Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning

Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.

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Faculty Opinions recommendation of Remote ischemic conditioning to protect against ischemia-reperfusion injury: a systematic review and meta-analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717954628.793461208 ◽

2012 ◽

Author(s):

Florian Falter

Keyword(s):

Systematic Review ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Meta Analysis ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning

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Remote Ischemic Conditioning against Ischemia/reperfusion Injury

Annual Update in Intensive Care and Emergency Medicine 2011 ◽

10.1007/978-3-642-18081-1_3 ◽

2011 ◽

pp. 26-36 ◽

Cited By ~ 1

Author(s):

P. Meybohm ◽

B. Bein

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning

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MINIMIZING ISCHEMIA REPERFUSION INJURY WITH CARIPORIDE AND GLYCERYL TRINITRATE DURING LONG-TERM PRESERVATION OF THE DONOR HEART FOR TRANSPLANTATION.

Transplantation Journal ◽

10.1097/00007890-200607152-01647 ◽

2006 ◽

Vol 82 (Suppl 2) ◽

pp. 616-617

Author(s):

&NA;

Keyword(s):

Glyceryl Trinitrate ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Donor Heart ◽

Long Term Preservation

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The application of remote ischemic conditioning in cardiac surgery

F1000Research ◽

10.12688/f1000research.11018.1 ◽

2017 ◽

Vol 6 ◽

pp. 928 ◽

Cited By ~ 3

Author(s):

Zeljko J. Bosnjak ◽

Zhi-Dong Ge

Keyword(s):

Cardiac Surgery ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Clinical Success ◽

Ischemia Reperfusion ◽

Preclinical Research ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Remote Conditioning ◽

Multicenter Clinical Trials

Perioperative myocardial ischemia and infarction are the leading causes of morbidity and mortality following anesthesia and surgery. The discovery of endogenous cardioprotective mechanisms has led to testing of new methods to protect the human heart. These approaches have included ischemic pre-conditioning, per-conditioning, post-conditioning, and remote conditioning of the myocardium. Pre-conditioning and per-conditioning include brief and repetitive periods of sub-lethal ischemia before and during prolonged ischemia, respectively; and post-conditioning is applied at the onset of reperfusion. Remote ischemic conditioning involves transient, repetitive, non-lethal ischemia and reperfusion in one organ or tissue (remote from the heart) that renders myocardium more resistant to lethal ischemia/reperfusion injury. In healthy, young hearts, many conditioning maneuvers can significantly increase the resistance of the heart against ischemia/reperfusion injury. The large multicenter clinical trials with ischemic remote conditioning have not been proven successful in cardiac surgery thus far. The lack of clinical success is due to underlying risk factors that interfere with remote ischemic conditioning and the use of cardioprotective agents that have activated the endogenous cardioprotective mechanisms prior to remote ischemic conditioning. Future preclinical research using remote ischemic conditioning will need to be conducted using comorbid models.

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Clinical translation of myocardial conditioning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00027.2018 ◽

2018 ◽

Vol 314 (6) ◽

pp. H1225-H1252 ◽

Cited By ~ 14

Author(s):

Hans Erik Bøtker ◽

Thomas Ravn Lassen ◽

Nichlas Riise Jespersen

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Blood Flow ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Acute Ischemia ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Flow Restriction

Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.

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Neural Mechanisms of Cardioprotection

Physiology ◽

10.1152/physiol.00037.2013 ◽

2014 ◽

Vol 29 (2) ◽

pp. 133-140 ◽

Cited By ~ 21

Author(s):

Andrey Gourine ◽

Alexander V. Gourine

Keyword(s):

Myocardial Infarction ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neural Mechanisms ◽

Vagal Activity ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Reflex Pathways ◽

Autonomic Reflex

This review highlights the importance of neural mechanisms capable of protecting the heart against lethal ischemia/reperfusion injury. Increased parasympathetic (vagal) activity limits myocardial infarction, and recent data suggest that activation of autonomic reflex pathways contributes to powerful innate mechanisms of cardioprotection underlying the remote ischemic conditioning phenomena.

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