Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.).
Pharmacol Rev. 2023 Jan;75(1):159-216. doi: 10.1124/pharmrev.121.000348. Epub 2022 Dec 8.
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. SIGNIFICANCE STATEMENT: Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.
预处理、后处理和心肌远程预处理增强了心脏耐受长时间缺血/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。尽管在过去 30 年的实验研究中已经阐明了许多导致内源性心脏保护的信号通路，但尚无用于该适应症的心脏保护药物。造成这种未能将心脏保护转化为患者受益的一个主要原因可能是，在对有前途的心脏保护疗法进行临床评估之前，缺乏对其进行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和合并症引起或与之相关的复杂疾病。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通路来影响心脏保护。本文的目的是回顾最近的证据，即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的临床前研究和临床研究时，迫切需要考虑到心血管危险因素以及合并症及其同时存在的药物的存在。这有望最大程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。
缺血性心脏病是主要的死亡原因；然而，目前市场上仍没有心脏保护药物。大多数心脏保护研究都是在没有合并症的情况下在缺血/再灌注动物模型中进行的；然而，缺血性心脏病是在其他系统性疾病（例如高血压、高血脂、糖尿病、动脉粥样硬化）的情况下发展的。在这里，我们重点介绍临床前和临床证据，这些证据表明这些合并症及其常规药物如何影响缺血/再灌注损伤，并干扰心脏保护策略。
