Effects of a pharmacologically-induced shift of hemoglobin-oxygen dissociation on myocardial energetics during ischemia in patients with coronary artery disease.

Abstract

BACKGROUND:

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).

METHODS AND RESULTS:

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).

CONCLUSIONS:

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.

• Authors: Samer S Najjar, Paul A Bottomley, Steven P Schulman, Michele M Waldron, Robert P Steffen, Gary Gerstenblith, Robert G Weiss
• Journal: Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance (J Cardiovasc Magn Reson) Vol. 7 Issue 4 Pg. 657-66 ( 2005) ISSN: 1097-6647 [Print] England
• PMID: 16136855 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Antisickling Agents
• Biomarkers
• Oxyhemoglobins
• Phosphorus Isotopes
• Propionates
• Phosphocreatine
• Adenosine Triphosphate
• efaproxiral

Topics

• Adenosine Triphosphate (blood)
• Aged
• Analysis of Variance
• Aniline Compounds (adverse effects, blood, pharmacology, therapeutic use)
• Antisickling Agents (adverse effects, blood, pharmacology, therapeutic use)
• Biomarkers (blood)
• Blood Flow Velocity (drug effects)
• Coronary Artery Disease (diagnosis, drug therapy, metabolism, physiopathology)
• Coronary Circulation (drug effects)
• Cross-Over Studies
• Double-Blind Method
• Exercise Test
• Female
• Humans
• Magnetic Resonance Spectroscopy (methods)
• Male
• Middle Aged
• Myocardial Ischemia (diagnosis, drug therapy, metabolism, physiopathology)
• Oxygen Consumption (drug effects)
• Oxyhemoglobins (drug effects, metabolism)
• Phosphocreatine (blood, drug effects)
• Phosphorus Isotopes
• Propionates (adverse effects, blood, pharmacology, therapeutic use)
• Treatment Outcome