Griet Jacobs1, Wouter Oosterlinck2, Tom Dresselaers3, Rachel Geenens2, Sara Kerselaers1, Uwe Himmelreich3, Paul Herijgers2, Rudi Vennekens4. 1. Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research (TRPLe), KU Leuven, Herestraat 49b802, Leuven 3000, Belgium. 2. Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Leuven, Belgium. 3. Department of Imaging and Pathology, Biomedical Magnetic Resonance Imaging Unit/Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium. 4. Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research (TRPLe), KU Leuven, Herestraat 49b802, Leuven 3000, Belgium rudi.vennekens@med.kuleuven.be.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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