Download Sympathetic and reflex abnormalities in heart failure secondary to

Clinical Science (2001) 101, 141–146 (Printed in Great Britain)
Sympathetic and reflex abnormalities in heart
failure secondary to ischaemic or idiopathic
dilated cardiomyopathy
Guido GRASSI*, Gino SERAVALLE†, Giovanni BERTINIERI‡, Carlo TURRI*,
Maria Luisa STELLA‡, Francesco SCOPELLITI* and Giuseppe MANCIA*
*Clinica Medica, University of Milano-Bicocca, Ospedale San Gerardo dei Tintori, Via Donizetti 106, 20052 Monza-Milan, Italy,
†Centro Auxologico Italiano, Via Spagnoletto 3, 20149 Milan, Italy, and ‡Centro di Fisiologia Clinica e Ipertensione,
Istituto di Ricovero e Cura a Carattere Scintifico, Ospedale Policlinico, Via F Sforza 35, 20122 Milan, Italy
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Congestive heart failure (CHF) is characterized by a sympathetic activation and a baroreflex
impairment whose degree is directly related to the clinical severity of the disease. However,
whether these abnormalities vary according to the ischaemic or idiopathic dilated nature of the
CHF state has not been conclusively documented. In patients with a clinically stable, chronic CHF
state in New York Heart Association functional class II and III, due either to ischaemic heart
disease (IHD ; n l 22, age 60.3p2.4 years, meanspS.E.M.) or to idiopathic dilated cardiomyopathy (IDC ; n l 20, age 58.9p2.8 years), and in 30 age-matched controls, we measured
arterial blood pressure (using a Finapres device), heart rate (by electrocardiogram) and
postganglionic muscle sympathetic nerve traffic (by microneurography) at rest and during
baroreceptor manipulation induced by the vasoactive drug-infusion technique. Blood pressure
values were not significantly different in CHF patients and controls. Compared with controls,
heart rate was similarly increased and left ventricular ejection fraction (by echocardiography)
similarly reduced in CHF patients with IHD or IDC. Muscle sympathetic nerve traffic was
significantly greater in CHF patients than in controls, and did not differ between patients with
IHD or IDC (67.3p4.2 and 67.8p3.8 bursts/100 heart beats respectively). This was also the case
for the degree of baroreflex impairment. These data show that CHF states due to IHD or to IDC
are characterized by a similar degree of peripheral sympathetic activation and by a similar
impairment of the baroreflex function. Thus the neuroadrenergic and reflex abnormalities
characterizing CHF are independent of its aetiology.
INTRODUCTION
Congestive heart failure (CHF) is characterized by a
sympathetic activation that has been shown to have a
prognostic significance, i.e. to be directly related to the
CHF severity and inversely related to patients’ survival
[1–6].
Whether the adrenergic overactivity typical of CHF is
different in CHF conditions of different aetiologies has
not been conclusively documented. This is because two
methods to quantify cardiac sympathetic influences (the
noradrenaline spillover into the coronary circulation and
the ["#$I]metaiodobenzylguanidine-imaging technique),
have shown them to be similarly increased in CHF due to
Key words : arterial baroreceptors, autonomic nervous system, heart failure, sympathetic activity.
Abbreviations : CHF, congestive heart failure ; IDC, idiopathic dilated cardiomyopathy ; IHD, ischaemic heart disease.
Correspondence : Professor Giuseppe Mancia at Clinica Medica, University of Milano-Bicocca (e-mail giuseppe.mancia!unimib.it)
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G. Grassi and others
ischaemic heart disease (IHD) or to idiopathic dilated
cardiomyopathy (IDC) [7,8]. However, greater levels of
plasma noradrenaline have been reported in IHD [2,9] as
compared with IDC, suggesting that peripheral sympathetic activation may be different in these two conditions. This is mechanistically plausible because : first,
sympathetic activity is characterized by a noticeable
regional heterogeneity [10,11] ; and secondly, in several
diseases cardiac adrenergic alterations do not bear a close
relationship with the peripheral ones [11–13]. Furthermore, a mechanism that plays an important role in the
sympathetic activation typical of CHF, i.e. the arterial
baroreflex dysfunction [14], may have differential influences on the heart and the systemic circulation [15,16].
In the present study, we have examined whether peripheral sympathetic activity and baroreflex modulation,
as assessed by microneurographic recording of sympathetic nerve traffic to the skeletal muscle district, differ
in patients with CHF of similar severity due to IHD or
IDC. It was thought that this might provide information
of clinical interest because : first, adrenergic activation
and baroreflex dysfunction are likely to have an independent prognostic influence [1–6,17] ; and secondly,
drugs interfering with the adrenergic cardiovascular drive
have been reported to differently affect survival in IHD
and IDC [18,19].
METHODS
Study population
The present study was performed on 42 patients of both
sexes ranging from 32 to 69 years who had : (i) a body
mass index (body weight in kilograms divided by the
square of the height in metres)
27 ; (ii) no history or
objective evidence of hypertension ; (iii) no clinical or
laboratory evidence of valvular heart disease, diabetes
mellitus or renal insufficiency ; (iv) no physical or
instrumental evidence of peripheral vascular disease, (v)
no history of coronary artery bypass surgery ; and (vi) a
clinically stable CHF belonging to the New York Heart
Association class II or III, and due either to IHD (n l 22)
or to IDC (n l 20).
The diagnosis of the IHD aetiology was based on : (i)
the history of a previous ( 6 months) myocardial
infarction and\or the electrocardiographic evidence of
myocardial infarction or ischaemia ; (ii) the echocardiographic evidence of regional alterations in left ventricular
wall motion ; (iii) the positive result of an echostress test
performed by dipyridamole or dobutamine ; and (iv) the
angiographic evidence of one or more haemodynamically
significant ( 70 % of the lumen) coronary artery stenoses. The diagnosis of IDC was made by : (i) the lack of
history of chest pain ; (ii) the absence of signs of ischaemia
or myocardial infarction at the electrocardiogram ; (iii)
# 2001 The Biochemical Society and the Medical Research Society
the uniform dilatation of the left ventricle at the echocardiogram, with no regional left ventricular dyskinesia
at the echostress test ; and (iv) the presence of a normal
coronary angiogram. IDC diseases due to cardiotoxic
drugs and\or substances (including alcohol abuse) were
excluded. All patients were hospitalized for at least 7
days. Pharmacological treatment based on angiotensinconverting-enzyme inhibitors, diuretics or digitalis was
withdrawn at least 6 days before the study, whereas
aspirin administration was not discontinued. Nitrates
were given according to clinical needs, but withdrawn if
administered during the 48 h preceding the study. Hospital inpatients (n l 30) recovering from non-cardiovascular disorders (pneumonia, gastrointestinal diseases,
urinary infections etc.) were selected as controls. Control
patients did not have hypertension, heart disease, diabetes
or other conditions known to affect neural cardiovascular
control, and were matched to CHF patients for gender,
age and body mass index. All patients included in the
study were in sinus rhythm. In both controls and
congestive CHF patients, blood counts, serum electrolytes and renal laboratory function tests were normal.
There were 12 smokers in the CHF group and seven in
the control group. Patients were not allowed to smoke
for the whole period of hospitalization, during which
they were not confined to bed, but were allowed to
engage in the recreational activities of inpatients (television watching, walking in the hospital ward, visit of
relatives etc). The study protocol was approved by the
Ethics Committee of Ospedale Policlinico, Milan and the
University of Milan-Bicocca. All patients gave written
consent to participate in the study after being informed of
its nature and purpose.
Measurements
Blood pressure was measured three times by a mercury
sphygmomanometer, the first and fifth Korotkoff sounds
being taken as markers of systolic and diastolic values
respectively. In addition, arterial blood pressure was
continuously monitored by a finger photoplethysmographic device (Finapres 2300 ; Ohmeda, Englewood,
CO, U.S.A.) capable of providing accurate and reproducible beat-to-beat systolic and diastolic values [13,20].
Heart rate was continuously monitored by a cardiotachometer triggered by the R wave of an electrocardiographic lead. The respiration rate was monitored
by a strain-gauge pneumograph positioned at the midchest level. Measurements included an echocardiogram
performed in M- and in B-mode. This allowed us to
assess left ventricular end-diastolic and end-systolic
diameters and volumes and to calculate left ventricular
ejection fraction [21]. Echocardiographic data were
collected by a single operator unaware of the experimental design. The within-operator coefficient of variation of left-ventricular end-diastolic diameter measurements (i.e. the within-operator reproducibility) was 6 %.
Sympathetic activation and heart failure aetiology
Multiunit recording of efferent postganglionic muscle
sympathetic nerve traffic was obtained through a tungsten microelectrode inserted into the right or left peroneal
nerve, as previously described [13,20,22]. The nerve signal
was amplified i70 000, fed through a bandpass filter
(700–2000 Hz), and integrated with a custom nerve traffic
analysis system (Bioengineering Department, University
of Iowa, Iowa City, IA, U.S.A.). Integrated nerve activity
was monitored by a loudspeaker, displayed on a storage
oscilloscope (model 511A ; Tektronix, Heerenveen, The
Netherlands), and recorded with blood pressure, heart
rate and respiratory movements on thermic paper by an
ink polygraph (Gould 3800 ; Gould Instruments, Cleveland, OH, U.S.A.). The muscle nature of sympathetic
nerve traffic was assessed according to the criteria
outlined in previous studies [13,20,22], and the recording
was accepted only if the signal-to-noise ratio exceeded
the value of 3. Under baseline resting conditions, postganglionic muscle sympathetic nerve traffic was quantified as bursts\min and bursts\100 heart beats. This
quantification was shown to be highly reproducible, i.e.
to differ by only 4.3 % when assessed on two separate
occasions by a single investigator [20].
Plasma noradrenaline was assayed by HPLC [23], and
plasma renin activity by RIA [24]. All measurements
were obtained from a blood sample drawn from a cannula
placed in an antecubital vein of the arm contralateral to
that used for sphygmomanometric and finger blood
pressure measurements.
Baroreceptor modulation of muscle sympathetic nerve
traffic and heart rate was assessed by intravenous infusion of vasoactive drugs [20]. Briefly, phenylephrine
was incrementally infused through the cannula placed
in an antecubital vein at doses of 0.3, 0.6 and
0.9 µg:kg−":min−". Nitroprusside was also infused incrementally in an antecubital vein at doses of 0.4, 0.8
and 1.2 µg:kg−":min−". Each infusion was maintained
for 5 min, and the drug initially infused was randomly
selected. The end of the first infusion was spaced from the
beginning of the second infusion by a recovery time of
45 min. Mean blood pressure (diastolic pressure plus 1\3
of pulse pressure), muscle sympathetic nerve traffic and
heart rate were averaged for 5 min before infusion and for
5 min of each step infusion. Baroreceptor modulation of
muscle sympathetic nerve traffic and heart rate was
estimated by calculating : (i) the change in the number of
bursts\min ; (ii) the % change in the integrated activity,
i.e. mean bursts amplitude times the number of bursts
over time ; and (iii) the absolute change in heart rate in
relation to the change in mean blood pressure induced by
each dose of phenylephrine and nitroprusside.
the supine position and fitted with the intravenous
cannulas, microelectrodes for the muscle sympathetic
nerve traffic recording and the other measuring devices.
A blood sample was then drawn, and the three sphygmomanometric blood pressure measurements were obtained. After a 30 min interval, blood pressure, heart rate,
respiration rate and muscle sympathetic nerve traffic
were continuously measured during : (i) an initial 10 min
baseline resting condition ; (ii) the intravenous infusion of
one vasoactive drug ; (iii) a 45 min recovery period
followed by a second 10 min baseline resting condition ;
and (iv) the intravenous infusion of the second vasoactive
drug.
Data analysis
Data were calculated by a single investigator unaware of
the patients’ classification. Values from individual subjects were averaged for the different groups and expressed
as meanspS.E.M. All statistical analyses were carried out
using the SPSS software package [25]. The statistical
significance of the difference in mean values was assessed
by two-way ANOVA. The two-tailed t test for unpaired
observations was used to locate the difference between
groups. The two-tailed t test for paired observations
was used to locate the difference between resting conditions and baroreceptor stimulation and deactivation.
Bonferroni’s correction for multiple comparisons was
used. A value of P 0.05 was taken as the level of
statistical significance.
RESULTS
Baseline values
Table 1 shows that CHF patients with IHD or IDC had
a similar age, gender distribution and New York Heart
Association functional class distribution. Blood pressure
(measured by sphygmomanometry or beat-to-beat at the
finger level), heart rate and left ventricular ejection
fraction were also similar between the two groups ;
however, a difference in left ventricular end-diastolic
diameter that was significantly greater in patients with
IDC was measured. This, however, was not accompanied
by any significant between-group difference in plasma
renin activity and noradrenaline values (Figure 1, upper
graphs). More importantly, muscle sympathetic nerve
traffic was not significantly different in CHF patients
with IHD and IDC, both when expressed as bursts\min
and when the number of sympathetic bursts was corrected for heart rate (Figure 1, lower graphs).
Protocol
Baroreflex responses
CHF patients and control subjects came to the laboratory
in the morning after a light breakfast. They were put in
As shown in Figure 2, the stepwise baroreceptor stimulation caused a progressively greater bradycardia and
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G. Grassi and others
Table 1 Baseline demographic, anthropometric, haemodynamic and echocardiographic
characteristics of control subjects and patients with CHF secondary to IHD or IDC
Values shown are meanspS.E.M. LVEDD, left ventricular end-diastolic diameter ; LVEF, left ventricular ejection fraction ; MBP,
mean blood pressure ; NYHA, New York Heart Association. Sphygmomanometric MBP was the average of three measurements.
*P 0.01 versus control subjects ; †P 0.05 versus CHF patients due to IHD.
Variable
Age (years)
Gender (male/female)
NYHA functional class (II/III)
Body mass index (kg/m2)
Sphygmomanometric MBP (mmHg)
Finger MBP (mmHg)
Heart rate (beats/min)
LVEF (%)
LVEDD (mm)
Respiration rate (breaths/min)
Figure 1
Control subjects
(n l 30)
CHF patients due to IHD
(n l 22)
CHF patients due to IDC
(n l 20)
55.0p1.9
25/5
60.3p2.4
20/2
10/12
25.0p0.6
92.6p1.8
89.4p2.2
79.0p3.0*
34.3p1.1*
64.5p1.8*
18.0p0.9
58.9p2.8
18/2
9/11
25.2p0.5
93.7p1.4
90.7p2.3
77.2p2.5*
33.1p1.6*
68.2p1.6*†
18.1p0.9
23.9p0.8
95.7p1.9
94.4p1.4
67.2p1.6
67.4p1.1
49.8p0.7
17.1p1.2
Sympathetic and renin–angiotensin activation in IHD and IDC
Baseline individual and mean values of plasma noradrenaline (NA), plasma renin activity (PRA) and muscle sympathetic nerve traffic [MSNA ; expressed as bursts incidence
over time (bursts/min) and corrected for heart rate values (bursts/100 heart beats)] in control subjects (=) and in patients with IHD ($) or IDC (#). NA and MSNA
values were always significantly different (*P 0.05, **P 0.01) between patients with CHF and control subjects, but not between patients with IHD and IDC. hb,
heart beat.
sympatho-inhibition, whereas the stepwise baroreflex
deactivation caused a progressively greater tachycardia
and sympathoexcitation. The magnitude of the reflex
heart rate and sympathetic nerve traffic changes was
similar in the two CHF groups.
Comparison with controls
In both CHF groups plasma renin activity, plasma
# 2001 The Biochemical Society and the Medical Research Society
noradrenaline and muscle sympathetic nerve traffic were
markedly greater than in controls, whereas baroreflex
modulation of heart rate and sympathetic nerve traffic
was markedly less (Figures 1 and 2). As expected,
compared with CHF patients, controls showed markedly
lower heart rate and left ventricular end-diastolic
diameter values and markedly greater left ventricular
ejection fraction values (Table 1).
Sympathetic activation and heart failure aetiology
Figure 2
Baroreflex, heart rate and MSNA curves in IHD and IDC
Changes in heart rate (HR ; expressed as beats/min) and muscle sympathetic nerve activity (MSNA ; expressed as bursts/min and % integrated activity [% i.a.])
accompanying stepwise reductions and increases in mean arterial blood pressure (MBP) induced by intravenous infusions of nitroprusside and phenylephrine respectively.
Values are meanspS.E.M. Stepwise HR and MSNA responses to nitroprusside and phenylephrine were always significantly different (*P 0.05, †P 0.01) between
patients with CHF secondary to ischaemic ($, dashed lines) or IDC (#, dotted lines) and control subjects (=, solid lines), but not between patients with ischaemic
and idiopathic dilated CHF.
DISCUSSION
Confirming previous findings of our group and others
[1,20,26,27], in our CHF patients plasma noradrenaline
and muscle sympathetic nerve traffic were markedly
increased compared with controls who were similar to
the CHF patients in age, gender, body mass index and
blood pressure values. The new finding of the present
study, however, is that muscle sympathetic nerve activity
is similarly increased in patients where CHF was due to
IDC and where a CHF of a similar clinical severity was
due to IHD. We can thus conclude that a typical
phenomenon of CHF, such as peripheral sympathetic
activation, is not influenced by the aetiology of this
condition. Interestingly, in CHF states due to IHD and
IDC plasma renin activity was also similarly increased
compared with controls. This suggests that not only
sympathetic activation but also activation of the renin–
angiotensin system (and thus possibly the neurohumoral
activation at large) which occurs in CHF is unrelated to
its aetiology.
Confirming previous data obtained by several investigators [14,17,20,28,29], baroreflex control of heart rate
and muscle sympathetic nerve traffic was much less
effective in CHF than in control subjects. Again, however, the loss of baroreflex control of peripheral sympathetic activity was similar in CHF states due to IHD or
to IDC. Thus a major mechanism regulating autonomic
functions is similarly impaired in CHF states that
originate from coronary heart disease and in those that do
not, presumably accounting for the similarity in their
sympathetic activation. It should be outlined that muscle
sympathetic nerve traffic was similar in patients with
IDC and IHD, although in the former group there was a
greater dilatation of the left ventricle, and thus a more
pronounced stimulation of cardiac volume receptors,
which powerfully inhibit sympathetic tone [30]. However, cardiac volume receptors have been reported to
undergo both functional impairment and structural
damage when exposed to persistent stimulation, such as
during chronic experimental CHF [30,31]. Furthermore,
the cardiopulmonary reflex has been found to be so
impaired in CHF patients as to lose most of its sympathoinhibitory influence [32–34]. This can explain why,
compared with CHF patients with IHD, sympathetic
activity was no less in patients with IDC, despite the fact
that the latter had a greater cardiac volume and, in
principle, more cardiac receptor stimulation.
Our study has both a limitation and a clinical implication. The limitation is that the microneurographic
approach only allows us to assess sympathetic nerve
traffic to skeletal muscle, leaving the question of whether,
in CHF patients with IHD and IDC, sympathetic activation is similar in visceral and other regional beds
unanswered. However, in the present study plasma
noradrenaline values were also similar between the two
groups, suggesting that this may indeed be the case, since
noradrenaline derives from secretion into neuroeffector
junctions of multiple districts, rather than only the
skeletal muscle [8,10,12].
The clinical implication refers to the hypothesis that
the different effects of treatment on survival in patients
with CHF secondary to IHD or IDC, reported in some
interventional trials [18,19], were dependent on a different
degree of sympathetic activation in the two conditions.
By showing that in our patients sympathetic nerve traffic
and plasma noradrenaline values were similar in these
two aetiologically different CHF states, the present study
demonstrates that this is not the case.
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Received 6 December 2000/8 February 2001; accepted 25 April 2001
# 2001 The Biochemical Society and the Medical Research Society