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(Circulation. 1995;92:1678-1679.)
© 1995 American Heart Association, Inc.
Articles |
`A Riddle Wrapped in a Mystery Inside an Enigma'
Winston S. Churchill, October 1, 1939
From Duke University Medical Center, Durham, NC.
Correspondence to Gary L. Stiles, MD, Division of Cardiology, Duke University Medical Center, Box 3444, Durham, NC 27710.
Key Words: Editorials • heart failure • receptors • adrenergic • alpha
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Introduction |
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 Top Introduction References |
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For the most part, the basic pathophysiological mechanisms involved in the perpetuation and exacerbation of congestive heart failure, as Churchill's quote aptly suggests, remain unknown. Why certain groups of patients do "relatively" well and others progress quickly is only beginning to be understood. The article by Parker et al1 in this issue of Circulation brings to the fore an important component of the autonomic nervous system, the presynaptic nerve terminal, which may well impact on the function of the heart in patients with congestive heart failure and thereby influence morbidity and mortality. The intriguing finding is that nonselective blockade of
-adrenergic receptors (ARs) in the
heart (selective injection of phentolamine into the left main
coronary artery) leads to an increased level of
norepinephrine (NE) in the coronary sinus
associated with an increase in left ventricular
contractility. These changes occur only in patients
with congestive heart failure, not in patients with normal left
ventricular function. The proposed mechanism for this is
that presynaptic 2-ARs are being blocked, leading to
enhanced NE release, and that "basal" release of NE is abnormally
high in patients with congestive heart failure.
The role of ARs in modulating cardiac function has long been
recognized. Classically, ß-ARs have been documented to increase
contractility, heart rate, electrical conduction, and
cardiac relaxation.2 These effects come about directly as
a result of catecholamines acting on the ß-ARs, which
reside on the functionally relevant cells (myocardial and conduction
tissue) in the heart.3 Much less is known about the
contributions of 1-ARs, which are known to be
present on myocardial cells, to cardiac function. It is becoming
clear that they can mediate positive inotropic effects and most likely
do so via activation of phospholipase C and increased
Ca2+ levels but independently of changes in
cAMP.4 5 Their effect appears to be modest compared
with that of ß-ARs.
Studies over the past decade have clearly documented that patients with
congestive heart failure have markedly elevated levels of
catecholamines (which are a marker of poor outcome), and
this is associated with ß-ARs that are decreased in both number and
function.6 The effect of congestive heart failure and
increased catecholamines on the 1-ARs is
much less clear. Most studies suggest that the quantity of
1-ARs is not changed in congestive heart failure but
function is either intact or slightly reduced.5 7
The study by Parker et al focuses not on the ARs located on myocardial
cells but rather the 2-ARs located on the presynaptic
nerve terminals on the heart. These receptors are known to inhibit the
release of NE from these terminals.8 Thus, NE released
from the terminal can feed back on the presynaptic terminal to inhibit
further release. This is a classic negative feedback loop. Evidence has
accumulated that there is increased sympathetic nervous activity in
congestive heart failure, with consequent increased levels of NE, and
that this may be caused by an increase in neuronal NE
release.9 Parker et al now find that not only is NE
elevated in congestive heart failure patients, but also, when a
nonselective -blocker is given, the levels of NE increase
further, and this increase in NE is associated with an increase in left
ventricular function (contractility).
Neither of these phenomena is seen in patients with normal left
ventricular function.1 This is an important
finding, because little information on the regulation of presynaptic NE
release in the heart has been pursued in health or disease. One could
easily imagine that this "abnormal" regulation of NE release
could be beneficial or detrimental. Elevated NE could help maintain
cardiac function, which would be helpful. On the other hand, if
increased NE is associated with poor outcome, then further increases in
congestive heart failure could increase mortality. This study raises
many questions that warrant further research.
First, are the findings presented really induced by specific
blockade of the presynaptic 2-ARs, or are they a
consequence of concomitant changes in coronary blood flow,
which can alter NE extraction? The increased flow could occur by
blockade of 1- or 2-ARs locally or
distally. These questions can be answered by use of
2-selective antagonists in place of
phentolamine and by actual measurement of coronary
blood flow.
Second, why doesn't the elevated NE already present in patients
with congestive heart failure feed back to shut off neural release of
NE, and why does blockade of 2-ARs markedly enhance NE
release only in patients with congestive heart failure? No answers are
currently available. The data suggest that perhaps there is a resetting
of the negative feedback loop in patients with congestive heart
failure, and whether this is cause or effect is certainly an area
needing much additional study.
A third question is why the increased NE translates into increased
contractility. Since both arterial and
coronary sinus NE levels are elevated in patients with
congestive heart failure, one would anticipate that the
ß-AR–adenylyl cyclase system would be largely desensitized,
precluding increases in contractility, and the
1-ARs would have been blocked by the administration of
phentolamine. The most likely explanation is that there was
still some responsiveness of the ß-AR system, even though systemic
effects of phentolamine such as afterload reduction cannot be
completely ruled out.
The importance of this study is that it raises another level of complexity in the regulation of cardiac function in patients with congestive heart failure. If, indeed, the mechanisms of release of NE presynaptically have become dysfunctional, then we must assess whether this is cause or effect. If it is causal in nature, what are the mechanisms that produce this dysregulation, and can this knowledge be used for therapeutic benefit? The authors quite rightly point out that a therapy that further increases NE, even if it does increase contractility in the short term, may not be beneficial in humans. Most interventions that have attempted to increase adrenergic drive with consequent increases in contractility either have resulted in no positive benefit in the long term or have produced detrimental effects. Recent studies in congestive heart failure also highlight the fact that therapeutic benefit for a given intervention may well be related to the underlying cause of the congestive heart failure, ie, ischemic versus nonischemic.10
Further studies on the role of presynaptic neural function in
congestive heart failure should incorporate sufficient numbers of
patients in each diagnostic category along with the use of
selective -blockers and actual measurements of cardiac NE
spillover. These studies would provide more definitive answers to
the intriguing questions raised. All rational approaches to
understanding the pathophysiology of congestive heart failure that have
potential therapeutic implications need to be undertaken. We clearly
have a long way to go in our attempts to change the outcomes of
patients with congestive heart failure.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.
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References |
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TopIntroductionReferences |
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1. Parker JD, Newton GE, Landzberg JS, Floras JS, Colucci WS. Functional significance of presynaptic
-adrenergic receptors in the failing and nonfailing human left
ventricle. Circulation. 1995;92:1793-1800.2. Katz AM. Cyclic adenosine monophosphate effects on the myocardium: a man who knows hot and cold with one breath. J Am Coll Cardiol. 1983;2:143-149. [Abstract]
3. Stiles GL. Adrenergic receptor responsiveness and congestive heart failure. Am J Cardiol. 1991;67:13C-17C. [Medline] [Order article via Infotrieve]
4.
Benfey RG. Function of myocardial
-adrenoceptors. J Auton Pharmacol. 1993;13:351-372.
5.
Bristow MR, Minobe W, Rasmussen R, Hershberger RB,
Hoffman BB. Alpha-1 adrenergic receptors in the nonfailing and
failing human heart. J Pharmacol Exp Ther. 1988;247:1039-1045.
6. Cohn JN, Levine TB, Olivari TB, Garberg O, Lara D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. [Abstract]
7.
Böhm M, Diet F, Feiler G, Kemkes B,
Erdmann E. -Adrenoceptors and
-adrenoceptor-mediated positive inotropic effects in failing
human myocardium. J Cardiovasc
Pharmacol. 1988;12:357-364. [Medline]
[Order article via Infotrieve]
8.
Grossman E, Rea RF, Hoffman A, Goldstein DS.
Yohimbine increases sympathetic nerve activity and
norepinephrine spillover in normal volunteers.
Am J Physiol. 1991;260:R142-R147.
9.
Grossman E, Chang PC, Hoffman A, Tamrat M, Goldstein
DS. Evidence for functional 2-adrenoceptors on
vascular sympathetic nerve endings in the human forearm.
Circ Res. 1991;69:887-897.
10.
Singh SN, Fletcher RD, et al. Amiodarone
in patients with congestive heart failure and
asymptomatic ventricular
arrhythmia. N Engl J Med. 1995;333:77-82.
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