The heart consists of several distinct regions, each with its unique electrophysiological characteristics and functions. Specifically, cardiac activity is managed by highly specialized cells that trigger polarization and depolarization of the heart muscle to provide natural intrinsic pacing. While the sino atrial (SA) node is the primary pacemaking unit of the heart, the atrio-ventricular (AV) node acts as a gatekeeper or valve between the atria and ventricles and controls ventricular response to supraventricular activation. The valve function of the AV node arises from cells that have longer postrepolarization refractoriness and very low excitability, which limit the maximum number of impulses that can traverse to the ventricles. AV node lacks sodium (Na+) channels, and conduction in the AV node is primarily governed by L-type Ca2+ channels.
Biologic treatment of the conduction system of the heart requires the introduction of biologic agents that are compatible and adaptable to the highly specialized cardiac cells. Further, cardiac cells are highly differentiated across the conduction zone. The channels in the SA node, for example, are different from the channels in the AV node. Similarly, the type of channels and composition thereof vary across the conduction system of the heart and provide varying contractility properties to the cardiac muscles. Accordingly, managing the channels is key to controlling cardiac arrhythmias. Realizing this fact, Donahue et al (Nature Medicine; 6(2) 1395-1398) have disclosed an approach of decreasing L-type Ca2+ current, by over expressing an inhibitory component of G-protein that modulates β-adrenergic response with an eventual goal of slowing the conduction in the AV node.
Currently, arrhythmias such as, for example, tachy and brady are managed using implantable devices. While these devices have proven to be excellent means for therapy delivery to manage cardiac disease, they do not reconstruct or restore a damaged conduction cellular structure to its normal condition. Conduction in cardiac tissue, including the AV node, involves cell-to-cell charge transfer. Charge from an upstream cell that has already been excited by a wave front initiated from the SA node is transferred to the next unexcited cell downstream thereby raising its intracellular and transmembrane potential. The downstream cell is excited when its transmembrane potential is raised to the Na+ channel or L-type Ca2+ channel (in the case of the AV node) threshold. As this downstream cell is excited, it relays charge to the next unexcited cell even further downstream. This process continues and results in continuous conduction at a macroscopic level, although the conduction at a microscopic scale is arguably saltatory in nature (Spach M S et al. 1990. Ann N Y Acad Sci; 591:62-74).
The microscopic and cellular basis of conduction gives insights into how the conduction can be influenced. One approach to manipulate cardiac conduction is to impose greater load on each cell so that charge transfer to the next unexcited cell downstream is slowed, thereby delaying its rise to excitation threshold and decreasing macroscopic conduction velocity. A greater electrotonic load on the AV node cells can be imposed by implanting inexcitable cells in the AV node that can sink current but are incapable of sourcing out current because of their inability to fire an action potential. Fibroblasts either autologously derived from the patient (e.g. by taking a muscle biopsy) or commercially obtained, can be one such cell type. However, if implanted in their native form, fibroblasts may couple poorly or fail to couple altogether with the AV node cells. To facilitate coupling, fibroblasts can be transfected ex-vivo with Cx43 (or other Cx isoforms like Cx40 and Cx45) before they are implanted into the AV node. To further increase the potency of electrotonic load they possess, fibroblasts may be transfected with voltage gated potassium channels [e.g. Kv2.1, which encodes for IK1 and Kv1.3, which encodes for another type of voltage dependent K+ channel (Feld Y et al. 2002. Circulation. 105: 522-529)]. As the charge is transferred to fibroblasts and their transmembrane potential raised, these channels open-up and produce outward current and hence can act to amplify the loading effect offered by fibroblasts.
Atrial fibrillation (AF) is a disease of epidemic proportions with over 2 million people affected in US alone, and this number is expected to grow to 5 million by the year 2050. Its prevalence doubles with each decade of life from ˜0.5% at age 50 to 9% at age 80. Present treatments are inadequate. Unlike ventricular arrhythmias, implantable devices are ineffective for treating atrial arrhythmias primarily because of their recurrent nature. Pharmacotherapy is the most common course of treatment for most patients. Two distinct treatment regimens are used—rhythm control and rate control. In rhythm control an effort is made to maintain the patient in sinus rhythm using cardioversion and antiarrhythmic drugs like amiodarone, sotalol and other class III drugs. In rate control the emphasis is on controlling the ventricular rate by modulating the AV node while letting the AF persist. Drugs like beta-blockers, diltiazem and verapimil are commonly used to achieve rate control. In the AFFIRM trial, a large (4060 patients) multicenter study comparing the two treatment strategies, no differences were found between the rhythm and rate control groups. In fact rate control group showed slightly lower mortality (the primary end point) although it did not reach statistical significance. Three other smaller trials (PIAF, RACE and STAF) reached the same conclusion i.e. no difference between rhythm and rate control groups. Moreover, in AFFIRM and PIAF trials that tracked hospital admissions, rate of hospitalization were statistically higher in rhythm control group than rate control.
Thus, rate control is an effective therapy for AF. Nevertheless, pharmacotherapy has several limitations. A subset (˜5%) of patients do not tolerate commonly prescribed drugs, and pharmacotherapy eventually fails in 70-90% patients. Since the drugs are systemically taken, side effects are common. Further, cumulative cost of drugs when added over the entire lifetime of a patient (who generally are younger than those presenting with ventricular arrhythmias) can be quite staggering
Hence there is a need for a system that can modulate the AV node and other cardiac conduction elements that may be damaged or malfunctioning. Further, there is a need to provide a systemic treatment of cardiac conductive tissue using biologic elements that cooperate with or influence the natural conduction channels in the heart.
The present invention addresses one or more of these needs. Furthermore, other desirable features and characteristics of the present invention will become apparent from the subsequent detailed description of the invention and the appended claims with the accompanying drawings and this background of the invention.