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.

Fig. 1

The concept of ischemia/reperfusion injury and cardioprotection by pre-, post-, and remote conditioning as well as by drugs is expressed graphically (black areas denote periods of ischemia). Myocardial ischemia and reperfusion lead to I/R injury characterized by the development of contractile dysfunction, arrhythmias, tissue necrosis (infarction), and microvascular damage. Ischemic preconditioning is a well-described acute and subacute adaptive response in which brief exposure to I/R by mechanical occlusion of coronary arteries markedly enhances the ability of the heart to withstand a subsequent ischemia/reperfusion injury. In this diagram, 2 brief periods of ischemia are used to precondition the myocardium against a subsequent period of ischemia that is longer than the preconditioning periods. Brief cycles of I/R applied following a longer period of ischemia also confer cardioprotection against the consequences of I/R, a phenomenon termed “ischemic postconditioning.” Brief cycles of I/R applied in a remote cardiac tissue or remote organ (in this diagram the upper limb by a pressure cuff) before, during, or right after a longer period of cardiac ischemia also provides cardioprotection, a phenomenon termed “remote conditioning.” The cardioprotective effect of conditioning strategies results in attenuation of I/R injury. Major cardiovascular risk factors and their medications influence the severity of ischemia/reperfusion injury and interferes with cardioprotective efficacy.

Fig. 2

This diagram shows some of the major cellular mechanisms suspected to contribute to cardioprotection induced by either mechanical or drug-induced conditioning stimulus of different cells of the heart tissue that leads to attenuation of I/R injury of the heart. Most of the cellular mechanisms of cardioprotection seems to be unexplored so far, as conditioning stimuli of cardioprotection is associated with extensive changes in cellular signaling that also includes global cardiac gene expression profile at the coding and noncoding RNA, proteome, and metabolome levels. AMPK, adenosine 5′-monophosphate activated protein kinase; ANT, adenine nucleotide translocase; cGMP, cyclic guanosine monophosphate; CYPD, cyclophilin D; NO, nitric oxide; GSK-3β, glycogen synthase kinase-3β; HSP, heat shock proteins; KATP,ATP-dependent potassium channel; MAPK, mitogen-activated protein kinase; miR, micro-RNA; mitoHKII, mitochondrial hexokinase II; mPTP, mitochondrial permeability transition pore; NLRP3, nucleotide-binding and oligomerization domain (NOD)-like receptor domain-containing protein 3; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; ROS, reactive oxygen species; STAT, signal transducers and activators of transcription; TNF, tumor necrosis factor.

Fig. 3

This diagram shows that different cardiovascular risk factors and comorbidities as well as their routine medications dramatically alter cardiac cellular signaling thereby interfering with cardioprotective mechanisms explored in drug-naive young healthy hearts used in the majority of preclinical studies.