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(Circulation. 1997;95:940-945.)
© 1997 American Heart Association, Inc.

Articles

Attenuated Cardiac Sympathetic Responsiveness During Dynamic Exercise in Patients With Heart Failure

Bengt Rundqvist, MD, PhD; Graeme Eisenhofer, PhD; Mikael Elam, MD, PhD; Peter Friberg, MD, PhD

the Heart and Lung Institute, Departments of Cardiology (B.R.) and Clinical Physiology (P.F.), and the Institute for Clinical Neuroscience, Department of Neurophysiology (M.E.), Sahlgrenska University Hospital, Goteborg, Sweden; and the Clinical Neuroscience Branch, National Institutes of Neurological Disorders and Stroke (G.E.), National Institutes of Health, Bethesda, Md.

Correspondence to Bengt Rundqvist, MD, Institute of Heart and Lung Diseases, Dept of Cardiology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden. E-mail bengtr@wlab.wall.gu.se.

	Abstract

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Background Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart.

Methods and Results Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (P<.05) at baseline in the patient group than in healthy subjects, whereas renal and whole-body NE spillovers were similar between the study groups. During exercise, cardiac NE spillover increased 13-fold (P<.05) in healthy subjects but only 5-fold (P<.05) in the cardiac failure group, the latter reaching a lower peak value (P<.05). In contrast, there was no difference between the study groups in either renal or whole-body NE spillover responsiveness to exercise.

Conclusions Patients with mild to moderate heart failure demonstrated a selective attenuation of cardiac sympathetic responsiveness during dynamic exercise. This attenuation may convey reduced inotropic and chronotropic support to the failing heart.

Key Words: norepinephrine • heart failure • nervous system, autonomic • exercise

	Introduction

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Exercise intolerance is a hallmark of congestive heart failure (CHF). Evaluation of the severity of CHF often requires exercise testing, because baseline measurements of cardiac performance do not correlate well with exercise capacity.^{1 2 3} Peak oxygen consumption during dynamic exercise is also a prognostic variable in CHF.^{4 5} However, the pathophysiological mechanisms behind the inability to increase cardiac output adequately during exercise are still not fully understood.

Several neuroendocrine systems are activated in CHF during baseline conditions, and previous studies^{6 7 8 9} demonstrated sympathetic overactivity in several organs. For the failing heart, increased norepinephrine (NE) release,⁷ impaired neuronal uptake of NE,^{10 11} and depletion of NE stores^{11 12} have been documented during baseline conditions. These changes may in turn contribute to an attenuated increase in cardiac NE turnover during dynamic exercise.¹² Together with changes in ß-adrenoceptor density and desensitization^{13 14} and altered signal transduction,¹⁵ noradrenergic mechanisms may be involved, at least in part, in impaired inotropic and chronotropic support to the failing heart during exercise.

Previous studies in CHF patients have shown varying results using changes in plasma NE as an index of sympathetic response during dynamic exercise. Both attenuated and exaggerated changes in plasma levels of NE have been demonstrated.^{16 17 18} In yet another report,¹⁹ using steady-state infusion of [³H]NE, cardiac, renal, and whole-body increases in NE spillover during dynamic exercise were normal in CHF patients, suggesting preserved sympathetic responsiveness. In contrast, a recent study¹² examining patients with more severe heart failure showed attenuated NE turnover and NE reuptake during supine cycling exercise. Hitherto, cardiac and renal sympathetic function during intense sympathetic activation has not been explored in patients with mild to moderate CHF. The current investigation extends previous studies^{12 16 17 18} in that it also assesses renal and whole-body sympathetic responsiveness simultaneously with the heart. Thus, the present study was undertaken to examine whether patients with mild to moderate CHF have preserved capacity to increase regional (in particular, cardiac) and whole-body NE release. This group was compared with a group of age-matched healthy subjects. Whole-body and regional NE spillovers from the heart and kidneys were determined by means of isotope dilution of [³H]NE.²⁰

	Methods

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Study Groups
Twenty-two patients with symptomatic CHF were examined. Their functional capacity corresponded to New York Heart Association functional class II or III, and a reduction in left ventricular ejection fraction (echocardiography²¹ ) to <45% was mandatory for inclusion in the study (Table 1). Subjects with significant noncardiac disease were excluded. All CHF patients were receiving stable medical treatment including diuretics and ACE inhibitors for >3 months. Eleven subjects were also taking digitalis. Patients were investigated in a stable clinical condition without recent (<3 months) acute ischemic events. Coronary angiography was performed to identify the presence of significant coronary artery disease as a possible cause of CHF. An age-matched control group comprising 15 healthy men was included in the study. These subjects were not taking any medication and presented a normal clinical status. The study protocol was approved by the ethics and isotope committees at Sahlgrenska University Hospital, Goteborg, Sweden. All subjects gave their consent to participate in the study.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics and Clinical Data

Exercise Testing
Within 1 week before cardiac catheterization (usually the day before), a maximal, upright cycle ergometer test was performed. Starting workload was 20 W for CHF patients and 50 W for healthy subjects. Workload was increased stepwise by 10 W every minute until exhaustion. Heart rate and rhythm were monitored from the ECG. Blood pressure was measured at each workload by standard cuff technique. None of the subjects showed significant angina pectoris, nor did significant cardiac arrhythmias occur during exercise. At the time of catheterization, supine bicycle exercise was performed at 50% of workload achieved during the upright maximal exercise testing.

Catheterization Procedure
Catheterization of the right side of the heart was performed in the morning after an overnight fast, and medication was withdrawn 12 hours before the investigation. Mean arterial blood pressure (MAP) and heart rate were recorded continuously by means of an indwelling catheter in the left radial or brachial artery. Cardiac pressures and flows were obtained by a balloon-tipped thermodilution catheter via the right internal jugular vein. In the same vein, a coronary sinus catheter (Wilton-Webster) was inserted (each patient had two sheaths). Coronary blood flow was determined by the retrograde thermodilution technique according to Ganz et al.²² When central hemodynamics had been obtained, we catheterized the right renal vein by replacing the thermodilution catheter with a 7F catheter. This experimental setup enabled simultaneous arterial, renal venous, and coronary sinus blood sampling. Renal plasma flow was calculated from the infusion clearance and renal fractional extraction of para-aminohippurate. Cardiac and total-body NE kinetics were assessed both at baseline and during supine exercise in all subjects, whereas renal kinetics were evaluated in eight CHF patients under both conditions. After completion of baseline measurements in the CHF group, the right renal vein catheter was removed and again replaced by a thermodilution catheter. Right atrial pressure and pulmonary artery pressure were then monitored continuously during exercise. After 10 minutes of cycling exercise, measurements of cardiac output, pulmonary artery pressure, pulmonary capillary wedge pressure, and coronary blood flow were performed and were immediately followed by blood sampling. In a subgroup of the CHF patients, the thermodilution catheter was once again replaced by a renal vein catheter to obtain renal NE kinetics and renal blood flow measurements during exercise. In these cases, renal venous blood sampling was not started until after at least 10 minutes' exercise. In the control group, coronary sinus and right renal vein catheters were positioned during both baseline and exercise conditions.

Radiotracer Infusion
All patients received a continuous infusion of tritiated NE (ring-labeled [³H]NE, 40 Ci/mmol; New England Nuclear) delivered via an antecubital vein at a rate of 1.3 µCi/min. The infusate contained acetic acid (2 mmol/L) and ascorbic acid (1 mmol/L) to stabilize the isotope.

Calculations
The total-body spillover of NE into plasma (SP_TB) and total-body plasma clearance of NE (CL_TB) were calculated according to Esler et al²⁰ :

where I is the infusion rate of [³H]NE (dpm/min), [³H]NE_a is the arterial tritiated NE concentration (dpm/mL), and NE_a is the arterial NE concentration (pmol/mL).

Organ spillover (heart, kidney) of NE into plasma (SP_organ) and the organ fractional extraction of NE (EX) were calculated as²³

where Q is the organ plasma flow (mL/min), NE_v is venous NE concentration (pmol/mL), and [³H]NE_v is venous concentration of tritiated NE (dpm/mL).

NE Assays
Blood samples were transferred immediately into ice-cold tubes containing either reduced glutathione and EDTA or heparin. Samples were centrifuged at 4°C. Plasma was then separated for storage at -80°C until assayed. Plasma concentrations of endogenous NE were determined by liquid chromatography with electrochemical detection. Timed collection of eluate leaving the detection unit allowed separation of [³H]NE for subsequent counting by liquid scintillation spectroscopy. Interassay coefficients of variation were 4.6% for endogenous NE and 3.2% for [³H]NE.

Statistics
Results are presented as mean±SE. Group comparisons were made by use of one-way ANOVA, with Scheffe's post hoc test used to identify differences among the various groups. For comparisons within groups, a paired two-tailed t test was used. A probability value <.05 was considered statistically significant. Nonnormal distributed NE kinetic data were transformed logarithmically before analysis. The Pearson correlation coefficient was used for correlation analysis.

	Results

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Hemodynamics
Heart rate and MAP values were similar among CHF patients and healthy subjects at baseline. There was a significant and similar increase in heart rate and MAP in both study groups during exercise (Table 2). Intracardiac pressures and cardiac index were normal or near normal in 50% of the CHF patients at baseline. In exercising CHF patients, pulmonary capillary wedge pressure and pulmonary artery pressure increased pathologically and increases in cardiac output were attenuated. Coronary blood flow did not differ between healthy subjects and patients at baseline but reached higher levels in healthy subjects during exercise (P<.05). Renal blood flow was lower in the CHF group than in healthy subjects, both at baseline and during exercise (P<.05). The exercise-induced reduction in renal blood flow, however, was similar in the two groups (Table 2).

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Data at Baseline and During Supine Cycling Exercise

Cardiac NE Kinetics
Baseline cardiac NE spillover was increased (P<.05) in CHF patients (Table 3; Figs 1 and 2). During exercise, cardiac NE spillover increased 13-fold in healthy subjects and 5-fold (P<.05) in CHF patients (Table 3 and Figs 1 and 2). Cardiac NE spillover peak value was also significantly lower in CHF patients (Table 3, Fig 2). Fractional extraction of [³H]NE across the heart at baseline was lower in the CHF group than in the control group (P<.05) and fell to a similar magnitude in both groups during exercise (Table 3).

View this table: [in this window] [in a new window]   Table 3. Norepinephrine Kinetics at Baseline and During Supine Cycling Exercise

View larger version (22K): [in this window] [in a new window]   Figure 1. Individually paired baseline and exercise values for cardiac norepinephrine (NE) spillover (top), renal NE spillover (middle), and total-body NE spillover (bottom) in healthy subjects and in patients with congestive heart failure.

View larger version (28K): [in this window] [in a new window]   Figure 2. Baseline and peak (supine bicycling exercise) levels of cardiac norepinephrine spillover in healthy subjects and in patients with congestive heart failure (CHF). Values are mean±SE. *P<.05 compared with healthy subjects.

Renal NE Kinetics
Baseline renal NE spillover did not differ between healthy subjects and CHF patients. During exercise, peak NE spillover from the kidneys tended to be higher in healthy subjects, but this difference was not statistically significant (Table 3, Fig 1). The relative increase in renal NE spillover was also similar between patients and healthy subjects.

Whole-Body NE Kinetics
Whole-body NE spillover was similar in both groups at baseline and during exercise. Likewise, the relative increases were also similar in magnitude (Table 3 and Fig 1). Whole-body NE clearance was lower (2.1 L/min) in the CHF group than in healthy subjects (2.5 L/min; P<.05) at baseline. During exercise, however, this difference was no longer present.

Correlations Between Regional NE Spillover and Hemodynamics
There was a positive correlation between baseline cardiac NE spillover and mean pulmonary artery pressure in the CHF group (r=.4, P<.05). However, no other significant correlations were found between baseline NE spillovers and baseline hemodynamic variables including heart rate, MAP, intracardiac pressures, and cardiac index. Moreover, no correlation was found between regional baseline NE spillover and exercise hemodynamics. During exercise, the correlation between cardiac NE spillover and pulmonary artery pressure became stronger (r=.6), and there was now also a positive correlation between total-body NE spillover and pulmonary artery pressure (r=.6, P<.05). A positive correlation was also found between the increase in heart rate and the increase in cardiac NE spillover in CHF patients (r=.7, P<.05).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study provides evidence for a selectively altered cardiac sympathetic function both at rest and during dynamic exercise in patients with mild to moderate CHF. These patients showed an augmented baseline cardiac NE spillover, whereas the increase during dynamic exercise was attenuated. Both relative increases and peak levels of cardiac NE spillover were lower among CHF patients, suggesting a reduced capacity to augment cardiac NE release, without showing a corresponding reduction in renal or overall sympathetic responsiveness. This attenuation in cardiac sympathetic activation may contribute to reduced inotropic and chronotropic support to the failing heart during exercise.

Differences in relative work intensity between the study groups cannot be ruled out because percent of VO₂ max was not estimated. However, similar overall and renal NE spillovers in the heart failure group and in healthy subjects, in contrast to attenuated cardiac NE spillover, argues for a selectively altered cardiac sympathetic responsiveness in heart failure patients even if their relative workload is not comparable. Thus, even if there exists a difference in work intensity between the groups, the prevailing workload in heart failure patients suggests an organ difference with regard to sympathetic responsiveness. Furthermore, exercise duration until blood sampling for NE kinetics did not differ between the groups. There were also similar changes in heart rate and blood pressure in the two study groups in response to exercise. Moreover, although the study design was aimed at achieving the same relative submaximal work intensity for the 10-minute period before blood sampling, the general impression was that CHF patients became more exhausted than control subjects.

Baseline NE spillover from the heart was higher in patients than in healthy subjects but lower than in previous reports.^{7 9} However, earlier studies have examined patients with severe heart failure in contrast to the present patients with mild to moderate heart failure. This difference probably explains the somewhat lower cardiac NE spillover in the current investigation.

Baseline fractional extraction of [³H]NE across the heart was lower in the CHF group, which is indicative of reduced NE uptake. A reduced NE uptake in CHF is caused, at least in part, by impaired neuronal reuptake of NE at rest.¹² During exercise, fractional extraction of [³H]NE across the heart decreased in both study groups. However, because extraction of NE is dependent on blood flow,²⁴ increases in coronary blood flow during exercise make it difficult to interpret the changes in [³H]NE extractions with regard to NE uptake mechanisms. Nevertheless, lower coronary blood flow in CHF patients during exercise in the present study may have facilitated NE uptake, which could be one mechanism contributing to a lower NE spillover in this group. However, because the relative fall in fractional extraction of [³H]NE across the heart was greater in the CHF group during exercise, and given the fact that [³H]NE extraction was markedly lower at baseline in the CHF group, it is unlikely that reuptake of NE would be higher during exercise among CHF patients than among healthy subjects. In addition, reduced neuronal NE reuptake has been demonstrated¹² both at baseline and during dynamic exercise in CHF patients, which is consistent with the lower cardiac extractions of the tracer during exercise in the present study. In conclusion, these findings support the concept that a reduced capacity for NE release is at hand, hence explaining the observation of reduced cardiac NE spillover in exercising CHF patients.

Increased cardiac NE spillover and impaired NE uptake at rest do provide a rationale for developing reduced myocardial vesicular NE content.¹² During conditions when release of NE is high and NE reuptake is still reduced relative to release, the already reduced NE stores possibly become even more jeopardized. The question arises whether the observed depletion of NE stores in CHF then compromises NE release during exercise. However, in the present study, there was a positive correlation (r=.7, P<.05) between baseline and exercise-stimulated NE spillovers from the heart in the CHF group, possibly arguing against depletion of NE stores being a major determinant for short-term exercise NE release.

Other changes in the failing heart, such as structural alterations within the myocardium, increased fibrosis, and impaired myocardial microcirculation, may also affect cardiac NE kinetics.^{7 24} For example, increased NE diffusion distance may reduce NE washout from the interstitium into plasma. Recent studies using cardiac NE-uptake imaging (by using tracer NE analogues) by -camera or positron emission tomography^{25 26 27 28} repeatedly have shown reduced uptake sites and a marked heterogeneity of tracer uptake in the left ventricle in CHF patients. In one of these studies,²⁸ tracer uptake correlated with myocardial NE content. These findings suggest heterogeneous denervation of sympathetic nerve endings in the failing myocardium. This interpretation is also consistent with a report²⁹ showing decreased density of cardiac neurons by pathological examination of tissue stripes from idiopathic dilated hearts. Hence, reduced myocardial neuronal density could be yet another potential mechanism limiting maximal NE release (and also NE reuptake) in CHF during exercise.

Attenuation of skeletal muscle metaboreceptor sympathetic response has been demonstrated in CHF patients during regional circulatory arrest.³⁰ Sympathetic responsiveness during static exercise, measured by direct nerve recordings, was preserved, which is consistent with the present findings of normal total-body and renal NE spillover responses during exercise. This was taken as an argument for central command as an important mechanism for increasing muscle sympathetic nerve activity in CHF.³⁰ In the present study, a negative correlation between mixed venous oxygen saturation (data not shown) and cardiac NE spillover during exercise, but not with cardiac output, was found, which may indicate reflex influences from metaboreceptors. However, it seems unlikely that these should affect cardiac sympathetic responsiveness selectively. It is more conceivable that correlations between exercise pulmonary artery pressure, oxygen extraction, and cardiac NE spillover reflect a relation between the degree of left ventricular dysfunction and sympathetic response. Likewise, a positive correlation between the relative increase in heart rate and cardiac NE spillover in the CHF group also argues for a link between cardiac performance and sympathetic responsiveness. On the other hand, there was no correlation between baseline sympathoactivation and cardiac filling pressures or cardiac output during exercise, suggesting that other mechanisms, not only overall cardiac performance, determine the degree of sympathoexcitation.

Previous studies^{16 17 18} assessing sympathetic responses in CHF by using plasma NE as an index of sympathetic activation during exercise have shown inconsistent results. These incongruous results may originate from different study populations and/or variation in work intensity. In one study,¹⁸ however, attenuation of the sympathetic response was similar in patients with moderate CHF compared with a more severe CHF group at the same relative work intensity by using percent of peak oxygen uptake. In the present study population, neither whole-body nor renal NE spillovers differed between patients and healthy subjects. However, in the current investigation, oxygen uptake was not determined. Hence, relative work intensity may have differed not only between the study groups but also when comparisons were made with other studies. Also, whether whole-body and renal sympathetic responsiveness become impaired when CHF progresses or work intensity increases remains to be examined. Consistent with our results, a prior study¹⁹ assessing NE spillover during exercise, designed primarily to evaluate changes in NE clearance, demonstrated preserved whole-body NE spillover responsiveness.

In summary, the present study has demonstrated a selective alteration in cardiac sympathetic function in patients with mild to moderate CHF both at baseline and during dynamic exercise. Increased cardiac NE spillover and reduced fractional extraction of [³H]NE at rest in the early phases of heart failure highlight a primary NE-handling abnormality in the heart, which probably also involves attenuated cardiac NE release during exercise, reflected as a lower peak cardiac NE spillover. This impairment may contribute to exercise intolerance in CHF.

	Acknowledgments

 
This study was supported by grants from Sahlgrenska University Hospital, The Swedish Medical Research Council (3546, 9047, and 11133), and the Swedish Heart and Lung Foundation (Drs Rundqvist and Friberg). The authors are grateful for the invaluable technical assistance of Anneli Ambring, Elsa Bang, Gun Bodehed, Gunilla Fritzon, and Douglas Hooper.

Received May 5, 1996; revision received September 23, 1996; accepted October 7, 1996.

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