Enhanced β-adrenergic cardiac reserve in Trpm4⁻/⁻ mice with ischaemic heart failure

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.

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.

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.