Download Is central nervous system processing altered in patients with heart

European Heart Journal (2004) 25, 952–962
Clinical research
Is central nervous system processing altered
in patients with heart failure?
Stuart D. Rosena,b,*, Kevin Murphyc, Alexander P. Leffb,
Vincent Cunninghamb, Richard J.S. Wiseb, Lewis Adamsc,
Andrew J.S. Coatsa, Paolo G. Camicib
a
Department of Heart Function, National Heart and Lung Institute, Imperial College, Royal Brompton Hospital,
London SW3 6NP, UK
b
MRC Clinical Sciences Centre, Imperial College, Hamersmith Hospital, London W12 OHS, UK
c
Department of Respiratory Physiology, National Heart and Lung Institute, Imperial College, Charing Cross Hospital,
London W68RP, UK
Received 13 April 2003; revised 11 March 2004; accepted 31 March 2004
Available online
KEYWORDS
Aims Breathlessness is a cardinal symptom of heart failure and the altered regulation
of breathing is common. The contribution of abnormal central nervous system activity
has not previously been investigated directly, although abnormal autonomic
responses have been described. Our aim was to assess whether heart failure patients
exhibit different patterns of regional brain activation after exercise stress.
Methods We used positron emission tomography with H2 15 O, to measure changes in
regional cerebral blood flow (rCBF) and absolute global cerebral blood flow (gCBF) in 6
male class II/III heart failure patients and 6 normal controls. Breathlessness (0–5
visual analogue scale) and respiratory parameters were measured at rest, after horizontal bicycle exercise and during isocapnic hyperventilation. CBF was measured in
each condition in all subjects.
Results Both groups were similarly breathless after exercise and the respiratory parameters were comparable. rCBF differences for the main comparison (exercise vs
hyperventilation) were: activation of the right frontal medial gyrus (P < 0:001;
Z ¼ 4:90) and left precentral gyrus (P < 0:03; Z ¼ 4:66) in controls but not in patients.
Both groups had rCBF increases in the left anterior cingulate (P < 0:05; Z ¼ 4:67)
and right dorsal cingulate cortex (P < 0:05; Z ¼ 4:66). The gCBF did not differ between
exercise, isocapnic hyperventilation and rest in patients but, in controls, gCBF was
greater after exercise compared to either isocapnic hyperventilation or rest.
Conclusion Heart failure patients had a distinct pattern of regional cortical activity
with exercise-induced breathlessness but unvarying CBF values between conditions.
These central neural differences in activity may contribute to some features of heart
failure, such as variability in symptoms and autonomic dysregulation.
c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
Heart failure;
Breathlessness;
Cerebral blood flow;
Exercise;
Brain;
Autonomic nervous system;
Positron emission
tomography
Introduction
* Corresponding author. Tel.: þ44-208-967-5359; fax: þ44-208-9675007.
E-mail address: [email protected] (S. D. Rosen).
In health, the regulation of breathing and cardiac
output is very closely co-ordinated, maximising the
0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ehj.2004.03.025
Is central nervous system processing altered in patients with heart failure?
953
List of Abbreviations
ANOVA
ANS
CHF
CNS
ECG
fR
gCBF
PCO2
PET
analysis of variance
autonomic nervous system
chronic heart failure
central nervous system
electrocardiogram
respiratory frequency
global cerebral blood flow
partial pressure of carbon dioxide
positron emission tomography
efficiency of oxygen transfer to the body and delivery
of oxygen at the tissue level. In cardiac or pulmonary
disease, when cardiac output or oxygenation is abnormal, overall cardiopulmonary efficiency declines and
the work of breathing is increased for the required
oxygen delivery required. Both diseases are associated
with breathlessness and fatigue, although the precise
mechanisms involved probably differ somewhat between them.1;2
In heart failure, even when objective signs of pulmonary disease are absent, some patients display lower
values of PCO2 and higher respiratory frequency (fRÞ .3 An
altered ventilatory response to exercise (VE –VCO2 slope)
has also been demonstrated and is an independent marker of prognosis.4–6 Dysregulation of breathing in chronic
heart failure (CHF) might involve changes of control at
several levels, ranging from peripheral ergoreflex activation7 and peripheral chemosensitivity,8 through abnormal autonomic reflexes9–11 to an altered central
command.12 Furthermore, the relationship of these
variables to the subjective sensation of breathlessness is
elusive.2;13;14
The role of the central nervous system (CNS) in the
regulation of breathing has been investigated in normal
individuals using several technologies,15–24 including
positron emission tomography (PET) with H2 15 O, one of
the most direct means of exploring neural function in
vivo in man.25–27 Regional cerebral blood flow (rCBF) is
measured as an index of regional synaptic activity during particular tasks or conditions.28
Although several independent methods (e.g., analysis of heart rate variability10–11 ) have pointed to abnormalities of automatic nervous system (ANS)
function in chronic heart failure (CHF), altered activity
of the CNS has not been systematically investigated.
Because known abnormalities of breathing regulation
have been demonstrated by other techniques, we
predicted that important functional abnormalities of
CNS activity might occur in CHF. We also sought to
clarify whether the wide variation in the experience of
breathlessness, known to correlate poorly with objective measures of impairment of cardiac function,14
might be explicable in terms of differences in cerebral
cortical activation. (We have previously demonstrated
this comparing painful and silent myocardial ischaemia.29 ) The specific hypothesis that we tested in this
study was that the pattern of CNS activation, during
rCBF
Sa O2
SPM
VCO2
VE
VE –VCO2 slope
vs
VT
regional cerebral blood flow
arterial oxygen saturation
Statistical parametric mapping
volume of CO2 exhaled
minute ventilation
ventilatory equivalent for CO2
versus
tidal volume
physical stress is different in patients with CHF from
that in age-matched normal controls.
Methods
Study population
Selection of heart failure patients
Six dextral male patients [age 62 (11) years], mean (SD)
were recruited from consecutive out-patients of Hammersmith and Charing Cross Hospitals over a period of 1.5 years.
All were patients with symptomatic systolic CHF, New York
Health Association (NYHA) class II or III, controlled on
medication. The aetiology of the CHF was coronary artery
disease with previous myocardial infarction in 5 cases and
idiopathic dilated cardiomyopathy in 1 case. During exercise
testing, 5/6 patients and all controls had ECGs that were
amenable to the detection of ischaemia; one patient was in
left bundle branch block. There was no detectable inducible
ischaemia during exercise in the study population. Echocardiography was performed according to standard protocols to
assess left ventricular function. Lung function tests were also
performed to exclude asthma or chronic obstructive pulmonary disease. Diabetes and autonomic neuropathy were
also excluded, the latter by standard bedside tests. In addition, subjects with unstable cardiovascular disease, drug or
alcohol addiction and those who had already undergone a
PET scan or any other study involving ionising radiation
within the last two years were excluded. Patients with
clinical evidence of cerebrovascular disease were also excluded. The 6 patients who satisfied the above criteria were
the result of investigating over 40 patients with CHF during
an 18-month period. The characteristics of the patient group
are shown in Table 1.
Control subjects
Six dextral normal sedentary male controls [age 67 (5) years,
P ¼ NS vs the patients] were also studied. These were selected
on the basis that they were both age- and sex-matched with
respect to the patients. They were recruited randomly from
hospital staff, visitors and relatives of patients on the basis of
reply to a general call for study volunteers. They all had clear
past medical histories with no background of cardiac or pulmonary disease, or risk factors for coronary artery disease. They
underwent the same detailed cardiopulmonary assessment as
the patients and demonstrated normal results, i.e., normal
resting and exercise ECGs, normal echocardiography and normal
lung function.
954
Table 1 Characteristics of the patients and controls
Patient Age
Height Weight Cause
Medication
Echocardiogram
1
67
164
62
AMI 5 years
S,A,D,AS
2
68
171
90
AMI 6 years
N,D,B,S,AS,F,AL
FS 26%; anteroseptal akin;
NS
inf hypokin
FS 27% apical and inf infarcts Ex 20 years
3
54
168
63
AMI 1.5 years
AS,A,D, Lithium
4
70
167
61
AMI 8 years
AS,D,N,A
5
71
166
111
AMI 4 years
A,Warfarin,N,D
6
45
185
84
DCM 4 years
Dig,amio,D,
Warfarin,S,A
FS 15% Ant and inf infarcts;
dil LA and LV
FS 16%; ant, apical and
infpost hypokin, apex akin
FS 3%; septum akin;
hypo through-out
FS 23%; apical hypo
Control Age
Height Weight Echocardiogram
Smoke
ECG
1
2
3
4
64
60
66
72
156
167
180
163
65
66
84
70
No
No
No
No
Within
Within
Within
Within
5
6
71
72
178
171
59
77
No WMA; FS 30%
No WMA; FS 29%
NS
NS
Ex 25 years
20/day for 56
years
NS
NS
WMA;
WMA;
WMA;
WMA;
FS
FS
FS
FS
33%
47%
29%
40%
normal
normal
normal
normal
Smoke
NS
NS
Ex 28 years
10 g/wk
ECG
Angiogram
NYHA
LBBB Negative maximal
DSE
Q V1-5; L-axis # ST I,
aVL,V3-6
Poor R V1-3;
nonspec # ST V5,6
Incomplete LBBB;
" LA; Inferolat ST/T; VE’s
Poor R V1-3; q in V4;
# T V1-6, I, aVL
# T inferolat;
Q V1-3; VE’s
90% prox LAD; Cx and RCA
II
Occ LAD; 70%RCA;
unobst Cx; Eff PCI-LAD
Small unobst arteries
II
80% mid LAD; Occ Cx after OM1;
Occ RCA; 3 SVG’s and LIMA
90% LAD; 90% Cx; Occ RCA;
LIMA to LAD; SVG’s: OM1 & RCA
Not performed (Patient refused)
II
III
III
II
limits
limits
limits
limits
Within normal limits
Within normal limits
Cause: AMI, acute myocardial infarction, number of years previously; DCM, dilated cardiomyopathy. Medication: S, statin; A, ACE-inhibitor; D, diuretic; AS, aspirin; N, nitrate; B, b-blocker; F, fibrate; AL, ablocker; Dig, digoxin; Amio, amiodarone. Echocardiogram ; FS, fractional shortening; ant, anterior; inf, inferior; infpost, inferoposterior; akin, akinesis; hypokin, hypokinesis; dil, dilated; LA, left atrium; LV, left
ventricle; WMA, wall motion abnormality. Smoke: smoker status; Ex, ex-smoker; NS, non-smoker. ECG: LBBB, left bundle branch block; DSE, dobutamine stress echocardiogram; L-axis, left axis deviation; # ST, ST
segment depression; " LA, left atrial enlargement; Nonspec, non-specific changes; Poor R, poor R wave development; ST/T, ST and T wave changes; VE’s, ventricular ectopic beats. Angiogram: LAD, left anterior
descending coronary artery; Cx, left circumflex artery; RCA, right coronary artery; prox, proximal stenosis; Occ, occluded; Unobst, unobstructed; Ef, effective; PCI, percutaneous coronary intervention; OM1, first
oblique marginal branch of circumflex; SVG, saphenous vein graft; LIMA, left internal mammary artery graft. NYHA: New York Heart Association heart failure class.
S. D. Rosen et al.
Is central nervous system processing altered in patients with heart failure?
Monitoring and measurements
Time 0
End list mode
Exercise at 50W
Peak of counts
Unloaded
exercise
End infusion
During the PET study, patients were monitored repeatedly using:
a 12 lead ECG (Marquette), continuous ECG for rhythm (Siracust), blood pressure (Dinamap), respiratory flow rate (ultrasonic flowmeter), end-tidal PCO2 (Capnograph), arterial oxygen
Count rise noted
PET scanning protocol
On a different day, patients and controls attended the MRC
Clinical Sciences Centre/IRSL, Hammersmith Hospital for PET
scanning. This was carried out using an ECAT EXACT3D tomograph (model 966, CTI, Knoxville, TN, USA).31;32 The acquisition system of this scanner has a flexible design which
can record data in both frame and list mode. List mode acquisition was used in the present study, thus providing efficiency of data storage and high temporal sampling with
flexible post-hoc frame re-binning. Emission scanning was
performed with an energy window of 350–650 keV. Transmission scanning was performed with a single photon point
source (150 MBq of 137 Cs, E ¼ 0:663 MeV, t1=2 ¼ 30:2 years),
contained in a small pellet which was driven in a fluid-filled
steel tube wound into a helix and positioned just inside the
detector ring.
A series of measurements of rCBF were carried out,
using H2 15 O as the flow tracer. For each CBF measurement,
6 mCi activity of H2 15 O were administered as a bolus over
160 s, (build-up period of 120 s, infusion for 20 s and flush
for 20 s).33 After cannulation of the radial artery and an
antecubital vein, patients and controls underwent a series
of 12 scans. These comprised 3 different conditions of rest,
post-exercise breathlessness and isocapnic hyperventilation
each repeated 4 times in a randomised sequence. The duration of each scan including the delay between scans was
8 min:
For each 8-min cycle, when the run was bicycle exercise,
there was unloaded exercise between t0 and 1.00 min, then
50W exercise between 1.00 and 4.00 min of the 8 min cycle.
When the run was isocapnic ventilation, each subject breathed
in time with a metronome at the same fR and VT as at the end
of the bicycle exercise condition, between 3.00 and 7.30 min
of the 8 min cycle. In all conditions, the H2 15 O build-up was
between t ¼ 1:30 and t ¼ 3:30 min, the infusion between 3.30
and 4.30 min, with the rise noted on the PET camera between
4.20 and 4.25 min, peaking at 4.55 min (Fig. 1). The list mode
acquisition was between 2.30 and 7.30 min. Scan acquisition
was performed immediately on cessation of cycling because
movement artefacts during cycling prevented the acquisition of
useful data.
During the scanning sequence, 200 mL of blood (5 mL/
min between 3.50 and 7.20 min of each cycle plus a discrete
5 mL sample at 6.50 min) was taken from each subject.
During each PET scan, blood was sampled continuously from a
radial arterial line for scintillation counting by an on-line
bismuth germanium oxide system. This allowed the rCBF
measurements to be quantified in absolute units (described
below).
In total, subjects had a radiation exposure of 3.54 mSv (12
runs, each equivalent to an exposure of 0.27 mSv, plus 0.3 mSv
for the transmission scan).
H215O infusion
Prior to the PET scanning session, all subjects underwent
clinical rehearsals at the Respiratory Physiology Laboratory,
Charing Cross Hospital to learn how to use the horizontal
exercise bicycle. They had a symptom-limited test during
which, in addition to continuous ECG, their blood pressure,
heart rate, ventilation (ultrasonic respiratory flowmeter),
PCO2 (capnograph) and oxygen saturation (finger oximeter)
was monitored. They also gave an estimate of their perceived breathlessness upon exertion using a modified Borg
scale;30 in this case, a 0–5 scale (0 ¼ no sense of breathlessness, 5 ¼ intolerably severe breathlessness) with increments of 0.5.
On a separate occasion, subjects were taught to copy the
rate and depth of breathing that they had displayed during the
practice horizontal bicycle test. This was to provide a control
condition for the physical respiratory efforts associated with
post-exercise breathlessness. However, to avoid hyperventilation-induced hypocapnia, we adjusted the amount of CO2 in
the inspired gas mixture, to keep the PCO2 in the normal
range. The condition was therefore termed ‘isocapnic hyperventilation’. From pilot work, we observed that isocapnic
ventilation alone generated very little sensation of breathlessness. The idea was therefore that in the analysis of the
scan data (described below), the exercise run, minus isocapnic
ventilation, would equate to (physical effort of respiration + sensation of dyspnoea) ) (physical effort of respiration),
i.e., as close as possible to a true representation of the sensation of dyspnoea.
Start list mode
Pre-scanning assessment
Run 1
Isocapnic hyperventilation;
Run 2
Rest 1;
Run 3
Horizontal bicycle exercise;
Run 4
Isocapnic hyperventilation;
Run 5
Rest 2;
Run 6
Horizontal bicycle exercise;
[4 min break to download data from PET camera to computer]
Run 7
Horizontal bicycle exercise;
Run 8
Isocapnic hyperventilation;
Run 9
Rest 3;
Run 10
Rest 4;
Run 11
Horizontal bicycle exercise;
Run 12
Isocapnic hyperventilation.
H215O build up
Population size
The sample size (6 patients and 6 controls) was chosen on the
basis of several previous brain PET studies of this nature, in
which this sample size was adequate to demonstrate significant
differences in regional cerebral blood flow.
955
8 minutes
Fig. 1 Acquisition schedule – post-exercise breathlessness.
956
S. D. Rosen et al.
saturation – Sa O2 (finger oximeter), a modified Borg scale of
perceived breathlessness and distress.
Analysis of PET images
PET images were transformed into a standard stereotactic
space. Regional blood flow measurements were corrected for
global changes in blood flow and comparisons of rCBF across
conditions were performed with the t statistic (more precisely a
block design ANCOVA) on a voxel by voxel basis by statistical
parametric mapping (SPM96) software (Wellcome Department of
Cognitive Neurology, Queen Square).34–37 rCBF changes related
to the post-exercise breathlessness runs were compared with
isocapnic hyperventilation runs as well as with baseline conditions. These analyses permitted the construction of statistical
parametric maps for the description of significant changes in
rCBF between the different test conditions. Significant changes
were identified by applying a statistical threshold of 0.05, corrected for multiple comparisons.
For the computation of global cerebral blood flow (gCBF),
arterial blood was sampled throughout the scanning procedure
from the radial arterial line. gCBF measurements were obtained
(mL blood/min/mL tissue) by means of least squares fits of total
tissue radioactivity using the Kety model.38
Statistical evaluation
Besides the use of SPM for the analysis of the rCBF data, the
intra-group respiratory variables, between different conditions,
were analysed with a 2 factor ANOVA (two-sided). However, due
to concerns over possible correlations between the post-exercise data and the isocapnic hyperventilation data, we compared
the respiratory variables between groups for the different conditions using two-tailed paired t tests. The t test was also used
to compare age and echocardiographic fractional shortening
between the study groups. The statistical comparisons were
performed using Statview SE+ Graphicsâ 4.0 software. Statistical significance was defined as P < 0:05.
Ethical considerations
This study was approved by the Research Ethics Committee,
Hammersmith Hospital and by the UK Administration of Radioactive Substances Advisory Committee (ARSAC). The investigation conformed with the principles outlined in the Declaration of
Helsinki (Cardiovascular Research 1997;35:2–4). All subjects
gave written informed consent for their participation in the
study.
Results
Patient and control characteristics are presented in Table 1. The only co-morbid illnesses were two previous
deep vein thromboses in patient 2 and diverticulosis in
patient 5. No control had any intercurrent illness, nor
was any taking medication. Lung function tests were
within normal limits in all cases. The details of the respiratory parameters are in Tables 2–4.
Respiratory parameters
NB: Values of Sa O2 were above 96% in all subjects at all
stages of testing and will therefore not be presented in
greater detail.
1. At rest. There were no significant differences between the patients and controls for inspiratory and expiratory times and volumes, PCO2 , heart rate, fR or Vi at
rest. (Table 2)
2. Isocapnic hyperventilation. The differences between isocapnic hyperventilation and rest for the two
groups are detailed in the Table 3. As can be seen, there
were no significant differences between the patients and
controls for the respiratory variables during isocapnic
hyperventilation.
Table 2 Respiratory parameters under resting conditions
Patient
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
5.47
1.73
1.89
2.28
1.91
1.91
2.39
1.44
2.82
2.17
4.87
1.57
27.11
29.72
25.90
29.51
34.91
35.34
75.4
101.0
59.0
85.0
49.0
66.1
7.92
19.07
13.60
13.59
8.91
17.47
9.18
13.27
12.66
7.06
9.52
8.89
Mean
P (vs Con)
2.53 ± 1.45
0.769
2.54 ± 1.25
0.781
30.41 ± 3.93
0.622
72.58 ± 18.72
0.25
13.42 ± 4.45
0.887
10.10 ± 2.39
0.988
Control
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
2.47
2.71
1.91
2.74
2.07
2.18
2.34
2.86
1.53
2.58
2.42
2.61
37.38
30.86
29.16
31.58
25.05
35.87
59.25
59.5
50.5
53.5
80.5
68.5
12.57
11.14
17.46
11.28
13.51
12.79
8.26
10.00
8.02
9.69
15.18
9.55
Mean
2.35 ± 0.38
2.39 ± 0.51
31.65 ± 3.93
61.96 ± 10.98
13.13 ± 2.57
10.12 ± 2.73
Ti , inspiratory time (s); Te , expiratory time (s); PCO2 , end tidal partial pressure of CO2 (mmHg); HR (beats min1 ); fR respiratory frequency
(min1 ); Vi , ventilation, i.e. expiratory volume fR (L min1 ); Con, Control subjects.
Is central nervous system processing altered in patients with heart failure?
957
Table 3 Respiratory parameters during isocapnic hyperventilation
Patient
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
1.52
1.65
1.78
1.53
2.12
0.99
1.66
0.94
2.18
1.72
1.91
1.18
32.60
31.35
39.32
41.26
29.51
34.59
87.74
90
62
81
51
73.28
19.02
23.63
15.59
18.43
15.40
27.72
34.71
23.13
21.22
15.56
29.10
30.65
Mean
P (vs Rest)
P (vs Con)
1.60 ± 0.42
0.198
0.515
1.60 ± 0.37
0.068
0.353
34.77 ± 4.82
0.204
0.190
74.35 ± 15.28
0.657
0.165
19.97 ± 5.01
0.006
0.298
25.73 ± 7.72
0.004
0.939
Control
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
1.62
1.40
1.98
1.60
2.02
1.72
1.53
1.54
1.67
1.50
2.02
3.43
39.41
36.81
38.96
35.73
36.99
37.35
63.25
58.75
48.5
55
77.25
68.25
19.02
21.88
16.47
19.47
15.00
11.71
28.08
29.95
14.85
43.51
14.71
25.73
Mean
P (vs Rest)
1.72 ± 0.24
0.044
1.95 ± 0.75
0.237
37.54 ± 1.39
0.019
61.83 ± 10.15
0.910
17.26 ± 3.63
0.010
26.14 ± 10.75
0.021
For legend, see Table 2, plus: IH, isocapnic hyperventilation.
Table 4 Respiratory parameters during post-exercise breathlessness
Patient
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
2.27
1.22
1.23
1.78
2.63
1.46
2.36
1.30
2.47
1.77
2.28
1.97
32.75
32.56
33.71
41.08
30.24
34.59
98.63
126.75
77.33
135.5
66.25
71.21
13.25
23.87
16.59
17.02
12.30
27.72
25.41
16.84
19.42
13.49
17.30
30.65
Mean
P (vs Rest)
P (vs IH)
P (vs Con)
1.76 ± 0.58
0.257
0.573
0.527
2.02 ± 0.44
0.360
0.133
0.236
33.39 ± 4.05
0.226
0.593
0.114
95.95 ± 29.53
0.194
0.140
0.686
16.99 ± 4.18
0.183
0.280
0.281
17.96 ± 4.15
0.002
0.042
0.719
Control
Ti
Te
PCO2
HR
fR
Vi
1
2
3
4
5
6
2.19
1.46
1.49
2.51
1.57
2.63
2.06
1.89
1.91
3.55
2.22
3.02
38.46
35.42
33.06
38.76
35.30
39.62
96.75
81.75
91.33
67
104
101.50
14.25
17.91
17.72
9.97
16.18
10.80
14.54
21.19
16.57
12.84
17.74
20.14
Mean
P (vs Rest)
P (vs IH)
1.97 ± 0.54
0.183
0.314
2.44 ± 0.71
0.872
0.259
36.77 ± 2.01
0.036
0.531
90.39 ± 13.94
0.003
0.002
14.47 ± 3.41
0.445
0.202
17.17 ± 3.57
0.002
0.079
For legend, see Table 2.
3. Post-exercise breathlessness. There was a non-significant trend for PCO2 to be lower after exercise in patients (33.4 ± vs 36.8 ± mmHg; P ¼ 0:114, two-tailed).
Otherwise, there were no significant differences between
the groups for the respiratory parameters (see Table 4).
Breathing is increased during exercise or hyperventilation and, as expected, the comparisons in Tables 2–4
reflect this.
Comparing post-exercise breathlessness to isocapnic
hyperventilation, no differences between groups for the
respiratory variables and heart rate were apparent (2tailed, paired t test), although there were differences in
these variables between the conditions (P ¼ 0:042 for
patients for Vi , and 0.002 for HR for controls]. No significant differences were found when testing for an interaction between these comparisons (CHF vs Controls
958
S. D. Rosen et al.
There were significant rCBF increases in common for the
patient and control groups with respect to the right
lentiform nucleus (28, 12, 4; Z ¼ 6:01; P ¼ 0:000 and 38,
)6, 6; Z ¼ 5:45; P ¼ 0:001) and left cerebellum ()32,
)54, )40; Z ¼ 4:92; P ¼ 0:015) (see Table 6).
3. Post-exercise breathlessness vs isocapnic hyperventilation. NB: This equates to {physical effort of respiration + sensation of dyspnoea} compared to the
physical effort of respiration alone. This main comparison identified the following areas of brain activation to
be common to both patients and controls: the left anterior cingulate gyrus ()28, 32, 10; Z ¼ 4:67; P ¼ 0:043),
and the right dorsal cingulate (18, )54, 26; Z ¼ 4:66;
P ¼ 0:045).
However, when patients and controls were compared
directly, the control group exhibited increased rCBF in
the right frontal medial gyrus (BA6; 2, )24, 64;
Z ¼ 4:9; P ¼ 0:01) and the left pre-central gyrus (BA4;
)18, 26, 62; Z ¼ 4:66; P ¼ 0:028), activations which were
not found in the patient group. See Fig. 2.
4. Absolute cerebral blood flow in the test conditions. In the patients, there were no significant differences in gCBF among the study conditions (0.51 ± 0.07
mL/min/mL after exercise; 0.51 ± 0.10 mL/min/mL
during isocapnic hyperventilation and 0.49 ± 0.09 mL/
min/mL at rest, P ¼ 0:89). In the controls, gCBF was
greater after exercise than after isocapnic hyperventilation (0.40 ± 0.24 mL/min/mL vs 0.35 ± 0.03 mL/min/
mL; P < 0:0001) and greater after exercise than at rest
(0.40 ± 0.24 mL/min/mL vs 0.35 ± 0.04 mL/min/mL;
P < 0:0001). There were no differences between the
and Post-exercise breathlessness vs isocapnic hyperventilation). For details, see Table 4.
Perception of breathlessness
There were no significant differences in the perception
of breathlessness between the patients and controls
within the test conditions. Both groups felt more
breathless during exercise compared to resting conditions (1.99 ± 0.48 vs 0.13 ± 0.16 P ¼ 0:0002, for patients
and 1.29 ± 1.14 vs 0.25 ± 0.61, P ¼ 0:03 for controls).
Both groups also felt more breathless after exercise
compared to during isocapnic hyperventilation
(1.99 ± 0.48 vs 0.33 ± 0.35, P ¼ 0:0004, for patients and
1.29 ± 1.14 vs 0.29 ± 0.48, P ¼ 0:039 for controls). For
both groups on 2 way ANOVA, post-exercise breathlessness vs isocapnic hyperventilation, P < 0:001.
PET findings
1. Post-exercise breathlessness vs rest. NB: This equates
to: {physical effort of respiration + sensation of dyspnoea} compared to rest. Areas of the brain activated in
this comparison, in both patients and controls, were the
right inferior temporal gyrus (BA 20; 60, )28, )22;
Z ¼ 5:53; P ¼ 0:001) and the right anterior insula (BA 45;
26, 14, 2; Z ¼ 4:91; P ¼ 0:016). There were no significant
areas of activation found in patients that were not found
in controls, nor vice versa (see Table 5).
2. Isocapnic hyperventilation vs rest. NB: This equates
to the physical effort of respiration compared to rest.
Table 5 Areas of increase in rCBF in controls only for the comparison (post exercise breathlessness vs rest)
LEFT
RIGHT
Area
x
y
z
Z
P
Insula/frontal op (BA 38)
Cerebellum
Cerebellum (vermis)
Pre-central gyrus (BA 4)
Post-central gyrus
Fusiform gyrus
)28
)32
)8
)4
14
)64
)56
)26
12
)36
)24
78
5.40
5.33
5.20
4.95
0.001
0.001
0.003
0.008
x
Y
z
Z
P
34
)64
)28
4.75
0.019
20
64
34
)24
)20
)64
84
)24
)28
5.13
4.87
4.75
0.004
0.011
0.019
Table 5 reports the co-ordinates in the x, y and z axes of the significant rCBF increases for the controls only, for the Comparison {post-exercise
breathlessness ) rest} with reference to the stereotactic space defined by the atlas of Talairach and Tournoux.36 Statistical magnitudes are expressed
as Z scores (Z) and P values. BA, Brodmann Area, frontal op, frontal operculum.
Table 6 Areas of increase in rCBF, in controls only for the comparison: (isocapnic hyperventilation vs rest)
LEFT
RIGHT
Area
x
y
z
Z
P
x
Z
P
Pre-central gyrus (BA 6)
Lentiform nucleus
Cerebellum
Inf parietal lobule (BA 40)
)60
)26
)10
0
)2
)58
18
6
)22
6.30
5.55
6.02
0.000
0.000
0.000
68
y
2
z
12
5.22
0.002
20
66
)70
)42
)24
46
5.56
5.43
0.000
0.001
Table 6 reports the co-ordinates in the x, y and z axes, of the significant rCBF increases for the controls only, for the comparison {isocapnic
hyperventilation ) rest} with reference to the stereotactic space defined by the atlas of Talairach and Tournoux.36 Statistical magnitudes are
expressed as Z scores (Z) and P values. BA, Brodmann Area; Inf, inferior.
Is central nervous system processing altered in patients with heart failure?
959
Abnormalities of respiratory function in heart
failure
Impaired ventilatory efficiency (altered VE –VCO2 slope)4–6
is an acknowledged feature of CHF patients and may have a
number of causes including central factors (e.g., chemoreceptor stimulation by hypoxia, hypercapnia or acidosis)8
and peripheral ones.7 Our CHF patients showed a trend
towards greater fR and lower PCO2 than the controls, although there were no statistically significant differences
in the respiratory variables compared to controls.
Perception of breathlessness in heart failure
Fig. 2 Regional cerebral blood flow increases for the comparison {Post
exercise breathlessness ) isocapnic hyperventilation} present in the
controls but not in the CHF patients. The activation of the medial postcentral gyrus (I) and left superior frontal gyrus (II) in the controls is evident. R, right; L, left; Ant, anterior; Post, posterior. For the stereotactic
co-ordinates, see text.
isocapnic hyperventilation condition and at rest. Between patients and controls, there were significant differences (P < 0:00001) for each of the 3 conditions.
Discussion
Principal findings of the study
We examined the central neural correlates of control of
breathing in CHF and found:
1. The respiratory parameters were mostly comparable
between the 2 groups for the different study conditions. However, during isocapnic hyperventilation
and after exercise the patients tended to shorter
breathing times, greater respiratory frequency and
lower PCO2 ;
2. There was little subjective difference between the
group of 6 Class II/III CHF patients and 6 age-matched
sedentary controls;
3. There were areas of brain activation common to both
groups – the right lentiform nucleus and left cerebellum in the isocapnic hyperventilation condition and
the right inferior temporal gyrus and right anterior insula after exercise. For the main effect (exercise vs
hyperventilation), a comparison which equates to
{physical effort of respiration + sensation of dyspnoea}
compared to physical effort of respiration alone, the
controls showed activations not present in the patients, chiefly the medial post-central gyrus and left
superior frontal gyrus;
4. Absolute gCBF did not differ significantly between the
study conditions in the patient group but in controls it
was significantly greater during post-exercise breathlessness than during either isocapnic hyperventilation
or the resting condition.
Breathlessness is a normal experience after excessive
physical exertion and is more pronounced in the physically deconditioned. It is also a cardinal symptom of CHF,
in which several mechanisms probably contribute to its
generation.1;2 Although counter-intuitive, there is little
or no relationship between symptoms of CHF and objective indices of function1;2;14 The issue is of obvious
clinical importance, with a spectrum of symptoms ranging from excessive, causing debility in patients with wellpreserved organ function on the one hand, to lack of an
important ‘early warning system’ in patients with significant pathology on the other. However, to date, the
role of the CNS in generating such variability of symptom
perception has not been studied directly. One of the
motives to perform the present study was to address this.
We attempted to identify if rCBF, in a particular cerebral
area, co-varied with the subjective sensation of breathlessness in the CHF patients. No such area was identified.
In fact there was less cerebral activation in the patients
than in the controls, although both groups had similar
subjective sensations of breathlessness. This subjective
similarity may itself be considered rather surprising.
Another situation in which reduced cortical activation
is observed is in habituation of the response to an aversive
stimulus.39;40 It could be conjectured that in CHF, there is
habituation to afferent signals at some level within the
neuraxis, which may be a factor in the complex relationship between symptoms and cardiac function in CHF.
Concerning the sensation of post-exercise breathlessness, the lack of a difference between CHF patients and
controls was rather unexpected. It is possible that the
patients lacked a stimulus of sufficient intensity to generate additional foci of activation. However, even if this
were the case, the subjective rating of breathlessness of
the patients was not less than that of the controls and,
furthermore, the haemodynamic responses were equivalent. Thus the principle negative finding of the study (the
areas of brain activation found in controls but not patients) still appears to be a significant observation and
one which requires explanation.
Functional imaging of the brain in the study of
respiratory control
Functional imaging (mainly PET with H2 15 O) has previously been used in studies of breathing regulation in
960
normal subjects during volitional inspiration15 and expiration.16 Subsequently, CO2 -stimulated breathing has
also been studied,18 with a control condition in the form
of passive isocapnic respiration at equivalent fR and VT .
Neuronal activation was identified in the upper brainstem, midbrain, hypothalamus, hippocampus, parahippocampus, fusiform gyrus, cingulate area, insula and
frontal, temporo-occipital and parietal cortices. Although the main focus of that study was the motor
control of breathing, the finding of substantial limbic
system activation, is significant in the context of perception of breathlessness, because the CO2 inhalation
produced a conscious urge to breathe that was often
severe enough to be described as breathlessness.
In a further investigation,17 the increase in breathing
during and after right leg bicycle was explored. As well as
demonstrating increases in rCBF in the ‘leg’ areas, there
were also increases in the superolateral cortical areas
bilaterally, previously noted to be activated during volitional breathing. After exercise, only the superolateral
areas continued to show increased rCBF; in this study
many of the subjects were feeling breathless during the
image acquisition because of the high exercise workload.
It should be emphasised however that, unlike the controls of our study, the subjects in these studies were
mainly young, fit males with an understanding of respiratory physiology.
More recently, Critchley et al., also using PET with
H2 15 O, identified the central neural correlates of exercise and mental stress,41 demonstrating rCBF increases in
the cerebellar vermis, right anterior cingulate and right
insula which covaried with mean arterial pressure. rCBF
increases were also found in the pons, cerebellum and
right insula which co-varied with heart rate. Decreases in
rCBF were reported for the pre-frontal and medial temporal regions. The areas identified were considered
representative of the regions involved in integrated
cardiovascular response patterns associated with volitional and emotional behaviours.
With respect to the current study’s normal subjects,
our principal findings are compatible with the above. We
found left insular activation during post-exercise
breathlessness; activation of this cerebral region was
also a feature of Banzett et al., study of air hunger,20 it
occurred in Corfield et al., study of CO2 -stimulated
breathing18 and in Williamson’s study of hypnotic sense
of effort.23 The cerebellar activation observed in our
study corresponds to similar activations in studies of
volitional inspiration by Ramsay et al.,16 and Colebatch
et al.,15 the vermis activation also features in the studies
of Pfeiffer on breathing against a resistive load21 and
that of Isaev24 as well as in the Corfield et al., CO2 stimulated breathing study.18 The latter study and Williamson’s hypnotic sense of effort study also feature
right anterior insular activation as found in our patients
and controls.23
With respect to the isocapnic hyperventilation condition in our controls, the activations of the cerebellum
and right superior frontal gyrus were also found in the
studies of Ramsay,16 Corfield,18 Fink17 and colleagues.
For our key comparison (post-exercise breathlessness vs
S. D. Rosen et al.
isocapnic hyperventilation) the left superior frontal
activation in our controls corresponds to that found in
Corfield’s CO2 study,18 whilst the left anterior cingulate
activation, common to our patients and controls features
in the studies of Fink,17 Williamson19;23 and Corfield.18
The most fascinating contrast in the present study,
however, is the absence of distinguishing activations
among the patients. The observation of no subjective
difference in the perception of breathlessness between
CHF patients and the controls suggests that the sensation
of breathlessness may depend upon different brain
mechanisms in CHF from those found in health. Alternatively, or additionally, there may be differences in
central command in relation to exercise in CHF.
Autonomic dysfunction in patients with heart
failure
Enhanced sympathetic activity is widely recognised as a
pathophysiological feature of CHF. Several independent
investigative techniques have pointed to abnormal neural regulation in CHF.10;11;42–47 In particular, an assortment of heart rate variability studies have indicated that
at different stages of CHF, there are differences in the
degree of alteration of neural regulation and the heart’s
responsiveness to it. However, the precise neurophysiological substrate of such abnormalities, including any
potential contribution of the higher centres of the CNS,
remains to be elucidated.
The present study is open and observational and its
principal value lies in the proposition of hypotheses. It is
possible that the apparent absence of cerebral activations
in the different conditions in the CHF patients might be
related to the reduced heart rate variability and baroreflex sensitivity known to occur in this disease. Unfortunately, we do not have specific data on heart rate
variability and baroreflex sensitivity in these particular
subjects, so any association remains speculative. It is
tempting to hypothesise that one mechanism maintaining
the degree of variability of these may be additional intermittent inputs from the cerebral cortex to the brainstem. A further prospective study with detailed autonomic
functional assessment is necessary to clarify this.
Cerebral vascular reactivity in heart failure
Cerebral autoregulation is a fundamental physiological
response to changes in systemic haemodynamic conditions and is well preserved in a wide range of conditions.
However, a number of studies have demonstrated that
cerebrovascular reactivity is attenuated in CHF. Paulson
and colleagues, measuring cerebral blood flow (CBF) by
the intracarotid xenon-133 (133 Xe) injection technique48
found mean CBF to be lower in patients with CHF. They
also found that CBF was not reduced further by administration of captopril, despite a marked reduction in blood
pressure. This effect was interpreted as a shift in the
limits of cerebral autoregulation, probably mediated by
larger cerebral arteries.49 More recently, Kamishirado
et al., measuring CBF by analysing the Patlak-Plot curve
obtained from radionuclide angiography, reported an
Is central nervous system processing altered in patients with heart failure?
increase in CBF in patients with CHF treated with enalapril, independent of any effect on cardiac output.50
Consistent with standard therapy for CHF, all but one of
our patients in the present study were treated with ACEinhibitors and therefore the relatively greater values of
gCBF that they had in all test conditions might be attributable to medical therapy. Other than treating all
controls with an ACE-inhibitor, it is difficult to envisage
how to remove this potentially confounding factor.
However, this does not necessarily account for the lack of
variability in gCBF in patients between conditions.
With regard to rCBF in CHF, in a recent paper, a swine
model of pacing-induced heart failure was described by
Caparas et al.51 CBF was found to be reduced compared
to controls both at rest and during treadmill exercise,
although there was a significant increase in CBF between
rest and exercise in the heart failure swine. Specific regions of blunted increase in perfusion were the parietal
and occipital cortex and the supra-pyramidal medulla. To
date, however, there have been no direct studies of rCBF
in vivo in man in cardiac disease. We employed the
technique of least squares fits of total tissue radioactivity using the Kety model.38 This was necessary because
the SPM analysis treats gCBF as a co-variate of no interest, so only relative increases in rCBF between conditions can be identified.
961
4. It has to be acknowledged that there has been multiplicity of statistical testing, particularly of the respiratory
data; in the presence of small sample sizes, there is
therefore a disproportionate risk of false positive results. However, the respiratory data are only a secondary
focus of the paper and the brain imaging data are more
significant and less susceptible to eccentric outcomes.
5. It is possible that certain cerebral regions identified
were only tangentially related to the conditions studied. Thus, we cannot exclude effects of mental counting during the isocapnic hyperventilation runs, in
which subjects set their respiratory frequency to
one initially derived from a metronome beat. The
pre-central activations may be associated with this.
6. The lack of a real-time autonomic marker of cardiac dysfunction has caused difficulties in the analysis of data for
this study. It is possible that the study was simply too focussed on the respiratory and neuroimaging aspects. No
continuous ECG data, from which a useful measure of autonomic activity might have been made, were obtained.
The authors hope to rectify this in subsequent work.
7. It must also be acknowledged that, certainly with respect to deductions made from the gCBF results,
there is reliance in the present study on intra-group
evaluations. Thus, in the absence of statistically significant differences, the implications of the observation must remain speculative.
Limitations of the study
1. We did not find a significant difference in subjective
breathlessness during exercise. This might be explained, at least in part, by the controls being (consistent with the demographics of heart failure) middleaged, deconditioned males rather than the more commonly studied young and fit individuals. The workload
was also not very demanding. From the perspective
of the participants however, the workload was considered ‘reasonable’ in terms of their activities of daily
life; their indications were that they would not generally exert themselves beyond this level. This relatively
low level of physical stress might have a bearing on the
lack of significant differences among the respiratory
variables. Furthermore, the number of patients studied is small, all were in NYHA classes II and III and all
were probably ‘low perceivers’ in terms of their sensation of breathlessness. On the positive side, the eventual population was tightly characterised and matching
was close between the controls and the patients.
2. It is certainly possible that widening of the age range
and inclusion of female subjects would yield different
results (we know, for example, that autonomic responses vary between sexes and age groups). A larger
study would be desirable, but the study protocol was
exacting.
3. In our quest for a ‘pure’ population of patients with
breathlessness due to CHF, those with respiratory disease were excluded. Among these may have been
some patients in whom impairment of lung function
was a direct consequence of their cardiac disease,
e.g., with bronchoconstriction provoked by an exercise-induced increase in end diastolic pressure.
Conclusion
We have investigated central neural activity in patients
with CHF and in matched controls in conditions of postexercise breathlessness, rest and a control condition,
isocapnic hyperventilation. Our principle finding is the
absence of specific cerebral regional activations in heart
failure patients, which are demonstrable in controls. As a
consequence of this, it is suggested that, in heart failure,
the perception of breathlessness and respiratory control
may depend upon different brain mechanisms from those
in health. We further noted a lack of significant change in
absolute blood flow between conditions in patients and
speculate that this might suggest a reduction in reactivity of the cerebral circulation. Such altered reactivity
might contribute to the generation of symptoms and/or
the autonomic dysfunction found in CHF.
Acknowledgements
This work was supported, in a large part, by the British
Heart Foundation, through Dr. Rosen’s Intermediate
Research Fellowship.
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