Clinical cardioprotection and the value of conditioning responses

Abstract

Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research, the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning and postconditioning have proven fertile in identification of experimental means of cardioprotection and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end effectors, may be poor choices for clinical exploitation. This includes evidence of age dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly used drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.

Regular treadmill exercise restores cardioprotective signaling pathways in obese mice independently from improvement in associated co-morbidities

“…Therefore, regular exercise is a powerful cardioprotective strategy that restores the activation of pro-survival signalling pathways and protects cardiac mitochondria. This is of major importance as both pre-and postconditioning failed to reduce myocardial infarct size in obese animals because of their inability to activate these cardioprotective pathways in obese conditions (for review, [8]). …”

“…Exercised animals have run 5/7 days during 4 weeks. The first week was an adaptation period with gradual speeds during 30 min (10,14,18,22,26, and 30 cm/s, 4° slope, 5 min each step for WT and 8,8,10,14,18, and 20 cm/s, 4° slope, 5 min each step for ob/ob). For the three other weeks, mice ran during one hour per day (30 and 20 cm/s for WT and ob/ob, respectively, 4° slope) without any exhaustion.…”

“…Indeed it has been previously reported that both pre-and postconditioning failed to reduce infarct size in obese animals probably because of their inability to activate the cardioprotective signalling pathways through kinase phosphorylations. [7][8][9]. Nevertheless, it is known that exercise is able to decrease cardiac events and mortality in obese or overweight patients [10][11][12].…”

Cardioprotection From Ischemia/Reperfusion Injury

“…The inactivation of GSK-3β inhibits the opening of the mitochondrial permeability transition pore (mPTP), which plays a crucial role in myocardial necrosis. 15, 16 Reactive oxygen species (ROS) production in mitochondria, where the mitochondrial ATP-dependent potassium channels play an essential role, is also involved in the cardioprotective mechanisms of ischemic preconditioning. 17 Although these findings are consistently observed in experimental models, applying ischemic preconditioning in the clinical setting is restricted to scheduled cardiac operation and elective PCI.…”

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

“…However, despite potent protection experimentally, the therapeutic potential of conditioning-based approaches has yet to be realized clinically. A number of factors may limit translation of conventional conditioning responses, including negative influences of age, disease, and common pharmacological agents (Miura and Miki, 2008;Peart and Headrick, 2009). It is thus important to investigate alternate or unconventional modes of cardioprotection, such as opioid-mediated sustained ligand-activated preconditioning (SLP) (Peart and Gross, 2004a).…”