Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na⁺ channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na⁺ channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na⁺ channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na⁺ channel blocker antiepileptic therapies. Thus, Na⁺ channel blockers should be considered for the clinical management of LQT in individuals with RTT.KEY WORDS: Long QT, Rett syndrome, Propranolol, Phenytoin, Arrhythmia, MECP2     

Lysophosphatidylcholine metabolism and cardiac arrhythmias

The ability of exogenous lysophosphatidylcholine (LPC) to produce electrophysiological abnormalities in cardiac tissues and cardiac arrhythmias in isolated hearts has been well documented. In this study, the arrhythmogenic nature of LPC in the rat, rabbit, and guinea pig hearts was studied. The rat heart was found to be the most susceptible to LPC-induced arrhythmias, while the guinea pig heart was the least susceptible. Perfusion with labelled LPC revealed that the severity of arrhythmias correlates well with the amount of labelled LPC found in the microsomal membrane. The biochemical basis for the differences in the accumulation of LPC in the microsomal membrane of different animal species was investigated. Our results strongly indicate that the LPC level in the microsomal membrane may be regulated by the activity of microsomal lysophospholipase.     

Gene therapy in cardiac arrhythmias

Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within the left bundle branch can provide stable heart rates. Genetic modification of the AV node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger. Lastly the ethical concerns need to be addressed.     

Effects of lysophosphoglycerides on cardiac arrhythmias

The accumulation of lysophosphoglycerides has been implicated as an important biochemical factor for cardiac arrhythmias. Recently, we demonstrated that lysophosphatidylcholine caused cardiac arrhythmias in the isolated hamster heart. In this study, the arrhythmogenic nature of various lysophosphoglycerides with respect to acyl chain lengths and base groups were assessed. We demonstrated that all naturally occurring lysolipids tested were arrhythmogenic at 0.05-0.10 mM. Arrhythmias were also observed with Triton X-100 or sodium laurylsulfate at 0.05-0.10 mM. Our data suggests that no correlation exists between the arrhythmogenic nature of the lysolipids and their critical micelle concentrations. We postulate that arrhythmias are produced by the detergent effect of lysophosphoglycerides.     

Brain-heart interactions and cardiac ventricular arrhythmias

A wide range of evidence implicates the brain as playing a significant role in ventricular arrhythmias and sudden cardiac death. The mechanism is thought to involve the intermediary of the autonomic nervous system. Here we briefly consider possible mechanisms by which central neural processing may modulate the myocardial electrophysiology and hence the arrhythmia substrate.     

心肌细胞缝隙连接重塑与心律失常

缝隙连接是相邻心肌细胞间电、化学偶联的通道,亦是心室肌成为功能性合胞体的重要结构.心肌有缝隙连接蛋白(connexin,CX) 40、43与45的表达,心室肌主要表达CX43.CX43形成的缝隙连接大部分呈点状分布于闰盘部位,心肌细胞膜侧面分布极少.心肌缺血-再灌注、肥厚、衰竭、高胆同醇与糖尿病条件下,心肌细胞缝隙连接...