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


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.
Najjar
Samer S
SS
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Bottomley
Paul A
PA
Schulman
Steven P
SP
Waldron
Michele M
MM
Steffen
Robert P
RP
Gerstenblith
Gary
G
Weiss
Robert G
RG
D000255:Adenosine Triphosphate / Q000097:blood; D000368:Aged; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000986:Antisickling Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001783:Blood Flow Velocity / Q000187:drug effects; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D010101:Oxygen Consumption / Q000187:drug effects; D010108:Oxyhemoglobins / Q000187:drug effects* / Q000378:metabolism*; D010725:Phosphocreatine / Q000097:blood / Q000187:drug effects; D010759:Phosphorus Isotopes; D011422:Propionates / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000814:Aniline Compounds; D000986:Antisickling Agents; D015415:Biomarkers; D010108:Oxyhemoglobins; D010759:Phosphorus Isotopes; D011422:Propionates; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; C067396:efaproxiral