European Heart Journal (1999) 20, 1609–1611
Article No. euhj.1999.1704, available online at http://www.idealibrary.com on
Editorials
Cardiac cachexia — lean and mean
See page 1667 for the article to which this editorial
refers
‘Let me have men about me that are fat, sleek headed
and such sleep o’nights. Yond Cassius has a lean and
hungry look. He thinks too much. Such men are
dangerous.’
Shakespeare, Julius Caesar.
The association of a wasting syndrome with cardiac
disease was described by Hippocrates many hundreds
of years ago[1]. Only recently, however, is the importance of cachexia on morbidity and mortality in
chronic heart failure being fully recognised. The
development of cachexia in chronic heart failure is
poorly understood. Impaired appetite or decreased
food intake has never been clearly or consistently
implicated in cardiac cachexia.[2–4] However, recently,
enhanced energy expenditure has been described in
chronic heart failure and could play a partial role in
cachexia, as may overactivity of the sympathetic
nervous system which is known to characterize
chronic heart failure[5,6]. What has been recognised
for some time is that wasted patients with heart
failure show activation of various cytokine systems,
most notably tumour necrosis factor alpha (TNF),
which is not demonstrated by patients with chronic
heart failure of normal weight and build[7,8]. Such
cytokine activation is likely to be involved in the
development of the cachectic state and may induce
further deterioration in left ventricular function[9].
More recently, the expectation that cachectic
patients may have reduced survival has been
confirmed[10] while many other differences between
cachectic and non-cachectic patients have been
observed including reduced strength and increased
fatigability[11], reduced bone mass[12], a ‘catabolic–
anabolic imbalance’[13] and insulin resistance[14].
In this issue Ponikowski and colleagues[15] report
abnormalities of ‘cardiorespiratory reflexes’ in a small
group of chronic heart failure patients, 13 of whom
were defined as ‘cachectic’. Their principal observations demonstrate an abnormal heart rate variability
profile (defined by a reduced low frequency component by spectral analysis), depressed baroreflex sensitivity and increased peripheral chemosensitivity.
0195-668X/99/221609+10 $18.00/0
What are the implications of these observations?
Since the importance of the autonomic nervous system in cardiovascular morbidity and mortality has
been recognised, many quantitative markers of autonomic activity have been developed. Although
measurement of heart rate variability probably represents one of the most promising, the significance and
meaning of the many different measures of heart rate
variability are more complex than generally appreciated. For example, of the many different techniques
in the analysis of heart rate variability the frequency
domain (spectral) technique, as utilized in this study,
measures more precisely the magnitude of the respiratory synchronous component. However, even this
technique provides only indirect information about
the integrated mechanisms of autonomic control.
While it is accepted that vagal activity is the major
contributor to the high frequency component of heart
rate variability, disagreement exists with respect to
the low frequency component. Some believe that low
frequency is a quantitative marker of sympathetic
modulations and others view low frequency as reflecting both sympathetic overactivity and vagal activity.
Baroreflex sensitivity, on the other hand, is usually
regarded as a measure of ‘vagal reflex activity’
because it quantifies the ability to increase cardiac
efferent activity in response to an increase in blood
pressure (usually by injection of phenylephrine). In
this study, a significant difference was noted in the
low frequency component of heart rate variability
and baroreflex sensitivity between cachectic and noncachectic chronic heart failure patients. However,
baroreflex sensitivity analysis was limited to 22
patients due to frequent ventricular or supraventricular extrasystoles, with eight or less being ‘cachectic’
patients (P=0·04). It would have been interesting
to examine the effects of beta-blockade on these
measures. Perhaps due to small patient numbers the
authors may have been restricted in this regard.
However, it would have been useful to know of the
numbers of patients on beta-blockers in each group,
at least to ensure that any differences observed were
not the result of a treatment effect.
Whilst activation of the sympathetic nervous system has been intensively studied and is known to
indicate poor prognosis, the possible consequences of
1999 The European Society of Cardiology
1610
Editorials
impaired cardiac parasympathetic control are less
widely appreciated. Low cardiac vagal tone, as manifest by reduced baroreflex sensitivity, was described in
chronic heart failure patients over 20 years ago[16],
and following myocardial infarction is associated
with arrhythmia and a poor outcome.[17]. Although
the pathophysiological mechanisms are unclear, the
authors now demonstrate that the degree of impairment in reflex control relates more closely to the
presence of wasting than to conventional markers of
the severity of heart failure. It is this which is important, and adds to the already considerable evidence
confirming ‘cachectic’ subjects are distinct from the
general heart failure population.
Although we now have a much greater understanding of the importance of cachexia in the syndrome of
heart failure, there remains an urgent need for wellcontrolled prospective studies to establish the initiating sequence, determine the natural history and time
course of the cachectic state and to examine possible
therapeutic interventions. To date, no study has
examined the transition of patients from normal build
to the wasted state. Central to this is to reach an
agreed definition of cardiac cachexia, as there has
been an inconsistency with previous studies. Retrospective ‘documentation’ of weight loss by asking
patients to estimate weight change has previously
been used, but is clearly too subject to error to be
meaningful. While any definition will be necessarily
arbitrary, it needs to include not only documented
non-intentional, non-oedematous weight loss, but
also a measure of the ‘cachectic’ state such as a
significantly abnormal body mass index or reduced
skin fold thickness. Advantages of the latter method
include more accurate assessment of body composition, and avoidance of the potential confounding
influence of residual fluid retention, although
it is more time consuming and requires skill to
perform. Techniques such as DEXA scanning are
expensive and time consuming, although, whole body
bioimpedance is simple and may be of value.
Heart failure is not the only chronic condition to be
associated with the wasting state. Patients with advanced cancer, emphysema, HIV (‘slim disease’) or
other chronic inflammatory or infective conditions
can develop a very similar clinical condition. No
study has examined these groups in parallel to determine whether they are similar in their pathophysiological mechanisms and adverse prognosis. Various
candidate therapeutic interventions are, however,
already in development for ‘cachectic’ states in various diseases. These include megestrol acetate and
eicosapentaenoic acid in cancer cachexia[18–21]. Interestingly, direct anti-TNF action by injectable antiTNF antibody has been unsuccessful in treating
Eur Heart J, Vol. 20, issue 22, November 1999
septic shock which is characterized by elevated
plasma TNF levels,[22] although rheumatoid
arthritis and complicated Crohn’s disease seem to
respond[23,24]. Large multicentre studies will soon
examine its effects in heart failure, (RECOVER,
RENAISSANCE) and it is interesting to note that
pentoxifyline may improve symptoms and left
ventricular function in patients with dilated cardiomyopathy, possibly due to its anti-TNF effects[25].
The demonstration of abnormal cardiorespiratory
reflex control in patients with cardiac cachexia
suggests intervention here may be yet another
therapeutic target, perhaps with beta-blockade.
D. R. MURDOCH
J. J. V. MCMURRAY
West Glasgow Hospitals University NHS Trust,
Glasgow, Scotland, U.K.
References
[1] Katz AM, Katz PB. Diseases of heart in works of Hippocrates. Br Heart J 1962; 24: 257–64.
[2] Zhao SP, Zeng LH. Elevated plasma levels of tumor necrosis
factor in chronic heart failure with cachexia. Int J Cardiol
1997; 58: 257–61.
[3] Ansari A. Syndromes of cardiac cachexia and the cachectic
heart: current perspective. Prog Cardiovasc Dis 1987; 30:
45–60.
[4] Morrison WL, Edwards RH. Cardiac cachexia. BMJ 1991;
302: 301–2.
[5] Riley M, Elborn JS, McKane WR, Bell N, Stanford CF,
Nicholls DP. Resting energy expenditure in chronic cardiac
failure. Clin Sci 1991; 80: 633–9.
[6] Poehlman ET, Scheffers J, Gottlieb SS, Fisher ML,
Vaitekevicius P. Increased resting metabolic rate in patients
with congestive heart failure. Ann Int Med 1994; 121: 860–2.
[7] McMurray J, Abdullah I, Dargie HJ, Shapiro D. Increased
concentrations of tumour necrosis factor in ‘‘cachectic’’
patients with severe chronic heart failure. Br Heart J 1991; 66:
356–8.
[8] Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated
circulating levels of tumor necrosis factor in severe chronic
heart failure. N Engl J Med 1990; 323: 236–41.
[9] Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub
MH, Polak JM. Tumor-necrosis-factor and inducible nitricoxide synthase in dilated cardiomyopathy. Lancet 1996; 347:
1151–5.
[10] Anker SD, Ponikowski P, Varney S et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet
1997; 349: 1050–3.
[11] Anker SD, Swan JW, Volterrani M et al. The influence of
muscle mass, strength, fatigability and blood flow on exercise
capacity in cachectic and non-cachectic patients with chronic
heart failure. Eur Heart J 1997; 18: 259–69.
[12] Anker SD, Clark AL, Teixeira MM, Hellewell PG, Coat AJS.
Loss of bone mineral in patients with cachexia due to chronic
heart failure. Am J Cardiol 1999; 83: 612–15.
[13] Anker SD, Chua TP, Ponikowski P et al. Hormonal changes
and catabolic/anabolic imbalance in chronic heart failure and
their importance for cardiac cachexia. Circulation 1997; 96:
526–34.
[14] Swan JW, Anker SD, Walton C et al. Insulin resistance in
chronic heart failure: relation to severity and etiology of heart
failure. J Am Coll Cardiol 1997; 30: 527–32.
Editorials
[15] Ponikowski P, Piepoli M, Chua TP et al. The impact of
cachexia on cardiorespiratory reflex control in chronic heart
failure. Eur Heart J 1999; 20: 1667–75.
[16] Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac
parasympathetic control in patients with cardiac disease. N
Engl J Med 1971; 285: 877–83.
[17] Farrell TG, Odemuyiwa O, Bashir Y et al. Prognostic value of
baroreflex sensitivity testing after acute myocardial-infarction.
Br Heart J 1992; 67: 129–37.
[18] Vadell C, Segui MA, GimenezArnau JM et al. Anticachectic
efficacy of megestrol acetate at different doses and versus
placebo in patients with neoplastic cachexia. American Journal Of Clinical Oncology-Cancer Clinical Trials 1998; 21:
347–51.
[19] Barber MD, Ross JA, Fearon KCH. An eicosapentaenoic
acid-enriched nutritional supplement reverses cachexia in
patients with advanced pancreatic cancer. Br J Surg 1998; 85:
46.
[20] Wigmore SJ, Fearon KCH, Maingay JP, Ross JA. Downregulation of the acute-phase response in patients with pan-
[21]
[22]
[23]
[24]
[25]
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creatic cancer cachexia receiving oral eicosapentaenoic acid is
mediated via suppression of interleukin-6. Clin Sci 1997; 92:
215–21.
Gagnon B, Bruera E. A review of the drug treatment of
cachexia associated with cancer. Drugs 1998; 55: 675–88.
Abraham E, Anzueto A, Gutierrez G et al. Double-blind
randomised controlled trial of monoclonal antibody to human
tumour necrosis factor in treatment of septic shock. Lancet
1998; 351: 929–33.
Stack WA, Mann SD, Roy AJ et al. Randomised controlled
trial of cdp571 antibody to tumour necrosis factor-alpha in
Crohn’s disease. Lancet 1997; 349: 521–4.
Elliott MJ, Maini RN, Feldmann M et al. Randomized
double-blind comparison of chimeric monoclonal-antibody to
tumor-necrosis-factor-alpha (Ca2) versus placebo in
rheumatoid-arthritis. Lancet 1994; 344: 1105–10.
Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P.
Randomised investigation of effects of pentoxifylline on leftventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998; 351: 1091–3.
European Heart Journal (1999) 20, 1611–1612
Article No. euhj.1999.1780, available online at http://www.idealibrary.com on
More is worse — ST-segment deviation in unstable
coronary artery disease
See page 1166 (issue 16) for the article to which this
Editorial refers
Unstable coronary artery disease encompasses a
heterogeneous group of patients with a variable
clinical background, different severity of the underlying coronary artery disease, large variation in
clinical course and variable risk of subsequent cardiac
events. Therefore, an early evaluation of possible
underlying mechanisms and an assessment of the
prognosis are important in an attempt to tailor
the treatment to the individual patient. Among the
variety of indicators that have been suggested for
these purposes, the resting 12-lead ECG holds a
unique position: it is easily obtained, universally
available, inexpensive and provides important
diagnostic and prognostic information.
In unstable coronary artery disease ST-segment deviations in the admission ECG carry a higher risk for
subsequent cardiac events than isolated T-wave inversions. A normal ECG generally indicates a favourable
prognosis. In a recent study of patients with unstable
coronary artery disease the 30-day rate of death from
myocardial infarction was 5, 6, 6 and 15% in those
with no ST-T changes, isolated T-wave inversion,
minor ST-segment elevation and ST-segment depression, respectively[1]. However, it must be recognized
that ‘T-wave inversion’ may range from deep sym-
metrical anterior T-wave inversion highly indicative of
a proximal stenosis of the left anterior descending
coronary artery, to unspecific minor T-wave inversion
or flattening. Furthermore, the number, location and
amount of ST-segment deviation yields prognostic information, for example the risk of death or myocardial
infarction increases in correspondence with the
amount of ST-segment depression[1].
However, the ECG at rest does not adequately
reflect the dynamic nature of coronary thrombosis
and myocardial ischaemia. As many as two thirds of
all ischaemic episodes in unstable coronary artery
disease are silent, that is they are not associated with
chest pain. Thus, even using repeated ECGs in conjunction with chest pain, most episodes of ischaemia
will be overlooked. Therefore, different technologies
for continuous monitoring of the ST-segment, such as
Holter monitoring, continuous vectorcardiography
and continuous 12-lead ECG monitoring have been
introduced, the two latter techniques with capacity
for on-line presentation. In continuous vectography,
the ST-vector magnitude, the sum of ST-segment
deviation in the three orthogonal leads X, Y and Z,
is the one used most commonly to monitor STsegments. Previous studies evaluating the prognostic
value of these techniques have focused on the number
and total duration of episodes of ST-segment
deviation. In these studies, 15–30% of unstable
1999 The European Society of Cardiology