Download Autonomic Abnormality in Chronic Heart Failure

84
Heart Rate Variability
24
Autonomic Abnormality in Chronic H e a r t Failure
evaluated by Heart Rate Variability
Massimo Piepoli MD & Andrew JS Coats, DM,FRCP
Department of Cardiac Medicine, Imperial College, National Heart &
Lung Institute, Dovehouse Street, London. SW3 6LY. UK
Chronic Heart Failure
Prior work [I], utilizing pharmacological manipulation of blood
pressure and analysis of resultant heart rate (HR) responses,
suggested that withdrawal of parasympathetictone is a component of
the autonomic dysfunction in chronic heart failure (CHF).
Subsequently chronic activation of the adrenergic system together
with impaired arterial baroreflex sensitivity have been also described
as part of the syndrome [2]. Reduced baroreflex sensitivity and
increased plasma noradrenaline levels have been shown to be
independent predictors of increased mortality in CHF [3].
Heart Rate Variability
The refinement of techniques for the assessment of heart rate
variability (HRV), which provides a reliable estimate of the
autonomic nervous system control of the cardiovascular system, has
permitted an analysis of autonomic tone at rest without the need for
provocative manoeuvres. Several studies have been published, but
all of them confirmed the observation of a reduced HRV, with'
increased sympathetic activation and depressed vagal tone in CHF
patients
The first works evaluated time domain indexes of HRV. In 1987,
analysing 24 hour Holter tapes. Kleiger et al. [4] reported that, of all
variables measured, a reduced HRV had the strongest univariate
correlation with mortality, directly related to left ventricular ejection
fraction and exercise capacity and inverse related to left ventricular
failure during myocardial infarction. After this report, HRV was
proposed as :I non invasive tool to investigate the autonomic
abnormalities in CHF. Eriksson et al [5] in a review of the risk
factors for heart failure in the general population, observed that
reduced HRV, ;is well as other variables (such as hypertension,
smoking. body weight o r heart volume) were independent risk
ractors. In the patients awaiting for cardiac transplantation, a reduced
HRV is superior to other prognostic indexes to assess the risk of
death [6].
Caruana et a1 [7], evaluating 24 hour ambulatory intra-uteri:!!
blood pressure recordings found that not only HRV was reduced but
also blood pressure variability in CHF with respect to normals and
that these indexes were correlated with the left ventricular ejection
fraction and pulmonary wedge pressure. Reduction in HRV and
increased HR in patients with CHF respect to controls was later
confirmed during over 24 hours recording iS.91. In a following
work, HRV although correlated with left ventricular ejection
fraction. did not provide any significant help in identifying CHF
patients at risk of sudden death [lo]. Coumel et al [ I I ] observed that
a short lasting treatment with beta-blocker slowed non-uniformly the
mean HR: -9.5% in normals and -19.1%in CHF. This confirmed a
sympathetic predominance in CHF which was reflected by the Bblockade induced HR decrease that was twice as marked in patients
as in controls. Also the indexes of vagal activity has been evaluated
in this syndrome. From 24 hour Holter monitoring Nolan et al [ 121
measured the number of times each R-R interval exceeded the
preceding R-R interval by more than 50 ms as an index of
parasympathetic activity and found that this parameter was
significantlycorrelated with [eft ventricular ejection fraction; thus the
degree of vagal withdrawal seemed to correlate with the severity of
heart failure.
More recently the use of power spectral analysis approach to
evaluate the variability of the cardiovascular signals allowed to
further investigate the sympatho-vagal balance in this syndrome.
Saul et al [ 131 observed that HRV was reduced at all frequencies
examined (from O.OIHz to 1.0 Hz) in CHF with respect to normals
and virtually absent at frequencies greater than 0.04 Hz. In fact the
very low frequency (LF) (defined as 0.OIHz to 0.04 Hz) less
cffcctively difl'erentiated CHF from controls, due to discrete (about
65 seconds, 0.015 Hz) oscillation in HR. which was associated with
ii similar pattern in respiratory activity in many of the patients with
CHF. These findings demonstrated a marked derangement of
autonomic control of the heart in CHF patients. The frequency
characteristics of HRV (absence of HRV above 0.04 Hz and relative
preserved very low frequency component) in these patients are
consistent with abnormal barorellex responsiveness to physiological
stimuli, and suggest that there is diminished vagal, but relatively
preserved sympathetic, modulation of HR.
In a subsequent study, it was confirmed the abnormal pattern of
HRV spectrum in CHF patients (affected by idiopathic dilated
cardiomyopathy) who presented absence of high frequency
component (HF) (defined as >O.lHz) and a predominant
sympathetically mediated LF area (defined as 0.02-0.1Hz) [14]. By
pharmacological interventions, which decreased vagal tone and
enhanced sympathetic activation, it was possible to induce in normal
subjects the same autonomic alterations typical of the CHF patients:
administration of atropine reduced the HF area (within the range
noted in patients with CHF); the administration of isoproterenol
augmented the LF area without changing the HF m a [l4]. These
findings suggest that augmented sympathetic drive itself does not
mimic the HRV spectrum of CHF and emphasizes that
parasympathetic withdrawal is a necessary component of the
autonomic profile.
Experimental studies in a paced canine model with the induction
of congestive heart failure resulted in alterations in the autonomic
profile that resembled those seen in humans with ventricular failure:
the prominent HF component of the spectrum at baseline, indicating
a predominance of parasympathetic tone, was absent after the
evolution of CHF with marked augmentation of the LF of the
spectrum. The power spectral analysis of HRV is able to detect the
autonomic profile characteristics of CHF, with increased
sympathetic tone and parasympathetic withdrawal. HRV seems also
to provide a noninvasive information regarding the neurohumoral
abnormality in CHF. In fact both time domain (standard deviation of
R-R interval) and frequency domain (LF and HF components)
parameters of HRV were correlated with indicators of
sympathoexcitation, muscle sympathetic nerve activity and plasma
noradrennlinc in CHF [IS].
Not uniform data have heen published regarding the correlation
between severity of CHF and indexes of HRV. While Nolan et a1
[ 121 reported a direct correlation between reduction in vagal activity
index and the severity of heart failure, Saul et al [I31 found no
significant correlation between spectral data and age or survival; a
weak correlation was present between LF component and several
Iineinodynomic varieblcs, such as pulmonary capillary wedge
pressure (r=-0.545). cardiac index ( ~ 0 . 4 6 6 )Kienzle
.
et a1 [IS]
reported that frequency domain parameters of HRV correlated
weekly but significantly with cardiac output (r = 0.49 and ~ 0 . 4 2
respectively), but all the other parameters of HRV (both in time and
frequency domain) did not correlate with index of severity of CHF
(left ventricular ejection fraction, cardiac output or functional
classification). Instead Stefanelli et a1 [I61 reported that in CHF the
overall 24-h HRV and nighvday HR ratio was reduced. depending
on the NYHA functional class. The typical morphology of R-R
interval histograms was a sensitive marker of the clinical state at
baseline: the higher the NYHA class, the smaller the R-R interval
variability and standard deviation of R-R intervals. They also
observed that the clinical deterioration after 6 months was
accompanied by a tendency to further shortening of the mean total
HRV. In patients with clinical improvement no significant change in
HRV was observed. They concluded that while severe clinical
disease progression may be. associated with further reductions in the
HRV, improvement in the clinical state of CHF is not necessarily
associated with changes in HR behaviour. More recently other
authors [I71observed that the more advanced state of severity in
CHF were associated with different patterns of HRV: while NYHA
class I1 showed predominance of LF components (a marker of
increased sympathetic activation) and a blunted response to tilting,
class III patients showed an unresponsiveness to tilting, and class IV
patients an even more depressed HRV indexes and an almost
absence of the LF components. Correlations between HRV indexes
and seventy in CHF have been also recently reported by Casolo et al
[IS] who observed that while time domains parameters correlated
well with.the degree of CHF severity, spectral components of HRV
did not show a progressive impairments: LF and HF decreased
severely from NYHA class I to class 11, with less reduction in the
more advanced classes. Instead Takase et a1 [ 191 reported that while
clinical deterioration and autonomic neuropathy were associated with
more severe depression of HRV (as assessed by standard deviation),
also after clinical improvement improvement in spectral analysis
index was observed with higher standard deviation. The different
methods and indexes used for assessing autonomic controls during
the evolution of the syndrome may at least partially explain the
discordant findings reported. We observed in fact 120) that the
different methods t~ assess sympathovagal balance (time domain and
frequency domain indexes) did not correlate, with the exception of
Heart Rate Variability
day and night-time HR and the expected inverse correlation between
LF and HF (r = -0.92). However. no method correlated significantly
with peak oxygen uptake. exercise tolerance or ejection fraction.
Thus in CHF the individual parameters of autonomic control seemed
to reflect different aspects of the circulatory control, hence a
comprehensive description of the autonomic tone may require
multiple methods.
The therapeutic approaches to this syndrome, have been also'
evaluated in relation to their capability to partially reverse the
autonomic abnormalities, assessed by HRV.
Flapan 1211 investigating the effect of with angiotensinconverting enzyme inhibitors (captopril) therapy, reported an
increase in HRV. The authors concluded that the results may be
relevant to the improved prognosis of this group of patients when
treated with angiotensin-converting enzyme inhibitors. Similar
beneficial effects on HRV by an other ACE-inhibitor drug
(zofenopril) [22] and by low dose scopolamine [23].
We have looked at the effects on the autonomic balance of
physical conditioning in CHF [20,24]. In a controlled cross-over
trial after 8 ,weeks of physical training at home, both time and
frequency domains indexes showed improvement in autonomic
balance. The circadian pattern of HRV in CHF patients and the
relative effect of physical training were also recently evaluated in the
24-hour recordings[25]. We found that the training improved all
HRV indexes, during different time intervals, suggesting that the
improvement was an inherent phenomenon rather than due to
increased physical activity. The preservation of a circadian variation
of the LF and the HF components of HRV in patients after both
training and detraining suggested that the syndrome of CHF is
characterised by a resetting of autonomic balance rather than
autonomic neuropathy (figure 1). The effect of short duration pulsed
inotrope therapy was assessed in C H F it induced a pharmacological
conditioning, similar to that induced by physical conditioning, with
up-regulation of the B-adrenoceptors and enhancement of the
chronotropic responsiveness 1261.
Figure 1. Circadian patterns of the LF and HF components of
HRV in controls (closed squares) and in CHFpatients after training
(open circles) and after de-training (closed circles). Note the higher
powers during the sleeping status in all groups and the higher
powers in normals compared to patients also after training and detraining and the higher powers after training compared to after detraining (reproduced from [25]).
85
Controversies
Several studies have been published during the last few years.
and probably even more will be presented in the near future.
However. some important debates are still open. First it is the
physiological meaning of the HRV findings. In fact it is well known
that the sympathovagal balance to the heart is tonically and phasically
modulated by the interaction of several factors: central neural
integration, peripheral receptor activation with inhibitory and
excitatory reflex mechanisms. However it still unclear what part of
the autonomic nervous system is specifically investigated by the
HRV technique. We recently evaluated whether HRV can
differentiate between sympathetic stimulation induced by
endogenous sympathetic stimulation (i.e. physical exercise) and
exogenous sympathetic stimulation (by inotrope infusion): exercise
and inotrope infusion produced similar changes in HRV (figure 2);
however plasma noradrenaline was elevated by exercise but
unchanged by dobutamine [27]. Therefore HRV could not
differentiate between the two sympathetic stimulations. indicating
that the degree of receptor stimulations rather than the level of
sympathetic drive would appear to determine the changes in HRV.
An other important point is how reproducible is this methodology
in a condition of profound autonomic imbalance such as CHF. A
considerable day-to day variation in 24 hour Holter monitoring was
reported in normals and also in CHF [28,29]; however stability from
short lasting recordings is not been established.
An abnormal HRV patter is evident in more advances stages of
CHF the original observation of Saul et al [13] was later confirmed
[ 17,301. i.e. the pattern of HRV in CHF patients is characterized by
depressed HRV with predominant very low frequency fluctuations.
whose exact origins are still under debate. In fact these fluctuations
niay be influenced by various physiological factors, like reninangiotensin system, thermal regulation [3 1,321. A possible origin
from abnormal respiratory pattern with Cheyne-Stokes respiration
was hypothcsised [33], which may induces an abnormal activity of
chemoreceptors: further investigation are needed to confirm this
hypothesis.
Figure 2. Changes in LF (upper) and HF (lower graph) of HRV
(means It standard error) during dobutamine infusions (open
symbols, continuous lines) and supine exercise tests (filled symbols,
dotted lines): *=p<O.OS vs. pre-dobutamine rest, #=p<O.OS vs. preexercise rest (reproduced from [27])
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86
Heart Rate Variability
References
I . Eckberg DL. Drabinsky M. Braunwald E. Defective cardiac
parasympathetic control in patients with heart disease. N Engl J
Med 1971; 285877-83.
2. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA,
Korner PI. Norepinephrine spillover to plasma in congestive
heart failure: Evidence of increased cardiorenal and total
sympathetic nerve activity. Circulation 1986;73615-21.
3. Leimbach WN Jr, Wallin BG, Victor RG. Aylward PE,
Sundolf G. Mark AL. Direct evidence from intraneural
recordings for increased central sympathetic outflow in patients
with heart failure. Circulation 1986;73:913-9
4. Kleiger RE,Miller JP, Bigger JT, Moss AJ and the Multicenter
Post-Infarction Research Group. Decreased heart rate variability
and its association with increased mortality after acute
mycocardial infarction. Am J Cardiol 1987;59;256-62
5 . Eriksson H, Svardsud? K. Larsson B, et al. Risk factors for
heart failure in the general population: the study of men born in
1913. Eur Heart J 1989;lO: 647-56
6. Binder T. Frey B, Porenta G, Heinz G, et al. Prognostic value
of heart rate variabilitv in Datients awaiting cardiac
transplantation. PACE 1992;lS: 2i15-20.
7 . Caruana MP, Lahiri A, Cashman PM. Altman DG, Raftery EB.
Effects of chronic congestive heart failure secondary to coronary
artery disease on the circadian rhythm of blood pressure and
heart rate. Am J Cardio1.1988;62:755-9
8. Hermida IS, de Jode P, Jarry G, et al. Sinus rhythm and
standard deviation in cardiac cycles. Influence of myocardial
status and beta-blocker treatment. Arch Ma1 Coeur Vaiss
1989;82:1993-2000
9 . Casolo G. Balli E, Taddei T. Amuhasi J. Gori C. Decreased
spontaneous heart rate viiriability in congestive heart failure. Am
J Ciirdiol 1989;64:1 162-7
10. Fei L, Keeling PJ, Gill JS. et al. Heart rate variability and its
relation to ventricular arrhythmia in congestive heart failure. Br
Heart J 1994;71:322-8
I I . Coumel P, Herniida JS. Wennerblom B. et al. Heart rate
variability in left ventricular hypertrophy and heart failure, and
the effects of beta-blockade. A non-spectral analysis of heart
rate variability in the frequency domain and in the time domain.
Eur Heart J 1991;12:412-22
12. N o h J. Flapan AD, Capewell S.MacDonald TM, Neilson JM,
Ewing DJ. Decreased cardiac parasympathetic activity in chronic
heart failure and its relation to left ventricular function.Br Heart
J 1992;67:482-5
13. Saul JP, Arai Y, Berger RD. Lilly LS, Colucci WS, Cohen RJ.
Assessment of autonomic regulation in chronic congestive heart
failure by heart rate spectral analysis. Am-J Cardiol
1988;61:1292-9.
14. Binklev PF. Nunziata E. Haas GJ. Nelson SD. Codv RJ.
Parasimpathetic withdrawal is an. integral component of
autonomic imbalance in congestive heart failure: demonstration
in human subjects and verification in a paced canine model of
ventricular failure. J Am Coll Cardiol 1991;18:464-72
15. Kienzle MG, Ferguson DW, Birkett CL, Myers GA. Berg WJ,
Mariano DJ. Clinical, hemodynamic and sympathetic neural
correlates of heart rate variability in congestive heart failure. Am
J Cardiol 1992;69:761-7
16. Stefenelli T. Bergler Klein J, Globits S. Pacher R, Glogar D.
Heart rate behaviour at different stages of,congestive heart
faihre. Eur Heart J 199213:902-7.
17. Guzzetti S, Cogliati C, Turiel M, Crema C, Lombardi F,
Malliani A. Sympathetic predominance fo:lowed by functional
Y
denervation in the progression of chronic heart failure. Eur
Heart J 1995; 16: 1100-7
18. Casolo G. Stroder P. Sulla A. Chelucci A. Freni A. Zerauschek
M. Heart’rate variability and functional &verity of congestive
heart failure secondary to coronary artery disease. Eur Heart J
1995;16:360-7
19. Takase B, Kurita A, Noritake M, et al.. Heart rate variability in
patients with diabetes mellitus, ischemic heart disease, and
congestive heart fiiiluw. J Electrocardiol 1992;25:79-88
20. Adamopoulos S,Piepoli M, McCance A. et al. Comparison of
different mcthods for assessing sympathovagal balance in
chronic congestive heart failure secondary to coronary artery
disease. Am J Cardiol 1992;70: 1576-82.
2 I . Flapan AD, Nolan J, Neilson JM, Ewing DJ. Effect of captopril
on cardiac parasympathetic activity in chronic cardiac failure
secondary to coronary artery disease. Am J Cardiol 1992;
69~532-5
22. Binkley PF. Haas GJ. Starling RC, et al. Sustained
augmentation of parasympathetic tone with angiotensinconverting enzyme inhibition in patients with congestive heart
failure. J Am Coll Cardiol 1993: 21:655-61
23. La Rovere MT. Mortara A. Pantaleo P. Maestri R, Cobelli F,
T a v a u i L. Scopolamine improves autonomic balance in
advanced congestive heart failure. Circulation 1994; W838-43
24. Coats AJS, Adamopoulos S. Radaelli A, et al. Controlled trial
of physical training in chronic heart failure: Exercise
performance, hemodynamics, ventilation and autonomic
function. Circulation 1992;85:2119-31.
25. Adamopoulos S,Ponikowski P, Cerquetani E. et al. Circadian
Pattern of Heart Rate Variability in Chronic Heart Failure
Patients: Effects of Physical Training. Eur Heart J 1995 (in
press)
26. Adamopoulos S, Piepoli M, Qiang F. et al. Short duration
pulsed inotrope therapy induces pharmacologicalconditioning in
congestive heart failure; up-regulates R-adrenoceptors and
enhances chronotropic responsiveness. Lancet 1995; 345344-9
27. Piepoli M. Adamopoulos S. Bemardi L, Sleight, P, Coats AJS,
Autonomic Cardiovascular Control in Heart Failure: power
spectal analysis of heart rate variability shows similarity
between exogenous and endogenous R-receptor stimulation. C1
Sci 1995; 89:155-164
28. Van-Hoogenhuyze D. Weinstein N. Martin GJ, et al.
Reproducibility and relation to mean heart rate of heart rate
variability in normal subjects and in patients with congestive
heart failure secondarv to coronarv
. arterv
, .disease Am J Cardiol
1991;68:1668-76
29. Stein PK. Rich MW, Rottman JN, Kleiger RE. Stability of
index of heart rate variability in patients with congestive heart
failure. Am J Cardiol 1995;129:975-81
30. Mortara A, La Rovere MT, Signorini MG, et al. Can power
spectal analysis of heart rate Variability identify a high risk
subgroup of congestive heart failure patients with excessive
sympathetic activation? A pilot study before and after heart
transplantation. Br Heart J 1994; 71: 422-430.
3 I . Akselrod S. Gordon D, Ubel FA, Shannon DC. Barger AC.
Cohen RJ. Power spectral analysis of heart rate fluctuations: a
quantitative probe of beat-to-beat cardiovascular control.
Science 198 1:213:22&223.
32. Sayers B Mck. Analysis of heart rate variability. Ergonomics
1973;16:17-32.
33. Ichmaru Y, Yanaga T. 24-hr ambulatory electrocardiographic
monitoring. Comput Biomed Res 1989;22225-33