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 April 13, 2003;
revised March 11, 2004;
accepted March 31, 2004
* Corresponding author. Tel.: +44-208-967-5359; fax: +44-208-967-5007
E-mail address: stuart.rosen{at}imperial.ac.uk
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Abstract |
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Methods We used positron emission tomography with H215O, 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 (05 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 () and left precentral gyrus (
) in controls but not in patients. Both groups had rCBF increases in the left anterior cingulate (
) and right dorsal cingulate cortex (
). 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.
Key Words: Heart failure Breathlessness Cerebral blood flow Exercise Brain Autonomic nervous system Positron emission tomography
List of Abbreviations: ANOVA analysis of variance ANS autonomic nervous system CHF chronic heart failure CNS central nervous system ECG electrocardiogram fR respiratory frequency gCBF global cerebral blood flow CO2 partial pressure of carbon dioxide PET positron emission tomography rCBF regional cerebral blood flow SaO2 arterial oxygen saturation SPM statistical parametric mapping
volume of CO2 exhaled VE minute ventilation VE
slope ventilatory equivalent for CO2 vs versus VT tidal volume
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Introduction |
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In heart failure, even when objective signs of pulmonary disease are absent, some patients display lower values of CO2 and higher respiratory frequency (fR).3 An altered ventilatory response to exercise (VE
slope) has also been demonstrated and is an independent marker of prognosis.46 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 reflexes911 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,1524 including positron emission tomography (PET) with H215O, one of the most direct means of exploring neural function in vivo in man.2527 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 variability1011) 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 physical stress is different in patients with CHF from that in age-matched normal controls.
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Methods |
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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.
Pre-scanning assessment
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), CO2 (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 05 scale (0=no sense of breathlessness, 5=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 CO2 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.
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 350650 keV. Transmission scanning was performed with a single photon point source (150 MBq of 137Cs, MeV,
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 H215O as the flow tracer. For each CBF measurement, 6 mCi activity of H215O 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:
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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 H215O build-up was between and
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.
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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).
Monitoring and measurements
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 CO2 (Capnograph), arterial oxygen saturation SaO2 (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).3437 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+ Graphics® 4.0 software. Statistical significance was defined as .
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;35:24). All subjects gave written informed consent for their participation in the study.
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Results |
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1. At rest. There were no significant differences between the patients and controls for inspiratory and expiratory times and volumes, CO2, heart rate, fR or
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.
3. Post-exercise breathlessness. There was a non-significant trend for CO2 to be lower after exercise in patients (33.4±vs 36.8±mmHg;
, 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 24 reflect this.
Comparing post-exercise breathlessness to isocapnic hyperventilation, no differences between groups for the respiratory variables and heart rate were apparent (2-tailed, paired t test), although there were differences in these variables between the conditions ( for patients for
, and 0.002 for HR for controls]. No significant differences were found when testing for an interaction between these comparisons (CHF vs Controls 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 , for patients and 1.29±1.14 vs 0.25±0.61,
for controls). Both groups also felt more breathless after exercise compared to during isocapnic hyperventilation (1.99±0.48 vs 0.33±0.35,
, for patients and 1.29±1.14 vs 0.29±0.48,
for controls). For both groups on 2 way ANOVA, post-exercise breathlessness vs isocapnic hyperventilation,
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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; ) and the right anterior insula (BA 45; 26, 14, 2;
). There were no significant areas of activation found in patients that were not found in controls, nor vice versa (see Table 5).
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However, when patients and controls were compared directly, the control group exhibited increased rCBF in the right frontal medial gyrus (BA6; 2, 24, 64; ) and the left pre-central gyrus (BA4; 18, 26, 62;
), activations which were not found in the patient group. See Fig. 2.
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Discussion |
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Abnormalities of respiratory function in heart failure
Impaired ventilatory efficiency (altered VE slope)46 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
CO2 than the controls, although there were no statistically significant differences in the respiratory variables compared to controls.
Perception of breathlessness in heart failure
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 well-preserved 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 H215O) has previously been used in studies of breathing regulation in 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 H215O, 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 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.10,11,4247 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 (133Xe) 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 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 ACE-inhibitors 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.
Limitations of the study
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Conclusion |
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Acknowledgments |
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References |
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