Cardioprotection: chances and challenges of its translation to the clinic

Heusch, Gerd

doi:10.1016/s0140-6736(12)60916-7

Cited by 480 publications

(406 citation statements)

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“…However, reperfusion also adds a component of injury to that incurred during ischemia and thus contributes to final infarct size [6,20,28]. It appears that all conditioning strategies which delay infarct size development and/or reduce infarct size act through attenuation of such reperfusion injury [7]. Apart from its contribution to cardiomyocyte necrosis, reperfusion is frequently also characterized by the development of areas of no-reflow within the previously ischemic myocardium [10].…”

mentioning

confidence: 99%

“…Ischemic postconditioning not only reduces infarct size [7], but also myocardial edema and in consequence the area at risk when delineated by T 2 -weighted MRI in pigs [16], and it also improves coronary microvascular perfusion in dogs [29], again emphasizing the intimate relationship between cardiomyocyte infarction and coronary microvascular obstruction and leaving potential causality unresolved.…”

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confidence: 99%

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Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship

2013

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Timely reperfusion is the only way to rescue ischemic myocardium from impending infarction. However, reperfusion also adds a component of injury to that incurred during ischemia and thus contributes to final infarct size [6,20,28]. It appears that all conditioning strategies which delay infarct size development and/or reduce infarct size act through attenuation of such reperfusion injury [7]. Apart from its contribution to cardiomyocyte necrosis, reperfusion is frequently also characterized by the development of areas of no-reflow within the previously ischemic myocardium [10]. Evidence for microvascular no-reflow by angiography or MRI despite successfully reopened epicardial coronary arteries in patients with myocardial infarction is associated with impaired recovery of ventricular function and worse survival [19].The coexistence of infarcted cardiomyocytes and areas of coronary microvascular no-reflow in reperfused myocardium is well established [13]; however the underlying mechanisms are not really clear. Several mechanisms can initiate no-reflow in previously ischemic myocardium: (a) embolization of particulate atherosclerotic debris from the culprit lesion into the coronary microcirculation, both after mechanical or thrombolytic reopening of epicardial coronary arteries The analysis of temporal and spatial relationships between infarcted myocardium and no-reflow is largely limited by methodological restraints. By definition, infarcted myocardium and no-reflow are confined to the previously ischemic area at risk. This appears trivial, but when analyzed by clinical imaging technology, the area at risk is often not determined or not clear. Slow/no-flow phenomena outside the area at risk may also occur but have a different underlying pathophysiology, e.g., reflex-mediated coronary vasoconstriction [4,8]. Myocardial infarction develops progressively during ischemia, and a separate component of irreversible injury is added during early reperfusion; the relative contribution of infarction which develops during ischemia and during reperfusion varies and depends on the duration of ischemia [3]. Even with gold standard technology (TTC staining) in the experiment, infarcted tissue is only recognized as such after several hours of reperfusion, and no distinction between myocardium infarcting during ischemia and during reperfusion is possible. No-reflow, as evidenced by lack of endothelial staining by thioflavin in the experiment [13], develops rapidly during early reperfusion and progresses over time [1,22,23]. Most studies indicate that no-reflow areas are This comment refers to the article available at

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Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship

2013

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“…Cardiac events in the isoflurane group could have arisen by chance or could be secondary to other factors, including microembolization, inadequate revascularization, or other mediators of cardiac injury. 1,6 In patients without diabetes, we cannot differentiate between the nonexistence of effect and the lack of power to detect it. Our clinical observations from the diabetes subgroup require further validation.…”

Section: Discussionmentioning

confidence: 99%

“…4 Unfortunately, pharmacologic or physical conditioning strategies are not effective in the aged or chronic diabetic heart due to corruption of cardioprotective signalling pathways and mitochondrial dysfunction. [5][6][7][8][9][10][11] As oxidative stress is a major factor in the pathophysiology of IRI, propofol, an anesthetic and phenolic antioxidant, could be a therapeutic alternative. 12,13 Nevertheless, metaanalyses of clinical trials show reduced indices of myocardial injury and dysfunction with inhalational agents compared with propofol anesthesia (2-4 lgÁmL…”

Section: Résumémentioning

confidence: 99%

Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

Ansley

Raedschelders

Choi

et al. 2015

Can J Anesth/J Can Anesth

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Purpose The efficacy of myocardial conditioning strategies is compromised in patients with advanced age, diabetes, or low ejection fraction. We conducted a singlecentre parallel-arm blinded randomized-controlled trial to determine whether propofol provides perioperative myocardial protection. Methods Patients enrolled in this study were scheduled for primary aortocoronary bypass surgery utilizing normothermic cardiopulmonary bypass (CPB) with blood cardioplegia. The participants were stratified by diabetic status and left ventricular ejection fraction and randomly assigned to receive either an elevated dose of propofolpreviously associated with experimental cardioprotectionor an isoflurane preconditioning regime. The primary endpoint was the coronary sinus (CS) concentration of 15-F 2t -isoprostane (isoP). Secondary endpoints included inhospital low cardiac output syndrome (LCOS) and major adverse cardiac events, 12-and 24-hr CS cardiac troponin I (cTnI) release, and myocardial B-cell lymphoma 2 (Bcl-2) protein expression. Results Data were analyzed from 125 of 137 randomized participants. Participants receiving propofol experienced a greater mean (SD) increase from baseline in CS 15-F 2t -isoP levels compared with those receiving isoflurane [26.9 (10.9) pgÁmL -1 vs 12.1 (10.4) pgÁmL -1 , respectively; mean difference, 14.8; 95% confidence interval (CI), 11.0 to 18.6; P \ 0.001] but a decreased incidence of LCOS (20.9% vs 57.1%, respectively; relative risk [RR],0.37; 95% CI, 0.22 to 0.62; P \ 0.001). The incidence of LCOS was similar between groups in participants without type 2 diabetes mellitus (DM2) (P = 0.382) but significantly decreased in the propofol DM2 subgroup compared with the isoflurane DM2 subgroup (17.9% vs 70.3%, respectively; RR, 0.26; 95% CI, 0.13 to 0.52; P \ 0.001). Propofol was associated with an increase in myocardial Bcl-2 protein expression (P = 0.005), a lower incidence of a CS cTnI threshold for myocardial infarction (P = 0.014), and fewer heart failure events (P \ 0.001). Conclusion Propofol may be a preemptive intraoperative cardioprotectant for patients with DM2 under conditions of normothermic CPB and blood cardioplegic arrest. The study is registered at www.clinicaltrials.gov (NCT00734383) and www.controlled-trials.com (ISRCTN70879185). RésuméObjectif L'efficacité des stratégies de conditionnement myocardique est compromise chez les patients âgés ainsi que chez ceux atteints de diabète ou présentant une fraction d'éjection faible. Nous avons réalisé une étude randomisée contrô lée unicentrique à bras parallèles et en aveugle afin de déterminer si le propofol procurait une protection myocardique en période périopératoire. Méthode Les patients enrô lés dans cette étude devaient subir une chirurgie de pontage aorto-coronarien primaire avec circulation extracorporelle (CEC) normothermique et cardioplégie sanguine. Les participants ont été stratifiés par statut diabétique et fraction d'éjection ventriculaire gauche, puis aléatoirement répartis en deux groupes, dont l'un recevrait...

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“…The translation to humans might be obtained either by viral vectors to deliver exogenous melusin genes or by pharmacological treatment capable to increase the expression of the endogenous melusin gene in patients with an high risk profile for heart ischemia. However, the translation of findings on cardioprotection from rodents to humans cannot be taken for granted [29] and analysis in larger mammals, such as the pigs, may be necessary to support translational application [31].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

et al. 2014

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Melusin is a muscle-specific protein which interacts with β1 integrin cytoplasmic domain and acts as chaperone protein. Its overexpression induces improved resistance to cardiac overload delaying left ventricle dilation and reducing the occurrence of heart failure. Here we investigated possible protective effect of melusin overexpression against acute ischemia/reperfusion (I/R) injury with or without Postconditioning cardioprotective maneuvers.Melusin-transgenic (Mel-TG) mice hearts were subjected to 30 minutes global ischemia followed by 60 minutes reperfusion. Interestingly, infarct size (IS) was reduced in Mel-TG mice hearts compared to wildtype (WT) hearts (40.3±3.5% Mel-TG vs. 59.5±3.8% WT hearts; n= 11 animals/group; P<0.05). The melusin protective effect was also demonstrated by measuring LDH release, which was 50% lower in Mel-TG compared to WT. Mel-TG hearts had a higher baseline level of AKT, ERK1/2 and GSK3β phosphorylation, and displayed increased phospho-kinases level after I/R compared to WT mice. Postischemic Mel-TG hearts displayed also increased levels of the antiapoptotic factor phospho-BAD.Importantly pharmacological inhibition of PI3K/AKT (Wortmannin) and ERK1/2 (U0126) pathways abrogated the melusin protective effect. Notably, HSP90, a chaperone known to protect heart from I/R injury, showed high levels of expression in the heart of Mel-TG mice suggesting a possible collaboration of this molecule with AKT/ERK/GSK3β pathways in the melusin-induced protection. Postconditioning, known to activate AKT/ERK/GSK3β pathways, significantly reduced IS and LDH release in WT hearts, but had no additive protective effects in Mel-TG hearts. These findings implicate melusin as an enhancer of AKT and ERK pathways and as a novel player in cardioprotection from I/R injury.

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Cardioprotection: chances and challenges of its translation to the clinic

Cited by 480 publications

References 104 publications

Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship

Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship

Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

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