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The effect of captopril on postural hemodynamics and autonomic responses in chronic heart failure
The effect of captopril on postural hemodynamics and autonomic responses chronic heart failure
in
Both postural abnormalities and autonomic dysfunction have been identified in patients with chronic congestive heart failure (CHF). However, the effect of long-term vasodilator therapy on these phenomena has not been assessed. In this study the hemodynamic and plasma norepinephrine (PNE) responses to upright posture, as well as the cold pressor test and Valsaiva’s maneuver in 12 patients with severe chronic CHF during both acute and long-term captoprii (CPT) therapy, were evaluated. This revealed an absence of the normal hemodynamic adjustments to upright posture and a blunted response of PNE. The heart rate and blood pressure responses to the cold pressor test and Vaisaiva’s maneuver were similarly blunted. The reflex adjustments of systemic resistance during tilt improved with CPT therapy, but the absence of reflex tachycardia in the upright posture persisted. Additionally, there was improvement of the PNE response, and the responses of heart rate and blood pressure to the cold pressor test were virtually normalized during tong-term CPT therapy. The abnormal response to the Vaisalva maneuver persisted. In conclusion, hemodynamic and reflex-mediated responses to upright posture and the standard assessment of autonomic control mechanisms revealed abnormal patterns in heart failure. While the hemodynamic adjustment to postural changes and sympathetic responsiveness were improved with CPT, complete correction of these abnormalities did not occur. Whether the improvement was a nonspecific vasodilator effect or the result of specific CPT therapy remains to be determined. (AM HEART J 104:1190, 1982.)
Robert
J. Cody, M.D. New York, N.Y.
Despite the widespread use of vasodilator therapy for the treatment of chronic congestive heart failure (CHF), two aspects of the potential response to this form of therapy have not received detailed attention. These are the hemodynamic changes that occur with assumption of the upright posture and the previously described abnormalities of autonomic responsiveness. In normal individuals’ and patients with hypertension,2 assumption of the upright posture results in peripheral pooling of blood due to the stress of gravity. This is reflected primarily as a decrease of cardiac output and a reduction of cardiac filling pressures. Orthostatic hypotension and fainting are averted, however, due to baroreceptor-mediated increases of both heart rate and systemic vascular resistance. It has been reported previously by Abelmann that patients with CHF do not demonstrate this peripheral pooling due to gravitational stress, so that heart rate and systemic vascular
From the Departments tal-Cornell University
of Medicine and Pharmacology, Medical Center.
Reprint requests: Robert J. Cody, M.D., d-3, New York Hospital-Cornell University St., New York, NY 10021.
1190
Cardiovascular Medical
New
York
Center, Center, 525
HospiSection E. 68th
resistance are essentially unchanged. The autonomic abnormalities in CHF, which appear to be both sympathetic and parasympathetic, have been described in both animal models and clinical studies.4-7 To precisely determine the autonomic responses to successful vasodilator management of advanced CHF, we have evaluated the effect of captopril (CPT) during both acute and long-term therapy on the postural and neurogenic abnormalities characteristically manifest in patients with severe CHF. METHODS Patient population. Following discontinuation of previous vasodilator therapy, 18 patients with severe chronic CHF underwent hemodynamic evaluation in both supine and tilt positions. Twelve of these patients also underwent autonomic studies and received CPT. In this group of 12, there were 11 men and one woman whose ages ranged from 20 to 75 years. Four patients were classified as New York Heart Association functional class III, and eight patients were functional class IV. Each patient was maintained on constant doses of digoxin and diuretics because of the severity of the heart disease, and each was placed on an 85 to 100 mEq sodium diet prior to hemodynamic study. Hemodynamic Acute hemodynamic evaluation. studies were performed in the morning following an 0002~8703/82/111190
+ 07$00.70/O
o 1982
The
C. V. Mosby
Co.
Volume Number
104 5, Part 2
CPT effects on posture
overnight fast, and the morning doses of digoxin and diuretics were withheld. Right-heart catheterization was performed, and cardiac output was determined by the thermal dilution technique. A cannula was placed in a peripheral artery for constant monitoring of blood pressure. Once catheters were placed, a 30- to 60-minute lead-in equilibration period was allowed. During this interval, blood pressureand heart rate responsesto the Valsalva manuever were continuously recorded while the patients performed forced expiration into a manometer. The cold pressortest consistedof immersing one hand in an ice-water bath for 1 minute, during which time heart rate and blood pressure were continuously recorded. Simultaneous determination of hemodynamic values and plasma norepinephrine (PNE) levels were obtained in both the supine position and following 60-degreehead-up tilt for a period of 10 minutes. The details of this method of study have been described previously.s Patients were then returned to the supine position for 30 minutes of reequilibration, at which time the hemodynamic determinations and blood sampling for PNE were repeated. At that point, a 25 mg doseof CPT wasadministered orally, and sequential hemodynamic measurements were obtained at 30-minute intervals. The peak responseto CPT was consideredto be the point of greatest change in mean arterial pressure, pulmonary wedge pressure, and cardiac output. Time of peak responseranged from 30 to 90 minutes for individual patients and conformed with the available data on the pharmacokinetics of CPT in CHF? At the time of peak response,supine and tilt hemodynamic determinations and blood samplingfor PNE levels were repeated. Long-term hemodynamic evaluation. Eight patients underwent repeat hemodynamic study following 8 weeks of oral CPT therapy (99 + 17 mg). At the time of the chronic study, five of eight patients developed orthostatic hypotension during head-up tilt, This was defined as greater than 10% reduction of blood pressurein response to the gravitational stress of tilt. These five patients received an infusion of 500 ml of normal saline solution over 10 minutes via the right atrial lumen of the SwanGanz catheter. After an additional 15-minute equilibration period, repeat determinations were obtained in both the supine and tilt positions. Autonomic testing. The reflex increase of heart rate and systemic vascular resistanceto opposethe peripheral pooling of gravitational stressis an overall reflection of the baroreceptor reflex arc. Similarly, the Valsalva manuever can assessthe overall reflex response.1oTherefore, all patients performed forced expiration into a manometer, generating a constant pressure of 30 to 40 mm Hg for a period of 15 to 20 seconds.During this time, continuous recordingsof heart rate and blood pressurewere obtained. Following releaseof the forced expiration, heart rate and blood pressurewere recorded for an additional 30 seconds to observe the phase IV Valsalva response. The cold pressortest was performed, with patients immersing one hand into an ice-water bath (0’ to 4’ C) for a period of 1 minute. This is a noxious stimulus, resulting in increased
dynamics
and PNE responses
in CHF
1191
Heart rate 60 L
Mean arterial pressure
Cardiac index
Systemic vascular resistance
100
y 80 6. L
::I:
1 \
2.00
c
--w-J
I .50L *----,,-
+
2400 1800
,200 v SUPINE Normal in=71 -
v TILT CHF (n=18)---
1. Overall hemodynamic responseto upright pasture in normal individuals ascompared with that of heart failure patients. Fig.
efferent sympathetic activity” with subsequentincreases of heart rate and blood pressure.Continuous recordingsof heart rate and blood pressure were obtained for all patients before, during, and after hand immersion. In addition, the PNE responseto tilt wasdetermined by the radioenzymatic assaytechnique of Peuler and Johnson.12 Studies in normal individuals. As part of this study, hemodynamic responsesto upright tilt and the Valsalva maneuver were obtained from historical data from normal individuals. Additionally, the cold pressor responsewas performed in eight normal individuals, with noninvasive determinations of heart rate and blood pressure. Statistical methods. Paired t analysis was used to compare the differences between supine and tilt values, with each patient serving as his own control. For the analysis of normal vs heart failure responseto the cold pressor test, paired t analysis was used. All values were expressedas mean + standard error of the mean. RESULTS Comparison of the normal and heart failure hemodynamic response to tilt. The overall hemodynamic
1192
Cody
American
I. Effect of acute CPT on the CHF tilt response in 12 patients*
Table
November. 1982 Heart Journal
II. Response to tilt in CHF with long-term CPT therapy in eight patients*
Table
--
Control Supine
Post-CPT Tilt
Supine
Control Tilt
Supine
Long-term Tilt
Supine
CPT
__.
Tilt -
HR MAP RAP PAP PWP CI SI SVR PVR PNE
86 79 11 38 26 1.57 19 1968 370 747
* * * f + k + i k f
4 2 2t 6t 2t 0.08 2 125 45 249
87 f 73 * 2&l 25 f 13 zt 1.49 + 18 + 2138 t 366 + 782 t
4 3 2 3 0.06 1 156 32 227
85 70 7 32 19 1.89 23 1477 303 476
+ + k +2 k t -t + +
5 2 2t 2t 2t 0.09t 2f 84t 30 71t
84 k 4 66 * 3 121
20 + 9k2 1.66 k 20 + 1758 i 311 2 615 f
2 0.09 1 135 34 78
HR = heart rate (bpm); MAP = mean systemic arterial pressure (mm Hg); RAP = right atria1 pressure (mm Hg); PAP = pulmonary arterial pressure (mm Hg); PWP = pulmonary capillary wedge pressure (mm Hg); CI = cardiac index (Llminlm’); SI = stroke index (ml/beat/m’); SVR = systemic vascular resistance (dynes set cm-9; PVR = pulmonary vascular resistance (dynes set cm-‘); PNE = plasma norepinephrine (pg/ml). *Based on data from Cody et al.* t = p < 0.01.
response to tilt for seven normal individuals and 18 heart failure patients was compared (Fig. 1). In normal individuals, the peripheral pooling of headup tilt resulted in a 22% reduction of cardiac index from 2;95 f 0.15 to 2.29 + 0.13 L/min/m2 (p < 0.05); similarly, stroke volume index decreased 27% from 37 -+ 1 to 27 + 1 ml/beat/m2 03 < 0.05). The 2% increase in mean arterial pressure from 90 + 2 to 92 + 3 mm Hg was not significant (p > 0.05). This was due to a 22% reflex increase of heart rate from 68 + 3 to 83 + 3 bpm (p < 0.05) and a 33 % reflex increase of systemic vascular resistance from 1266 f 143 to 1684 -t 211 dynes . set . cmV5 (p < 0.05). In contrast, these compensatory changes were not observed in CHF patients. On tilt, cardiac index decreased only 7%) from 1.7i f 0.08 to 1.58 -+ 0.06 L/min/m2 @ > 0.05), and the 5% change in stroke volume index from 21 & 2 to 20 f 1 ml/ beat/m2 (p > 0.05) was minimal. The 5% change in mean arterial pressure from 83 2 5 to 78 +- 3 mm Hg was not appreciably different (p > 0.05). Moreover, heart rate remained unchanged from the supine level of, 86 + 3 bpm, and there was minimal change of systemic vascular resistance from the baseline value of 1944 +- 105 dynes . set . cmm5 (both p > 0.05). In four normal individuals, simultaneous pulmonary wedge pressure and right atrial pressure decreased on tilt from 5 +- 3 to 2.5 +- 1 mm Hg and 3 + 2 to 0 +- 1 mm Hg, respectively. During the tilt of CHF patients, reduction of pulmonary wedge pressure from 23 _+ 2 to 11 f 2 mm Hg and decline of right atria1 pressure from 9 & 2 to 1 -+ 1 mm Hg were both highly significant 0, < 0.001).
HR MAP RAP PWP CI SI SVR PNE
87 80 11 25 1.60 19 1916 591
k k t k k k + 2
5 2 3t 37 0.09 2 136 113
87 -t 74 f 3k2 14 $ 1.49 + 18 + 2122 i 620 +-
5 4 3 06 1
194 137
82 71 5 16 1.99 25 1484 336
k rt * f + k -+ -f-
5 5t 1t 2t 0.13t 27 134 69t
85 i 60 -+ 021 6t2 1.76 + 22 k 1536 5 407 t
6 4
0.11 2 137 67
Abbreviations same as in Table I. *Based on data from Cody et al.’ t = p at least < 0.02.
Effects of acute and long-term CPT therapy. The response to head-up tilt was acutely evaluated in 12 CHF patients before and after administration of a 25 mg oral dose of CPT (Table I). Response in the control tilt group was similar to that in the larger heart failure group described above, with reduction of right atria1 pressure from 11 f 2 to 2 2 1 mm Hg (p < O.Ol), decrease of pulmonary artery pressure from 38 + 6 to 25 rf: 2 mm Hg (p < O.Ol), and decline of pulmonary wedge pressure from 26 + 2 to 13 _+ 3 mm Hg (p < 0.01). Despite these significant reductions of cardiac filling pressures, there was no significant reduction in the cardiac or stroke volume indices (p > 0.05). In this setting, neither the small decrease of mean arterial pressure from 79 +- 2 to 73 + 3 mm Hg nor the minimal changes in heart rate and systemic vascular resistance were significant. Following acute CPT therapy, significant reductions of cardiac filling pressures were again noted (Table I). However, there was greater evidence of peripheral pooling due to gravitational stress as cardiac and stroke volume indices decreased from 1.89 +- 0.09 to 1.66 _+ 0.09 L/min/m2 (p < 0.01) and from 23 f 2 to 20 + 1 ml/beat/m2 (p < O.Ol), respectively. Mean arterial pressure was not significantly changed from the supine value of 70 f 2 mm Hg (p > 0.05), while the calculated systemic vascular resistance increased from 1477 +- 84 to 1758 A 135 dynes . set . cmm5 (p < 0.01). It is noteworthy that PNE levels did not elevate significantly during the control tilt, but they did rise from 476 k 71 to 615 + 78 pg/ml (p < 0.01) following acute CPT ingestion. Following acute CPT therapy, none of the CHF patients demonstrated appreciable orthostatic hypotension on tilt. Eight patients were maintained on CPT chronically and had repeat hemodynamic testing at 8 weeks of therapy (Table II). During long-term CPT therapy, the overall supine hemodynamic improve-
Volume Number
104 5. Part 2
CPT effects on posture dynamics and PNE responses in CHF
1193
20 HR
A%
2 $J lots
Orthostofic HyrgtteunpSlon
Control (N=8) AC. Captopril Chr. Captopril Chr. Captopril Chr. Capt!pril 1, (post-salme) 10
Pulmonary
(N=8) (N=8) (N=5) (N=5)
SUPINE - 0 0 0 v A
1 20
TILT - a l n
T A I 30
wedge pressure
Fig. 2. Left ventricular function during tilt as judged from the relationship between pulmonary wedgepressure and stroke volume index. (From Cody I&J, Franklin KW, Kluger J, Laragh JH: Mechanisms governing the postural response,andbaroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. By permissionof the American Heart Association, Inc.)
In the head-up position, several observations were notable. Cardiac filling pressures were once again significantly reduced @ < 0.02) compared with the supine values (Table II). As with the acute tilt, there was an insignificant (p > 0.05) reduction of mean arterial pressure, cardiac and stroke volume indices, and systemic vascular resistance; however, following CPT, the reduction of mean arterial pressure from 71 f 5 to 60 f 4 mm Hg was considerable (p < 0.02), with a z 10% fall of blood pressure (72 f 6 vs 56 of: 4 mm Hg) on tilt observed in five CHF patients. To correct orthostatic hypotension in these individuals, 500 ml of normal saline solution was infused into the right atrium over 10 minutes. Fifteen minutes following completion of the infusion, the tilt was repeated and orthostatic hypotension was abolished, as only mean arterial pressure changed from 76 rt_ 8 to 73 +- 8 mm Hg on tilt 0, > 0.05). There was no significant increase @ > 0.05) of calculated systemic vascular resistance on tilt in either the larger group of eight or the subgroup of five patients with orthostatic hypotension before administration of saline solution. However, in the subgroup of five patients evaluated after saline solution infusion, the correction of orthostatic hypotension was associated with a signiment was maintained.
10
base -----
Control Acute
captopril
1 min Chronic -Normals
TFpc.05
captopril (N=8)
*l*pc.Ol
Fig. 3. Heart rate and blood pressureresponsesto the cold pressor test were assessedin eight heart failure patients at all stagesof CPT therapy and comparedto the responses of eight aged-matched normal individuals (heavy solid lines). (From Cody RJ, Franklin KW, Kluger 3, Laragh JH: Mechanisms governing the postural response,and baroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. By permissionof the American Heart Association, Inc.)
ficant increase of the calculated systemic vascular resistance during tilt from the supine value of 1455 f 229 to 1722 + 229 dynes . set . crnm5 (p < 0.05). During long-term CPT therapy, the supine PNE level of 336 k 69 pg/ml was significantly decreased compared to the supine control value of 591 f 113 pgjml (p < 0.05). However, during the long-term post-CPT tilt, PNE increased from 336 + 69 to 407 rt 67 pg/ml (p < 0.02). This significant increase was also observed in the subgroup of five patients who had developed orthostatic hypotension on tilt. The relationship between pulmonary wedge pressure and stroke volume index was evaluated during tilt and was reassessed following both acute and chronic CPT therapy (Fig. 2). Prior to initiation of CPT therapy, left ventricular function demonstrated a flat response to upright posture, with little change in stroke volume index despite a substantial reduction of pulmonary wedge pressure on tilt.
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Cody
American
November, 1982 Heart Journal
4. Valsalva’s maneuver in a patient with chronic CHF. Shown are the heart rate, blood pressure,and mean atria1 pressureresponses.A, Control. B, Two months after CPT.
Fig.
Following CPT therapy, there was an upward and leftward shift of this relationship, indicating improvement of left ventricular function in both the supine and upright positions. Response to the cold pressor maneuver. Heart rate and blood
to the cold pressor test during
test
and Vatsalva’s
pressure responses all stages of CPT
therapy were compared to those of a group of aged-matched normal individuals (Fig. 3). The normal cold pressor response of increases in heart rate and blood pressure at 1 minute of hand immersion was modified in the CHF patients, with little increase of these variables. Following acute CPT therapy, there was a small but significant increase of
Volume Number
104 5, Part 2
CPT effects on posture
systolic blood pressure but no change in heart rate or diastolic blood pressure. With long-term CPT therapy, all variables were normally augmented. Response to Valsalva’s maneuver. In contrast to the cold pressor test, there was little change in heart rate of pulse pressure during phases II and IV of the Valsalva maneuver. The classic square-wave description of the Valsalva maneuver was present at all stages of therapy for most patients (Fig. 4, A). In several patients there was some narrowing of pulse pressure during phase II and a small phase IV blood pressure overshoot (Fig. 4, B); however, these changes were not uniformly present. Furthermore, the heart rate remained unchanged in most patients during phase IV. DISCUSSION Comparison of the normal and heart failure hemodynamic response to tilt. Brigden and Sharpey-SchaferI
first documented abnormalities of flow in heart failure patients in the semierect position over 25 years ago. This observation was further clarified by Abelmann during head-up tilt. In normal individuals, head-up tilt results in reflex stimulation of tachycardia and increased systemic vascular resistance to orthostatic hypotension that would otherwise occur in the presence of significant peripheral pooling of blood and decrease of cardiac output due to gravitational stress. In the present study, as in the study by Abelmann, CHF patients did not demonstrate a reduction of cardiac output in response to the gravitational stress of head-up tilt. Hence, no changes in heart rate or systemic vascular resistance occurred. This response was relatively uniform, with no difference for ischemic or nonischemic etiologies of heart failure. However, several additional points were observed; notably, the upright posture did result in a significant reduction of cardiac filling pressures so that in the upright position these were essentially in the normal range. Furthermore, there was an absence of the normal increase of PNE on tilt. It has been previously observed that the normal reflex increases of plasma renin activity and plasma aldosterone during tilt do not occur in heart failure patients.8 Interestingly, it has been postulated that the mechanism of these postural changes relates to absence of peripheral pooling due to relatively fixed vasoconstriction or to the increase of circulating pressure. If this were the case, in accord with the observations described herein, a significant improvement of the response to tilt following improvement of cardiac function with vasodilator therapy would be anticipated. Effects of converting enzyme inhibition dynamic response to tilt. One difficulty
on the hemo-
in assessing
dynamics
and PNE
responses
in CHF
1195
the effects of vasodilators on the hemodynamic response to upright tilt is that by definition these drugs lower peripheral resistance. Therefore, the extent of increase of systemic vascular resistance on tilt may be blunted. Although this might be the case when comparing supine resistance values before and after CPT, no significant blunting of the resistance response to upright posture was observed in hypertensive patients receiving CPT during both acute and chronic studies even in the presence of diuretic therapy.*, I4 With acute CPT therapy, a significant fall of cardiac index did occur on tilt in the CHF patients (Table I). Yet, orthostatic hypotension did not occur; thus, the calculated systemic vascular resistance was significantly increased. During chronic CPT therapy, the fall of cardiac index on tilt did result in orthostatic hypotension, so the calculated systemic vascular resistance was not significantly raised (Table II). It is noteworthy that the calculated systemic vascular resistance was elevated following sodium repletion in the individuals receiving long-term CPT therapy. This suggests that in the presence of adequate sodium repletion the resistance response to tilt was normalized with both acute and long-term CPT therapy. Additional evidence of autonomic reflex improvement in CPTmanaged CHF patients was the enhanced relationship between pulmonary wedge pressure and stroke volume index in both supine and upright positions during therapy with this converting enzyme inhibitor. These findings suggest that vasodilator therapy does result in at least partial correction of the postural abnormalities noted in patients with CHF. However, the observation of the persistent absence of tachycardia on tilt is perplexing. During the control tilt, it would be easy to explain the absence of tachycardia on the basis that cardiac index did not fall appreciably during tilt. However, during both acute and chronic CPT therapy, there was peripheral pooling with a decrease of cardiac index on tilt, sufficient to promote a reflex increase of systemic vascular resistance. Moreover, during chronic CPT therapy the stimulus for tachycardia was even greater due to the presence of documented orthostatic hypotension during tilt in some patients. Thus the absence of heart rate elevation may partly reflect some persistent abnormality of autonomic function in the patients in this study. Effect of CPT on the autonomic chronic heart failure. In patients
abnormalities
of
with CHF, PNE levels are inversely correlated with resting cardiac index,*5**6 and during chronic CPT therapy, the increase of cardiac index has been correlated with the reduction of supine norepinephrine levels.15
1196
Cody
With both acute and chronic CPT therapy, supine values of PNE were lower than those during the control phase. Further, during both acute and longterm tilt, PNE levels increased significantly. Since the normal response of PNE to tilt is a two- to threefold increase compared to the supine values, it is reasonable to assume that the increase of PNE during tilt in the present study represented improved sympathetic responsiveness. The notable abnormality of autonomic function observed in this study was the persistently abnormal Valsalva maneuver. The bradycardia usually observed during the phase IV overshoot of the Valsalva manuever is believed to be secondary to efferent vagal tone. Therefore, as heart rate did not change during the Valsalva manuever in the present study, the possibility of a persistent parasympathetic abnormality is raised. It is known that patients with chronic CHF have a blunted heart rate response to the administration of atropine,6v7 and in a study of the tilt response in patients with Chagas’ cardiomyopathy, the absence of reflex tachycardia on tilt was thought to be secondary to the absence of parasympathetic withdrawal.17 Conclusions. The response to upright posture in patients with chronic heart failure is distinguished by an absence of the normal hemodynamic adjustments to gravitational stress and abnormalities of both hormonal and autonomic compensatory changes. Overall, the response to CPT during both acute and long-term therapy was characterized by improvement of the response of systemic vascular resistance to upright posture, improvement of left ventricular function in both supine and upright positions, and improvement of sympathetic responsiveness. Persistent abnormalities in the heart rate response to tilt and the Valsalva maneuver were curious findings. Whether the observed improvement was due to vasodilator-induced augmentation of left ventricular function or was a specific response to CPT itself is not clear, but the potential to partially reverse both postural and autonomic abnormalities may be an important consideration in the evaluation of the long-term response to vasodilator therapy.
American
November, 1982 Heart Journal
REFERENCES
1. Tuckman J, Shillingford J: Effect of different degrees of tilt on cardiac output, heart rate, and blood pressure in normal man. Br Heart J 26~32, 1965. 2. Cody RJ, Tarazi RC, Bravo EL, Fouad FM Hemodynamics of orally active converting enzyme inhibitor (SQ 14225) in hypertensive patients. Clin Sci Mol Med 55:453,1978. 3. Abelmann WH: Alterations in orthostatic tolerance after myocardial infarction and in congestive heart failure. Cardiology 61 (Suppl 1):236, 1976. 4. Eckbere DL. Drabinskv M. Braunwald E: Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 285:877, 1971. 5. Higgins CB, Vatner SF, Eckberg DL, Braunwald E: Alterations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 51:715, 1972. 6. Goldstein RE, Beiser GD, Stampfer M, Epstein SE: Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36~571, 1975. 7. Amorim DS, Heerk Jenner D, Richardson P, Dargie HJ, Brown M, Olsen EGJ, Goodwin JF: Is there autonomic impairment in congestive (dilated) cardiomyopathy? Lancet 1:525,1981. a. Cody RJ, Franklin KW, Kluger J, Laragh JH: Mechanisms governing the postural response, and baroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. 9. Cody RJ, Schaer GL, Covit AB, Pondolfino K, Williams G: Pharmacokinetics of captopril in chronic congestive heart failure. Clin Pharmacol Ther (In press.) IO. Sharpey-Schafer EP: Effects of Valsalva’s maneuver on the normal and failing circulation. Br Med J 1:693, 1955. 11. Ibrahim MM Localization of lesion in patients with idiopathic orthostatic hypotension. Br Heart J 37:868, 1975. 12. Peuler JD, Johnson GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine, and dopamine. Life Sci 21:625, 1977. 13. Brisden W. Sharoev-Schafer EP: Postural changes in ueriuherarblood kow in cases with left heart failure. Clin Sci Qi93, 1950. 14. Cody RJ, Bravo EL, Fouad FM, Tarazi RC: Cardiovascular reflexes during chronic converting enzyme inhibition and sodium depletion: The response to tilt in hypertensive patients. Am J Med 71:442, 1981. 15. Cody RJ, Franklin KW, Kluger J, Laragh JH: Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril. Am J Med 72:791, 1982. 16. Maurer W, Tschada R, Manthey J, Hausen M, Kubler W: Inverse relationshin between cardiac index and plasma catecholamines in patients with heart failure (abst). Am J Cardiol 49:1036, 1982. 17. Marin Neto JA, Gallo L Jr, Manco JC, Rassi A, Amor DS: Mechanisms of tachycardia on standing: Studies in normal individuals and in chronic Chagas’ heart patients. Cardiovasc Res 14:541, 1980.
in
Both postural abnormalities and autonomic dysfunction have been identified in patients with chronic congestive heart failure (CHF). However, the effect of long-term vasodilator therapy on these phenomena has not been assessed. In this study the hemodynamic and plasma norepinephrine (PNE) responses to upright posture, as well as the cold pressor test and Valsaiva’s maneuver in 12 patients with severe chronic CHF during both acute and long-term captoprii (CPT) therapy, were evaluated. This revealed an absence of the normal hemodynamic adjustments to upright posture and a blunted response of PNE. The heart rate and blood pressure responses to the cold pressor test and Vaisaiva’s maneuver were similarly blunted. The reflex adjustments of systemic resistance during tilt improved with CPT therapy, but the absence of reflex tachycardia in the upright posture persisted. Additionally, there was improvement of the PNE response, and the responses of heart rate and blood pressure to the cold pressor test were virtually normalized during tong-term CPT therapy. The abnormal response to the Vaisalva maneuver persisted. In conclusion, hemodynamic and reflex-mediated responses to upright posture and the standard assessment of autonomic control mechanisms revealed abnormal patterns in heart failure. While the hemodynamic adjustment to postural changes and sympathetic responsiveness were improved with CPT, complete correction of these abnormalities did not occur. Whether the improvement was a nonspecific vasodilator effect or the result of specific CPT therapy remains to be determined. (AM HEART J 104:1190, 1982.)
Robert
J. Cody, M.D. New York, N.Y.
Despite the widespread use of vasodilator therapy for the treatment of chronic congestive heart failure (CHF), two aspects of the potential response to this form of therapy have not received detailed attention. These are the hemodynamic changes that occur with assumption of the upright posture and the previously described abnormalities of autonomic responsiveness. In normal individuals’ and patients with hypertension,2 assumption of the upright posture results in peripheral pooling of blood due to the stress of gravity. This is reflected primarily as a decrease of cardiac output and a reduction of cardiac filling pressures. Orthostatic hypotension and fainting are averted, however, due to baroreceptor-mediated increases of both heart rate and systemic vascular resistance. It has been reported previously by Abelmann that patients with CHF do not demonstrate this peripheral pooling due to gravitational stress, so that heart rate and systemic vascular
From the Departments tal-Cornell University
of Medicine and Pharmacology, Medical Center.
Reprint requests: Robert J. Cody, M.D., d-3, New York Hospital-Cornell University St., New York, NY 10021.
1190
Cardiovascular Medical
New
York
Center, Center, 525
HospiSection E. 68th
resistance are essentially unchanged. The autonomic abnormalities in CHF, which appear to be both sympathetic and parasympathetic, have been described in both animal models and clinical studies.4-7 To precisely determine the autonomic responses to successful vasodilator management of advanced CHF, we have evaluated the effect of captopril (CPT) during both acute and long-term therapy on the postural and neurogenic abnormalities characteristically manifest in patients with severe CHF. METHODS Patient population. Following discontinuation of previous vasodilator therapy, 18 patients with severe chronic CHF underwent hemodynamic evaluation in both supine and tilt positions. Twelve of these patients also underwent autonomic studies and received CPT. In this group of 12, there were 11 men and one woman whose ages ranged from 20 to 75 years. Four patients were classified as New York Heart Association functional class III, and eight patients were functional class IV. Each patient was maintained on constant doses of digoxin and diuretics because of the severity of the heart disease, and each was placed on an 85 to 100 mEq sodium diet prior to hemodynamic study. Hemodynamic Acute hemodynamic evaluation. studies were performed in the morning following an 0002~8703/82/111190
+ 07$00.70/O
o 1982
The
C. V. Mosby
Co.
Volume Number
104 5, Part 2
CPT effects on posture
overnight fast, and the morning doses of digoxin and diuretics were withheld. Right-heart catheterization was performed, and cardiac output was determined by the thermal dilution technique. A cannula was placed in a peripheral artery for constant monitoring of blood pressure. Once catheters were placed, a 30- to 60-minute lead-in equilibration period was allowed. During this interval, blood pressureand heart rate responsesto the Valsalva manuever were continuously recorded while the patients performed forced expiration into a manometer. The cold pressortest consistedof immersing one hand in an ice-water bath for 1 minute, during which time heart rate and blood pressure were continuously recorded. Simultaneous determination of hemodynamic values and plasma norepinephrine (PNE) levels were obtained in both the supine position and following 60-degreehead-up tilt for a period of 10 minutes. The details of this method of study have been described previously.s Patients were then returned to the supine position for 30 minutes of reequilibration, at which time the hemodynamic determinations and blood sampling for PNE were repeated. At that point, a 25 mg doseof CPT wasadministered orally, and sequential hemodynamic measurements were obtained at 30-minute intervals. The peak responseto CPT was consideredto be the point of greatest change in mean arterial pressure, pulmonary wedge pressure, and cardiac output. Time of peak responseranged from 30 to 90 minutes for individual patients and conformed with the available data on the pharmacokinetics of CPT in CHF? At the time of peak response,supine and tilt hemodynamic determinations and blood samplingfor PNE levels were repeated. Long-term hemodynamic evaluation. Eight patients underwent repeat hemodynamic study following 8 weeks of oral CPT therapy (99 + 17 mg). At the time of the chronic study, five of eight patients developed orthostatic hypotension during head-up tilt, This was defined as greater than 10% reduction of blood pressurein response to the gravitational stress of tilt. These five patients received an infusion of 500 ml of normal saline solution over 10 minutes via the right atrial lumen of the SwanGanz catheter. After an additional 15-minute equilibration period, repeat determinations were obtained in both the supine and tilt positions. Autonomic testing. The reflex increase of heart rate and systemic vascular resistanceto opposethe peripheral pooling of gravitational stressis an overall reflection of the baroreceptor reflex arc. Similarly, the Valsalva manuever can assessthe overall reflex response.1oTherefore, all patients performed forced expiration into a manometer, generating a constant pressure of 30 to 40 mm Hg for a period of 15 to 20 seconds.During this time, continuous recordingsof heart rate and blood pressurewere obtained. Following releaseof the forced expiration, heart rate and blood pressurewere recorded for an additional 30 seconds to observe the phase IV Valsalva response. The cold pressortest was performed, with patients immersing one hand into an ice-water bath (0’ to 4’ C) for a period of 1 minute. This is a noxious stimulus, resulting in increased
dynamics
and PNE responses
in CHF
1191
Heart rate 60 L
Mean arterial pressure
Cardiac index
Systemic vascular resistance
100
y 80 6. L
::I:
1 \
2.00
c
--w-J
I .50L *----,,-
+
2400 1800
,200 v SUPINE Normal in=71 -
v TILT CHF (n=18)---
1. Overall hemodynamic responseto upright pasture in normal individuals ascompared with that of heart failure patients. Fig.
efferent sympathetic activity” with subsequentincreases of heart rate and blood pressure.Continuous recordingsof heart rate and blood pressure were obtained for all patients before, during, and after hand immersion. In addition, the PNE responseto tilt wasdetermined by the radioenzymatic assaytechnique of Peuler and Johnson.12 Studies in normal individuals. As part of this study, hemodynamic responsesto upright tilt and the Valsalva maneuver were obtained from historical data from normal individuals. Additionally, the cold pressor responsewas performed in eight normal individuals, with noninvasive determinations of heart rate and blood pressure. Statistical methods. Paired t analysis was used to compare the differences between supine and tilt values, with each patient serving as his own control. For the analysis of normal vs heart failure responseto the cold pressor test, paired t analysis was used. All values were expressedas mean + standard error of the mean. RESULTS Comparison of the normal and heart failure hemodynamic response to tilt. The overall hemodynamic
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I. Effect of acute CPT on the CHF tilt response in 12 patients*
Table
November. 1982 Heart Journal
II. Response to tilt in CHF with long-term CPT therapy in eight patients*
Table
--
Control Supine
Post-CPT Tilt
Supine
Control Tilt
Supine
Long-term Tilt
Supine
CPT
__.
Tilt -
HR MAP RAP PAP PWP CI SI SVR PVR PNE
86 79 11 38 26 1.57 19 1968 370 747
* * * f + k + i k f
4 2 2t 6t 2t 0.08 2 125 45 249
87 f 73 * 2&l 25 f 13 zt 1.49 + 18 + 2138 t 366 + 782 t
4 3 2 3 0.06 1 156 32 227
85 70 7 32 19 1.89 23 1477 303 476
+ + k +2 k t -t + +
5 2 2t 2t 2t 0.09t 2f 84t 30 71t
84 k 4 66 * 3 121
20 + 9k2 1.66 k 20 + 1758 i 311 2 615 f
2 0.09 1 135 34 78
HR = heart rate (bpm); MAP = mean systemic arterial pressure (mm Hg); RAP = right atria1 pressure (mm Hg); PAP = pulmonary arterial pressure (mm Hg); PWP = pulmonary capillary wedge pressure (mm Hg); CI = cardiac index (Llminlm’); SI = stroke index (ml/beat/m’); SVR = systemic vascular resistance (dynes set cm-9; PVR = pulmonary vascular resistance (dynes set cm-‘); PNE = plasma norepinephrine (pg/ml). *Based on data from Cody et al.* t = p < 0.01.
response to tilt for seven normal individuals and 18 heart failure patients was compared (Fig. 1). In normal individuals, the peripheral pooling of headup tilt resulted in a 22% reduction of cardiac index from 2;95 f 0.15 to 2.29 + 0.13 L/min/m2 (p < 0.05); similarly, stroke volume index decreased 27% from 37 -+ 1 to 27 + 1 ml/beat/m2 03 < 0.05). The 2% increase in mean arterial pressure from 90 + 2 to 92 + 3 mm Hg was not significant (p > 0.05). This was due to a 22% reflex increase of heart rate from 68 + 3 to 83 + 3 bpm (p < 0.05) and a 33 % reflex increase of systemic vascular resistance from 1266 f 143 to 1684 -t 211 dynes . set . cmV5 (p < 0.05). In contrast, these compensatory changes were not observed in CHF patients. On tilt, cardiac index decreased only 7%) from 1.7i f 0.08 to 1.58 -+ 0.06 L/min/m2 @ > 0.05), and the 5% change in stroke volume index from 21 & 2 to 20 f 1 ml/ beat/m2 (p > 0.05) was minimal. The 5% change in mean arterial pressure from 83 2 5 to 78 +- 3 mm Hg was not appreciably different (p > 0.05). Moreover, heart rate remained unchanged from the supine level of, 86 + 3 bpm, and there was minimal change of systemic vascular resistance from the baseline value of 1944 +- 105 dynes . set . cmm5 (both p > 0.05). In four normal individuals, simultaneous pulmonary wedge pressure and right atrial pressure decreased on tilt from 5 +- 3 to 2.5 +- 1 mm Hg and 3 + 2 to 0 +- 1 mm Hg, respectively. During the tilt of CHF patients, reduction of pulmonary wedge pressure from 23 _+ 2 to 11 f 2 mm Hg and decline of right atria1 pressure from 9 & 2 to 1 -+ 1 mm Hg were both highly significant 0, < 0.001).
HR MAP RAP PWP CI SI SVR PNE
87 80 11 25 1.60 19 1916 591
k k t k k k + 2
5 2 3t 37 0.09 2 136 113
87 -t 74 f 3k2 14 $ 1.49 + 18 + 2122 i 620 +-
5 4 3 06 1
194 137
82 71 5 16 1.99 25 1484 336
k rt * f + k -+ -f-
5 5t 1t 2t 0.13t 27 134 69t
85 i 60 -+ 021 6t2 1.76 + 22 k 1536 5 407 t
6 4
0.11 2 137 67
Abbreviations same as in Table I. *Based on data from Cody et al.’ t = p at least < 0.02.
Effects of acute and long-term CPT therapy. The response to head-up tilt was acutely evaluated in 12 CHF patients before and after administration of a 25 mg oral dose of CPT (Table I). Response in the control tilt group was similar to that in the larger heart failure group described above, with reduction of right atria1 pressure from 11 f 2 to 2 2 1 mm Hg (p < O.Ol), decrease of pulmonary artery pressure from 38 + 6 to 25 rf: 2 mm Hg (p < O.Ol), and decline of pulmonary wedge pressure from 26 + 2 to 13 _+ 3 mm Hg (p < 0.01). Despite these significant reductions of cardiac filling pressures, there was no significant reduction in the cardiac or stroke volume indices (p > 0.05). In this setting, neither the small decrease of mean arterial pressure from 79 +- 2 to 73 + 3 mm Hg nor the minimal changes in heart rate and systemic vascular resistance were significant. Following acute CPT therapy, significant reductions of cardiac filling pressures were again noted (Table I). However, there was greater evidence of peripheral pooling due to gravitational stress as cardiac and stroke volume indices decreased from 1.89 +- 0.09 to 1.66 _+ 0.09 L/min/m2 (p < 0.01) and from 23 f 2 to 20 + 1 ml/beat/m2 (p < O.Ol), respectively. Mean arterial pressure was not significantly changed from the supine value of 70 f 2 mm Hg (p > 0.05), while the calculated systemic vascular resistance increased from 1477 +- 84 to 1758 A 135 dynes . set . cmm5 (p < 0.01). It is noteworthy that PNE levels did not elevate significantly during the control tilt, but they did rise from 476 k 71 to 615 + 78 pg/ml (p < 0.01) following acute CPT ingestion. Following acute CPT therapy, none of the CHF patients demonstrated appreciable orthostatic hypotension on tilt. Eight patients were maintained on CPT chronically and had repeat hemodynamic testing at 8 weeks of therapy (Table II). During long-term CPT therapy, the overall supine hemodynamic improve-
Volume Number
104 5. Part 2
CPT effects on posture dynamics and PNE responses in CHF
1193
20 HR
A%
2 $J lots
Orthostofic HyrgtteunpSlon
Control (N=8) AC. Captopril Chr. Captopril Chr. Captopril Chr. Capt!pril 1, (post-salme) 10
Pulmonary
(N=8) (N=8) (N=5) (N=5)
SUPINE - 0 0 0 v A
1 20
TILT - a l n
T A I 30
wedge pressure
Fig. 2. Left ventricular function during tilt as judged from the relationship between pulmonary wedgepressure and stroke volume index. (From Cody I&J, Franklin KW, Kluger J, Laragh JH: Mechanisms governing the postural response,andbaroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. By permissionof the American Heart Association, Inc.)
In the head-up position, several observations were notable. Cardiac filling pressures were once again significantly reduced @ < 0.02) compared with the supine values (Table II). As with the acute tilt, there was an insignificant (p > 0.05) reduction of mean arterial pressure, cardiac and stroke volume indices, and systemic vascular resistance; however, following CPT, the reduction of mean arterial pressure from 71 f 5 to 60 f 4 mm Hg was considerable (p < 0.02), with a z 10% fall of blood pressure (72 f 6 vs 56 of: 4 mm Hg) on tilt observed in five CHF patients. To correct orthostatic hypotension in these individuals, 500 ml of normal saline solution was infused into the right atrium over 10 minutes. Fifteen minutes following completion of the infusion, the tilt was repeated and orthostatic hypotension was abolished, as only mean arterial pressure changed from 76 rt_ 8 to 73 +- 8 mm Hg on tilt 0, > 0.05). There was no significant increase @ > 0.05) of calculated systemic vascular resistance on tilt in either the larger group of eight or the subgroup of five patients with orthostatic hypotension before administration of saline solution. However, in the subgroup of five patients evaluated after saline solution infusion, the correction of orthostatic hypotension was associated with a signiment was maintained.
10
base -----
Control Acute
captopril
1 min Chronic -Normals
TFpc.05
captopril (N=8)
*l*pc.Ol
Fig. 3. Heart rate and blood pressureresponsesto the cold pressor test were assessedin eight heart failure patients at all stagesof CPT therapy and comparedto the responses of eight aged-matched normal individuals (heavy solid lines). (From Cody RJ, Franklin KW, Kluger 3, Laragh JH: Mechanisms governing the postural response,and baroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. By permissionof the American Heart Association, Inc.)
ficant increase of the calculated systemic vascular resistance during tilt from the supine value of 1455 f 229 to 1722 + 229 dynes . set . crnm5 (p < 0.05). During long-term CPT therapy, the supine PNE level of 336 k 69 pg/ml was significantly decreased compared to the supine control value of 591 f 113 pgjml (p < 0.05). However, during the long-term post-CPT tilt, PNE increased from 336 + 69 to 407 rt 67 pg/ml (p < 0.02). This significant increase was also observed in the subgroup of five patients who had developed orthostatic hypotension on tilt. The relationship between pulmonary wedge pressure and stroke volume index was evaluated during tilt and was reassessed following both acute and chronic CPT therapy (Fig. 2). Prior to initiation of CPT therapy, left ventricular function demonstrated a flat response to upright posture, with little change in stroke volume index despite a substantial reduction of pulmonary wedge pressure on tilt.
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November, 1982 Heart Journal
4. Valsalva’s maneuver in a patient with chronic CHF. Shown are the heart rate, blood pressure,and mean atria1 pressureresponses.A, Control. B, Two months after CPT.
Fig.
Following CPT therapy, there was an upward and leftward shift of this relationship, indicating improvement of left ventricular function in both the supine and upright positions. Response to the cold pressor maneuver. Heart rate and blood
to the cold pressor test during
test
and Vatsalva’s
pressure responses all stages of CPT
therapy were compared to those of a group of aged-matched normal individuals (Fig. 3). The normal cold pressor response of increases in heart rate and blood pressure at 1 minute of hand immersion was modified in the CHF patients, with little increase of these variables. Following acute CPT therapy, there was a small but significant increase of
Volume Number
104 5, Part 2
CPT effects on posture
systolic blood pressure but no change in heart rate or diastolic blood pressure. With long-term CPT therapy, all variables were normally augmented. Response to Valsalva’s maneuver. In contrast to the cold pressor test, there was little change in heart rate of pulse pressure during phases II and IV of the Valsalva maneuver. The classic square-wave description of the Valsalva maneuver was present at all stages of therapy for most patients (Fig. 4, A). In several patients there was some narrowing of pulse pressure during phase II and a small phase IV blood pressure overshoot (Fig. 4, B); however, these changes were not uniformly present. Furthermore, the heart rate remained unchanged in most patients during phase IV. DISCUSSION Comparison of the normal and heart failure hemodynamic response to tilt. Brigden and Sharpey-SchaferI
first documented abnormalities of flow in heart failure patients in the semierect position over 25 years ago. This observation was further clarified by Abelmann during head-up tilt. In normal individuals, head-up tilt results in reflex stimulation of tachycardia and increased systemic vascular resistance to orthostatic hypotension that would otherwise occur in the presence of significant peripheral pooling of blood and decrease of cardiac output due to gravitational stress. In the present study, as in the study by Abelmann, CHF patients did not demonstrate a reduction of cardiac output in response to the gravitational stress of head-up tilt. Hence, no changes in heart rate or systemic vascular resistance occurred. This response was relatively uniform, with no difference for ischemic or nonischemic etiologies of heart failure. However, several additional points were observed; notably, the upright posture did result in a significant reduction of cardiac filling pressures so that in the upright position these were essentially in the normal range. Furthermore, there was an absence of the normal increase of PNE on tilt. It has been previously observed that the normal reflex increases of plasma renin activity and plasma aldosterone during tilt do not occur in heart failure patients.8 Interestingly, it has been postulated that the mechanism of these postural changes relates to absence of peripheral pooling due to relatively fixed vasoconstriction or to the increase of circulating pressure. If this were the case, in accord with the observations described herein, a significant improvement of the response to tilt following improvement of cardiac function with vasodilator therapy would be anticipated. Effects of converting enzyme inhibition dynamic response to tilt. One difficulty
on the hemo-
in assessing
dynamics
and PNE
responses
in CHF
1195
the effects of vasodilators on the hemodynamic response to upright tilt is that by definition these drugs lower peripheral resistance. Therefore, the extent of increase of systemic vascular resistance on tilt may be blunted. Although this might be the case when comparing supine resistance values before and after CPT, no significant blunting of the resistance response to upright posture was observed in hypertensive patients receiving CPT during both acute and chronic studies even in the presence of diuretic therapy.*, I4 With acute CPT therapy, a significant fall of cardiac index did occur on tilt in the CHF patients (Table I). Yet, orthostatic hypotension did not occur; thus, the calculated systemic vascular resistance was significantly increased. During chronic CPT therapy, the fall of cardiac index on tilt did result in orthostatic hypotension, so the calculated systemic vascular resistance was not significantly raised (Table II). It is noteworthy that the calculated systemic vascular resistance was elevated following sodium repletion in the individuals receiving long-term CPT therapy. This suggests that in the presence of adequate sodium repletion the resistance response to tilt was normalized with both acute and long-term CPT therapy. Additional evidence of autonomic reflex improvement in CPTmanaged CHF patients was the enhanced relationship between pulmonary wedge pressure and stroke volume index in both supine and upright positions during therapy with this converting enzyme inhibitor. These findings suggest that vasodilator therapy does result in at least partial correction of the postural abnormalities noted in patients with CHF. However, the observation of the persistent absence of tachycardia on tilt is perplexing. During the control tilt, it would be easy to explain the absence of tachycardia on the basis that cardiac index did not fall appreciably during tilt. However, during both acute and chronic CPT therapy, there was peripheral pooling with a decrease of cardiac index on tilt, sufficient to promote a reflex increase of systemic vascular resistance. Moreover, during chronic CPT therapy the stimulus for tachycardia was even greater due to the presence of documented orthostatic hypotension during tilt in some patients. Thus the absence of heart rate elevation may partly reflect some persistent abnormality of autonomic function in the patients in this study. Effect of CPT on the autonomic chronic heart failure. In patients
abnormalities
of
with CHF, PNE levels are inversely correlated with resting cardiac index,*5**6 and during chronic CPT therapy, the increase of cardiac index has been correlated with the reduction of supine norepinephrine levels.15
1196
Cody
With both acute and chronic CPT therapy, supine values of PNE were lower than those during the control phase. Further, during both acute and longterm tilt, PNE levels increased significantly. Since the normal response of PNE to tilt is a two- to threefold increase compared to the supine values, it is reasonable to assume that the increase of PNE during tilt in the present study represented improved sympathetic responsiveness. The notable abnormality of autonomic function observed in this study was the persistently abnormal Valsalva maneuver. The bradycardia usually observed during the phase IV overshoot of the Valsalva manuever is believed to be secondary to efferent vagal tone. Therefore, as heart rate did not change during the Valsalva manuever in the present study, the possibility of a persistent parasympathetic abnormality is raised. It is known that patients with chronic CHF have a blunted heart rate response to the administration of atropine,6v7 and in a study of the tilt response in patients with Chagas’ cardiomyopathy, the absence of reflex tachycardia on tilt was thought to be secondary to the absence of parasympathetic withdrawal.17 Conclusions. The response to upright posture in patients with chronic heart failure is distinguished by an absence of the normal hemodynamic adjustments to gravitational stress and abnormalities of both hormonal and autonomic compensatory changes. Overall, the response to CPT during both acute and long-term therapy was characterized by improvement of the response of systemic vascular resistance to upright posture, improvement of left ventricular function in both supine and upright positions, and improvement of sympathetic responsiveness. Persistent abnormalities in the heart rate response to tilt and the Valsalva maneuver were curious findings. Whether the observed improvement was due to vasodilator-induced augmentation of left ventricular function or was a specific response to CPT itself is not clear, but the potential to partially reverse both postural and autonomic abnormalities may be an important consideration in the evaluation of the long-term response to vasodilator therapy.
American
November, 1982 Heart Journal
REFERENCES
1. Tuckman J, Shillingford J: Effect of different degrees of tilt on cardiac output, heart rate, and blood pressure in normal man. Br Heart J 26~32, 1965. 2. Cody RJ, Tarazi RC, Bravo EL, Fouad FM Hemodynamics of orally active converting enzyme inhibitor (SQ 14225) in hypertensive patients. Clin Sci Mol Med 55:453,1978. 3. Abelmann WH: Alterations in orthostatic tolerance after myocardial infarction and in congestive heart failure. Cardiology 61 (Suppl 1):236, 1976. 4. Eckbere DL. Drabinskv M. Braunwald E: Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 285:877, 1971. 5. Higgins CB, Vatner SF, Eckberg DL, Braunwald E: Alterations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 51:715, 1972. 6. Goldstein RE, Beiser GD, Stampfer M, Epstein SE: Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36~571, 1975. 7. Amorim DS, Heerk Jenner D, Richardson P, Dargie HJ, Brown M, Olsen EGJ, Goodwin JF: Is there autonomic impairment in congestive (dilated) cardiomyopathy? Lancet 1:525,1981. a. Cody RJ, Franklin KW, Kluger J, Laragh JH: Mechanisms governing the postural response, and baroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long-term converting enzyme inhibition. Circulation 66:135, 1982. 9. Cody RJ, Schaer GL, Covit AB, Pondolfino K, Williams G: Pharmacokinetics of captopril in chronic congestive heart failure. Clin Pharmacol Ther (In press.) IO. Sharpey-Schafer EP: Effects of Valsalva’s maneuver on the normal and failing circulation. Br Med J 1:693, 1955. 11. Ibrahim MM Localization of lesion in patients with idiopathic orthostatic hypotension. Br Heart J 37:868, 1975. 12. Peuler JD, Johnson GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine, and dopamine. Life Sci 21:625, 1977. 13. Brisden W. Sharoev-Schafer EP: Postural changes in ueriuherarblood kow in cases with left heart failure. Clin Sci Qi93, 1950. 14. Cody RJ, Bravo EL, Fouad FM, Tarazi RC: Cardiovascular reflexes during chronic converting enzyme inhibition and sodium depletion: The response to tilt in hypertensive patients. Am J Med 71:442, 1981. 15. Cody RJ, Franklin KW, Kluger J, Laragh JH: Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril. Am J Med 72:791, 1982. 16. Maurer W, Tschada R, Manthey J, Hausen M, Kubler W: Inverse relationshin between cardiac index and plasma catecholamines in patients with heart failure (abst). Am J Cardiol 49:1036, 1982. 17. Marin Neto JA, Gallo L Jr, Manco JC, Rassi A, Amor DS: Mechanisms of tachycardia on standing: Studies in normal individuals and in chronic Chagas’ heart patients. Cardiovasc Res 14:541, 1980.