phosphocreatine and Coronary-Artery-Disease

Topics: Acute Disease; Coronary Artery Disease; Cytokines; Humans; Inflammation; Myocardial Ischemia; Phosphocreatine

Conventional strategies to treat myocardial ischemia include interventions that reduce oxygen demand and/or increase myocardial blood flow. Animal experiments suggest that right-shifting the hemoglobin-oxygen dissociation curve may also attenuate the metabolic consequences of myocardial ischemia. We evaluated whether exercise-induced myocardial ischemia can be alleviated in subjects with coronary artery disease (CAD) by enhancing oxygen release with an allosteric modifier of hemoglobin's affinity for oxygen (RSR13).. Seven subjects with CAD underwent a randomized, double-blind, cross-over study of the metabolic consequences of RSR13 administration on myocardial ischemia. Myocardial high-energy phosphates were quantified with 31P nuclear magnetic resonance (NMR) spectroscopy before, during, and after isometric handgrip-exercise. Subjects underwent NMR studies at baseline and on two separate occasions following the infusion of RSR13 (100 mg/kg) or placebo. RSR13 infusion significantly increased mean p50 by 8.1 +/- 2.7 mmHg at the end of the infusion, and it was still elevated by 4.9 +/- 3.3 mmHg after the completion of the treadmill tests while placebo had no effect. The myocardial creatine-phosphate (PCr) to adenosine-triphosphate (ATP) ratio decreased during handgrip-exercise in the baseline studies (from 1.39 +/- 0.23 before exercise to 0.95 +/- 0.21 during handgrip-exercise, p = 0.0001) and in the placebo studies (from 1.29 +/- 0.16 to 0.98 +/- 0.37, p = 0.06) but not during administration of RSR13 (from 1.28 +/- 0.18 to 1.02 +/- 0.24, p = 0.12). However, the mean values of cardiac PCr/ATP during handgrip-exercise did not differ significantly among the three measurements (baseline, placebo, RSR13).. A single infusion of RSR13 to subjects with CAD increased mean p50 by 4.9-8.1 mmHg but did not significantly alter myocardial PCr/ATP during exercise. This is the largest right-shift in hemoglobin-oxygen binding affinity achieved in CAD subjects, and it did not provide clear evidence of protection from cardiac ischemia.

Topics: Adenosine Triphosphate; Aged; Analysis of Variance; Aniline Compounds; Antisickling Agents; Biomarkers; Blood Flow Velocity; Coronary Artery Disease; Coronary Circulation; Cross-Over Studies; Double-Blind Method; Exercise Test; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardial Ischemia; Oxygen Consumption; Oxyhemoglobins; Phosphocreatine; Phosphorus Isotopes; Propionates; Treatment Outcome

The usefulness of phosphorus-31 nuclear magnetic resonance spectroscopy (31P NMRS) for detecting heart graft rejection after transplantation has been investigated by several researchers, and it has thus been demonstrated to be a valid technique for detecting acute myocardial rejection. In this study, we investigated the value of 31P NMRS to assess chronic cardiac allograft rejection. Lewis rat hearts were transplanted into the femoral region of F-344 rat recipients which were treated with cyclosporine, 5mg/kg body weight, by a daily intramuscular injection for 30 days beginning on the day of transplantation. The control isografts employed Lewis donors and recipients not given cyclosporine. The ratios of phosphocreatine (PCr) to inorganic phosphate (Pi), beta-adenosine triphosphate (beta-ATP) to Pi, and PCr to beta-ATP were monitored using surface coil 31P NMRS. 31P NMRS was performed 3, 30, and 60 days after transplantation, and the degree of the rejection and arteriosclerosis of the coronary arteries were then assessed histologically. The PCr:Pi and beta-ATP:Pi ratios for the allografts demonstrated a significant decrease on postoperative day (POD) 60 from that on POD 30 (PCr:Pi, P < 0.001; beta-ATP:Pi, P < 0.01). Although a significant difference existed between the isografts and allografts on POD 60 (PCr: Pi, P < 0.01; beta-ATP:P, P < 0.01), no significant difference was found in the PCr:beta-ATP ratio between the allografts and the isografts. On POD 60, the allografts showed significant graft rejection and arteriosclerotic changes in the coronary arteries. These findings therefore demonstrated the effectiveness of 31P NMRS for detecting chronic graft rejection in a rat model.

Topics: Adenosine Triphosphate; Animals; Chronic Disease; Coronary Artery Disease; Coronary Vessels; Cyclosporine; Graft Rejection; Graft Survival; Heart Transplantation; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus; Phosphorus Isotopes; Rats; Rats, Inbred F344; Rats, Inbred Lew; Transplantation, Homologous

The relationships between contractile function, myocardial oxygen consumption, and tissue high energy phosphate and lactate content were investigated during partial coronary flow disruption. The experimental preparation was an isolated, isovolumic retrograde blood-perfused rabbit heart. Both developed pressure (r = 0.94) and dp/dt (r = 0.95) exhibited strong linear correlations with myocardial oxygen consumption that were stable for up to 45 min after blood flow reduction. In contrast, tissue high energy phosphate content exhibited nonlinear relationships with both developed pressure and oxygen consumption such that systolic mechanical function and oxidative metabolism declined to 20 and 30% of control values, respectively, before significant abnormalities in myocardial high energy phosphate stores were observed. Similarly, developed pressure and oxygen consumption decreased to 36 and 48% of control, respectively, before abnormal tissue lactate content was detected. The results of this study indicate that: (a) mechanical function is closely related to the rate of oxidative energy production during partial coronary flow disruption, and (b) despite the development of significant contractile dysfunction, tissue high energy phosphate content remains at normal levels except under the most severely flow-deprived conditions. The preservation of tissue energy stores can be explained by the apparent coupling of contractile performance to oxidative energy production, which could function to maintain myocardial energy balance during partial coronary flow restriction.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Blood Flow Velocity; Blood Pressure; Blood Volume; Coronary Artery Disease; Energy Metabolism; Lactates; Male; Myocardial Contraction; Myocardium; Oxygen Consumption; Perfusion; Phosphates; Phosphocreatine; Rabbits