Internotional Elsewer
CARD10
Journul of Curdiofogv.
179
29 (1990) 179- 184
01136
Plasma atria1 natriuretic factor concentration during maximal cardiopulmonary exercise in men with mild heart failure Torbjern ’ Cardiopulmonary
Omland
‘, St%le Barvik ‘, AsbjDrn Aakvaag and Kenneth Dickstein ’
2, Torbjprrn Aarsland
Exercrse Laboratory, Medical Depurtmenr. Cenrrul Hosprtal rn Rogoland, Staounger. Biochemical Endocrrnology. Huukeland Hospitul. Bergen, Nomy (Received
16 January
1990; revision
accepted
Noruqv;
’
.’ Lahoruto~v for
6 April 1990)
Omland T, Barvik S, Aakvaag A, Aarsland T, Dickstein K. Plasma atria1 natriuretic factor concentration during maximal cardiopulmonary exercise in men with mild heart failure. Int J Cardiol 1990;29:179-184. The response in terms of production of atria1 natriuretic factor to maximal cardiopulmonary exercise was investigated in 13 patients with mild heart failure (New York Heart Association function class II) secondary to previous myocardial infarction. Exercise induced a rapid and gradually increasing production of atrial natriuretic factor. The concentration at the termination of the test was statistically higher than at rest (64.5 f 9.7 versus 119.4 f 18.3 pmol/l. P = 0.001). Resting levels of the natriuretic factor correlated well to levels at peak exercise (r = 0.797, P = 0.001). The increase in concentration from rest to peak exercise (atrial natriuretic factor delta) was inversely correlated to the peak consumption of oxygen (r = - 0.584, P = 0.036), indicating that the response to exercise is not attenuated in the patients with most marked functional impairment. The relationship between resting levels of atrial natriuretic factor and peak consumption of oxygen did not reach statistical significance (r = -0.421, P= 0.152), but a significant inverse relationship was observed between concentration at peak exercise and peak consumption of oxygen (r= - 0.671, P = 0.012). Levels of atrial natriuretic factor during peak exercise are related to functional impairment in mild heart failure and may discriminate between the functional capacity of patients belonging in the same class of clinical function. Key words:
Atria1 natriuretic
factor;
Exertion;
Heart
Introduction Resting levels of atria1 natriuretic factor are elevated in chronic heart failure. A relationship
Correspondence to: T. Omland, Cardiopulmonary Exercise Laboratory, Medical Dept.. Central Hospital in Rogaland, N-4000 Stavanger, Norway. This work was supported by a grant from the “Blix Family Medical Research Fund”. Torbjarn Omland was supported by a grant from SR-Bank, Sandnes. Norway.
0167-5273/90/$03.50
‘(” 1990 Elsevier Science
Publishers
failure
has been described between the concentration of atria1 natriuretic factor in the plasma and the severity of chronic heart failure based on hemodynamic criteria and on clinical classification [l-3]. Recently, the effect of exercise on the concentration of this hormone in the plasma in patients with cardiac disease has been studied, and an increase has been demonstrated in the concentration during incremental exercise [1,4-71. A significant correlation between levels of the natriuretic factor and left ventricular filling and right atrial
B.V. (Biomedical
Division)
180
pressures has also been demonstrated during exercise [7]. Additional information concerning the profile of production of atria1 natriuretic factor during exercise is required in order to shed further light on its role in the early stages of heart failure. Key questions in this context, and the main objectives of the present study, were to investigate whether the response to exercise in terms of production of the natriuretic factor is attenuated in functionally impaired subjects, and whether a relationship between levels of the factor and functional capacity, as expressed by peak consumption of oxygen, exists in patients with mild heart failure.
Materials and Methods Study population Included in the study were 13 male patients with documented myocardial infarction. Time elapsed from myocardial infarction to investigation ranged from 20 to 127 months. The patients’ average age was 67 years (range 60-75 years). The study population represented a homogeneous group; all 13 patients belonged to Class II of the classification of the New York Heart Association, All patients required treatment for symptomatic chronic heart failure with digitalis (13 patients), furosemide (13 patients), enalapril (12 patients) and isosorbide dinitrate (3 patients). None of the patients had peripheral edema. Informed consent was obtained from all patients participating in the study. Protocol for exercise testing All patients had been tested previously, and were familiar with both the laboratory personel and equipment. Routine spirometry was performed to rule out respiratory dysfunction. Testing was performed approximately 3 hours following a light meal. The exercise equipment consisted of an upright, electrically braked bicycle ergometer (Mijnhardt model KEM III) and a 12 lead modified electrocardiograph (KONE 620) which recorded heart rate continuously. Following a period of rest of 5 minutes sitting on the bicycle, the subjects breathed for 2 minutes through a
mouthpiece connected to a gas-analyzing system prior to starting pedalling. The work rate was programmed to increase smoothly with a continuous ramp protocol corresponding to a 15 Watt increment per minute. Patients were instructed to exercise maximally to end point determined by symptoms. Acquisition of respiratory gas exchange data The patients breathed through a mouthpiece with a volume of 100 ml connected to a non-rebreathing valve. Air was removed from the mouthpiece at a constant rate of 175 ml/min and delivered to analyzers of oxygen and carbon dioxide. Expired air was delivered to a device for measuring flow. The data for gas exchange were collected on a breath-by-breath basis, using a computerized system (Medical Graphics Corporation System 2001). The technique involves rapid responding analyzers connected to a waveform analyzer and a host computer. The fraction of oxygen was measured using a permanent zirconium oxide electrochemical cell. The fraction of carbon dioxide was measured using a dual-beam infrared absorption chamber. The air flow was measured using a pneumotachygraph and a variable pressure transducer. The waveform analyzer performed integration and cross-product analysis every 10 milliseconds on phase-aligned signals from the respective analyzers. Blood sampling procedures Blood was sampled from a polyethylene catheter (Viggo) inserted percutaneously into the left brachial artery. The catheter was connected to a high-pressure heparinized saline solution (10 units/ml) through an automatic flushing device. Blood sampling was started approximately 30 minutes after insertion of the catheter, and the subjects rested on the bicycle for at least 5 minutes before the test commenced. For analysis of atria1 natriuretic factor, samples were drawn twice during the 2 minute initial resting phase. During the exercise phase, blood was drawn every 3 minutes. One sample was drawn at peak work load and the final sample 5 minutes after exercise termination.
181
To avoid dilution with flushing fluid, 2 ml were drawn from the catheter prior to each blood collection. For analysis of atria1 natriuretic factor, 5-ml samples were collected into chilled plastic tubes containing ethylenediaminetetraacetic acid and aprotinin (Trasylol 20000 kallikrein inactivator units/ml), immediately placed on ice and centrifuged within 20 minutes. Plasma samples were stored at - 70 o C until analyzed. Radioimmunoassay The plasma level of atria1 natriuretic factor was measured using a kit from Amersham International, U.K. and included extraction on a C,,, octadecyl silica microcolumn. Blood samples from each subject were analyzed in one batch of assays. The limit of detection was 1.7 fmol/tube, which in a normal assay corresponds to 5.0 pmol/l. Recovery was 70.3 _t 1.7% (mean + SEM). The intraassay coefficient of variation was 7.2% (n = 10) at the level of 20 pmol/l and 2.6% (n = 10) at the level of 73 pmol/l. The interassay coefficient of variation was 12.9% (n = 7) at the level of 22 pmol/l and 6.2% (n = 14) at the level of 82 pmol/l. All values for atria1 natriuretic factor are corrected for recovery and are presented in pmol/l.
observed between maximum exercise and levels 5 minutes after exercise (119.4 + 18.3 versus 123.2 + 17.9 pmol/l). Heart rate at rest was 72.5 + 4.4 beats per minute. An increase to 142.8 &-5.8 beats per minute was seen at the peak of exercise, followed by a decrease to 87.4 + 4.7 beats per minute 5 minutes after exercise, The ratio of elimination of carbon dioxide to consumption of oxygen measured at the peak of exercise was 1.23 + 0.02, indicating anaerobiosis. Peak consumption of oxygen averaged 19.9 f 0.7 ml/kg per minute. Resting values of the natriuretic factor showed a strong positive correlation to levels at peak exercise, in other words, patients with the highest resting levels also achieved the highest levels at exhaustion (r = 0.797, P = 0.001). No significant correlation was demonstrated between peak consumption of oxygen and levels of atria1 natriuretic factor at rest (r = - 0.421. P = 0.152). but peak consumption of oxygen was negatively correlated both to the increase in concentration of atria1 natriuretic factor during exercise testing (peak oxygen consumption vs atria1 natriuretic factor delta: r = -0.584, P = 0.036) as well as to the concentration at peak exercise (peak oxygen consumption versus peak exercise atria1 natriuretic factor: r = -0.671, P = 0.012). Correlation coefficients between selected variables are summarized in Table 1.
Statistics TABLE
Data are expressed as mean f standard error of the mean. Comparisons between values before, during and after exercise were performed by the Wilcoxon signed rank test. The coefficient of correlation was determined by the Spearman rank test.
Results Resting levels of the natriuretic factor were considerably higher than the reference values of our laboratory (7-23 pmol/l, healthy subjects). During exercise, the concentration of the natriuretic factor rose gradually from rest to the termination of exercise (64.5 & 9.7 vs 119.4 + 18.3 pmol/l, P = 0.001). No significant change was
1
Correlation
coefficients
between
selected
Variables ANF ANF ANF ANF ANF ANF ANF
rest
VS.
rest
VS.
rest
vs.
peak Ex rest delta peak Ex
vs. VS.
vs. vs.
ANF ANF ANF ANF peak Peak peak
delta peak Ex post Ex post Ex VO, VOz VO,
variables. r
P
0.525 0.797 0.786 0.929 - 0.421 - 0.584 - 0.671
0.065 0.001 0.001 C 0.001 0.152 0.036 0.012
ANF rest = concentration of atria1 natriuretic factor at rest. ANF delta = increase in concentration of atria1 natriuretic factor during exercise. ANF peak Ex = concentration of atria1 natriuretic factor at peak exercise. ANF post Ex = concentration of atrial natriuretic factor 5 minutes after exercise. Peak VOz = peak consumption of oxygen.
182
Discussion Myocardial infarction may result in varying degrees of functional impairment. The combination of impaired ventricular function and an abnormal response to exercise is characteristic of chronic heart failure. Assessment of functional capacity by means of cardiopulmonary exercise testing and measurements of peak consumption of oxygen has proved to be an objective and reproducible tool in the evaluation of the severity of chronic heart failure, superior to clinical classification and hemodynamic measurements at rest [8]. The magnitude of the production of atria1 natriuretic factor in response to exercise is variable in patients with heart disease, and this can at least partially explain why some studies report significant increases in levels of the natriuretic factor [1,4,6,7] while others fail to demonstrate any significant increases [9]. In the present study, a significant increase in the concentration of atria1 natriuretic factor was observed during exercise testing, despite large variation in concentrations both at rest and at termination of exercise (Fig. 1). Atria1 distention is a major mechanism regulating release of atria1 natriuretic factor, and a relationship between atria1 pressures and levels of
1
oi 0
3
6
peak
post
Time - min Fig. 1. Levels of atria1 natriuretic factor in the plasma (mean& SEM) at rest (O), at two timepoints during exercise (3 and 6 minutes, corresponding to a work load of 45 and 90 Watts, respectively). at peak exercise (peak) and 5 minutes after exercise (post) (n = 13). Asterisks indicate significance of difference from baseline as follows: P < 0.05 (1 symbol), P < 0.01 (2 symbols).
atria1 natriuretic factor levels has been convincingly demonstrated in congestive heart failure [l]. Peak consumption of oxygen is an objective and reproducible parameter describing functional capacity, and a relationship between peak consumption and pulmonary capillary wedge pressure, pulmonary arterial mean pressure and total pulmonary resistance has been shown [lo]. Based on this information, a relationship between levels of atria1 natriuretic factor and peak consumption of oxygen would be expected and, recently, this relationship was confirmed [9]. A heterogeneous group of cardiac patients with differing diagnoses (idiopathic dilated cardiomyopathy, ischemic cardiomyopathy and mitral valvular regurgitation) and functional class (II-IV, range of peak consumption of oxygen 6.5 to 21.3 ml/kg per minute was investigated, and an inverse relationship was found between resting levels of atria1 natriuretic factor and peak consumption of oxygen. The relationship, however, is not uniform. In a study of healthy subjects, no relationship was demonstrated between concentrations at the peak of exercise and maximal work load [II]. A major objective of the present study was, therefore, to investigate whether an inverse relationship between functional capacity and levels of atria1 natriuretic factor is valid in patients with mild degree of functional impairment, and this was demonstrated by our finding of a significant inverse relationship between levels of atria1 natriuretic factor during peak exercise and peak consumption of oxygen (Fig. 2). The sensitivity of measurements of atrial natriuretic factor in the plasma in the assessment of functional impairment is not known. Measurements could possibly discriminate between the functional capacity of patients belonging to the same class of clinical function. The present study shows that the inverse relationship between atria1 natriuretic factor and peak consumption of oxygen is valid in patients who, by clinical assessment, are homogeneous with respect to functional capacity. This potentially important finding may indicate that atria1 natriuretic factor is a more sensitive marker of functional impairment than clinical assessment, but further work is required in order to evaluate the role of the natriuretic factor as a
183
01 14
16
16
20
Peak Oxygen Consumption
22
24
- mllkglmin
Fig. 2. Correlation between concentration of atria1 natriuretic factor in the plasma at peak exercise and peak consumption of oxygen in patients with mild heart failure (n = 13; r = - 0.671; P = 0.012).
marker of functional capacity compared to other methods. A new and interesting observation made in the present study is that levels of atria1 natriuretic factor at peak exercise are better correlated to, and therefore probably a better predictor of, peak consumption of oxygen than levels of atria1 natriuretic factor at rest. This observation should be confirmed by subsequent investigation. Increased levels of atria1 natriuretic factor at rest, as observed in the present study, could indicate increased left or right atria1 pressure at rest. Prolonged atria1 distention could theoretically influence the relationship between atria1 pressure and release of atria1 natriuretic factor. A depletion of stores of atria1 natriuretic factor caused by chronic atria1 pressure overload could result in attenuated release of atria1 natriuretic factor in response to acute stimuli. Alternatively, chronic stimulation could result in resetting of the relationship between atria1 pressure and release of atria1 natriuretic factor with a maintained release of atria1 natriuretic factor in response to acute
stimuli as a consequence. A major objective of the present study was to evaluate whether any of these patterns of release could be observed in patients with mild heart failure. Cardiac filling pressures increase during exercise in patients with chronic heart failure [lo], and exercise is, therefore, a suitable stimulus for the study of release of atria1 natriuretic factor in patients with slightly impaired functional capacity. Previous studies have yielded diverging results. Dietz et al. [6] found maintained production of atria1 natriuretic factor in response to acute stimuli in cardiac patients, while Raine et al. [l] demonstrated a significantly lower response of release of atria1 natriuretic factor to exercise in patients with elevated atria1 pressures at rest compared to cardiac patients with atria1 pressures within the normal range at rest. Data from the present study fail to support the concept of attenuated release of atria1 natriuretic factor in response to exercise in patients with more severe functional impairment. An inverse relationship between atria1 natriuretic factor delta and peak consumption of oxygen was demonstrable, that is. the patients with more severe functional impairment achieved the largest increase in concentration of atria1 natriuretic factor during exercise testing. Levels of atria1 natriuretic factor are generally increased in heart failure, but it remains unclear whether its theoretically beneficial actions are physiologically effective, or if it should be regarded more as a marker of the degree of heart failure rather than as a biologically active hormone. A decreased renal responsiveness to the natriuretic factor in humans with heart failure has been suggested because no significant change in sodium excretion or urine volume was observed during infusion of the factor [12]. In the present study we failed to find attenuation of the response of the factor to exercise in the patients with most marked functional impairment. indicating that impaired release in response to acute stimuli is unlikely to be an important factor in the pathogenesis of chronic heart failure. Data from the present study support the concept that atria1 natriuretic factor may be a clinically useful marker of functional impairment. Values during peak exercise appear to discriminate between the functional
184
capacity of cardiac patients clinical function class.
belonging
to the same
Acknowledgements Technical assistance from Mrs. Aagot Kirkebq Mrs. Helle Svanes and Mr. Kurt Tjelta is gratefully acknowledged.
References
6
7
8 9
Raine AEG, Eme P, Btirgisser.
E, et al. Atrial natriuretic peptide and atria1 pressures in patients with congestive heart failure. N Engl J Med 1986;315:533-537. Bates ER, Shenker Y, Greklin RJ. The relationship between plasma levels of immunoreactive atria1 natriuretic hormone and hemodynamic function in man. Circulation 1986;73: 1155-1161. Hara H, Ogihara T, Shima J, et al. Plasma atrial natriuretic peptide as an index for the severity of congestive heart failure, Clin Cardiol 1987;10:437-442. Nishikimi T. Kohno M, Matsuura T. et al. Effect of exercise on circulating atria1 natriuretic polypeptide in valvular heart disease. Am J Cardiol 1986;58:1119-1120. Petzl DH, Hartter E, Osterode W, BBhm H. Woloszczuk
10
11
12
W. Atria1 natriuretic peptide release due to physical exercise in healthy persons and cardiac patients. Klin Wochenschr 1987;65:194-196. Dietz R. Purgaj J. Lang RE, Schiimig A. Pressure-dependent release of atria1 natriuretic peptide (ANP) in patients with chronic cardiac disease: does it reset? Klin Wochenschr 1986;64 Suppl 6142-46. Nishikimi T, Kohno M, Itagane H, et al. Influence of exercise on plasma atria1 natriuretic factor in patients with myocardial infarction. Am Heart J 1988; 115: 753-760. Franciosa JA. Exercise testing in chronic congestive heart failure. Am J Cardiol 1984;53:1447-1450. Leinonen H, Naveri H, Tikkanen I, Sovijarvi A. Fyhrquist F. Basal and exercise plasma levels of atria1 natriuretic factor in congestive heart failure. Am Heart J 1988:116:209-211. Franciosa JA, Baker BJ, Seth L. Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure. Am Heart J 1985;110:807-813. Bollerslev J, Svanegard J, Blaabjerg 0. Pindborg T. Atria1 natriuretic peptide in relation to physical exercise. Stand J Clin Invest 1987;47:681-683. Crozier IG, Nicholls MC, Ikram H, Espiner EA. Gomez HJ, Warner J. Haemodynamic effects of atria1 natriuretic peptide infusion in heart failure. Lancet 1986;ii:1242-1244.
CARD10
Journul of Curdiofogv.
179
29 (1990) 179- 184
01136
Plasma atria1 natriuretic factor concentration during maximal cardiopulmonary exercise in men with mild heart failure Torbjern ’ Cardiopulmonary
Omland
‘, St%le Barvik ‘, AsbjDrn Aakvaag and Kenneth Dickstein ’
2, Torbjprrn Aarsland
Exercrse Laboratory, Medical Depurtmenr. Cenrrul Hosprtal rn Rogoland, Staounger. Biochemical Endocrrnology. Huukeland Hospitul. Bergen, Nomy (Received
16 January
1990; revision
accepted
Noruqv;
’
.’ Lahoruto~v for
6 April 1990)
Omland T, Barvik S, Aakvaag A, Aarsland T, Dickstein K. Plasma atria1 natriuretic factor concentration during maximal cardiopulmonary exercise in men with mild heart failure. Int J Cardiol 1990;29:179-184. The response in terms of production of atria1 natriuretic factor to maximal cardiopulmonary exercise was investigated in 13 patients with mild heart failure (New York Heart Association function class II) secondary to previous myocardial infarction. Exercise induced a rapid and gradually increasing production of atrial natriuretic factor. The concentration at the termination of the test was statistically higher than at rest (64.5 f 9.7 versus 119.4 f 18.3 pmol/l. P = 0.001). Resting levels of the natriuretic factor correlated well to levels at peak exercise (r = 0.797, P = 0.001). The increase in concentration from rest to peak exercise (atrial natriuretic factor delta) was inversely correlated to the peak consumption of oxygen (r = - 0.584, P = 0.036), indicating that the response to exercise is not attenuated in the patients with most marked functional impairment. The relationship between resting levels of atrial natriuretic factor and peak consumption of oxygen did not reach statistical significance (r = -0.421, P= 0.152), but a significant inverse relationship was observed between concentration at peak exercise and peak consumption of oxygen (r= - 0.671, P = 0.012). Levels of atrial natriuretic factor during peak exercise are related to functional impairment in mild heart failure and may discriminate between the functional capacity of patients belonging in the same class of clinical function. Key words:
Atria1 natriuretic
factor;
Exertion;
Heart
Introduction Resting levels of atria1 natriuretic factor are elevated in chronic heart failure. A relationship
Correspondence to: T. Omland, Cardiopulmonary Exercise Laboratory, Medical Dept.. Central Hospital in Rogaland, N-4000 Stavanger, Norway. This work was supported by a grant from the “Blix Family Medical Research Fund”. Torbjarn Omland was supported by a grant from SR-Bank, Sandnes. Norway.
0167-5273/90/$03.50
‘(” 1990 Elsevier Science
Publishers
failure
has been described between the concentration of atria1 natriuretic factor in the plasma and the severity of chronic heart failure based on hemodynamic criteria and on clinical classification [l-3]. Recently, the effect of exercise on the concentration of this hormone in the plasma in patients with cardiac disease has been studied, and an increase has been demonstrated in the concentration during incremental exercise [1,4-71. A significant correlation between levels of the natriuretic factor and left ventricular filling and right atrial
B.V. (Biomedical
Division)
180
pressures has also been demonstrated during exercise [7]. Additional information concerning the profile of production of atria1 natriuretic factor during exercise is required in order to shed further light on its role in the early stages of heart failure. Key questions in this context, and the main objectives of the present study, were to investigate whether the response to exercise in terms of production of the natriuretic factor is attenuated in functionally impaired subjects, and whether a relationship between levels of the factor and functional capacity, as expressed by peak consumption of oxygen, exists in patients with mild heart failure.
Materials and Methods Study population Included in the study were 13 male patients with documented myocardial infarction. Time elapsed from myocardial infarction to investigation ranged from 20 to 127 months. The patients’ average age was 67 years (range 60-75 years). The study population represented a homogeneous group; all 13 patients belonged to Class II of the classification of the New York Heart Association, All patients required treatment for symptomatic chronic heart failure with digitalis (13 patients), furosemide (13 patients), enalapril (12 patients) and isosorbide dinitrate (3 patients). None of the patients had peripheral edema. Informed consent was obtained from all patients participating in the study. Protocol for exercise testing All patients had been tested previously, and were familiar with both the laboratory personel and equipment. Routine spirometry was performed to rule out respiratory dysfunction. Testing was performed approximately 3 hours following a light meal. The exercise equipment consisted of an upright, electrically braked bicycle ergometer (Mijnhardt model KEM III) and a 12 lead modified electrocardiograph (KONE 620) which recorded heart rate continuously. Following a period of rest of 5 minutes sitting on the bicycle, the subjects breathed for 2 minutes through a
mouthpiece connected to a gas-analyzing system prior to starting pedalling. The work rate was programmed to increase smoothly with a continuous ramp protocol corresponding to a 15 Watt increment per minute. Patients were instructed to exercise maximally to end point determined by symptoms. Acquisition of respiratory gas exchange data The patients breathed through a mouthpiece with a volume of 100 ml connected to a non-rebreathing valve. Air was removed from the mouthpiece at a constant rate of 175 ml/min and delivered to analyzers of oxygen and carbon dioxide. Expired air was delivered to a device for measuring flow. The data for gas exchange were collected on a breath-by-breath basis, using a computerized system (Medical Graphics Corporation System 2001). The technique involves rapid responding analyzers connected to a waveform analyzer and a host computer. The fraction of oxygen was measured using a permanent zirconium oxide electrochemical cell. The fraction of carbon dioxide was measured using a dual-beam infrared absorption chamber. The air flow was measured using a pneumotachygraph and a variable pressure transducer. The waveform analyzer performed integration and cross-product analysis every 10 milliseconds on phase-aligned signals from the respective analyzers. Blood sampling procedures Blood was sampled from a polyethylene catheter (Viggo) inserted percutaneously into the left brachial artery. The catheter was connected to a high-pressure heparinized saline solution (10 units/ml) through an automatic flushing device. Blood sampling was started approximately 30 minutes after insertion of the catheter, and the subjects rested on the bicycle for at least 5 minutes before the test commenced. For analysis of atria1 natriuretic factor, samples were drawn twice during the 2 minute initial resting phase. During the exercise phase, blood was drawn every 3 minutes. One sample was drawn at peak work load and the final sample 5 minutes after exercise termination.
181
To avoid dilution with flushing fluid, 2 ml were drawn from the catheter prior to each blood collection. For analysis of atria1 natriuretic factor, 5-ml samples were collected into chilled plastic tubes containing ethylenediaminetetraacetic acid and aprotinin (Trasylol 20000 kallikrein inactivator units/ml), immediately placed on ice and centrifuged within 20 minutes. Plasma samples were stored at - 70 o C until analyzed. Radioimmunoassay The plasma level of atria1 natriuretic factor was measured using a kit from Amersham International, U.K. and included extraction on a C,,, octadecyl silica microcolumn. Blood samples from each subject were analyzed in one batch of assays. The limit of detection was 1.7 fmol/tube, which in a normal assay corresponds to 5.0 pmol/l. Recovery was 70.3 _t 1.7% (mean + SEM). The intraassay coefficient of variation was 7.2% (n = 10) at the level of 20 pmol/l and 2.6% (n = 10) at the level of 73 pmol/l. The interassay coefficient of variation was 12.9% (n = 7) at the level of 22 pmol/l and 6.2% (n = 14) at the level of 82 pmol/l. All values for atria1 natriuretic factor are corrected for recovery and are presented in pmol/l.
observed between maximum exercise and levels 5 minutes after exercise (119.4 + 18.3 versus 123.2 + 17.9 pmol/l). Heart rate at rest was 72.5 + 4.4 beats per minute. An increase to 142.8 &-5.8 beats per minute was seen at the peak of exercise, followed by a decrease to 87.4 + 4.7 beats per minute 5 minutes after exercise, The ratio of elimination of carbon dioxide to consumption of oxygen measured at the peak of exercise was 1.23 + 0.02, indicating anaerobiosis. Peak consumption of oxygen averaged 19.9 f 0.7 ml/kg per minute. Resting values of the natriuretic factor showed a strong positive correlation to levels at peak exercise, in other words, patients with the highest resting levels also achieved the highest levels at exhaustion (r = 0.797, P = 0.001). No significant correlation was demonstrated between peak consumption of oxygen and levels of atria1 natriuretic factor at rest (r = - 0.421. P = 0.152). but peak consumption of oxygen was negatively correlated both to the increase in concentration of atria1 natriuretic factor during exercise testing (peak oxygen consumption vs atria1 natriuretic factor delta: r = -0.584, P = 0.036) as well as to the concentration at peak exercise (peak oxygen consumption versus peak exercise atria1 natriuretic factor: r = -0.671, P = 0.012). Correlation coefficients between selected variables are summarized in Table 1.
Statistics TABLE
Data are expressed as mean f standard error of the mean. Comparisons between values before, during and after exercise were performed by the Wilcoxon signed rank test. The coefficient of correlation was determined by the Spearman rank test.
Results Resting levels of the natriuretic factor were considerably higher than the reference values of our laboratory (7-23 pmol/l, healthy subjects). During exercise, the concentration of the natriuretic factor rose gradually from rest to the termination of exercise (64.5 & 9.7 vs 119.4 + 18.3 pmol/l, P = 0.001). No significant change was
1
Correlation
coefficients
between
selected
Variables ANF ANF ANF ANF ANF ANF ANF
rest
VS.
rest
VS.
rest
vs.
peak Ex rest delta peak Ex
vs. VS.
vs. vs.
ANF ANF ANF ANF peak Peak peak
delta peak Ex post Ex post Ex VO, VOz VO,
variables. r
P
0.525 0.797 0.786 0.929 - 0.421 - 0.584 - 0.671
0.065 0.001 0.001 C 0.001 0.152 0.036 0.012
ANF rest = concentration of atria1 natriuretic factor at rest. ANF delta = increase in concentration of atria1 natriuretic factor during exercise. ANF peak Ex = concentration of atria1 natriuretic factor at peak exercise. ANF post Ex = concentration of atrial natriuretic factor 5 minutes after exercise. Peak VOz = peak consumption of oxygen.
182
Discussion Myocardial infarction may result in varying degrees of functional impairment. The combination of impaired ventricular function and an abnormal response to exercise is characteristic of chronic heart failure. Assessment of functional capacity by means of cardiopulmonary exercise testing and measurements of peak consumption of oxygen has proved to be an objective and reproducible tool in the evaluation of the severity of chronic heart failure, superior to clinical classification and hemodynamic measurements at rest [8]. The magnitude of the production of atria1 natriuretic factor in response to exercise is variable in patients with heart disease, and this can at least partially explain why some studies report significant increases in levels of the natriuretic factor [1,4,6,7] while others fail to demonstrate any significant increases [9]. In the present study, a significant increase in the concentration of atria1 natriuretic factor was observed during exercise testing, despite large variation in concentrations both at rest and at termination of exercise (Fig. 1). Atria1 distention is a major mechanism regulating release of atria1 natriuretic factor, and a relationship between atria1 pressures and levels of
1
oi 0
3
6
peak
post
Time - min Fig. 1. Levels of atria1 natriuretic factor in the plasma (mean& SEM) at rest (O), at two timepoints during exercise (3 and 6 minutes, corresponding to a work load of 45 and 90 Watts, respectively). at peak exercise (peak) and 5 minutes after exercise (post) (n = 13). Asterisks indicate significance of difference from baseline as follows: P < 0.05 (1 symbol), P < 0.01 (2 symbols).
atria1 natriuretic factor levels has been convincingly demonstrated in congestive heart failure [l]. Peak consumption of oxygen is an objective and reproducible parameter describing functional capacity, and a relationship between peak consumption and pulmonary capillary wedge pressure, pulmonary arterial mean pressure and total pulmonary resistance has been shown [lo]. Based on this information, a relationship between levels of atria1 natriuretic factor and peak consumption of oxygen would be expected and, recently, this relationship was confirmed [9]. A heterogeneous group of cardiac patients with differing diagnoses (idiopathic dilated cardiomyopathy, ischemic cardiomyopathy and mitral valvular regurgitation) and functional class (II-IV, range of peak consumption of oxygen 6.5 to 21.3 ml/kg per minute was investigated, and an inverse relationship was found between resting levels of atria1 natriuretic factor and peak consumption of oxygen. The relationship, however, is not uniform. In a study of healthy subjects, no relationship was demonstrated between concentrations at the peak of exercise and maximal work load [II]. A major objective of the present study was, therefore, to investigate whether an inverse relationship between functional capacity and levels of atria1 natriuretic factor is valid in patients with mild degree of functional impairment, and this was demonstrated by our finding of a significant inverse relationship between levels of atria1 natriuretic factor during peak exercise and peak consumption of oxygen (Fig. 2). The sensitivity of measurements of atrial natriuretic factor in the plasma in the assessment of functional impairment is not known. Measurements could possibly discriminate between the functional capacity of patients belonging to the same class of clinical function. The present study shows that the inverse relationship between atria1 natriuretic factor and peak consumption of oxygen is valid in patients who, by clinical assessment, are homogeneous with respect to functional capacity. This potentially important finding may indicate that atria1 natriuretic factor is a more sensitive marker of functional impairment than clinical assessment, but further work is required in order to evaluate the role of the natriuretic factor as a
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16
20
Peak Oxygen Consumption
22
24
- mllkglmin
Fig. 2. Correlation between concentration of atria1 natriuretic factor in the plasma at peak exercise and peak consumption of oxygen in patients with mild heart failure (n = 13; r = - 0.671; P = 0.012).
marker of functional capacity compared to other methods. A new and interesting observation made in the present study is that levels of atria1 natriuretic factor at peak exercise are better correlated to, and therefore probably a better predictor of, peak consumption of oxygen than levels of atria1 natriuretic factor at rest. This observation should be confirmed by subsequent investigation. Increased levels of atria1 natriuretic factor at rest, as observed in the present study, could indicate increased left or right atria1 pressure at rest. Prolonged atria1 distention could theoretically influence the relationship between atria1 pressure and release of atria1 natriuretic factor. A depletion of stores of atria1 natriuretic factor caused by chronic atria1 pressure overload could result in attenuated release of atria1 natriuretic factor in response to acute stimuli. Alternatively, chronic stimulation could result in resetting of the relationship between atria1 pressure and release of atria1 natriuretic factor with a maintained release of atria1 natriuretic factor in response to acute
stimuli as a consequence. A major objective of the present study was to evaluate whether any of these patterns of release could be observed in patients with mild heart failure. Cardiac filling pressures increase during exercise in patients with chronic heart failure [lo], and exercise is, therefore, a suitable stimulus for the study of release of atria1 natriuretic factor in patients with slightly impaired functional capacity. Previous studies have yielded diverging results. Dietz et al. [6] found maintained production of atria1 natriuretic factor in response to acute stimuli in cardiac patients, while Raine et al. [l] demonstrated a significantly lower response of release of atria1 natriuretic factor to exercise in patients with elevated atria1 pressures at rest compared to cardiac patients with atria1 pressures within the normal range at rest. Data from the present study fail to support the concept of attenuated release of atria1 natriuretic factor in response to exercise in patients with more severe functional impairment. An inverse relationship between atria1 natriuretic factor delta and peak consumption of oxygen was demonstrable, that is. the patients with more severe functional impairment achieved the largest increase in concentration of atria1 natriuretic factor during exercise testing. Levels of atria1 natriuretic factor are generally increased in heart failure, but it remains unclear whether its theoretically beneficial actions are physiologically effective, or if it should be regarded more as a marker of the degree of heart failure rather than as a biologically active hormone. A decreased renal responsiveness to the natriuretic factor in humans with heart failure has been suggested because no significant change in sodium excretion or urine volume was observed during infusion of the factor [12]. In the present study we failed to find attenuation of the response of the factor to exercise in the patients with most marked functional impairment. indicating that impaired release in response to acute stimuli is unlikely to be an important factor in the pathogenesis of chronic heart failure. Data from the present study support the concept that atria1 natriuretic factor may be a clinically useful marker of functional impairment. Values during peak exercise appear to discriminate between the functional
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capacity of cardiac patients clinical function class.
belonging
to the same
Acknowledgements Technical assistance from Mrs. Aagot Kirkebq Mrs. Helle Svanes and Mr. Kurt Tjelta is gratefully acknowledged.
References
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