Studies on the Electrophysiological and Calcium Handling Mechanisms and Therapeutic Strategies of Atrial Arrhythmias and Myocardial Dysfunction Induced by Polymicrobial Septic Shock

Septic shock is a serious systemic disorder characterized by multiple hemodynamic derangements and cardiac dysfunction associated high mortality. Myocardial dysfunction is a common complication of sepsis in patients and in animal models of endotoxemia and contributes to the high mortality in sepsis. It is deserve to develop effective approaches for preventing cardiac dysfunction during sepsis. Accumulating evidence demonstrated that endotoxin (LPS)-induced cardiac dysfunction is mediated by NF-B-modulated overproduction of multiple pro-inflammatory mediators and NO synthase. Consequently, sustained release of NO may cause contractile dysfunction during sepsis. Several mechanisms were suggested to contribute to the depression of myocardial contractility and they include impairment of -adrenergic signaling, defective Ca2+ transport and impaired myofibrillar function. With regard to the cellular Ca2+ transport in sepsis, most of the reported data indicate that reduced Ca2+ influx through L-type Ca2+ channels contributes to myocardial contractile depression in endotoxemia. In addition, the defect of intracellular Ca2+ handling may also contribute to contractile dysfunction. The decrease of L-type calcium current (ICa,L) density was usually associated with a shortening of action potential duration (APD), and decreased cell contraction and intracellular Ca2+ concentration. The shortening of APD may cause either by the decrease of ICa,L or the activation of K+ outward currents. Sepsis is also associated with increased incidence of atrial arrhythmias. Alterations in structure and function of atrial ion channels associated with sepsis may play a role in causing the electrophysiological abnormalities. However, the precise underlying mechanisms are poorly investigated. Curcumin is a natural polyphenolic compound. Previous studies have shown that curcumin exerts a protective effect in LPS-induced septic shock by improving survival and attenuates organ dysfunction, including that of the liver, kidneys, small bowel, and lung. The underlying mechanism includes regulation inflammatory/anti-inflammatory cytokine expression and inhibition of NF-B activation. However, its potential value in improving sepsis-induced cardiac dysfunction has not been evaluated. In this project, we intend to examine the detailed mechanisms responsible for the electromechanical dysfunction and atrial arrhythmias as well as to verify and the therapeutic potential of curcumin on such conditions in cecal ligature and puncture (CLP)-induced septic guinea pig and rat models. After 16-20 h flollow-up after surgery, the influences of drug treatment on the hemodynamic parameters will be evaluated with PV catheter system. The electrophysiological properties of conduction system and atrial arrhythmia vulnerability will be determined in isolated hearts. The effects on action potential will be determined in atrial and ventricular tissues. Besides, the ionic currents and intracellular Ca2+ transient will be measured by patch-clamping and fluorescent imaging techniques. The expression of mRNA and proteins levels for Ca2+ handling and ionic channel proteins will also be determined in cardiac tissues.We expect that this project can provide the important information about the precise underlying mechanisms and the protective effects of curcumin on sepsis-induced electrical and mechanical dysfunctions

Project ID:PC10401-0195
External Project ID:NSC102-2320-B182-035-MY3