MD1 Depletion Predisposes to Ventricular Arrhythmias in the Setting of Myocardial Infarction

Background Myeloid differentiation protein 1 (MD1) is expressed in the human heart and is a negative regulator of Toll-like receptor 4 (TLR4) signalling. MD1 exerts anti-arrhythmic effects. Aim The aim of this study was to determine the role of MD1 in myocardial infarction (MI)-related ventricular arrhythmias (VAs). Method Myocardial infarction was induced by surgical ligation of the left anterior coronary artery in MD1 knockout (KO) mice and their wild-type littermates. Myocardial infarction-induced vulnerability to VAs and its underlying mechanisms were evaluated. Results Myeloid differentiation protein 1 was downregulated in the MI mice. Myeloid differentiation protein 1 deficiency decreased post-MI left ventricular (LV) function and increased the infarct size. The MI mice exhibited prolonged action potential duration (APD), enhanced APD alternans thresholds, and a higher incidence of VAs. Myocardial infarction-induced LV fibrosis and inflammation decreased the expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1, increased Cav1.2 expression, and disturbed Ca2+ handling protein expression. These MI-induced adverse effects were further exacerbated in KO mice. Mechanistically, MD1 deletion markedly enhanced the activation of the TLR4/calmodulin-dependent protein kinase II (CaMKII) signalling pathway in post-MI mice. Conclusions Myeloid differentiation protein 1 deletion increases the vulnerability to VAs in post-MI mice. This is mainly caused by the aggravated maladaptive LV fibrosis and inflammation and interference with the expressions of ion channels and Ca2+ handling proteins, which is related to enhanced activation of the TLR4/CaMKII signalling pathway. Myeloid differentiation protein 1 (MD1) is expressed in the human heart and is a negative regulator of Toll-like receptor 4 (TLR4) signalling. MD1 exerts anti-arrhythmic effects. The aim of this study was to determine the role of MD1 in myocardial infarction (MI)-related ventricular arrhythmias (VAs). Myocardial infarction was induced by surgical ligation of the left anterior coronary artery in MD1 knockout (KO) mice and their wild-type littermates. Myocardial infarction-induced vulnerability to VAs and its underlying mechanisms were evaluated. Myeloid differentiation protein 1 was downregulated in the MI mice. Myeloid differentiation protein 1 deficiency decreased post-MI left ventricular (LV) function and increased the infarct size. The MI mice exhibited prolonged action potential duration (APD), enhanced APD alternans thresholds, and a higher incidence of VAs. Myocardial infarction-induced LV fibrosis and inflammation decreased the expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1, increased Cav1.2 expression, and disturbed Ca2+ handling protein expression. These MI-induced adverse effects were further exacerbated in KO mice. Mechanistically, MD1 deletion markedly enhanced the activation of the TLR4/calmodulin-dependent protein kinase II (CaMKII) signalling pathway in post-MI mice. Myeloid differentiation protein 1 deletion increases the vulnerability to VAs in post-MI mice. This is mainly caused by the aggravated maladaptive LV fibrosis and inflammation and interference with the expressions of ion channels and Ca2+ handling proteins, which is related to enhanced activation of the TLR4/CaMKII signalling pathway.