Download Editorial - Circulation

Editorial
Rate Control
Is Local Better?
Paul J. Wang, MD
T
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
strate 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 longterm administration of drug or biological agents, whereas
transarterial delivery and endocardial delivery are most suited
to immediate delivery to achieve ablative or cellular
alteration.
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
he 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 ␤-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 ␮g/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 demonThe opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
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
[email protected]
(Circulation. 2006;113:2374-2376.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.626036
2374
Wang
TABLE 1.
Methods of Local Delivery
Intramyocardial
Via the endocardium
Via the epicardium
Endocardial
Transvascular
Via the coronary arterial system
Via the cardiac venous system
Epicardial
System administration with local targeting
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
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
TABLE 2.
Agents for Local Delivery
Embolic substances
Rate Control: Is Local Better?
2375
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.
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.
Cytotoxic
Ethanol
Chemotherapeutic agents
Antiarrhythmic agents
Adrenergic antagonists; sympathomimetic and parasympathomimetic
AGENTS
Biological agents
Antibody-bound agents
Nanoparticles and inorganic agents
Neurohormonal agents
Prostaglandins
References
1. Waldo AL. A perspective on rate control in the treatment of atrial
fibrillation. Clin Cardiol. 2004;27:121–124.
2. Ross HM, Kocovic DZ, Kowey PR. Pharmacologic therapies for atrial
fibrillation. Am J Geriatr Cardiol. 2005;14:62– 67.
3. Khan IA, Nair CK, Singh N, Gowda RM, Nair RC. Acute ventricular rate
control in atrial fibrillation and atrial flutter. Int J Cardiol. 2004;97:7–13.
4. Sigg DC, Hiniduma-Lokuge P, Coles JA Jr, Falkner P, Rose R, Urban JF,
Ujhelyi MR. Focal pharmacological modulation of atrioventricular nodal
conduction via implantable catheter: novel therapy for atrial fibrillation?
Circulation. 2006;113:2383–2390.
5. Doss MX, Koehler CI, Gissel C, Hescheler J, Sachinidis A. Embryonic
stem cells: a promising tool for cell replacement therapy. J Cell Mol Med.
2004;8:465– 473.
2376
Circulation
May 23, 2006
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
6. Reek S, Geller JC, Schildhaus H-U, Mahnkopf D, Mittag J, Klein HU.
Catheter ablation of ventricular tachycardia by intramyocardial injection
of ethanol in an animal model of chronic myocardial infarction. J Cardiovasc Electrophysiol. 2004;15:332–341.
7. Inoue H, Waller BF, Zipes DP. Intracoronary ethyl alcohol or phenol
injection ablates aconitine-induced ventricular tachycardia in dogs. J Am
Coll Cardiol. 1987;10:1342–1349.
8. Wang PJ, Sosa-Suarez G, Friedman PL. Modification of human atrioventricular nodal function by selective atrioventricular nodal artery catheterization. Circulation. 1990;82:817– 829.
9. Friedman PL, Selwyn AP, Edelman E, Wang PJ. Effect of selective
intracoronary antiarrhythmic drug administration in sustained ventricular
tachycardia. Am J Cardiol. 1989;64:475– 480.
10. Brugada P, de Swart H, Smeets JL, Wellens HJ. Transcoronary chemical
ablation of ventricular tachycardia. Circulation. 1989;79:475– 482.
11. Kay GN, Epstein AE, Bubien RS, Anderson PG, Dailey SM, Plumb
VJ. Intracoronary ethanol ablation for the treatment of recurrent sustained
ventricular tachycardia. J Am Coll Cardiol. 1992;19:159 –168.
12. Kay GN, Bubien RS, Dailey SM, Epstein AE, Plumb VJ. A prospective
evaluation of intracoronary ethanol ablation of the atrioventricular conduction system. J Am Coll Cardiol. 1991;17:1634 –1640.
13. Costeas XF, Berul CI, Foote CB, Homoud MK, Marx GR, Smith JJ, Estes
NA III, Wang PJ. Transcoronary ethanol ablation of the atrioventricular
node in a young patient with tricuspid atresia. Pacing Clin Electrophysiol.
1998;21:620 – 623.
14. Strickberger SA, Foster PR, Wang PJ, Okishige K, Friedman PL. Intracoronary infusion of dilute ethanol for control of ventricular rate in
15.
16.
17.
18.
19.
20.
patients with atrial fibrillation. Pacing Clin Electrophysiol. 1993;16:
1984 –1993.
Wang PJ, Ursell PC, Sosa-Suarez G, Okishige K, Friedman PL. Permanent AV block or modification of AV nodal function by selective AV
nodal artery ethanol infusion. Pacing Clin Electrophysiol. 1992;15:
779 –789.
Karagueuzian HS, Ohta M, Drury JK, Fishbein MC, Meerbaum S, Corday
E, Mandel WJ, Peter T. Coronary venous retroinfusion of procainamide:
a new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction. J Am Coll
Cardiol. 1986;7:551–563.
Ayers GM, Rho TH, Ben-David J, Besch HR Jr, Zipes DP. Amiodarone
instilled into the canine pericardial sac migrates transmurally to produce
electrophysiologic effects and suppress atrial fibrillation. J Cardiovasc
Electrophysiol. 1996;7:713–721.
Avitall B, Hare J, Zander G, Bockoff C, Tchou P, Jazayeri M, Akhtar M.
Iontophoretic transmyocardial drug delivery: a novel approach to antiarrhythmic drug therapy. Circulation. 1992;85:1582–1593.
Bruckl H, Panhorst M, Schotter J, Kamp PB, Becker A. Magnetic particles as markers and carriers of biomolecules. IEE Proc Nanobiotechnnology. 2005;152:41– 46.
Michels S, Michels R, Simader C, Schmidt-Erfurth U. Verteporfin
therapy for choroidal hemangioma: a long-term follow-up. Retina. 2005;
25:697–703.
KEY WORDS: Editorials 䡲 antiarrhythmia agents
catheters 䡲 fibrillation
䡲
atrioventricular node
䡲
Rate Control: Is Local Better?
Paul J. Wang
Circulation. 2006;113:2374-2376
doi: 10.1161/CIRCULATIONAHA.106.626036
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2006 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/113/20/2374
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/