Biological Therapies for the Treatment of Cardiac Arrhythmias (original) (raw)

Gene Therapy for Cardiac Arrhythmias

Annals of the New York Academy of Sciences, 2004

In this review, we examine the current state of gene therapy for the treatment of cardiac arrhythmias. We describe advances and challenges in successfully creating and incorporating gene vectors into the myocardium. After summarizing the current scientific research in gene transfer technology, we then focus on the most promising areas of gene therapy at this time, which is the treatment of atrial fibrillation and ventricular tachyarrhythmias. We also review the scientific literature to determine how gene therapy could potentially be used to treat patients with cardiac arrhythmias.

Gene therapy approaches to ventricular tachyarrhythmias

Journal of Electrocardiology, 2007

Ventricular tachycardia arising from a healed myocardial infarction scar continues to be a signficiant cause of morbidity and mortality. Drug therapy has been inadequate to meet this challenge, and implantible devices are limited by expense and technical problems. We have proposed the use of gene therapy for cardiac arrhythmias. In this review, we present a model of post-infarct ventricular tachycardia, a method for gene delivery to this area, and results KCNH2-G628S gene transfer to manipulate cellular refractory properties in the arrhythmia model.

Biological therapies targeting arrhythmias: are cells and genes the answer?

Expert Opinion on Biological Therapy

Introduction: The clinical presentation of arrhythmias ranges from mild symptoms such as dizziness, to life-threatening circulatory collapse. Current management includes medical therapy and procedures such as ablation or device implantation, however these strategies still pose a risk of side effects, while some patients remain symptomatic. Areas covered: Advancement in our understanding of how arrhythmias develop on the cellular level has made more targeted approaches possible. In addition, contemporary studies have found that several genes are involved in the pathogenesis of arrhythmias. Interestingly, gene and cell therapies allow treatments to be locally applied, bypassing systemic side effects in most occasions. Expert opinion: Pre-clinical studies have shown promising results in animal models of arrhythmias. However, more work is needed before this becomes a clinically viable option.

Gene therapy strategies for cardiac electrical dysfunction

Journal of Molecular and Cellular Cardiology, 2011

Cardiac disease is frequently associated with abnormalities in electrical function that can severely impair cardiac performance with potentially fatal consequences. The available therapeutic options have some efficacy but are far from perfect. The curative potential of gene therapy makes it an attractive approach for the treatment of cardiac arrhythmias. To date, gene therapy research strategies have targeted three major classes of cardiac arrhythmias: 1) ventricular arrhythmias, 2) atrial fibrillation, and 3) bradyarrhythmias. Various vehicles for gene transfer have been employed with adeno-associated viral gene delivery being the preferred choice for long-term gene expression, and adenoviral gene delivery for short-term proof of concept work. In combination with the development of novel delivery methods, gene therapy may prove to be an effective strategy to eliminate the most debilitating of arrhythmias.

Gene therapy for ventricular tachyarrhythmias

Gene Therapy, 2012

Cardiac arrest is the leading cause of death in the United States and other developed countries. Ventricular tachyarrhythmias are the most prominent cause of cardiac arrest, and patients with structural heart disease are at increased risk for these abnormal heart rhythms. Drug and device therapies have important limitations that make them inadequate to meet this challenge. We and others have proposed development of arrhythmia gene therapy as an alternative to current treatment methods. In this review, I discuss the basic mechanisms of ventricular arrhythmias and summarize the literature on the use of gene therapy for ventricular tachyarrhythmias.

Cell Therapy for Modification of the Myocardial Electrophysiological Substrate

Circulation, 2008

Background-Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels. Methods and Results-To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84Ϯ8 ms (cycle length, 200 ms) to 154Ϯ13 ms (PϽ0.01). Margatoxin partially reversed this effect (effective refractory period, 117Ϯ8 ms; PϽ0.01). In contrast, effective refractory period did not change in nontransplanted sites (86Ϯ7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73Ϯ5 to 88Ϯ4 ms; PϽ0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results. Conclusions-Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness. (Circulation. 2008;117:720-731.)

Modulation of Ventricular Function through Gene Transfer in vivo

Proceedings of The National Academy of Sciences, 1998

We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca 2؉ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 ؋ 10 9 pfu of recombinant adenoviral vectors carrying cDNA for either PL, ␤-galactosidase (␤-gal), or modified green f luorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.␤gal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 ؎ 12.9 mmHg, n ‫؍‬ 8) compared with uninfected hearts (92.5 ؎ 3.5 mmHg, n ‫؍‬ 6) or hearts infected with Ad.␤gal (92.6 ؎ 5.9 mmHg, n ‫؍‬ 6). Both peak rate of pressure rise and pressure fall (؉3, 210 ؎ 298 mmHg͞s, ؊2, 117 ؎ 178 mmHg͞s, n ‫؍‬ 8) were decreased in hearts overexpressing PL compared with uninfected hearts (؉5, 225 ؎ 136 mmHg͞s, ؊3, 805 ؎ 97 mmHg͞s, n ‫؍‬ 6) or hearts infected with Ad.␤gal (؉5, 108 ؎ 167 mmHg͞s, ؊3, 765 ؎ 121 mmHg͞s, n ‫؍‬ 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 ؎ 3.2 ms, n ‫؍‬ 8) compared with uninfected hearts (18.5 ؎ 1.0 ms, n ‫؍‬ 6) or hearts infected with Ad.␤gal (20.8 ؎ 2.1 ms, n ‫؍‬ 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.

Gene and cell therapies for the failing heart to prevent sudden arrhythmic death

Minerva cardioangiologica, 2012

Current therapies for treatment and prevention of sudden cardiac death have certain limitations, and a search for new therapeutic approaches is desirable to reduce the burden of sudden arrhythmic death. Gene therapy and stem cell therapy have been investigated as new, valuable tools in treating cardiac diseases such as arrhythmias. In this review, the basics of each modality, important related experimental and clinical studies, and potential advantages and limitations of these treatments will be discussed. The future success of gene and cell therapy to become practical clinical tools greatly depends on our understanding of the mechanisms of ventricular arrhythmia and the mechanisms of action of gene and cell therapy.

Animal models of arrhythmia: classic electrophysiology to genetically modified large animals

Nature Reviews Cardiology, 2019

Arrhythmias are an important health-care issue affecting millions of people worldwide 1-4. Various types of arrhythmias exist, ranging from less harmful, premature capture beats to sinoatrial or atrioventricular (AV) conduction block and from rare familial arrhythmia syndromes to the most common sustained arrhythmia, atrial fibrillation (AF). The overall prevalence of arrhythmias is approximately 3.4% (1.4% in individuals aged <18 years and 10.1% in individuals aged >75 years) 5. Arrhythmias are the main reason for sudden cardiac death (SCD), which accounts for 25% of all deaths 6-11 , and are associated with substantial morbidity, such as a fivefold increased risk of stroke in AF 9,12-15. Therapeutic strategy depends on the arrhythmia and can include drug therapy, catheter ablation, device implantation and treatment of concomitant diseases 12,16. Current treatment strategies have substantially improved survival but remain ineffective in many patients and are associated with numerous complications 17,18 and adverse effects 19. Therefore, today's largely symptomatic treatments have to be improved by innovative therapies that would ideally target causal proarrhythmic mechanisms 20. The pathophysiological basis of arrhythmias is complex and still incompletely understood, but similarities in the fundamental mechanisms between different forms of arrhythmias have been identified 21,22. In general, bradyarrhythmias or tachyarrhythmias occur because of primary or secondary alterations in important myocardial electrical properties, such as excitation or impulse formation, conduction and repolarization. In the heart, the sinus node acts as a pacemaker, generating electrical impulses. Other regions of the heart also have pacemaker activity but are physiologically suppressed by the sinus node. Altered ion channel expression or function can augment pacemaker function, a process called enhanced automaticity, leading to arrhythmias 23. Given that the sinus node is highly innervated by the autonomic nervous system, changes in the autonomic tone can also affect automaticity, leading to sinus tachycardia or bradycardia 24,25. Ca 2+ accumulation, for example, during atrial tachycardia or in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), results in multiple maladaptive changes, such as a subsequent Ca 2+ leak from the sarcoplasmic reticulum that causes a depolarizing current, leading to delayed afterdepolarizations. These alterations cause progressive depolarization of the cell and ectopic firing called triggered activity that

Regenerative therapies in electrophysiology and pacing

Journal of Interventional Cardiac Electrophysiology, 2008

The prevention and treatment of cardiac arrhythmias conferring major morbidity and mortality is far from optimal, and relies heavily on devices and drugs for the partial successes that have been seen. The greatest success has been in the use of electronic pacemakers to drive the hearts of patients having high degree heart block. Recent years have seen the beginnings of attempts to use novel approaches available through gene and cell therapies to treat both brady-and tachyarrhythmias. By far the most successful approaches to date have been seen in the development of biological pacemakers. However, the far more difficult problems posed by atrial fibrillation and ventricular tachycardia are now being addressed. In the following pages we review the approaches now in progress as well as the specific methodologic demands that must be met if these therapies are to be successful.