Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart towithstand 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 themarket 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 comorbiditiesmay impact on cardioprotection by againmodifying cellular signaling pathways. The aimof this article is to review the recent evidence that cardiovascular risk factors aswell as comorbidities and theirmedicationsmay modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors aswell as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. Thiswill hopefullymaximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patientswithmultiple comorbidities. © 2023 by The Author(s)