Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities.

中文翻译：

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心血管不可改变的危险因素、合并症和药物与缺血/再灌注损伤以及药物治疗和缺血调理的心脏保护的相互作用

心肌的预处理、后处理和远程调节增强了心脏承受长期缺血/再灌注损伤的能力，并有可能为心脏保护提供新的治疗范例。虽然过去 30 年的实验研究已经阐明了许多导致内源性心脏保护的信号通路，但市场上还没有针对该适应症的心脏保护药物。未能将心脏保护转化为患者利益的一个可能主要原因是在临床评估之前缺乏对有前景的心脏保护疗法的严格和系统的临床前评估，因为人类缺血性心脏病是一种由心血管危险因素引起或与之相关的复杂疾病和合并症。这些危险因素和合并症会引起细胞信号级联的根本改变，从而影响缺血/再灌注损伤的发展和对心脏保护干预措施的反应。此外，一些用于治疗这些合并症的药物可能会通过再次改变细胞信号传导途径来影响心脏保护。本文的目的是回顾最近的证据，表明心血管危险因素以及合并症及其药物可能会改变对心脏保护干预措施的反应。我们强调，在设计用于识别和验证心脏保护药物靶点和临床研究的临床前研究时，迫切需要考虑心血管危险因素以及合并症及其伴随药物的存在。这有望最大限度地提高为大多数患有多种合并症的患者开发合理的有效心脏保护疗法的成功率。