title: Enhanced β-adrenergic cardiac reserve in Trpm4⁻/⁻ mice with ischaemic heart failure.
abstract: OBJECTIVE
  Heart failure (HF) is a complex syndrome characterized by critically reduced cardiac contractility and function. We have shown previously that Transient Receptor Potential Melastatin 4 protein (TRPM4) functions as a Ca(2+)-activated non-selective cation channel and constitutes a novel regulator of ventricular contractility. In healthy Trpm4-deficient (Trpm4(-/-)) mice, we observed increased cardiac contractile function after β-adrenergic stimulation. In the current study, cardiac performance was examined in wild-type (WT) and Trpm4(-/-) mice with severe ischaemic HF.
  
  
  RESULTS
  Myocardial infarction (MI) was induced in WT and Trpm4(-/-) C57Bl6/N mice by ligation of the left anterior descending artery. During the first week after MI, mortality was higher in WT mice. Both groups showed similar infarct-typical ECG patterns during follow-up period. After 10 weeks, reduced ejection fraction and severe dilatation, determined by cardiac MRI, confirmed the development of HF in both genotypes. In vivo pressure-conductance analysis revealed no differences in cardiac contractility in basal conditions. However, during β-adrenergic stimulation, cardiac performance was significantly different between WT and Trpm4(-/-) mice. In contrast to increasing contractility in Trpm4(-/-) mice, WT mice showed a deteriorated cardiac performance. Also 30% of WT animals died during isoprenaline infusion vs. no Trpm4(-/-) mice. Infarct size, determined post mortem, was equal in WT and Trpm4(-/-) hearts.
  
  
  CONCLUSIONS
  Deletion of the Trpm4 gene in mice improved survival and significantly enhanced β-adrenergic cardiac reserve after inducing ischaemic HF. This suggests that pharmacological or genetic down-regulation of TRPM4 function might be a novel strategy in the management of HF.
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research (TRPLe), KU Leuven, Herestraat 49b802, Leuven 3000, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Jacobs
authors.affiliation: Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Leuven, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Oosterlinck
authors.affiliation: Department of Imaging and Pathology, Biomedical Magnetic Resonance Imaging Unit/Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaers
authors.affiliation: Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Leuven, Belgium.
authors.forename: Rachel
authors.initials: R
authors.lastname: Geenens
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research (TRPLe), KU Leuven, Herestraat 49b802, Leuven 3000, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Kerselaers
authors.affiliation: Department of Imaging and Pathology, Biomedical Magnetic Resonance Imaging Unit/Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research (TRPLe), KU Leuven, Herestraat 49b802, Leuven 3000, Belgium rudi.vennekens@med.kuleuven.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004562:Electrocardiography; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000150:complications* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012720:Severity of Illness Index; D013318:Stroke Volume / Q000187:drug effects; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; D007545:Isoproterenol
keywords: Cardiac contractility; Heart failure; Ion channel; TRPM4; β-Adrenergic stimulation