What is Wrong With Cardiac Conditioning? We May be Shooting at Moving Targets

Abstract

Early recanalization of the occluded culprit coronary artery clearly reduces infarct size in both animal models and patients and improves clinical outcomes. Unfortunately, reperfusion can seldom be accomplished before some myocardium infarcts. As a result there has been an intensive search for interventions that will make the heart resistant to infarction so that reperfusion could salvage more myocardium. A number of interventions have been identified in animal models, foremost being ischemic preconditioning. It protects by activating signaling pathways that prevent lethal permeability transition pores from forming in the heart's mitochondria at reperfusion. Such conditioning can be accomplished in a clinically relevant manner either by staccato reperfusion (ischemic postconditioning) or by pharmacological activation of the conditioning signaling pathways prior to reperfusion. Unfortunately, clinical trials of ischemic postconditioning and pharmacologic conditioning have been largely disappointing. We suggest that this may be caused by inappropriate use as models intended to mimic the clinical scenario of young healthy animals that receive none of the many drugs currently given to our patients. Patients may be resistant to some forms of conditioning because of comorbidities, for example, diabetes, or they may already be conditioned by adjunct medications, for example, P2Y12 inhibitors or opioids. Incremental technological improvements in patient care may render some approaches to cardioprotection redundant, and thus the clinical target may be continually changing, while our animal models have not kept pace. In remote conditioning, a limb is subjected to ischemia/reperfusion prior to or during coronary reperfusion. Its mechanism is not as well understood as that of ischemic preconditioning, but the results have been very encouraging. In the present article, we will review ischemic, remote, and pharmacologic conditioning and possible confounders that could interfere with their efficacy in clinical trials in 2 settings of myocardial ischemia: (1) primary angioplasty in acute myocardial infarction and (2) elective angioplasty.

The Highly Selective Caspase-1 Inhibitor VX-765 Provides Additive Protection Against Myocardial Infarction in Rat Hearts When Combined With a Platelet Inhibitor

“…We postulate that because P2Y 12 inhibitors are themselves postconditioning agents, they render any additional interventions that work through convergent mechanisms redundant. 2,4 Thus, it is imperative that efficacy testing of novel cardioprotective interventions in animal models of AMI must be performed in the presence of a P2Y 12 inhibitor to validate potential utility for augmenting outcomes in today’s patients. Only interventions that can provide additional protection beyond that from a platelet inhibitor will have any chance of clinical efficacy.…”

Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration

“…Conflicting findings may be due to differences between the animal models studied and humans [48, 98, 100], or to limitations in study designs [48]. In human studies, it is also very likely to be due to co-morbidity [48, 98, 101], co-medication and differing anaesthetic protocols [98, 101–105], heterogeneity in study designs [48, 62], and other factors that cannot be predicted due to an incomplete understanding of the mechanisms and interaction of neural and humoral pathways in RIC. As a consequence, confounding factors are likely to be unwittingly present in studies, which could result in misleading conclusions.…”

New and revisited approaches to preserving the reperfused myocardium

“…Several reasons have been proposed to explain why adjunctive therapies have not been effective in reducing infarct size and improving outcomes after MI in the clinical trial setting, including the lack of reproducibility and rigour in preclinical studies; use of preclinical models that do not adequately reflect clinical comorbidities such as advanced age; and administration of pharmacological agents too late to have an effect on infarct size. Furthermore, antiplatelet agents such as P2Y 12 -receptor blockers are commonly prescribed to these patients before primary angioplasty, and might mask the protective postconditioning effects of adjunctive therapies 5 . In the setting of acute MI, these antiplatelet agents help to maintain vessel patency after percutaneous coronary intervention (PCI).…”

“…As a consequence, therapeutic strategies that target ischaemic preconditioning 8 or postconditioning 6 as a means for cardioprotection after MI did not reduce infarct size in animal hearts beyond the effects of the antiplatelet agents. The first clinical trial to evaluate the efficacy of ischaemic postconditioning after acute MI reported promising findings, but subsequent trials that were conducted after platelet inhibitors came into widespread use in patients undergoing PCI yielded either neutral results, or demonstrated only marginal benefit with postconditioning 5,9,10 . Although the use of platelet inhibitors might not be the only confounding factor in these studies, any intervention that cannot provide additional cardioprotective effects beyond that of an antiplatelet agent in the setting of MI (as seen in the animal studies) is unlikely to improve outcomes.…”