Ivabradine and metoprolol differentially affect cardiac glucose metabolism despite similar heart rate reduction in a mouse model of dyslipidemia.

Abstract

While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. β-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB+/+;LDLR-/-). Following a longitudinal study design, we used 3- and 6-mo-old mice, untreated or treated for 3 mo with ivabradine or metoprolol. Cardiac function was evaluated in vivo and ex vivo in working hearts perfused with 13C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared with 3-mo-old, 6-mo-old dyslipidemic mice had similar cardiac hemodynamics in vivo but impaired (P < 0.001) contractile function (aortic flow: -45%; cardiac output: -34%; stroke volume: -35%) and glycolysis (-24%) ex vivo. Despite inducing a similar 10% HRR, ivabradine-treated hearts displayed significantly higher stroke volume values and glycolysis vs. their metoprolol-treated counterparts ex vivo, values for the ivabradine group being often not significantly different from 3-mo-old mice. Further analyses highlighted additional significant cardiac alterations with disease progression, namely in the total tissue level of proteins modified by O-linked N-acetylglucosamine (O-GlcNAc), whose formation is governed by glucose metabolism via the hexosamine biosynthetic pathway, which showed a similar pattern with ivabradine vs. metoprolol treatment. Collectively, our results emphasize the implication of alterations in cardiac glucose metabolism and signaling linked to disease progression in our mouse model. Despite similar HRR, ivabradine, but not metoprolol, preserved cardiac function and glucose metabolism during disease progression.

• Authors: Fanny Vaillant, Benjamin Lauzier, Matthieu Ruiz, Yanfen Shi, Dominic Lachance, Marie-Eve Rivard, Virginie Bolduc, Eric Thorin, Jean-Claude Tardif, Christine Des Rosiers
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 311 Issue 4 Pg. H991-H1003 (10 01 2016) ISSN: 1522-1539 [Electronic] United States
• PMID: 27496881 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Adrenergic beta-1 Receptor Antagonists
• Benzazepines
• Cardiovascular Agents
• RNA, Messenger
• Ivabradine
• Metoprolol
• Glucose

Topics

• Adrenergic beta-1 Receptor Antagonists (pharmacology)
• Animals
• Benzazepines (pharmacology)
• Bradycardia
• Cardiovascular Agents (pharmacology)
• Disease Models, Animal
• Dyslipidemias (metabolism)
• Echocardiography
• Energy Metabolism (drug effects)
• Female
• Glucose (metabolism)
• Glycolysis (drug effects)
• Heart (drug effects)
• Heart Rate (drug effects)
• Hemodynamics (drug effects)
• Ivabradine
• Longitudinal Studies
• Male
• Metoprolol (pharmacology)
• Mice
• Myocardium (metabolism)
• RNA, Messenger (drug effects, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Stroke Volume
• Telemetry
• Transcriptome