Exogenous Creatine Phosphate Research Articles

High-Energy Phosphates and Ischemic Heart Disease: From Bench to Bedside.

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.

Myocardial Protective Effect of Exogenous Creatine Phosphate in Children Undergoing Open Heart Surgery

Objective: To explore the protective role of exogenous Creatine Phosphate (PCr) in the postoperative cardiac muscle recovery in children undergoing open heart surgery. Material and methods: 63 cases of congenital heart disease were randomly divided into 3 groups; A, B and C; 21 cases in each group. Myocardial perfusion fluids were made of the same amount of blood in the St, Thomas Hospital cardioplegic solution type 2 (STH 2). In B and C group, intraoperative myocardial perfusion solution added with exogenous CP. All the groups were postoperatively treated with general fluid therapy, while group C was given postoperative intravenous exogenous CP. Trends of myocardial enzyme at different time points were monitored. Results: At the end of surgery (T2), enzyme levels in the plasma were significantly increased, no difference between the groups B and C but were significantly lower than that in group A (P<0.05); after surgery myocardial enzyme levels recovered fastest in Group C, slowest in A group, the differences between each group were significant (P<0.05). Conclusions: Perioperative and postoperative exogenous PCr have myocardial protective effect and accelerate the repair of injured myocardium due to ischemia during open heart surgery in children.

The Effect of Exogenous Creatine Phosphate on Myocardial Injury After Percutaneous Coronary Intervention

To evaluate the effect of exogenous creatine phosphate (CP) on myocardial injury after percutaneous coronary intervention (PCI). Four hundred patients were divided to receive conventional therapy (control group) or 3-day intravenous infusion of CP after PCI (CP group). Levels of creatine kinase MB (CK-MB) and troponin I (TnI) were measured before and on postprocedural day 3. Postprocedural CK-MB and TnI in the CP group were significantly increased compared to the control group. In the CP group, 8.0% and 5.0% of patients had an increase in CK-MB 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (19.0% and 9.0%, respectively); 12.0% and 10.0% of patients had an increase in TnI 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (21.0% and 18.0%, respectively). Exogenous CP was helpful to reduce myocardial injury after PCI.

Role of creatine phosphate as a myoprotective agent during coronary artery bypass graft in elderly patients

To evaluate the myocardial protective effect of exogenous creatine phosphate added to a cardioplegic solution for elderly patients undergoing a coronary artery bypass graft (CABG) in China. Twenty-four patients (age>65 years) who underwent CABG were randomly divided into a control group (n=12) and an experimental group (n=12). The concentrations of malonyldehyde and superoxide dismutase in the blood were measured before aortic clamping and at 0, 30, 60, and 120 min after the release of aortic clamping. Creatine phosphokinase (CK), creatine phosphokinase-MB (CK-MB), lactate dehydrogenase, and cardiac troponin T were measured before aortic clamping and at 2, 24, and 48 h after the release of aortic clamping. Myocardial ultrastructures were examined under an electron microscope. The concentrations of malonyldehyde in both groups increased after the release of aortic clamping (at 0, 30, 60, and 120 min), but were higher in the control group compared with the experimental group (P<0.01). The concentrations of superoxide dismutase in both groups were decreased after the release of aortic clamping and were higher in the experimental group compared with the control group (P<0.01) at 0, 30, 60, and 120 min after the release of aortic clamping. The values of CK, CK-MB, lactate dehydrogenase, and cardiac troponin T at 2, 24, and 48 h after the release of the aortic clamping were lower in the experimental group than in the control group (P<0.01). Electron microscopy showed that the mitochondria in the experimental group were histologically better than those in the control group. Exogenous creatine phosphate added to the cardioplegia solution can provide energy to myocardial cells and can relieve ischemia/reperfusion-related injury in elderly patients during CABG in China.

Clinical Study of the Protective Effect of Exogenous Creatine Phosphate on Ischemic Myocardium during Open Heart Surgery

This study was designed to evaluate the myocardial protective effect of exogenous creatine phosphate (CP) added to cardioplegic solution for use in open heart surgery. Ninety-eight patients were divided into a control group (n = 44) and a CP group (n =54). The spontaneous recovery rate of heart beat after aortic declamping was recorded and changes of serum enzymes including CPK, LDH, CPK-MB, HBDH, and AST were evaluated. The ultrastructural alterations of the myocardial tissue were observed in 4 patients (2 cases from each group) who had cardiac valve replacement. The spontaneous recovery rate of heart beat in the CP group was significantly higher than the control group (39/54 versus 22/44 ), and the peak values of leakage of serum enzymes of the control group appeared earlier and receded later than those of the CP group. Electron microscope examination revealed better preservation of the ultrastructures of the myocardial tissue in the CP group than that of the control group. This data indicates that exogenous creatine phosphate added to the cardioplegic solution offers a better protective effect on the ischemic myocardium during open heart surgery.

MgADP Promotes a Catch-Like State Developed through Force-Calcium Hysteresis in Tonic Smooth Muscle

Tonic rabbit femoral artery and phasic rabbit ileum smooth muscles permeabilized with Triton X-100 were activated either by increasing [Ca 2+] from pCa > 8.0 to pCa 6.0 (calcium-ascending protocol) or contracted at pCa 6.0 before lowering [Ca 2+] (calcium-descending protocol). The effects of, respectively, high [MgATP]/low [MgADP] [10 mM MgATP + creatine phosphate (CP) + creatine kinase (CK)] or low [MgATP]/[MgADP] (2 mM MgATP, 0 CP, 0 CK) on the “force-[Ca]” relationships were determined. In femoral artery at low, but not at high, [MgATP]/[MgADP] the force and the ratio of stiffness/force at pCa 7.2 were significantly higher under the calcium-descending than calcium-ascending protocols (54% vs. 3% of P o, the force at pCa 6.0) (force hysteresis); the levels of regulatory myosin light chain (MLC 20) phosphorylation (9 ± 2% vs. 10 ± 2%) and the velocities of unloaded shortening V 0 (0.02 ± 0.004 l/s with both protocols) were not significantly different. No significant force hysteresis was detected in rabbit ileum under either of these experimental conditions. [MgADP], measured in extracts of permeabilized femoral artery strips by two methods, was 130–140 μM during maintained force under the calcium-descending protocol. Exogenous CP (10 mM) applied during the descending protocol reduced endogenous [MgADP] to 46 ± 10 μM and abolished force hysteresis: residual force at low [Ca 2+] was 17 ± 5% of maximal force. We conclude that the proportion of force-generating nonphosphorylated (AM dp) relative to phosphorylated cross-bridges is higher on the Ca 2+-descending than on the Ca 2+-ascending force curve in tonic smooth muscle, that this population of positively strained dephosphorylated cross-bridges has a high affinity for MgADP, and that the dephosphorylated AM dp · MgADP state makes a significant contribution to force maintenance at low levels of MLC 20 phosphorylation.

St. Thomas' Hospital cardioplegia: Enhanced protection with exogenous creatine phosphate

Experimentally, creatine phosphate (CP) improves postischemic recovery of function and reduces postischemic arrhythmias. We studied 50 patients undergoing valve replacement. They were randomized into either a control group, who received St. Thomas' Hospital cardioplegic solution No. 1, or a CP-treated group, receiving the same cardioplegic solution plus CP (10 mmol/L). There were no preoperative clinical differences between groups. Assessment was by electrocardiographic analysis, inotropic drug requirement, quantitative birefringence, myocardial high-energy phosphate content, function, and semiquantitative ultrastructural assessment. Direct-current shocks were reduced in the CP-treated group (0.88 +/- 0.15) compared with the control group (1.40 +/- 0.14; p < 0.02), as was the total number of joules (22.0 +/- 3.5 versus 34.4 +/- 3.7, respectively; p <0.02). The incidence of spontaneous sinus rhythm was higher in the CP-treated group (40% versus 8%; p < 0.05) and the incidence of postoperative arrhythmias, lower (8% versus 32%; p < 0.05). Prolonged inotropic administration (12 hours or longer) occurred in fewer patients in the CP-treated group (4% versus 28%; p < 0.05). Response to inotropic support (in the subset of patients requiring this treatment) was significantly greater in the CP-treated group than in the control group. There were no differences in recovery of function, birefringence changes, myocardial high-energy phosphate content, or ultrastructure between groups. St. Thomas' Hospital cardioplegic solution No. 1 plus CP enhanced myocardial protection and conferred a direct benefit to the patient by reducing postoperative arrhythmias and need of prolonged inotropic support.

Exogenous creatine phosphate, added to St Thomas' Hospital cardioplegia no 1 (STH1), enhances myocardial protection in valve surgery patients

Exogenous creatine phosphate, added to St Thomas' Hospital cardioplegia no 1 (STH1), enhances myocardial protection in valve surgery patients

Biochemical changes induced in the myocardial cell during cardioplegic arrest supplemented with creatine phosphate

The purpose of this work was to evaluate the biochemical changes in the myocardial cell using cardioplegia supplemented with creatine phosphate (CP). Many previous studies have demonstrated the beneficial effect of CP on the ischemic myocardium and its mechanism of action has been assumed to be mainly extracellular. Based on the assumption that CP could also exert some influence on myocardial cellular metabolism, this investigation was carried out. Forty patients undergoing mitral valve replacement were divided into two groups: group 1 was treated with standard cardioplegic solution, and group 2 was treated with cardioplegic solution enriched with CP at a concentration of 10 mmol/L. Samples of papillary muscle, obtained from the removed valve, were studied by means of biochemical methods in order to assess the enzyme activities and the metabolites of the different biochemical pathways related to energy metabolism in the myocardial cell. One papillary muscle sample was used to determine enzyme activities spectrophotometrically; another was used to evaluate metabolite concentrations by spectrophotometric or spectrophotofluorimetric methods. The rate of spontaneous functional recovery after rewarming and weaning from cardiopulmonary bypass (CPB) also was evaluated. In group 2, the V max of enzymatic activities was significantly greater (hexokinase, malate dehydrogenase, glutamate dehydrogenase, total NADH cytochrome c reductase) and a better functional state of the heart was observed after CPB. On the basis of the clinical and biochemical data, it is concluded that the myocardium was better preserved when CP was added to the cardioplegic solution. Therefore, the results suggest a possible interaction of exogenous CP with cellular metabolism.

Protection of isolated rat heart from oxidative stress by exogenous creatine phosphate

The influence of exogenous creatine phosphate (CP) on peroxidative heart injury was investigated in two experimental models: isolated working rat hearts and myocardial membrane preparations. In the first model the addition of 190 μ m hydrogen peroxide to the perfusion buffer caused a marked decrease of aortic flow, minute work and peak aortic pressure, and leakage of intracellular enzymes. In the presence of 10 m m CP the hemodynamic damage produced by the same concentration of hydrogen peroxide was significantly lower and enzyme release was also remarkably reduced. The protection was concentration-dependent and the whole structure of the molecule was required since creatine was found to be ineffective. In the absence of hydrogen peroxide, CP and creatine did not affect heart peformance. In microsomal membrane preparations CP decreased the formation of thiobarbituric acid-reactive material (malonaldehyde) induced by hydrogen peroxide in the presence of ferrous ions. This protection was concentration-dependent and occurred at physiological concentrations of CP. Also in this experimental model creatine had no effect and creatine plus inorganic phosphate was much less active than CP. The influence of CP on oxidative heart stress could account for the beneficial effect of this substance in different models of ischemic injury.

Protection of myocardial cells from oxidative stress by exogenous creatine phosphate in isolated rat hearts

Protection of myocardial cells from oxidative stress by exogenous creatine phosphate in isolated rat hearts

Effect of creatine phosphate administration on the rat heart adenylate pool

Creatine phosphate (CP) has been shown to possess some pharmacological properties. When added to cardioplegic solutions it improves their myocardial protection. Furthermore exogenous creatine phosphate shows an anti-arrhythmic effect in the experimental animal and appears to decrease lactate formation following haemorrhagic shock. These properties have been ascribed to the conservation of the tissue stores of ATP. Recently Down et al. have observed higher rat heart levels of ATP and creatine phosphate after the intravenous administration of creatine phosphate. Since it is difficult to find the conditions for an increase of the adenylate pool, it seems of interest to establish whether the ATP increase is due to a rise of the total adenylate pool or of the energy charge or of both. Similarly the higher creatine phosphate concentration may be ascribed to a variation of the CP/creatine ratio or to an increase in the creatine plus CP pool. In the present paper we report that the administration of creatine phosphate raises both the adenylate pool and the energy charge. An increase of creatine and the creatine phosphate pool was also observed.

Creatine phosphate: An additive myocardial protective and antiarrhythmic agent in cardioplegia

The potential for enhancing myocardial protection by adding high-energy phosphates to cardioplegic solutions was investigated in a rat heart model of cardiopulmonary bypass and ischemic arrest. Creatine phosphate (CP) was evaluated as an additive to the St. Thomas' Hospital cardioplegic solution. Dose-response studies (CP 0 to 50 mmol/L) revealed 10.0 mmol/L as the optimal concentration which improved recovery of aortic flow and cardiac output after a 40 minute period of normothermic (37 degrees C) ischemic arrest from 21.2% +/- 5.4% and 32.8% +/- 4.6% in the CP-free control group to 82.5% +/- 3.7% and 82.6% +/- 4.2% (p less than 0.001), respectively. Creatine kinase (CK) leakage was reduced by 68.7% (p less than 0.001) in the CP group. With hypothermic (20 degrees C) ischemia (240 minutes) and multidose (every 30 minutes) cardioplegia, recoveries of aortic flow and cardiac output were improved from 33.1% +/- 8.4% and 42.2% +/- 7.7% in the CP-free control group to 77.9% +/- 4.2% and 79.6% +/- 4.3% (p less than 0.001), respectively, in the drug group. In addition to improving function and decreasing CK release, CP reduced reperfusion arrhythmias, significantly decreasing the time between cross-clamp removal and return of regular rhythm and also completely obviating the need for electrical defibrillation. 51Chromium-ethylenediaminetetraacetic acid (51Cr-EDTA), an extracellular space marker, was used to study the disappearance of CP from the cardioplegic solution during its stasis in the heart. Upon reperfusion, two thirds of the infused dose appeared unchanged in the coronary effluent; the remainder was either degraded or accumulated by the myocardium. Despite its alleged inability to enter the myocardial cell, exogenous CP exerts potent protective and antiarrhythmic effects when added to the St. Thomas' Hospital cardioplegic solution. Although the mechanism of action remains to be elucidated, it may involve binding or uptake of the drug.

Effect of exogenous Creatine Phosphate on the metabolic and contractile state of the isolated perfused rabbit heart in the early phase of hypoxia

Effect of exogenous Creatine Phosphate on the metabolic and contractile state of the isolated perfused rabbit heart in the early phase of hypoxia