Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias

Abstract
Cardiac function depends on the appropriate timing and synchronization of the mechanical contraction in various regions of the heart as well as on achieving the appropriate heart rate. These properties are ensured through the hierarchical organization and electrical specialization of the cardiac conduction system, which are governed by the differential expression of cardiac ion channels in each component ([42][1]). Cardiac electrical excitation originates in the sinoatrial (SA) node, propagates through the atria to the atrioventricular (AV) node, and then activates the ventricles through the specialized His-Purkinje system. Cardiac arrhythmias are defined as any deviation from the normal pattern or rate of the cardiac electrical excitation. These rhythm disorders represent one of the more common causes of worldwide morbidity and mortality and create a major burden on the health care systems. For example, sudden cardiac death due to ventricular tachyarrhythmias claims approximately 300,000 lives per year in the United States ([19][2]), and atrial fibrillation, which affects more than 2 million Americans, is the single most important cause of ischemic strokes in the elderly population ([33][3]). Traditionally, cardiac arrhythmias can be classified into rhythm disorders that result in abnormally low heart rate (bradyarrhythmias) usually requiring the implantation of a permanent electronic pacemaker or those that produce an abnormally fast and uncoordinated beating rate (tachyarrhythmias). The clinical consequences of the latter may range from simple palpitations to sudden cardiac death, rendering the diagnosis and clinical management of these rhythm disturbances an important and challenging aspect of modern cardiology. Currently, antiarrhythmic strategies are aimed at modifying the abnormal electrophysiological substrate and can be broadly classified into three categories: pharmacotherapy, focal injury (surgery or catheter ablation), and implantable devices. Pharmacotherapy has been the mainstay of antiarrhythmic therapy for decades. Traditionally, antiarrhythmic drugs have been classified based on their electrophysiological effects at the cellular level, namely, their ability to modify excitatory currents, action potential duration, or automaticity. Antiarrhythmic medications were shown to be capable of suppressing different types of cardiac arrhythmias. Yet, the utility of these pharmacological agents has been significantly hampered by their global cardiac action, relatively low efficacy, their often poorly tolerated systemic side effects, and, most importantly, by their significant proarrhythmic effects leading in some studies to a paradoxical increase in mortality ([6][4]). Radiofrequency catheter ablation has revolutionized the field of clinical electrophysiology by providing cardiologists with a possible curative approach for a number of arrhythmias while abolishing the need for life-long pharmacological treatment. Consequentially, radiofrequency catheter ablation has become the treatment of choice for the majority of the supraventricular arrhythmias and some types of ventricular tachycardias ([41][5]). Nevertheless, this approach is still restricted to only a minority of the patients suffering from arrhythmias with the more common rhythm disorders (atrial fibrillation and ventricular tachycardia) being less amenable to this form of treatment. Implantable devices such as pacemakers and defibrillators have become the treatment of choice for a number of cardiac arrhythmias. It is estimated that around 250,000 electronic pacemakers and 60,000 defibrillators are implanted annually in the United States. Pacemakers represent the current state-of-the-art treatment for bradyarrhythmias, whereas implantable cardiac defibrillators (ICDs) have now been successfully used for more than two decades for the palliative treatment of life-threatening ventricular arrhythmias. The benefit from this strategy for high-risk patients (namely, those with reduced left ventricular function, survivors of sudden death, etc.) was clearly demonstrated in a number of large randomized studies ([1][6], [30][7]). Yet, this strategy, despite being lifesaving, does not prevent the emergence of these arrhythmias. In addition, implantable cardiac defibrillators require a lifetime commitment to repeated surgical implantation procedures at a significant expense, may be associated with severe complications, and may not benefit low-risk patients such as those with relatively preserved left ventricular function. The lack of optimal therapeutic options for several types of cardiac arrhythmias motivates the pursuit for alternative therapeutic paradigms. Recent advances in molecular and cell biology and in tissue engineering technologies have paved the way to the development of a new and exciting field in biomedicine. This approach seeks to devise new biological solutions to replace or modify the function of diseased, absent, or malfunctioning tissue. The heart represents an attractive candidate for this emerging field, and cell and gene therapies have already been proposed as novel strategies to improve myocardial perfusion and contractile properties for the treatment of chronic ischemic heart disease and congestive heart failure ([14][8], [17][9], [37][10]). These same technologies could also theoretically be used to modify the electrophysiological properties of the heart, providing a new and exciting strategy for the treatment of cardiac arrhythmias. This may be achieved through manipulation of the expression of the different cardiac ion channels, modulators of ion channel function, or proteins involved in cell-to-cell interactions. Interestingly, this strategy has already been used extensively in the past mainly as a molecular genetic approach to alter cardiac excitability and thereby dissect the contribution of different elements to the electrophysiological phenotype of the heart or for the creation of animal models of...
Keywords