doi: 10.1161/CIRCULATIONAHA.106.626036
(Circulation. 2006;113:2374-2376.)
© 2006 American Heart Association, Inc.
Editorial |
Rate Control
Is Local Better?
From Stanford University School of Medicine, Stanford, Calif.
Correspondence to Paul J. Wang, MD, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5233. E-mail pwang{at}cvmed.stanford.edu
Key Words: Editorials • antiarrhythmia agents • atrioventricular node • catheters • fibrillation
The control of ventricular rate plays an important role in the management of patients with atrial fibrillation, decreasing symptoms and improving cardiac function, exercise capacity, and quality of life.1–3 Oral or intravenous agents are routinely administered to achieve adequate control of the ventricular rate by modulating atrioventricular nodal function. The systemic effects of calcium channel antagonists and ß-adrenergic receptor antagonists on blood pressure and other adverse effects, however, may limit use of these agents in some patients. In other patients, it may be difficult to achieve adequate rate control with the use of pharmacological agents.
Article p 2383
In their article in this issue of Circulation, Sigg et al4 describe the novel approach of delivering pharmacological agents via a luminal catheter secured to the region of the atrioventricular node. Using a steerable electrophysiological catheter, they locate the His bundle potential and the coronary sinus ostium and display these positions in 2 orthogonal planes. The luminal catheter is screwed into the myocardium, and third-degree atrioventricular block resulting from the injection of a 1-mg dose of acetylcholine is used to confirm the proper positioning of the luminal catheter. The authors demonstrate that varying degrees of atrioventricular nodal blockade may be achieved by continuous infusion of acetylcholine at rates between 10 and 200 µg/min. In comparison, the intravenous injection of 1 mg acetylcholine did not cause atrioventricular block in any animal, demonstrating that a significant part of the effect of the direct luminal infusion was local. The authors provide histological evidence that the luminal catheter was positioned within or near the edge of the triangle of Koch, confirming the accuracy of the positioning method. In addition, no significant histological abnormalities were observed.
This article by Sigg et al4 illustrates the potential for the local delivery of pharmacological therapy via an infusion catheter screwed into the atrioventricular nodal region. Their study serves as a "proof-of-principle" experiment for ability of this drug delivery system to have local electrophysiological effects without significant systemic effects. They demonstrate that it is possible to modulate the effect on atrioventricular nodal function, potentially permitting such local therapy to be modulated in a closed-loop control system. Such modulation would permit the automatic delivery of agents in response to therapeutic need, in a manner that is currently only available in intravenous injection systems such as insulin pumps. Furthermore, drug delivery might be triggered automatically by the onset of an arrhythmia that is detected by an implantable device.
There are a number of limitations of the authors’ study and the approach of infusion into the myocardium via a catheter-based system. The authors have not yet investigated the chronic effects of saline, drug vehicle, or drug on the histological and electrophysiological characteristics of the tissue. There is a potential for cell necrosis over time as the result of intramyocardial delivery of antiarrhythmia agents. Direct infusion may also result in a fibrous reaction that might decrease the ability of the agents to diffuse over time. It is possible for other agents to be delivered that might be used to minimize this fibrous reaction. Patency of the luminal catheter needs to be assessed over time and may be maintained with the use of a very slow continuous infusion.
There are a number of methods of delivering drug locally to the myocardium. The various routes of local delivery may be divided into the following categories: (1) intramyocardial, from either the endocardium or epicardium; (2) endocardial; (3) transvascular, via either coronary arterial or cardiac venous systems; (4) epicardial; or (5) via systemic administration with local targeting (Table 1). A wide range of agents may be delivered locally (Table 2). Intramyocardial delivery, cardiac venous delivery, epicardial delivery, and systemic administration with local targeting are most suited to long-term administration of drug or biological agents, whereas transarterial delivery and endocardial delivery are most suited to immediate delivery to achieve ablative or cellular alteration.
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Pharmacological, biological, and ablative agents may be delivered intramyocardially. The study by Sigg et al4 provides a novel method of pharmacological infusion directly into the myocardium. Agents may be injected directly into the myocardium from the endocardial or epicardial approach. Intramyocardial drug delivery of biological agents such as stem cells has been used for myocardial cell repair.5 Ablative agents such as ethanol or phenol can be injected endocardially or epicardially into the myocardium to treat arrhythmias.6,7
Theoretically, it may be possible to place agents at the endocardial surface. There is relatively little experience delivering agents endocardially because of the technical difficulty of keeping the agents against the endocardial surface for the time needed to achieve a therapeutic effect, an approach analogous to transdermal application. Because intracardiac devices would likely be needed for most endocardial applications, this approach would be suited only to ablative interventions and not long-term drug therapy.
Transvascular approaches may be separated into transarterial and transvenous coronary interventions. Wang et al8 demonstrated that the infusion of procainamide via selective catheterization of the atrioventricular nodal artery resulted in acute modulations of atrioventricular nodal function. Antiarrhythmic agents may also be delivered via selective coronary arterial branches. Friedman et al9 demonstrated that lidocaine or procainamide may be delivered for modulation of ventricular electrophysiological properties. Brugada et al10 and Kay et al11 have demonstrated that selective coronary arterial catheterization may be used successfully to deliver ethanol for ablation of ventricular tachycardia. Atrioventricular nodal modification can also be achieved with selective delivery of ethanol or embolic substances via the atrioventricular nodal artery.12–15 Antiarrhythmic agents have been delivered via the coronary sinus and selectively via cardiac venous branches. Karagueuzian et al16 demonstrated that the retroperfusion of procainamide in the coronary sinus may be used to suppress ventricular tachycardia. Pharmacological cardioversion may also be possible via coronary sinus retroperfusion. Delivery of biological agents via the transvascular approach has been proposed or tested. Transarterial approaches are unlikely to be used for long-term administration of agents because of the limitation of arterial embolism. However, cardiac venous retroperfusion might be more amenable to long-term local delivery.
Pericardial access has been introduced as a method for delivering pharmacological and biological agents. Ayers et al17 demonstrated that pericardial installation of antiarrhythmic agents may suppress atrial fibrillation. Avitall et al18 have demonstrated that using an electric field epicardially results in greater penetration of antiarrhythmic drugs delivered by a process called iontophoresis. Epicardial drug administration would be a suitable long-term delivery system, particularly in the atrium. The primary technical challenge would be to simply the implantation technique and administration device. The adoption of this technique also requires acceptance of the pericardial route as a means for myocardial access.
Some agents may be delivered systemically but activated or concentrated locally. Magnetic particles19 may contain pharmacological agents, antibody-bound agents, or biological agents and may be administered intravenously and concentrated in a region under the control of a magnetic source. Light or other part of the electromagnetic spectra may be used to activate drugs locally.20 For long-term administration, for this approach to become feasible, the agents must be able to be activated noninvasively without a substantial amount of equipment.
In summary, the potential to treat arrhythmias locally without systemic administration may avoid many noncardiac adverse effects. Such alternatives to oral and parenteral delivery via an implantable system would permit a continuous infusion and more precise titration of drug effect with the use of an apparatus similar to the insulin pump. The addition of a closed-loop feedback control would result in a therapeutic effect that would be self-modulating in response to changes in physiological conditions. Perhaps, therefore, the greatest value of the report by Sigg et al is to provide an impetus for the development of innovative strategies for dynamic local drug delivery for antiarrhythmic and cardiovascular therapies for the future.
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Acknowledgments |
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Disclosures
Dr Wang has received research support and clinical studies support from Guidant Corporation, Medtronic, Inc, and St. Jude; has received research, educational, or fellowship grants from Guidant Corporation, Medtronic, Inc, St. Jude, Siemens, Boston Scientific, Biosense Webster Johnson and Johnson, and CryoCath, Inc; has served on the speakers bureau of Guidant Corporation, Medtronic, Inc, and St. Jude; and has received honoraria from Guidant Corporation, Medtronic, Inc, and St. Jude.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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