证CAESAR，我们测试了缺血预处理减少3个物种（2个部位/物种）的梗死面积的能力：小鼠（每组n = 22 - 25），兔（每组n = 11 - 12）和猪（每组n = 13）。在此验证阶段，（1）我们建立了研究方案，在各中心之间得出相似的结果，并证实缺血预处理显著降低了所有物种的梗死面积;（2）我们成功建立了一个多中心结构，以支持CAESAR的操作，包括每个物种的2个外科中心，一个病理学核心（评估梗死面积），生物标志物核心（测量血浆心肌肌钙蛋白水平）和数据协调中心-所有这些都由外部方案审查和监测委员会监督。CAESAR是可操作的，产生可重复的结果，可以检测心脏保护，并提供了一种机制，用于评估潜在的梗死保留疗法，其严格程度类似于多中心，随机，对照临床试验。这是一种革命性的心脏保护新方法。重要的是，我们提供了最先进的，详细的协议（“CAESAR协议”），用于测量小鼠，兔和猪的梗死面积的方式是严格的，准确的，可重复的。
Rationale: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies.Objective: To develop a multicenter, randomized, controlled, clinical trial-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies.Methods and Results: With support from the National Heart, Lung, and Blood Institute, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning to reduce infarct size in 3 species (at 2 sites/species): mice (n=22-25 per group), rabbits (n=11-12 per group), and pigs (n=13 per group). During this validation phase, (1) we established protocols that gave similar results between centers and confirmed that ischemic preconditioning significantly reduced infarct size in all species and (2) we successfully established a multicenter structure to support CAESAR's operations, including 2 surgical centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center-all with the oversight of an external Protocol Review and Monitoring Committee.Conclusions: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter, randomized, controlled clinical trials. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of-the-art, detailed protocols ("CAESAR protocols") for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible.