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

Abstract

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.

Sex Difference in Cardioprotection against Acute Myocardial Infarction in MAO-B Knockout Mice In Vivo

“…Apart from sex hormones, differences are found in the regulation of the cell survival pathways in males and females [ 16 ]. Cardioprotection in female rats after I/R is mediated by altered mitochondrial enzyme activity that encompasses a phosphoinositide-3-kinase (PI3K)-mediated reduction in ROS generation and a better removal of ROS by-products [ 37 ].…”

“…If patients survive a severe MI, the heart function deteriorates, and heart failure (HI) often develops. While reperfusion through primary percutaneous coronary intervention is the only possibility to reduce myocardial infarct size, reperfusion itself induces further damage to the heart muscle, known as reperfusion injury [ 15 , 16 ].…”

Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study

“…1 Thus, there is still an unmet need for developing novel strategies to reduce myocardial ischaemia/reperfusion (I/R) injury and its long-term consequences to improve the standard of care. [2][3][4] Remote ischaemic conditioning (RIC) is a cardioprotective method that is elicited by short-term, non-lethal cycles of ischaemia and reperfusion to an organ or tissue other than the heart. [5][6][7][8][9] RIC can be applied before [remote ischaemic preconditioning (RIPC)], or during myocardial ischaemia [remote ischaemic perconditioning (RIPerC)], or at the beginning of coronary reperfusion (remote ischaemic postconditioning (RIPostC)], showing potential clinical applicability, for example, by cyclic inflation and deflation of a pressure cuff placed on an extremity of the patient.…”

Diazoxide is a powerful cardioprotectant but is not feasible in a realistic infarct scenario

“…Despite a myriad of preclinical studies that demonstrated reduced infarct size and reduced coronary microvascular obstruction by mechanical or pharmacological cardioprotective interventions, the translation of cardioprotection to patient benefit has been largely disappointing so far ( 4 – 6 ). The lack of translation has been attributed to two major factors: (1) The recruitment of low-risk patients into cardioprotection trials in whom it was difficult to show a further reduction in mortality and heart failure development ( 7 , 8 ); (2) The typical presence of advanced age, comorbidities, and co-medications in patients which were, however, not present in most preclinical studies but interfere with the signal transduction of cardioprotection ( 9 ). The signal transduction of cardioprotection by ischaemic conditioning and many pharmacological agents comprises an action on the sarcolemma and its channels and receptors, an activation of cytosolic protein kinase cascades, and ultimately an action on mitochondria and their function ( 10 ).…”