The myocardial protective effects of adenosine pretreatment in children undergoing cardiac surgery: a randomized controlled clinical trial

Jin, Zhenxiao; Duan, Weixun; Chen, Min; Yu, Shiqiang; Zhang, Haopeng; Feng, Guanli; Xiong, Lei

doi:10.1016/j.ejcts.2010.12.052

Cited by 23 publications

(11 citation statements)

References 24 publications

(23 reference statements)

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“…Many studies have implicated activation of calcineurin in I/R damage in neurons [50, 51], lung [52], kidney [53], and heart [54–57]. Pharmacological studies using cyclosporine A (CsA) to inhibit calcineurin need to be interpreted with caution because CsA also inhibits the mitochondrial permeability transition pore (MPTP) in a calcineurin-independent fashion and MPTP is an important component of the cascade through which I/R damage occurs [58].…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological studies using cyclosporine A (CsA) to inhibit calcineurin need to be interpreted with caution because CsA also inhibits the mitochondrial permeability transition pore (MPTP) in a calcineurin-independent fashion and MPTP is an important component of the cascade through which I/R damage occurs [58]. However, FK506, does not inhibit MPTP and has also been shown to be cardioprotective in rat models of I/R [54–57, 59]. Our studies would suggest there are time of day differences in the activation of calcineurin in response to I/R, however, we were not able to detect significant AM/PM differences in in vitro biochemical assays of total calcineurin activity in heart tissue extracts (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion

Rotter

Grinsfelder

Parra

et al. 2014

Journal of Molecular and Cellular Cardiology

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Many important components of the cardiovascular system display circadian rhythmicity. In both humans and mice, cardiac damage from ischemia/reperfusion (I/R) is greatest at the transition from sleep to activity. The causes of this window of susceptibility are not fully understood. In the murine heart we have reported high amplitude circadian oscillations in expression of the cardioprotective protein regulator of calcineurin 1 (Rcan1). This study was designed to test whether Rcan1 contributes to the circadian rhythm in cardiac protection from I/R damage. Wild type (WT), Rcan1 KO, and Rcan1-Tg mice, with cardiomyocyte-specific overexpression of Rcan1, were subjected to 45 minutes of myocardial ischemia followed by 24 hours of reperfusion. Surgeries were performed either during the first two hours (AM) or the last two hours (PM) of the animal’s light phase. The area at risk was the same for all genotypes at either time point; however, in WT mice, PM-generated infarcts were 78% larger than AM-generated infarcts. Plasma cardiac troponin I levels were likewise greater in PM-operated animals. In Rcan1 KO mice there was no significant difference between the AM- and PM-operated hearts, which displayed greater indices of damage similar to that of PM-operated WT animals. Mice with cardiomyocyte-specific over expression of human RCAN1, likewise, showed no time-of-day difference, but had smaller infarcts comparable to those of AM-operated WT mice. In vitro, cardiomyocytes depleted of RCAN1 were more sensitive to simulated I/R and the calcineurin inhibitor, FK506, restored protection. FK506 also conferred protection to PM-infarcted WT animals. Importantly, transcription of core circadian clock genes was not altered in Rcan1 KO hearts. These studies identify the calcineurin/Rcan1-signaling cascade as a potential therapeutic target through which to benefit from innate circadian changes in cardiac protection without disrupting core circadian oscillations that are essential to cardiovascular, metabolic, and mental health.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion

Rotter

Grinsfelder

Parra

et al. 2014

Journal of Molecular and Cellular Cardiology

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“…Studies of intravenous adenosine prior to and during heart surgery have been modest in both size and effect 166–168 . Acadesine, a drug thought to increase adenosine levels in ischemic tissues, was compared with placebo in 2,698 patients undergoing CABG.…”

Section: Clinical Applications Of Pkc Regulatorsmentioning

confidence: 99%

Protein kinase C, an elusive therapeutic target?

Mochly‐Rosen

Das

Grimes

2012

Nat Rev Drug Discov

467

474

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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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“…A recent randomized trial looking at the effects of adenosine pretreatment in children undergoing cardiac surgery to repair congenital heart defects found that children in the adenosine group had less myocardial injury as shown by lower troponin levels, less inotropic requirements and shorter intensive care unit stays [46]. However, this trial was relatively small.…”

Section: Adenosinementioning

confidence: 96%

Myocardial protection from ischemia-reperfusion injury post coronary revascularization

Binder¹,

Ali²,

Chawla³

et al. 2015

Expert Review of Cardiovascular Therapy

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Effective primary and secondary prevention and advances in cardiac surgery have significantly improved the care and outcomes of patients with myocardial ischemia. While timely reperfusion has proved to be an invaluable tool, ischemia-reperfusion injury represents a mechanism that may limit its effectiveness. Numerous experimental studies have shown effective protection from ischemia-reperfusion injury in animal models, but translation into clinical practice has been less successful. This article summarizes the role of ischemia-reperfusion injury in the pathophysiology of ischemic heart disease and gives an overview of the various modalities that have been developed in order to provide myocardial protection from reperfusion injury in clinical practice.

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The myocardial protective effects of adenosine pretreatment in children undergoing cardiac surgery: a randomized controlled clinical trial

Abstract: This study demonstrates that adenosine pretreatment is protective of the myocardium during open-heart surgery in pediatric patients.

Cited by 23 publications

References 24 publications

Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion

Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion

Protein kinase C, an elusive therapeutic target?

Myocardial protection from ischemia-reperfusion injury post coronary revascularization

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