Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Christiane Vettel; Marta Lindner; Matthias Dewenter; Kristina Lorenz; Constanze Schanbacher; Merle Riedel; Simon Lämmle; Simone Meinecke; Fleur E Mason; Samuel Sossalla; Andreas Geerts; Michael Hoffmann; Frank Wunder; Fabian J Brunner; Thomas Wieland; Hind Mehel; Sarah Karam; Patrick Lechêne; Jérôme Leroy; Grégoire Vandecasteele; Michael Wagner; Rodolphe Fischmeister; Ali El-Armouche

doi:10.1161/CIRCRESAHA.116.310069

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Circ Res. 2017 Jan 6;120(1):120-132. doi: 10.1161/CIRCRESAHA.116.310069. Epub 2016 Oct 31.

Authors

Christiane Vettel¹, Marta Lindner¹, Matthias Dewenter¹, Kristina Lorenz¹, Constanze Schanbacher¹, Merle Riedel¹, Simon Lämmle¹, Simone Meinecke¹, Fleur E Mason¹, Samuel Sossalla¹, Andreas Geerts¹, Michael Hoffmann¹, Frank Wunder¹, Fabian J Brunner¹, Thomas Wieland¹, Hind Mehel¹, Sarah Karam¹, Patrick Lechêne¹, Jérôme Leroy¹, Grégoire Vandecasteele¹, Michael Wagner¹, Rodolphe Fischmeister¹, Ali El-Armouche²

Affiliations

¹ From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.).
² From the Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany (C.V., M.D., M.R., S.M.); UMR-S 1180, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France (M.L., H.M., S.K., P.L., J.L., G.V., R.F.); Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Germany (M.D.); Institute of Pharmacology and Toxicology, University of Würzburg and Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany (K.L., C.S.); Comprehensive Heart Failure Center, University of Würzburg, and West German Heart and Vascular Center Essen, Germany (K.L.); Department of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., M.W., A.E.-A.); Department of Cardiology and Pneumology, Center of Molecular Cardiology, UMG Heart Center, Georg August University Medical School Göttingen, Germany (F.E.M., S.S.); Department of Internal Medicine III, Cardiology and Angiology, University of Kiel, Germany (S.S.); BAYER Pharma AG, Wuppertal, Germany (A.G., M.H., F.W.); University Heart Center, Department of General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Germany (F.J.B.); and DZHK (German Centre for Cardiovascular Research), partner sites Heidelberg/Mannheim, Göttingen and Hamburg/Kiel/Lübeck, Germany (C.V., M.D., M.R., S.M., F.E.M., S.S., F.J.B., T.W.). [email protected] [email protected].

PMID: 27799254
DOI: 10.1161/CIRCRESAHA.116.310069

Abstract

Rationale: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.

Objective: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.

Methods and results: Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca²⁺-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca²⁺ leakage and lower basal phosphorylation levels of Ca²⁺-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.

Conclusions: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.

Keywords: cardiac arrhythmia; catecholamine; cyclic GMP-stimulated phosphodiesterase; heart rate; myocardial contraction.

MeSH terms

Animals
Arrhythmias, Cardiac / chemically induced
Arrhythmias, Cardiac / metabolism*
Arrhythmias, Cardiac / prevention & control
Cardiotonic Agents / metabolism*
Catecholamines / toxicity
Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors
Cyclic Nucleotide Phosphodiesterases, Type 2 / biosynthesis*
Dogs
Female
Imidazoles / pharmacology
Isoproterenol / toxicity*
Male
Mice
Mice, Transgenic
Myocardial Contraction / drug effects
Myocardial Contraction / physiology*
Myocardial Infarction / metabolism*
Myocardial Infarction / physiopathology
Triazines / pharmacology

Substances

2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one
Cardiotonic Agents
Catecholamines
Imidazoles
Triazines
Cyclic Nucleotide Phosphodiesterases, Type 2
Isoproterenol