Post-Reperfusion Myocardial Infarction

Mangano, Dennis T.; Miao, Yinghui; Tudor, Iulia Cristina; Dietzel, Cynthia

doi:10.1016/j.jacc.2006.04.044

Cited by 83 publications

(25 citation statements)

References 26 publications

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“…Indeed, there are many studies on human myocardium showing that ischaemic preconditioning can be elicited in experimental conditions, and protects against standardised ischaemic and reperfusion insult [22][23][24]. The same was shown with various forms of pharmacological preconditioning [25][26][27][28]. Currently, no experimental study has shown that human myocardium can be remotely preconditioned against standardised ischaemic/hypoxic insult.…”

Section: Discussionmentioning

confidence: 99%

Remote Ischaemic PrEconditioning of Human Myocardium (RIPE): study protocol for a double-blinded randomised controlled trial

et al. 2018

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A b s t r a c tBackground: Remote preconditioning has been shown to be a potent protective phenomenon in many animals. Several studies aimed to demonstrate it was feasible in humans by trying to show its protective effect during cardiac surgery. Of these, some small studies and one larger trial were positive while two other bigger studies showed no effectiveness of remote preconditioning as assessed by levels of postoperatively released cardiac markers. Recently, two large clinical trials also failed to prove the benefit of remote preconditioning in cardiac surgery. No study showed that remote preconditioning actually increases resistance of human myocardium to standardised ischaemic and reperfusion stimulus in experimental settings. In animal studies, remote preconditioning was shown to improve mitochondrial function and structure, but such data on human myocardium are scarce. Aim:The aim of the study is to determine whether remote preconditioning protects human myocardium against ischaemia-reperfusion injury in both in vivo and in vitro conditions. Methods:The trial is designed as a single-centre, double-blinded, sham-controlled trial of 120 patients. We randomise (1:1) patients referred for coronary artery bypass grafting for stable coronary artery disease to remote preconditioning or "sham" intervention. The remote preconditioning is obtained by three cycles of 5 min inflation and 5 min deflation of a blood pressure cuff on the right arm. Postoperative course including myocardial enzymes profile will be analysed. Moreover, in the in-vitro arm the clinically preconditioned myocardium will be assessed for function, mitochondria structure, and mitochondria-dependent apoptosis. The informed consent of all patients is obtained before enrolment into the study by the investigator. The study conforms to the spirit and the letter of the declaration of Helsinki. Results and conclusions:In case the effect of remote preconditioning is not measurable in ex-vivo assessment, any future attempt at implementing this phenomenon in clinical practice may be futile and should not be continued until the effect can be confirmed in a controlled experimental setting. The study might therefore indicate future directions in trials of clinical implementation of remote preconditioning. INTRODUCTIONNo experimental study showed that human myocardium can be remotely preconditioned against standardised ischaemic/hypoxic insult. We aim to remove this major knowledge gap by applying remote preconditioning to the patient and studying ex-vivo the myocardium obtained thereafter. We assume that we will be able to show that remote preconditioning by brief periods of ischaemia of the arm protects segments of human right atrial appendage myocardium subjected to simulated hypoxia and reoxygenation in-vitro.This proof of principle is crucial. In case the effect of remote preconditioning is not measurable in ex-vivo assessment, any future attempt at implementing this phenomenon in clinical practice may be futile and should not be continued until the e...

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Section: Discussionmentioning

confidence: 99%

Remote Ischaemic PrEconditioning of Human Myocardium (RIPE): study protocol for a double-blinded randomised controlled trial

et al. 2018

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“…Acadesine, a drug thought to increase adenosine levels in ischemic tissues, was compared with placebo in 2,698 patients undergoing CABG. The study missed its primary endpoint of reduction of myocardial infarction and secondary endpoint of a composite of cardiac death, myocardial infarction, or stroke at postoperative day 4 169 . In the small subset of patients experiencing post-operative myocardial infarction, two-year mortality was reduced from 27.8% to 6.5% (p=0.006) 169 .…”

Section: Clinical Applications Of Pkc Regulatorsmentioning

confidence: 99%

“…The study missed its primary endpoint of reduction of myocardial infarction and secondary endpoint of a composite of cardiac death, myocardial infarction, or stroke at postoperative day 4 169 . In the small subset of patients experiencing post-operative myocardial infarction, two-year mortality was reduced from 27.8% to 6.5% (p=0.006) 169 . A more recent study of acadesine in CABG patients was stopped prematurely for futility after failing to show an effect on the composite outcome of 28 day mortality, nonfatal stroke, and severe left ventricular dysfunction (5.1% acadesine vs. 5% placebo) 170 .…”

Section: Clinical Applications Of Pkc Regulatorsmentioning

confidence: 99%

Protein kinase C, an elusive therapeutic target?

Mochly‐Rosen

Das

Grimes

2012

Nat Rev Drug Discov

475

493

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Preface Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumor promoter phorbol ester in 19821. Although initial therapeutic efforts focused on cancer, additional diseases, including diabetic complications, heart failure, myocardial infarction, pain and bipolar disease were targeted as researchers developed a better understanding of the roles that PKC’s eight conventional and novel isozymes play in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This review will provide a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

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“…At the same time a number of clinical trials aimed at repurposing drugs that were approved for the treatment of metabolic disorders in other organs were not successful [133]. For example, Acadesine [134], a nonspecific agent targeting AMP-dependent protein kinase, L-arginine [135], an alternative energy substrate utilized in the treatment of other mitochondrial myopathies, and adenosine receptor agonists [136, 137] did not improve the conditions of myocardial infarction patients.…”

Section: Intracellular Energetic Units In Diseased Heartsmentioning

confidence: 99%

Mechanotransduction and Metabolism in Cardiomyocyte Microdomains

Pasqualini

Nesmith

Horton

et al. 2016

BioMed Research International

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Efficient contractions of the left ventricle are ensured by the continuous transfer of adenosine triphosphate (ATP) from energy production sites, the mitochondria, to energy utilization sites, such as ionic pumps and the force-generating sarcomeres. To minimize the impact of intracellular ATP trafficking, sarcomeres and mitochondria are closely packed together and in proximity with other ultrastructures involved in excitation-contraction coupling, such as t-tubules and sarcoplasmic reticulum junctions. This complex microdomain has been referred to as the intracellular energetic unit. Here, we review the literature in support of the notion that cardiac homeostasis and disease are emergent properties of the hierarchical organization of these units. Specifically, we will focus on pathological alterations of this microdomain that result in cardiac diseases through energy imbalance and posttranslational modifications of the cytoskeletal proteins involved in mechanosensing and transduction.

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Post-Reperfusion Myocardial Infarction

Abstract: Acadesine is the first therapy proven to be effective for reducing the severity of acute post-reperfusion MI, substantially reducing the risk of dying over the 2 years after infarction.

Cited by 83 publications

References 26 publications

Remote Ischaemic PrEconditioning of Human Myocardium (RIPE): study protocol for a double-blinded randomised controlled trial

Remote Ischaemic PrEconditioning of Human Myocardium (RIPE): study protocol for a double-blinded randomised controlled trial

Protein kinase C, an elusive therapeutic target?

Mechanotransduction and Metabolism in Cardiomyocyte Microdomains

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