Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury

Davidson, Sean M.; Ferdinándy, Péter; Andreadou, Ioanna; Bøtker, Hans Erik; Heusch, Gerd; Ibáñez, Borja; Ovize, Michel; Schulz, Rainer; Yellon, Derek M.; Hausenloy, Derek J.; Garcı́a-Dorado, David

doi:10.1016/j.jacc.2018.09.086

Cited by 502 publications

(415 citation statements)

References 60 publications

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“…Although the mechanistic pathways contributing to hypothermic cardioprotection are not fully elucidated, this study presents a new approach in combining distinct pharmacological and mechanical therapeutic strategies to improve additively the clinical outcome. Such combinations of therapeutic solutions could represent the future of therapeutic approaches in myocardial infarction [8]. During acute myocardial ischemia, pharmacological compounds are unable to reach the compromised tissues due to limited blood flow; however, combination therapy with a physical intervention such as therapeutic hypothermia could provide a new clinical avenue for early intervention.…”

Section: Discussionmentioning

confidence: 99%

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

et al. 2019

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Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

et al. 2019

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“…Experimental studies indicate that pharmacological approaches aimed at preventing MPTP have cardioprotective effects in the context of myocardial ischaemia reperfusion . However, translation of this concept into the clinic has been disappointing, suggesting that targeting a single intracellular molecule, such as the MPTP or dynamin‐related protein 1 (Drp1), may not be sufficient to create cardioprotection . It emphasizes that more mechanistic insight about the mode of action of cardioprotective modalities is needed.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 However, translation of this concept into the clinic has been disappointing, [11][12][13][14][15][16][17] suggesting that targeting a single intracellular molecule, such as the MPTP or dynamin-related protein 1 (Drp1), 18 may not be sufficient to create cardioprotection. 19,20 It emphasizes that more mechanistic insight about the mode of action of cardioprotective modalities is needed.…”

Section: Introductionmentioning

confidence: 99%

Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST‐segment elevation myocardial infarction

Bøtker

Cabrera-Fuentes

Ruiz‐Meana

et al. 2020

J Cellular Molecular Medi

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Pre‐clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI‐9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co‐medication into account may be of paramount importance during the design of pre‐clinical and clinical studies testing mitoprotective drugs.

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“…The translation of cardioprotection by ischemic conditioning to clinical practice has been largely disappointing so far (Heusch ; Davidson et al. ). Such failure of translation is, apart from details of the underlying signal transduction of cardioprotection and strategies of its recruitment (Heusch ; Andreadou et al.…”

Section: Introductionmentioning

confidence: 99%

“…The translation of cardioprotection by ischemic conditioning to clinical practice has been largely disappointing so far (Heusch 2017;Davidson et al 2019a). Such failure of translation is, apart from details of the underlying signal transduction of cardioprotection and strategies of its recruitment (Heusch 2015;Andreadou et al 2019;Davidson et al 2019b;Hausenloy et al 2019aHausenloy et al ,2019bZuurbier et al 2019), due to the lack of an optimal algorithm of the conditioning stimulus (duration and number of ischemia/reperfusion cycles, as well as its temporal distance to the index ischemia).…”

Section: Introductionmentioning

confidence: 99%

Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning

et al. 2019

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We determined the impact of sex on the magnitude of cardioprotection by local and remote ischemic preconditioning ( IPC and RIPC ) and of ischemic/reperfused peripheral tissue mass on protection by RIPC . Hearts of female and male Lewis rats were excised, perfused with buffer, and underwent either IPC by 3 × 5/5 min global zero‐flow ischemia/reperfusion ( GI /R) or time‐matched perfusion ( TP ) before 30/120 min GI /R. In a second approach, anesthetized female and male Lewis rats underwent RIPC , 3 × 5/5 min ischemia/reperfusion of one or both hindlimbs (1‐ RIPC or 2‐ RIPC ), or placebo. Thirty minutes after the RIPC /placebo protocol, hearts were excised and subjected to GI /R. In female and male hearts, infarct size was less with IPC than with TP before GI /R ( IPC + GI /R female : 12 ± 5%; IPC + GI /R male : 12 ± 7% vs. TP + GI /R female : 33 ± 5%; TP + GI /R male : 37 ± 7%, P < 0.001). With 2‐ RIPC , infarct size was less than with 1‐ RIPC in female and male rat hearts, respectively (2‐ RIPC + GI /R female : 15 ± 5% vs. 1‐ RIPC + GI /R female : 22 ± 7%, P = 0.026 and 2‐ RIPC + GI /R male : 16 ± 5% vs. 1‐ RIPC + GI /R male : 22 ± 8%, P = 0.016). Infarct size after the placebo protocol and GI /R was not different between female and male hearts (36 ± 8% vs. 34 ± 5%). Sex is no determinant of IPC ‐ and RIPC ‐induced cardioprotection in isolated Lewis rat hearts. RIPC ‐induced cardioprotection is greater with greater mass of ischemic/reperfused peripheral tissue.

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Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury

Cited by 502 publications

References 60 publications

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST‐segment elevation myocardial infarction

Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning

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