ABSTRACT
Introduction: A critical mechanism of how hypoxia/ischemia causes irreversible myocardial injury is through the exhaustion of adenosine triphosphate (ATP). Cyclocreatine (CCr) and its water-soluble salt Cyclocreatine-Phosphate (CCrP) are potent bioenergetic agents that preserve high levels of ATP during ischemia.
Areas covered: CCr and CCrP treatment prior to the onset of ischemia, preserved high levels of ATP in ischemic myocardium, reduced myocardial cell injury, exerted anti-inflammatory and anti-apoptotic activities, and restored contractile function during reperfusion in animal models of acute myocardial infarction (AMI), global cardiac arrest, cardiopulmonary bypass, and heart transplantation. Medline and Embase (1970 – Feb 2019), the WIPO databank (up to Feb 2019); no language restriction.
Expert opinion: This review provides the basis for a number of clinical applications of CCrP and CCr to minimize ischemic injury and necrosis. One strategy is to administer CCrP to AMI patients in the pre-hospital phase, as well as during, or after Percutaneous Coronary Intervention (PCI) procedure to potentially achieve protection of the myocardium, reduce infarcted-size, and, thus, limit the progression to heart failure. Another clinical applications are in predictable myocardial ischemia where pretreatment with CCrP would likely improve outcome and quality of life of patients who will undergo cardiopulmonary bypass for coronary revascularization and end-stage heart failure patients scheduled for heart transplantation.
Article highlights box
Ischemia causes irreversible myocardial injury through the exhaustion of the high-energy source ATP.
Reduced ATP levels during ischemia is associated with the release of the cardiac-derived inflammatory mediator, named Nourin, tissue inflammation, apoptosis, and reduction of contractile function.
The administration of the bioenergetic agents, CCr and CCrP preserved high levels of myocardial ATP and reduced myocardial cell injury, circulating Nourin, tissue inflammation and apoptosis, as well as restored immediate contractile function.
CCr and CCrP showed their cardioprotective properties in animal models of AMI, global cardiac arrest, cardiopulmonary bypass, and heart transplantation.
CCrP can be administered to acute myocardial infarction patients in the pre-hospital phase, as well as during, or some hours after PCI procedure to potentially achieve protection of a greater amount of myocardium, reduce the infarcted scar size, and, thus, limit the deleterious remodeling that leads to heart failure.
CCrP can be administered to predictable myocardial ischemia where pretreatment of surgical patients with CCrP would likely improve outcome and quality of life of patients who will undergo cardiopulmonary bypass for coronary revascularization and end-stage heart failure patients scheduled for heart transplantation procedure.
The U.S. Food & Drug Administration (FDA) has awarded CCrP the Orphan Drug Status with the designation of: ‘Prevention of Ischemic Injury to Enhance Cardiac Graft Recovery and Survival in Heart Transplantation’.
CCr can be administered prophylactically to likely protect against ischemia-induced heart damage in ischemic heart disease (IHD) patients and patients with high risk for cardiovascular diseases.
Acknowledgments
The authors would like to thank Mrs. Amy Robinson for proofing and editing the prepared manuscript.
Declaration of interest
SA Elgebaly is the Founder and CEO of Nour Heart, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.