Editorials 1615
heart transplant recipients without evidence of
cardiac reinnervation is another reason to challenge
the ventricular baroreceptor hypothesis in vasovagal
syncope'4'. Finally, the group of Morita et a/.'5' made
the interesting observation that during hypotensive
haemorrhage in unanaesthetized animals, there was a
decrease in afferent renal nerve activity. This decrease
was not prevented by vagal denervation which seems
to indicate that it does not depend on stimulation of
cardiac receptors. On the other hand, the decrease in
afferent renal nerve activity was prevented by block-
ade of opiate receptors by naloxone. The latter obser-
vation, among others, raised the question of a
possible role of endogenous opioid mechanisms in
vasovagal attacks.
In 1994, Wallbridge and colleagues'61 demon-
strated an increase in plasma /?-endorphin levels prior
to the onset of syncope in subjects with vasovagal
attacks induced by tilt-testing. In a follow-up to these
preliminary results, the same group reports in this
issue^4' on the failure of naloxone to modify the
vasovagal response in well characterized subjects with
frequent spontaneous syncope and a reproducible
vasovagal response to tilt-testing. Their observation
leads to the conclusion that endogenous opioid
mechanisms are not an important trigger for vaso-
vagal events in humans, but probably relate to co-
release with adrenocorticotrophic hormone from the
pituitary in response to stimulation of low-pressure
atrial baroreceptors by relative central hypovolamia.
I found this paper interesting for three differ-
ent reasons: (1) In spite of its frequency and of its
easier diagnosis since the introduction of head-up
tilt-testing, vasovagal syncope remains a condition
which is poorly understood. The hypothesis implying
that the mechanism of syncope may be similar to the
Bezold-Jarich reflex is undoubtedly attractive but
is contradicted by several experimental or clinical
European Heart Journal (1996) 17, 1615-1617
Heart failure patients: why do they fatigue, how do they
get better?
See page 1678 for the article to which this Editorial
refers
The study of heart failure has changed. First we
assumed that poor myocardial contractility causes all
observations. Further research is justified in that area.
(2) Opioids may play an important role in modify-
ing baroreceptor physiology and substantial experi-
mental literature supports the concept of a sympatho-
inbitory action of these agents. Their effects, however,
are not easy to investigate since opioids do not act
in isolation but rather as neuromodulators. They
surely deserve further attention (3) The discussion
on the mechanisms of the vasovagal syncope raises
renewed interest in the fascinating and broad
discipline of 'neurocardiology'. The complexity of
the numerous electrophysiological mechanisms and
neuroendocrine systems involved in cardiovascular
Downloaded from https://academic.oup.com/eurheartj/article/17/11/1615/480494 by guest on 19 July 2021
regulation also constitutes an attractive area for
future research.
H. E. KULBERTUS
Cardiology,
CHU San Tilman,
Liege, Belgium
References
[1] Lewis T. Vasovagal syncope and the carotid sinus mechanism.
Br Med J 1932; 1: 873-6.
[2] Barcroft H, McMichael J, Sharpey-Schafer EP. Post-
haemorrhagic fainting. Study by cardiac output and forearm
flow. Lancet 1994; i. 489-91
[3] Hainsworth R. Syncope and fainting. In: Autonomic Failure. A
textbook of Clinical Disorders of the Autonomic Nervous
System, 3rd edn. Bannister R, Mathias CJ, eds. Oxford: Oxford
Medical Publications, 1992: 761-78
[4] Wallbridge DR, Maclntyre HE, Gray CE Oldroyd KG,
Rae AP, Cobbe SM. Role of endogenous opioids and
catecholamines in vasovagal syncope. Eur Heart J 1996; 17:
1729-36.
[5] Morita M, Nishida Y, Motochigawa H et al. Opiate
receptor-mediated decrease in renal nerve activity during
hypotensive hemorrhage in conscious rabbits. Circ Res 1988;
63: 165-72.
[6] Wallbridge DR, Maclntyre HE, Gray CE et al. Increase in
plasma /J-endorphins precedes vasodepressor syncope. Br Heart
j 1994; 7. 446-48.
the symptoms, and that treatments that increased
contractility would both make patients feel better and
live longer. This was a mistake. Later the importance
of the body's reflex responses to the ventricular
dysfunction were appreciated and their importance
1616 Editorials
in the progression of the condition was noted. Treat-
ments that inhibited this excessive vasoconstriction
and neuro-hormonal activation were shown to be the
most effective at improving prognosis and symptoms.
Only very much more recently was it realized that
we did not even know what caused the symptoms
limiting exercise in most of our stable well-diuresed
patients. The theories of backward heart failure
causing dyspnoea by congestion of the lungs and
poor cardiac output explaining muscular fatigue have
been disproved.
Chronic heart failure is a multi-organ disorder
in which the left ventricular dysfunction itself,
although of paramount importance in setting things
in motion, becomes accompanied by a panoply of
reflex, hormonal and metabolic disturbances which
can dominate the clinical picture, and profoundly
influence the symptoms of the patient. So much so
that in some regards it has much in common with
apparently unrelated conditions such as cancer
cachexia, the 'slim disease' of AIDS or end-stage liver
disease. All are associated by neuro-hormonal acti-
vation, skeletal muscle wasting and severe exercise
intolerance. Could there be a common final wasting
syndrome in all these conditions?
In the search for the pathophysiology explain-
ing exercise intolerance in heart failure much atten-
tion has focused on the cause of muscular fatigue.
Many studies attest to abnormal bulk, strength,
fatiguability, histology, enzymic content, and in vivo
metabolism of chronic heart failure. In a severe form
these muscle changes, as in cardiac cachexia, are
associated with a very poor prognosis. We know little
of the genesis of these changes. Perhaps inactivity
plays a role; in cachexia cytokine activation and loss
of normal anabolic function are probably important
as well. There is also almost certainly an impact of
impaired nutritive blood flow, due to reflex vaso-
constriction, capillary rarefaction and deficient
endothelial vasodilator function. What then do we
know about therapeutic interventions to correct
these abnormalities, thereby hopefully correcting the
enigmatic fatigue of these patients?
Muscle metabolic abnormalities in developing
heart failure can be avoided by appropriately timed
exercise training in a rat post-infarction model1'1. In
established heart failure training can improve single-
limb metabolism'21, large muscle bulk function'3' and
mitochondrial pathophysiology141. Even low inten-
sity training of individual muscle groups can 'add
up' to improved whole body exercise performance'51.
What is even more interesting is what does not
reliably improve the muscle function, e.g. cardiac
transplantation'61, perhaps in part explaining why
exercise tolerance and symptoms often remain
Eur Heart J, Vol 17, November 1996
extremely poor after this procedure'71. The paper by
Schaufelberger and colleagues from Goteborg in this
issue181, sheds interesting light on this issue. They
have confirmed some previously described histo-
logical and enzymic abnormalities in chronic heart
failure, and demonstrated that some of these can be
improved by 3 months enalapril treatment. Muscle
fibre size areas were increased, and there was an
increase in the glycolytic enzyme lactate dehydro-
genase, but there was no increase in capillarization
of the muscle or in oxidative enzyme activities.
A type II statistical error in these negative finding
is possible, given the inevitably small sample size
Downloaded from https://academic.oup.com/eurheartj/article/17/11/1615/480494 by guest on 19 July 2021
of this double biopsy study, but it also raises
the spectre that we still do not know how the
angiotensin-converting enzyme inhibitors do their
work. It may not be haemodynamic, it may not be
specific to a reduction in circulating angiotensin II,
and it may depend more on local autocrine systems
within many organs including skeletal muscle.
Although Drexler has shown a long-term benefit
of angiotensin-converting enzyme inhibition on
increasing muscle blood flow191, the results of
Schaufelberger's study suggest no increase in capil-
lary density and an increase only in a glycolytic
enzyme, raising the fascinating possibility that in
these patients the muscle is being driven harder and
hence is dependent on increasing its anaerobic capac-
ity, suggesting the possibility of further improvement
with specific blood flow enhancing agents, such as
those correcting endothelial dysfunction. Whilst this
study cannot answer all the myriad questions that
remain about the genesis, implications and thera-
peutic targets revealed by an appreciation of the
importance of muscle pathophysiology in heart fail-
ure, it does encourage us to delve deeper into the
mechanisms of action of agents that do improve
symptoms, and to test out strategies that might
augment these improvements yet further. We will
find only what we seek, and in heart failure, that
means looking at the complexity of the patho-
physiology of the condition in the intact human
patient. It is often how systems interact with each
other that generates understanding and novel treat-
ment strategies. Heart disease is at the centre of
internal medicine and for heart failure this means
we will hear more of autonomic, endocrine, meta-
bolic and cytokine abnormalities, which by detailed
clinical investigation will lead to previously un-
dreamt of opportunities to intervene for the benefit
to of our patients.
A. J. S. COATS
National Heart and Lung Institute,
Dovehouse Street,
London SW3 6LY, U.K.

References
[1] Brunotte F, Thompson CH, Adamopoulos S el al. Rat skeletal
muscle metabolism in experimental heart failure: Effects of
physical training. Acta Physiol Scand 1995; 154: 439-47.
[2] Minotti JR, Johnson EC, Hudson TH et al. Skeletal muscle
response to exercise training in congestive heart failure. J Clin
Invest 1990; 86: 751-8.
[3] Adamopoulos S, Coats AJ, Brunotte F el al. Physical training
improves skeletal muscle metabolism in patients with chronic
heart failure. J Am Coll Cardiol 1993; 21- 1101-6.
[4] Hambrecht R, Niebauer J, Fiehn E el al. Physical training in
patients with stable chronic heart failure: effects on cardio-
respiratory fitness and ultrastructural abnormalities of leg
muscles. J Am Coll Cardiol 1995; 25: 1239-49.
[5] Koch M, Douard H, Broustet JP. The benefit of graded physical
exercise in chronic heart failure Chest 1992; 101: 231S-235S.
European Heart Journal (1996) 17, 1617-1618
Diastolic dysfunction and ANP/BNP levels
See page 1694 for the article to which this Editorial
refers
Doctors who work in diabetes or in hypertension
have the luxury of one parameter (blood sugar
or blood pressure) against which the diagnosis can
be made and the treatment monitored. Sadly, in
cardiology and especially in heart failure, we have no
such single parameter to guide us.
Even if we restrict ourselves to systolic heart
failure, there is not one single parameter. Tradition-
ally most large studies have used the left ventricular
ejection fraction as their principal entry criteria,
despite recognised limitations, such as a low left
ventricular ejection fraction did not even predict the
development of heart failure in the SAVE study' 1 ' and
it is not as good a prognostic predictor as left
ventricular end systolic volume121. Cardiac output
per se might be the ideal parameter but is seldom
measured.
This situation becomes even more complex
when we recognise that heart failure may not simply
be systolic dysfunction but that diastolic abnormali-
ties may also be relevant. If defining and measuring
systolic dysfunction was tricky, defining and measur-
ing diastolic dysfunction has been even more com-
plex. Nevertheless, admirable progress has been made
in this difficult area. Abnormal diastolic mitral flow
patterns have been characterized on the basis of the
E/A ratio and the deceleration time of the E wave into
either non-restrictive or restrictive patterns. A recent
important publication suggests that in patients with
Editorials 1617
[6] Stratton JR, Kemp GJ, Daly RC, Yacoub M, Rajagopalan B.
Effects of cardiac transplantation on bioenergetic abnormalities
of skeletal muscle in congestive heart failure. Circulation 1994,
89: 1624-31.
[7] Walden JA, Stevenson LW, Dracup K, Wilmarth J,
Kobashigawa J, Moriguchi J Heart transplantation may not
improve quality of life for patients with stable heart failure.
Heart Lung 1989; 18: 497-506.
[8] Schaufelberger M, Andersson G, Eriksson BO, Gnmby G,
Held P, Swedberg K. Skeletal muscle changes in patients with
chronic heart failure before and after treatment with enalapril.
Eur Heart J 1996; 17: 1678-85.
[9] Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann
M, Just H. Contrasting peripheral short-term and long-term
effects of converting enzyme inhibition in patients with conges-
tive heart failure. A double-blind, placebo-controlled trial.
Downloaded from https://academic.oup.com/eurheartj/article/17/11/1615/480494 by guest on 19 July 2021
Circulation 1989; 79: 491-502.
systolic failure, a shortened E deceleration time (a
restrictive pattern) is the most powerful indicator of
cardiac death or transplantation'31.
A different but related notion among heart
failure investigators is the idea that measuring
natriuretic peptide levels might give added useful
information. This information might be valuable in
two ways. Firstly, natriuretic peptide levels may be of
value to help diagnose heart failure or even select
patients for echocardiography where echocardio-
graphic resources are scarce. Secondly, natriuretic
peptide levels may give added information on prog-
nosis over and above traditional measures of disease
severity. For example, Hall et a/.1'1 showed clearly
that N-terminal pro atrial natriuretic factor values
were predictive of a poor outcome over and above
other predictors such as left ventricular ejection
fraction. We recently found the same for BNP[4].
In this issue Yu et al.[5] bring these two ideas
together. In this paper, they studied 68 patients who
had definite systolic heart failure. It is firstly import-
ant to realise that this paper is about diastolic func-
tion in patients with known systolic dysfunction. It
tells us nothing about the entity of diastolic dysfunc-
tion in the presence of normal systolic function. In
this paper they found that all but 7% of their patients
with systolic dysfunction had diastolic abnormalities
of some kind. The restrictive filling pattern described
above was found in 62% of these patients. When they
compared those with versus those without the restric-
tive pattern, plasma levels of ANP and BNP were
much higher in those with the restrictive pattern.