Plasma Norepinephrine in Congestive Heart Failure
JAMES A. THOMAS, MD* BERNARD H. MARKS, MD+ Detroit, Michigan
From the Department of Pharmacology, Wayne State University, School of Medicine’; and the Department of Internal Medicine, Harper Hospital, Detroit Medical Center,+ Detroit, Michigan. This work was supported by grants from the Michigan Heart Association, Southfietd, Michigan and Grant 5 ROl HL 1755503 from the National Institutes of Health, Bethe&, Maryfand. Manuscript received April 6, 1977; revised manuscript received July 18, 1977, accepted July 21, 1977. Address for reprlnts: James A. Thomas, MD, Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201.
Resting plasma concentrations of norepinephrine, dapamine-beta-hydroxylase enzyme activity and peripheral blood lymfihocyte beta adrenergic receptor sensitivity to isoproterenol as reflectied in cyclic 3’,5’adenosine monophosphate (CAMP) generation were &died in patients with congestive heart failure due to atherosclerotic heart disease or to congestive cardiomyopathy or hypertensive cardioyascular disease. Systolic time intervals were also measured in nonhypqrtenslve patlents and correlated with the plasma norepinephrine concentration. Control patients were hospital employees without a previous history of heart disease or hypertension, and were matched for a* to eliminate the effect of increasing age on the plasma norepinephrine concentration. The results of this study clearly demonstrate that the plasma norepinephrlne concentration Is directly related to the degree of left ventricular dysfunction in patients wlth congestive heart fallure. When the systolic time intervals were correlated with the plasma norepikphrine levels, a significant prolongation of the preeJectlon period wgs observed with progressively increasing plasma concentrations of norepinephrlne. The reverse was true for the left ventricular ejection tlme, which demonstrated a significant inverse relation with the plasma norepipephrlne concentration. The ratio of the preelection period to the left vgntricular ejection time, which is a reflection of left ventricular functloq significantly increased with increasing levels of plasma norepinephrlne. In addition, plasma lymphocytes from patients with the greatest degree of left ventricular dysfunction failed to generate normal amounts of CAMP alter beta adrenerglc receptor stlmulatlon with isoproterenol. It Is suggested that beta adrenergic receptors are desensitized In these patients and that this desensitization contributes to the observed alteratlcins In myocardial contractility.
The role of the sympathetic nervous system remains poorly understood in both compensated and decompensated congestive heart failure, although an augmentation of sympathetic nervous activity in heart failure has previously been described.r An increase in impulse traffic in sympathetic nerves leads to the release of the endogenous neurotransmitter norepinephrine and its synthetic enzyme dopamine-beta-hydroxylase, and it has been proposed that the release of the latter enzyme might be used clinically to reflect changes in overall sympathetic nervous activity.2 Release of norepinephrine is followed by the stimulation of adrenergic receptors, either in the heart or in other sympathetic beds throughout the body. This sequence of events is capable of increasing both contractility and the frequency of contractions of cardiac muscle3 and is also capable of producing many extracardiac manifestations. These are reflected in a reduction of cutaneous blood flo~,~ the presence of venoconstriction,s-7 elevation of renal vascular resistances and augmentation of plasma catecholamines during exercise9 associated with an increase in the urinary excretion of catecho1amines.l
February 1979
The American Journal of CARDIOLOGY
Vdume 41
233
NOREPINEPHRINE IN HEART FAILURE-THOMAS
AND MARKS
The augmentation in plasma norepinephrine concentration in patients with congestive failure during exercise was originally reported by Chidsey et a1.g and was interpreted as an indication of an increased sympathetic outflow, providing an important cardiovascular supportive mechanism in these patients. Associated with this increased noradrenergic activity was an apparently normal adrenal medullary catecholamine release process, reflected in normal plasma and urinary levels of epinephrine. 1,gThis implied that sympathetic beds other than the adrenal medulla were responsible for this augmentation of noradrenergic activity. Many investigatorslo-l3 have reported a depletion of myocardial norepinephrine in congestive failure, both in human subjects and in experimental animal models. The mechanism of this depletion of the cardiac sympathetic neurotransmitter has not yet been elucidated. It remains to be established whether prolonged increases in cardiac sympathetic activity could lead to an exhaustion of the noradrenergic stores of the heart.l It is clear, however, that cardiac sympathetic nerves release norepinephrine and dopamine-beta-hydroxylase from their nerve terminals and that norepinephrine
interacts with cardiac beta receptors, which are the sites for the modulation of intracell biochemical events that utilize cyclic 3’,5’-adenosine monophosphate (CAMP) as the second messenger.14 The search for an appropriate human in vitro model with which to study the beta adrenergic-CAMP relation led Scott15 to demonstrate the stimulation of adenylate cyclase from human lymphocytes by epinephrine in broken cell preparations. Parker et a1.16then studied peripheral blood lymphocytes from patients with bronchial asthma in search of possible alterations in cyclic 3’,5’-CAMP metabolism. Cells from asthmatic patients, at the time that the asthmatic condition was most severe, were found to have a highly significant decrease in their CAMP response to beta adrenergic agents as compared to normal control cells. These same cells, however, had an unaltered response to stimulants that activate adenylate cyclase by mechanisms other than through the beta receptor, thus demonstrating that the defect in catecholamine responsiveness was at the level of the beta adrenergic receptor. The present study was undertaken to reinvestigate the functional activity of the sympathetic nervous sys-
TABLE I Characteristics of 19 Patients Grouped Accordina to Severity of Cardiac Failure on Admission NYHA Class
Case no.
Race
HR
BP
Diagnosis
NE
DBH
Adm
Dis
Adm
Dis
Adm
Dis
0.26 1.2
0.90 0.33
853 382
604 350
Class II 1’ 2’
61M 69F
$ Mean & SEM
:
54M 75F 64.7 4.6
W B
2327106 160/60
HCVD HCVD
II II
II
11 134188 O/60
ASHD
II
III
0.65 0.51 0.66 0.19
0.41 0.56 0.55 0.13
589 415 560 108
467 430 463 53
HCVD HCVD HCVD CCM
Ill Ill Ill Ill
II II II Ill
0.68 1.80 2.30 1.00 1.20
0.24 0.23 0.77 0.54 1.50
236 113” 471 515
2030 59 426 387
CCM ASHD
Ill
II 11
0.82 2.50 1.47 0.28
0.51 0.60 0.63 0.16
331 243 273 70
226 189 213 59
IV
II
1; IV
II Ill III
0.37 0.25 0.24 2.40 1.10 1.90 1.40 1.40 1.12 0.29
409 881 329 457 268
88 5
0.25 1.20 2.00 2.20 1.50 3.70 0.88 2.10 1.73 0.37
16; 209 341 93
626 714 349 569 0 321 403 415 79
83 4
1.41 0.20
0.82 0.15
362 55
350 46
:8 112 76 77 13
Class Ill :* ;* 9 :: Mean f SEM
63F 49F 56F 6OF 71M
100
38M 60M 56.7 4.0
zz 81.7 6.0
6”: 88
180/130 150192 12OJ80 ‘1”3”0:‘9”0” 106180 112182
Class IV 12’ *
:;t 18 19 Moan f SEM
61F 58M 57M 75F 48M 26M 56F 56F 54.6 4.9
Total Mean f SEM
57.5 2.7
;: 15
96 1:: 100 70
is
150/76 190/l 10 100160 160/78 120170 112170 120170 100180
HCVD HCVD ASHD ASHD ASHD %M” CCM
Iv” IV IV
v”
f Ill
* On methyldopa. t Died. Adm = admission; ASHD = atherosclerotic heart disease: B = black: BP = blood pressure (mm Hg) on admission; CCM = congestive cardiomyopathy; Dis = discharge; DBH = dopamine-beta-hydroxylase (nanomole/ml per hour); F = female; HR = heart rate (beats/min) on admission; HCVD = hypertensive cardiovascular disease: NE = norepinephrine (ng/ml); NYHA Class = New York Heart Association functional class; SEM = standard error of the mean; W = white.
234
February 1978
The American Journal of CARDIOLOGY
Volume 41
NOREPINEPHRINEIN HEART FAILURE-THOMAS AND MARKS
tern, and its relation
to compensated and decompensated heart failure. Plasma norepinephrine and dopamine-beta-hydroxylase levels were measured to assess sympathetic neuronal activity. The ability of peripheral blood lymphocytes to generate CAMP in the presence of beta receptor agonists was tested as a reflection of beta adrenergic receptor sensitivity. Systolic time interval measurements were used as a noninvasive technique for estimating changes in cardiac contractility and were correlated with the plasma catecholamine levels. The results of this study suggest that plasma levels of norepinephrine correlate very well with the functional cardiac status of patients with congestive heart failure. In addition, grossly elevated levels of plasma norepinephrine occur with chronic cardiac decompensation,
0
#
8
0 0 0 0
0 0 .
t
and this may be associated with the development of desensitization of cardiac beta adrenergic receptors.
0
0
Study Subjects Nineteen patients were included in this study. Six patients had atherosclerotic heart disease, and five patients were diagnosed as having congestive cardiomyopathy. Eight patients had hypertensive cardiovascular disease, and six of these patients were taking at least 750 mg/day of methyldopa (Table I). This medication was being taken at the time of admission to the study, and was continued throughout the observation period. All patients received a digitalis preparation (digoxin), a diuretic agent (furosemide or hydrochlorothiazide) and a potassium supplement both before entry into the study and during the course of the observation period. The functional cardiac status at the time of admission of each patient, as described by the New York Heart Association Criteria Committe,17 ranged from slightly compromised to severely compromised (Class II-IV). The physiologic cardiac diagnosis of left ventricular failure required one or more of the following criteria: (1) radiologic
evidence of a sudden increase in left ventricular size, (2) a ventricular third sound or summation gallop sound over the left ventricle in the absence of mitral regurgitation, (3) angiocardiographic evidence of a dilated left ventricle and a cardiac output below 2.7 liters/min per m2, or (4) manifestations of pulmonary congestion or pulmonary edema in the presence of a large left ventricle. Patients in the study ranged in age from 26 to 75 years, with a mean age of 50.1. Ten of the patients were women, and nine were men. Control patients were hospital employees without any prior history of hypertension or heart disease. Control patients were matched for age to eliminate the effect of increasing age on the plasma norepinephrine concentration.ls Protocol: Blood was obtained from an antecubital vein while the subjects were supine and at rest for at least 5 minutes; indwelling catheters were not utilized. Blood specimens for norepinephrine and dopamine-beta-hydroxylase measurements and lymphocyte purification, were obtained from patients at the time of admission to the study, and every third morning between 7:00 and 8:00 AM with the patient at rest. Measurements of the blood pressure, heart rate and systolic time intervals were simultaneously obtained with the subject at rest and in the supine position. Systolic time interval measurements were taken as close to the day of admission as possible. Repeat measurements of time intervals were performed randomly throughout the hospital course. In all cases, systolic time interval measurements were always taken on the same morning during which a plasma specimen was obtained for the measurement of norepinephrine and dopamine-
0
.
“cantd
I
II
m
Ip
Functional Cardiac Status FIGURE 1. Functional cardiac status (New York Heart Association class) versus plasma norepinephrine concentrations in control subjects and in patients with congestive heart failure. Open circles represent admission values and closed circles represent discharge values for concentrations of plasma norepinephrine (no. = 13 for each group). Control values are as indicated (no. = 23). The mean f standard error of the mean is indicated by the solid bar for each functional class. = probability value (p)
JAMES A. THOMAS, MD* BERNARD H. MARKS, MD+ Detroit, Michigan
From the Department of Pharmacology, Wayne State University, School of Medicine’; and the Department of Internal Medicine, Harper Hospital, Detroit Medical Center,+ Detroit, Michigan. This work was supported by grants from the Michigan Heart Association, Southfietd, Michigan and Grant 5 ROl HL 1755503 from the National Institutes of Health, Bethe&, Maryfand. Manuscript received April 6, 1977; revised manuscript received July 18, 1977, accepted July 21, 1977. Address for reprlnts: James A. Thomas, MD, Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201.
Resting plasma concentrations of norepinephrine, dapamine-beta-hydroxylase enzyme activity and peripheral blood lymfihocyte beta adrenergic receptor sensitivity to isoproterenol as reflectied in cyclic 3’,5’adenosine monophosphate (CAMP) generation were &died in patients with congestive heart failure due to atherosclerotic heart disease or to congestive cardiomyopathy or hypertensive cardioyascular disease. Systolic time intervals were also measured in nonhypqrtenslve patlents and correlated with the plasma norepinephrine concentration. Control patients were hospital employees without a previous history of heart disease or hypertension, and were matched for a* to eliminate the effect of increasing age on the plasma norepinephrine concentration. The results of this study clearly demonstrate that the plasma norepinephrlne concentration Is directly related to the degree of left ventricular dysfunction in patients wlth congestive heart fallure. When the systolic time intervals were correlated with the plasma norepikphrine levels, a significant prolongation of the preeJectlon period wgs observed with progressively increasing plasma concentrations of norepinephrlne. The reverse was true for the left ventricular ejection tlme, which demonstrated a significant inverse relation with the plasma norepipephrlne concentration. The ratio of the preelection period to the left vgntricular ejection time, which is a reflection of left ventricular functloq significantly increased with increasing levels of plasma norepinephrlne. In addition, plasma lymphocytes from patients with the greatest degree of left ventricular dysfunction failed to generate normal amounts of CAMP alter beta adrenerglc receptor stlmulatlon with isoproterenol. It Is suggested that beta adrenergic receptors are desensitized In these patients and that this desensitization contributes to the observed alteratlcins In myocardial contractility.
The role of the sympathetic nervous system remains poorly understood in both compensated and decompensated congestive heart failure, although an augmentation of sympathetic nervous activity in heart failure has previously been described.r An increase in impulse traffic in sympathetic nerves leads to the release of the endogenous neurotransmitter norepinephrine and its synthetic enzyme dopamine-beta-hydroxylase, and it has been proposed that the release of the latter enzyme might be used clinically to reflect changes in overall sympathetic nervous activity.2 Release of norepinephrine is followed by the stimulation of adrenergic receptors, either in the heart or in other sympathetic beds throughout the body. This sequence of events is capable of increasing both contractility and the frequency of contractions of cardiac muscle3 and is also capable of producing many extracardiac manifestations. These are reflected in a reduction of cutaneous blood flo~,~ the presence of venoconstriction,s-7 elevation of renal vascular resistances and augmentation of plasma catecholamines during exercise9 associated with an increase in the urinary excretion of catecho1amines.l
February 1979
The American Journal of CARDIOLOGY
Vdume 41
233
NOREPINEPHRINE IN HEART FAILURE-THOMAS
AND MARKS
The augmentation in plasma norepinephrine concentration in patients with congestive failure during exercise was originally reported by Chidsey et a1.g and was interpreted as an indication of an increased sympathetic outflow, providing an important cardiovascular supportive mechanism in these patients. Associated with this increased noradrenergic activity was an apparently normal adrenal medullary catecholamine release process, reflected in normal plasma and urinary levels of epinephrine. 1,gThis implied that sympathetic beds other than the adrenal medulla were responsible for this augmentation of noradrenergic activity. Many investigatorslo-l3 have reported a depletion of myocardial norepinephrine in congestive failure, both in human subjects and in experimental animal models. The mechanism of this depletion of the cardiac sympathetic neurotransmitter has not yet been elucidated. It remains to be established whether prolonged increases in cardiac sympathetic activity could lead to an exhaustion of the noradrenergic stores of the heart.l It is clear, however, that cardiac sympathetic nerves release norepinephrine and dopamine-beta-hydroxylase from their nerve terminals and that norepinephrine
interacts with cardiac beta receptors, which are the sites for the modulation of intracell biochemical events that utilize cyclic 3’,5’-adenosine monophosphate (CAMP) as the second messenger.14 The search for an appropriate human in vitro model with which to study the beta adrenergic-CAMP relation led Scott15 to demonstrate the stimulation of adenylate cyclase from human lymphocytes by epinephrine in broken cell preparations. Parker et a1.16then studied peripheral blood lymphocytes from patients with bronchial asthma in search of possible alterations in cyclic 3’,5’-CAMP metabolism. Cells from asthmatic patients, at the time that the asthmatic condition was most severe, were found to have a highly significant decrease in their CAMP response to beta adrenergic agents as compared to normal control cells. These same cells, however, had an unaltered response to stimulants that activate adenylate cyclase by mechanisms other than through the beta receptor, thus demonstrating that the defect in catecholamine responsiveness was at the level of the beta adrenergic receptor. The present study was undertaken to reinvestigate the functional activity of the sympathetic nervous sys-
TABLE I Characteristics of 19 Patients Grouped Accordina to Severity of Cardiac Failure on Admission NYHA Class
Case no.
Race
HR
BP
Diagnosis
NE
DBH
Adm
Dis
Adm
Dis
Adm
Dis
0.26 1.2
0.90 0.33
853 382
604 350
Class II 1’ 2’
61M 69F
$ Mean & SEM
:
54M 75F 64.7 4.6
W B
2327106 160/60
HCVD HCVD
II II
II
11 134188 O/60
ASHD
II
III
0.65 0.51 0.66 0.19
0.41 0.56 0.55 0.13
589 415 560 108
467 430 463 53
HCVD HCVD HCVD CCM
Ill Ill Ill Ill
II II II Ill
0.68 1.80 2.30 1.00 1.20
0.24 0.23 0.77 0.54 1.50
236 113” 471 515
2030 59 426 387
CCM ASHD
Ill
II 11
0.82 2.50 1.47 0.28
0.51 0.60 0.63 0.16
331 243 273 70
226 189 213 59
IV
II
1; IV
II Ill III
0.37 0.25 0.24 2.40 1.10 1.90 1.40 1.40 1.12 0.29
409 881 329 457 268
88 5
0.25 1.20 2.00 2.20 1.50 3.70 0.88 2.10 1.73 0.37
16; 209 341 93
626 714 349 569 0 321 403 415 79
83 4
1.41 0.20
0.82 0.15
362 55
350 46
:8 112 76 77 13
Class Ill :* ;* 9 :: Mean f SEM
63F 49F 56F 6OF 71M
100
38M 60M 56.7 4.0
zz 81.7 6.0
6”: 88
180/130 150192 12OJ80 ‘1”3”0:‘9”0” 106180 112182
Class IV 12’ *
:;t 18 19 Moan f SEM
61F 58M 57M 75F 48M 26M 56F 56F 54.6 4.9
Total Mean f SEM
57.5 2.7
;: 15
96 1:: 100 70
is
150/76 190/l 10 100160 160/78 120170 112170 120170 100180
HCVD HCVD ASHD ASHD ASHD %M” CCM
Iv” IV IV
v”
f Ill
* On methyldopa. t Died. Adm = admission; ASHD = atherosclerotic heart disease: B = black: BP = blood pressure (mm Hg) on admission; CCM = congestive cardiomyopathy; Dis = discharge; DBH = dopamine-beta-hydroxylase (nanomole/ml per hour); F = female; HR = heart rate (beats/min) on admission; HCVD = hypertensive cardiovascular disease: NE = norepinephrine (ng/ml); NYHA Class = New York Heart Association functional class; SEM = standard error of the mean; W = white.
234
February 1978
The American Journal of CARDIOLOGY
Volume 41
NOREPINEPHRINEIN HEART FAILURE-THOMAS AND MARKS
tern, and its relation
to compensated and decompensated heart failure. Plasma norepinephrine and dopamine-beta-hydroxylase levels were measured to assess sympathetic neuronal activity. The ability of peripheral blood lymphocytes to generate CAMP in the presence of beta receptor agonists was tested as a reflection of beta adrenergic receptor sensitivity. Systolic time interval measurements were used as a noninvasive technique for estimating changes in cardiac contractility and were correlated with the plasma catecholamine levels. The results of this study suggest that plasma levels of norepinephrine correlate very well with the functional cardiac status of patients with congestive heart failure. In addition, grossly elevated levels of plasma norepinephrine occur with chronic cardiac decompensation,
0
#
8
0 0 0 0
0 0 .
t
and this may be associated with the development of desensitization of cardiac beta adrenergic receptors.
0
0
Study Subjects Nineteen patients were included in this study. Six patients had atherosclerotic heart disease, and five patients were diagnosed as having congestive cardiomyopathy. Eight patients had hypertensive cardiovascular disease, and six of these patients were taking at least 750 mg/day of methyldopa (Table I). This medication was being taken at the time of admission to the study, and was continued throughout the observation period. All patients received a digitalis preparation (digoxin), a diuretic agent (furosemide or hydrochlorothiazide) and a potassium supplement both before entry into the study and during the course of the observation period. The functional cardiac status at the time of admission of each patient, as described by the New York Heart Association Criteria Committe,17 ranged from slightly compromised to severely compromised (Class II-IV). The physiologic cardiac diagnosis of left ventricular failure required one or more of the following criteria: (1) radiologic
evidence of a sudden increase in left ventricular size, (2) a ventricular third sound or summation gallop sound over the left ventricle in the absence of mitral regurgitation, (3) angiocardiographic evidence of a dilated left ventricle and a cardiac output below 2.7 liters/min per m2, or (4) manifestations of pulmonary congestion or pulmonary edema in the presence of a large left ventricle. Patients in the study ranged in age from 26 to 75 years, with a mean age of 50.1. Ten of the patients were women, and nine were men. Control patients were hospital employees without any prior history of hypertension or heart disease. Control patients were matched for age to eliminate the effect of increasing age on the plasma norepinephrine concentration.ls Protocol: Blood was obtained from an antecubital vein while the subjects were supine and at rest for at least 5 minutes; indwelling catheters were not utilized. Blood specimens for norepinephrine and dopamine-beta-hydroxylase measurements and lymphocyte purification, were obtained from patients at the time of admission to the study, and every third morning between 7:00 and 8:00 AM with the patient at rest. Measurements of the blood pressure, heart rate and systolic time intervals were simultaneously obtained with the subject at rest and in the supine position. Systolic time interval measurements were taken as close to the day of admission as possible. Repeat measurements of time intervals were performed randomly throughout the hospital course. In all cases, systolic time interval measurements were always taken on the same morning during which a plasma specimen was obtained for the measurement of norepinephrine and dopamine-
0
.
“cantd
I
II
m
Ip
Functional Cardiac Status FIGURE 1. Functional cardiac status (New York Heart Association class) versus plasma norepinephrine concentrations in control subjects and in patients with congestive heart failure. Open circles represent admission values and closed circles represent discharge values for concentrations of plasma norepinephrine (no. = 13 for each group). Control values are as indicated (no. = 23). The mean f standard error of the mean is indicated by the solid bar for each functional class. = probability value (p)
