(Circulation. 2000;102:e170.)
© 2000 American Heart Association, Inc.
Correspondence |
Effects of Amiodarone on Heart Cells
Second Department of Cardiology, Evangelismos General Hospital, 28 Doukissis Plakentias Street,, 115 23, Ambelokipi, Athens, Greece, geros@compulink.gr
Cardiovascular Institute, Michael Reese Hospital, Chicago, Illinois
To the Editor:
We read with interest the article by Ide et al.1 The authors showed that amiodarone protects cardiac myocytes against injury mediated by oxidative stress, and they conclude that this antioxidant action of amiodarone may contribute to the beneficial effects of this drug in patients with ischemic heart disease and heart failure.2 Although this mechanism may well be active for the cardiac myocyte, the myocytes comprise a minor fraction of the total cell population of the heart, and the influence of amiodarone on other heart cells is largely unknown.
Cell death by apoptosis has been proposed as a possible
mechanism for end-stage heart failure and for the deterioration of the
heart, even in patients with moderate heart
failure. It also has
been proposed that the expression of tumor necrosis factor-
(TNF-) increases oxidative stress and induces apoptosis in the
heart. The recent demonstration that amiodarone decreases TNF-
production by human blood mononuclear cells in response to3
lipopolysaccharide s consistent with that theory. However, the finding that amiodarone
treatment is associated with an increase in TNF- levels in patients
with ischemic
cardiomyopathy4 does
not support the existence of such a mechanism in vivo. Moreover, recent
unpublished data from our laboratory show that amiodarone and its
metabolite desethylamiodarone induce apoptosis in lung alveolar
epithelial cells at doses equal to the therapeutic serum concentration
of amiodarone. These agents are directly cytotoxic for lung fibroblasts
and endothelial cells, albeit at somewhat higher concentrations, and on
this basis, direct cytotoxicity has been proposed as a mechanism for
amiodarone-induced pulmonary
toxicity.5
Clearly, the existing data imply that amiodarone has different effects on different cell types, an issue that has not been explored rigorously in the heart. These contradictory data may explain why most published double-blind randomized clinical trials fail to demonstrate decreased mortality from amiodarone administration.
References
-
Ide
T, Tsutsui H, Kinugawa S, et al. Amiodarone protects cardiac
myocytes against oxidative injury by its free radical scavenging
action. Circulation. 1999;100:690–692.
[Abstract/Free Full Text]
-
Filippatos
G, Leche C, Sunga R, et al. Expression of FAS adjacent to fibrotic foci
in the failing heart is not associated with increased apoptosis.
Am J Physiol.1999;277:H445–H451.
-
Matsumori
A, Ono K, Nishio R, et al. Amiodarone inhibits production of tumor
necrosis factor- by human mononuclear cells: a possible mechanism
for its effect in heart failure. Circulation. 1997;96:1386–1389.
[Abstract/Free Full Text]
-
Oral H,
Fisher SG, Fay WP, et al. Effects of amiodarone on tumor necrosis
factor- levels in congestive heart failure secondary to ischemic or
idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;83:388–391.[Medline]
[Order article via Infotrieve]
-
Reasor
MJ, Kacew S. An evaluation of possible mechanisms underlying
amiodarone-induced pulmonary toxicity. Proc Soc Exp Biol
Med. 1996;212:297–304.[Abstract]
Response
Department of Cardiovascular Medicine Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku,, Fukuoka, 812-8582, Japan, prehiro@cardiol.med.kyushu-u.ac.jp
Department of Biophysics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
We are grateful to Filippatos and Uhal for their valuable comments on our study. We demonstrated that amiodarone is a free radical scavenger by using electron paramagnetic resonance spectroscopy, and we determined that it exerts protective effects against exogenously generated oxygen free radical–mediated cardiac injury.R1 Filippatos and Uhal pointed out several important issues, especially when extending our in vitro results into the in vivo setting. First, amiodarone is cytotoxic; this might be due, at least in part, to the induction of apoptosis. However, apoptosis occurs at relatively high concentrations of amiodarone, and it has not yet been demonstrated in cardiac myocytes. Second, amiodarone may promote the production of cytokines, which might be involved in the pathogenesis of heart failure. Finally, although we used isolated intact cardiac myocyte preparations to avoid the confounding systemic effects of amiodarone and to examine its direct effects on myocytes, the drug does exert various effects on other types of cells.
It is clearly not possible for us to comment on whether the "extra-antiarrhythmic" effects of amiodarone are beneficial or harmful in the treatment of patients with ischemic heart disease and congestive heart failure. Nevertheless, recent studies have suggested that oxidative stress plays an important role in the initiation and progression of heart failure,R2 R3 and the antioxidant properties of cardiovascular drugs might contribute to their beneficial effects in the treatment of patients.R4 R5 Therefore, our study suggested that this area of investigation deserves attention.
References
-
Ide T, Tsutsui H, Kinugawa S, et al. Amiodarone protects cardiac
myocytes against oxidative injury by its free radical scavenging
action. Circulation. 1999;100:690–692.
-
Ide T, Tsutsui H, Kinugawa S, et al. Mitochondrial electron transport complex
I is the potential source of oxygen free radicals in the failing
myocardium. Circ Res. 1999;85:357–363.
[Abstract/Free Full Text]
-
Ide T,
Tsutsui H, Kinugawa S, et al. Direct evidence for increased hydroxyl
radicals originated from superoxide in the failing myocardium.
Circ Res. 2000;86:152–157.
[Abstract/Free Full Text]
-
Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta
adrenoceptor antagonist, is an antioxidant and free radical scavenger.
J Pharmacol Exp Ther. 1992;263:92–98.
[Abstract/Free Full Text]
-
Tsutsui H, Ide, T, Kinugawa S, et al. Protective effects of carvedilol against
oxygen radical-mediated cardiac myocyte injury. J
Cardiovasc Pharmacol. 1999;34(suppl 4):S73–S76.\.
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