Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations

Hausenloy, Derek J.; Baxter, GF; Bell, Robert M.; Bøtker, Hans Erik; Davidson, Sean M.; Downey, James M.; Heusch, Gerd; Kitakaze, Masafumi; Lecour, Sandrine; Mentzer, Robert M.; Mocanu, Mihaela M.; Ovize, Michel; Schulz, Rainer; Shannon, Richard P.; Walker, John M.; Walkinshaw, Gail; Yellon, Derek M.

doi:10.1007/s00395-010-0121-4

Cited by 221 publications

(150 citation statements)

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“…Then, ATP is depleted, so necrotic and mitochondrial death pathway occurs with the opening of mitochondrial permeability transition pore (mPTP). [1][2][3] The concept of myocardial cell injury occurring after ischemia/reperfusion (I/R) involves two major hypotheses: increases in intracellular calcium and/or the accumulation of reactive oxygen species (ROS). The latter causing the sarcolemmal peroxidation of the cellular phospholipid layer, leads to the loss of cellular integrity and facilitating calcium entry.…”

Section: Introductionmentioning

confidence: 99%

Gallic Acid and Cyclosporine Mixture and their Effects on Cardiac Dysfunction Induced by Ischemia/Reperfusion and eNOS/iNOS Expression

Badavi

Sadeghi

Dianat

et al. 2017

International Journal of Cardiovascular Sciences

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Section: Introductionmentioning

confidence: 99%

Gallic Acid and Cyclosporine Mixture and their Effects on Cardiac Dysfunction Induced by Ischemia/Reperfusion and eNOS/iNOS Expression

Badavi

Sadeghi

Dianat

et al. 2017

International Journal of Cardiovascular Sciences

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“…Over the past 3 decades, a number of pharmacological cardioprotection strategies were discovered in experimental studies (9). Researches involved conditioning mechanisms have revealed multiple receptors, pathways and end effectors, all of which can be pharmacologically stimulated, such as agents acting on cardiomyocyte receptors (adenosine, bradykinin, opioids, glucagon-like peptide 1, atrial natriuretic peptide, erythropoeitin, insulin), agents acting on intracellular signal transduction pathways (phosphodiesterase-5 inhibitors, glyceryl trinitrate or nitroglycerin, atorvastatin, delcasertib, nicorandil) and agents acting on the mitochondria (cyclosporine-A) (10)(11)(12)(13).…”

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confidence: 99%

“…However, none has been translated into clinical practice with the exception of early reperfusion (14)(15)(16). The reasons for the failure to translate pharmacologic conditioning strategies of cardioprotective effects from the bench to bedside have been extensively discussed in the literatures (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19). Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies.…”

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confidence: 99%

“…Some experts concluded that the causes of failure can be attributed to inadequacy animal IRI models used in the preclinical cardioprotection studies. Nonetheless, in the position paper which published in 2013 (3), the experts concluded that the failure was not be due to a shortage of potential cardioprotective strategies discovered in the pre-clinical experimental setting (14), but was be due to the inability to successfully translate these promising therapies into interventions that actually improved the outcomes in patients (3,(8)(9)(10)(11)(14)(15)(16)(17)(18)(19).…”

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confidence: 99%

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At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury

Pan

2016

Ann. Transl. Med.

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The study by Bian et al. (1) found that luteolin (Lut) inhibited myocardial ischemia/reperfusion injury (IRI) by decreasing miR-208b-3p and increasing Ets1 expression levels in rats. Cokkinos (2) has written an editorial commentary for this study and considered it to be elegant. However, he also raised several interesting questions about the study. As the members of the investigate team, we would like to discuss these issues with counterparts.The first question is how relevant to the clinical situation are results on IRI alleviation in the experimental setting. In the commentary, Cokkinos (2) cited the position paper of the Working Group of Cellular Biology of the Heart of the European Society of Cardiology (3) which published in Cardiovasc Res, 2013. According to the position paper, the experts concluded that there was no effective proven therapy against IRI. It is widely recognized that it is not always possible to translate animal experiments into clinical therapy.First of all, we reviewed the relative literatures about cardioprotection including the position paper. As now wellknown, coronary heart disease (CHD) is the leading cause of death worldwide. The main therapeutic strategy in CHD is reperfusion that could be succeeded either medicine or operation (4,5). However, its major pathophysiological manifestation is myocardial IRI. Despite all of optimal therapies, the morbidity and mortality of CHD remain significant. As such, to find more effective cardioprotective strategies has never been so pressing, novel therapeutic strategies are required to protect the heart from the detrimental effects of IRI, in order to reduce myocardial injury, preserve cardiac function and improve clinical outcomes in patients with CHD (6,7).Over the last few decades, understanding of the pathophysiology of IRI and concepts of cardioprotection has been revolutionised. Newer strategies such as ischemic preconditioning (IPC), ischemic postconditioning, and remote IPC have been shown to condition the myocardium to IRI and thus reduce the final myocardial infarct size (7). The elucidation of underlying mechanisms in different forms of ischemic conditioning has identified novel targets for cardioprotection amenable to pharmacological manipulation, so called pharmacological conditioning (8).The study for a pharmacological strategy to protect the heart against IRI preceded the discovery of IPC by many years. Over the past 3 decades, a number of pharmacological cardioprotection strategies were discovered in experimental studies (9). Researches involved conditioning mechanisms have revealed multiple receptors, pathways and end effectors, all of which can be pharmacologically stimulated, such as agents acting on cardiomyocyte receptors (adenosine, bradykinin, opioids, glucagon-like peptide 1, atrial natriuretic peptide, erythropoeitin, insulin), agents acting on intracellular signal transduction pathways (phosphodiesterase-5 inhibitors, glyceryl trinitrate or

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“…The difficulties of extrapolation of pre-clinical successes to the clinical arena have previously been identified and discussed [15]. Reproducibility has been such a problem in cardioprotection that Roberto Bolli recently formed a consortium of four institutions under the aegis of the National Institutes of Health.…”

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confidence: 99%

Does mild hypothermia protect against reperfusion injury? The debate continues

2011

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Mild hypothermia (32-35°C) salvages ischemic myocardium and reduces infarct size in hearts undergoing ischemia/reperfusion. It is clear that a cardioprotective effect is evident when the heart is cooled during ischemia, and the protection is greater as the duration of normothermic ischemia is increasingly limited. The effect of cooling just before and at reperfusion is more controversial. Multiple experimental studies have revealed no effect of mild hypothermia on myocardial infarction when cooling was initiated in the waning minutes of ischemia. But Götberg et al. have demonstrated a small effect in pigs cooled with cold intravenous saline and a venous thermode, although the effect of cooling during ischemia continued to be more prominent. Clinical studies have been disappointing, and possible explanations are offered. Götberg's new data are encouraging, but it is questioned whether this is the correct time to conduct a new large-scale clinical trial.In animal models of coronary artery occlusion/reperfusion cardiac temperature is known to be a major determinant of infarct extension, along with collateral blood flow and risk zone size [2,4,23]. Cooling to 4°C (deep hypothermia) has long been used to protect the heart during open heart surgery and transplantation. In those cases, the heart is quiescent and metabolism is greatly curtailed. What is surprising is that mild hypothermia (32-35°C) is also quite protective. Mild hypothermia has the advantage that, under those conditions, the heart beats normally which allows simple whole body cooling without the need for cardiovascular support. Chien et al. [2] reported that for each degree C decrement of the core temperature in rabbits undergoing 30 min of ischemia followed by reperfusion infarct size was reduced by an average of 8% of the risk zone. When induced during the ischemic process, mild hypothermia is, therefore, one of the most potent cardioprotective strategies yet to be identified.Studies of therapeutic whole body cooling have limited the range of cooling to be no lower than 32°C because lowering the temperature below 30°C is life-threatening. But 32°C is already quite protective [18]. This protective effect of whole body cooling against infarction has been reported for many experimental animal species (pigs [3, 4, 21, 22], rats [28], rabbits [2, 9, 12, 13, 18, 27], dogs [23]). Mild hypothermia also attenuates no-reflow [1,5,9], postischemic left ventricular dysfunction [26], and remodeling [14]. As emphasized by two recent reviews [11,25], the evidence for a cardioprotective effect of therapeutic mild hypothermia against ischemic injury is very strong.An important consideration in therapeutic hypothermia is not only its dose (depth of cooling) but also its schedule. All investigators would probably agree that hypothermia is most protective when present during ischemia. We have found that the magnitude of the protection depends upon how much of R. Tissier INSERM, Unité 955,

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Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations

Cited by 221 publications

References 68 publications

Gallic Acid and Cyclosporine Mixture and their Effects on Cardiac Dysfunction Induced by Ischemia/Reperfusion and eNOS/iNOS Expression

Gallic Acid and Cyclosporine Mixture and their Effects on Cardiac Dysfunction Induced by Ischemia/Reperfusion and eNOS/iNOS Expression

At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury

Does mild hypothermia protect against reperfusion injury? The debate continues

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