Abstract
The purpose of this review is to bridge the gap between clinical and basic research through providing a comprehensive and concise description of the cellular and molecular aspects of cardioprotective mechanisms and a critical evaluation of the clinical evidence of high-energy phosphates (HEPs) in ischemic heart disease (IHD). According to the well-documented physiological, pathophysiological and pharmacological properties of HEPs, exogenous creatine phosphate (CrP) may be considered as an ideal metabolic regulator. It plays cardioprotection roles from upstream to downstream of myocardial ischemia through multiple complex mechanisms, including but not limited to replenishment of cellular energy. Although exogenous CrP administration has not been shown to improve long-term survival, the beneficial effects on multiple secondary but important outcomes and short-term survival are concordant with its pathophysiological and pharmacological effects. There is urgent need for high-quality multicentre RCTs to confirm long-term survival improvement in the future.
Highlights
The heart is more than a hemodynamic pump
The ischemic myocardium preferentially utilizes the energy contained in endogenous creatine phosphate (CrP), followed by adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) (Figure 4) [62,63,64,65,66,67]
Main mechanisms maintaining the intracellular to extracellular concentration and charge gradients include: [1] pumping Ca2+ out of the cytoplasm by the plasma membrane Ca2+ ATPase [93], [2] exchange of Ca2+ for Na+ driven by the intracellular to extracellular concentration gradient of Na+ as a result of the plasma membrane Na+K+ ATPase [94], [3] sequestration of cytoplasm Ca2+ in sarcoplasmic reticulum (SR) by the SR Ca2+ ATPase [95], and [4] accumulation of intracellular Ca2+ by oxidation-dependent calcium sequestration inside the mitochondria [96]
Summary
The heart is more than a hemodynamic pump. It is an organ that needs energy from metabolism [1]. CrP is the storage and transport carrier of energy, which serves to transfer the HEP-bond from the site of ATP production to the site of ATP utilization through “CrP shuttle” (Figure 1) [28,29,30,31,32,33,34,35]. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CK, creatine kinase; CrP, creatine phosphate; HEP, high-energy phosphate; OP, oxidative phosphorylation; SP, substrate phosphorylation. The HEPs synthesized by glycolysis are far from meeting the energy requirements of heart Under such condition, the ischemic myocardium preferentially utilizes the energy contained in endogenous CrP, followed by ATP, ADP, and adenosine monophosphate (AMP) (Figure 4) [62,63,64,65,66,67]. The following we will focus on the pathophysiological and pharmacological effects of exogenous CrP, including but not limited to supplementing cellular energy
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