(Hypertension. 1995;26:719.)
© 1995 American Heart Association, Inc.
Articles |
Suppressing Sympathetic Activation in Congestive Heart Failure
A New Therapeutic Strategy
From the Tzanio Hospital, Piraeus, Greece, and the Hypertension and Atherosclerosis Section of the Department of Medicine, Boston (Mass) University School of Medicine.
Correspondence to Haralambos Gavras, MD, Chief, Hypertension and Atherosclerosis Section, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118.
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Abstract |
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Abstract Neurohormonal activation with increased plasma renin activity and norepinephrine and vasopressin levels is characteristic of congestive heart failure and contributes to further decompensation and poor prognosis. We treated 20 such patients with the centrally acting sympathoinhibitory drug clonidine 0.15 mg BID and obtained hemodynamic measurements by cardiac catheterization and plasma neurohormone levels before and 2 to 3 hours after the first dose; in 7 patients, these measurements were taken again after 1 week of therapy. The initial dose produced significant decreases of 8% in mean arterial pressure, 23% in right atrial pressure, 21% in pulmonary capillary wedge pressure, 19% in mean pulmonary artery pressure, and 12% in heart rate; a 17% increase in stroke volume; and no significant changes in cardiac output and systemic vascular resistance. All changes remained virtually constant after 1 week. Plasma norepinephrine decreased by 28% after the initial dose and 62% after 1 week (P<.01), whereas plasma renin activity remained essentially unchanged. Plasma vasopressin tended to increase, its levels being inversely correlated with those of posttreatment norepinephrine (r=-.48, P<.03). Patients with baseline norepinephrine levels >0.400 ng/mL had significantly poorer baseline hemodynamic parameters and tended to show more improvement with clonidine, although their data remained significantly worse than patients whose baseline norepinephrine was within the normal range. Sympathetic suppression with clonidine in congestive heart failure reduces preload, heart rate, and arterial pressure, all indexes of myocardial energy demand; the lack of significant reduction in systemic vascular resistance and increase in cardiac output might be attributable in part to enhanced release of vasopressin. The data suggest that suppression of activated pressor neurohormones is a rational approach to treatment of congestive heart failure.
Key Words: hormones • norepinephrine • clonidine • heart failure, congestive
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Introduction |
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Neuroendocrine activation is one of the hallmarks of decompensated CHF. Elevated plasma levels of pressor hormones, such as norepinephrine, the renin-angiotensin-aldosterone axis, and vasopressin have been repeatedly documented in various studies.1 2 Teleologically, this activation would be intended to restore circulatory pressure and volume by stimulating myocardial contractility, constricting peripheral arteries, and promoting sodium and fluid retention. Although these changes may be effective in the short term, eventually they lead to increased afterload and preload with myocardial exhaustion and further decompensation. Indeed, high circulating levels of neurohormones are considered to be a marker of poor prognosis,3 4 and elevated norepinephrine levels may be downright cardiotoxic.5 6
Accordingly, therapy of chronic CHF has moved in recent years from
symptomatic treatment with diuretics and inotropes
to interventions targeting specific mechanisms. Suppression of the
renin-angiotensin-aldosterone axis,
first proposed in the late 1970s,7 8 has now become
standard therapy, shown to offer not only symptomatic
relief but also reduced mortality.9 10 Inhibition of
vasopressin has shown benefit experimentally11 12 and
clinically13 14 but is not yet an established therapy,
partly for lack of a convenient oral agent. Sympathetic blockade with
peripheral 
-adrenergic or ß-adrenergic
receptor blockers has had a jagged course: Initial benefits with
prazosin were found to be short-lived,15 16 probably
because of tachyphylaxis. Various ß-blocking agents produced
symptomatic improvement in terms of exercise capacity and
quality of life but gave inconsistent results in terms of
prolonged survival.17 18 Centrally mediated sympathetic
inhibition has rarely been attempted in the past and only in
short-term studies,19 20 21 apparently for fear of a
presumed negative inotropic effect.
In this open-label pilot study, we present the hemodynamic and neurohormonal effects of central sympathetic inhibition with clonidine after a single oral dose and after 1 week’s sustained therapy in patients with New York Heart Association class III or IV CHF.
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Methods |
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Patient Population
The study group included 20 patients (18 men and 2 women), 41 to 72 years old (mean, 62±7 years) with chronic class III or IV CHF according to the criteria set by the New York Heart Association. Underlying causes included coronary artery disease in 13 patients, idiopathic dilated cardiomyopathy in 4, hypertensive cardiomyopathy in 1, and valvular heart disease in 2 (mitral valve regurgitation in 1 and aortic and tricuspid valve regurgitation in the other).
All patients were admitted to the Cardiology Department of Tzanio Hospital with acute pulmonary edema and were treated initially with salt restriction, digoxin, diuretics, and nitrates. When patients had been stable for 4 days, they were informed about the study and enrolled after they had signed an informed consent form.
Throughout the study, patients were maintained on a low-sodium diet (2 g/d), with all previous medications withheld the day before hemodynamic evaluation, so that baseline hemodynamics were measured at 48 hours after the last dose of medication.
Protocol
In the first part of the study, all patients were studied during
cardiac catheterization before and 2 to 3 hours after
the administration of 0.15 mg of clonidine PO. Baseline pressure
measurements were obtained with the patient in the supine position 2
hours after initiation of the catheterization (ie, 2
hours of resting with catheters in place) to ensure
hemodynamic stability. Blood samples for PRA,
catecholamines (norepinephrine and
epinephrine), and AVP were drawn at baseline. Samples of 5 mL
for each hormone were collected in EDTA in chilled tubes on ice. They
were centrifuged immediately, and the plasma was separated and
frozen immediately at -80°C until assay for PRA,22 for
norepinephrine and epinephrine,23 and
for AVP.24 Clonidine was then administered orally, and the
same measurements were performed 2 to 3 hours later after a period of
rest in the catheterization laboratory. Eight of these
patients agreed to participate in the second part of the study as well.
These patients received digitalis, diuretics, and clonidine
0.15 mg BID for 1 week. After 1 week and at 48 hours after the last
dose of digitalis and diuretics and 12 hours after the last
dose of clonidine, seven patients were recatheterized for
hemodynamic studies and hormonal measurements at the
new baseline. One patient refused to undergo another
catheterization at the end of the week-long
treatment. Two other patients underwent the full first part of the
protocol again, but their postclonidine data are not included in the
analysis.
Hemodynamic Measurements
A 7F balloon-tipped flow-directed Swan-Ganz catheter
(Abbott CCS) was inserted via the right femoral vein, positioned in the
pulmonary artery, and connected to a standard TP-400T
(Nihon-Kohden) transducer for direct measurement of left
ventricular systolic and
end-diastolic pressures. The transducer had the
appropriate frequency response for detection of small pressure
differences. Aortic pressure was measured during the few seconds of
withdrawal of the catheter in the ascending aorta. Both pressure
transducers were connected to an eight-level cardiac
catheterization monitor system (RMC-1.100
Nihon-Kohden), and ECG and pressure waveforms (graphics) were displayed
and thereafter recorded at a speed of 50 or 100 mm/s on a Thermal
Array Recorder. PCWP and left ventricular
end-diastolic pressure values were constantly checked
to ascertain accuracy of recordings. MAP and mean MPAP were
automatically calculated from the integrated signals of aortic pressure
and PAP. Left ventricular pressure and its first derivative
(dP/dt) were simultaneously recorded. CO (in liters per
minute) was measured by the thermodilution method with a CO computer
(model 3300, Abbot). Thermodilution curves were obtained after 10 mL of
saline injection in the proximal part of the Swan-Ganz catheter, and
the final values were the averages of five measurements not differing
by more than 5%. In patients with atrial fibrillation, 10
thermodilution curves were obtained for the mean value. After
thermodilution measurement of CO was obtained, the following
parameters were calculated automatically according to
hemodynamic equations.
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where LVSP is left ventricular systolic pressure, LVDP is left ventricular diastolic pressure, and AOSP is aortic systolic pressure.
Ejection fraction was obtained from a standard biplanar
ventriculography performed at the end of the procedure, after injection
of 
40 to 45 mL of contrast agent at the rate of 14 to 16 mL/s and
pressure of 450 psi, and recorded on film at 50 frames per second.
Ejection fraction was calculated by the area-length method.
Statistical Analysis
Results were analyzed by paired t test and by
linear regression analysis and presented as mean±SD.
Differences were considered to be significant if P<.05.
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Results |
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All patients had baseline ejection fraction <40% (average, 28±7%), with two as low as 15%. All but one (who had a MAP of 140 mm Hg) were normotensive. Their hemodynamic and hormonal data before and after the first dose and the new baseline after 1 week of therapy are shown in the accompanying tables and figures. It is apparent in Table 1 that the first dose of clonidine produced a significant fall in blood pressure, HR, RAP, and PCWP and a significant increase in SVI. All these improvements were maintained in the seven patients who were restudied after 1 week on clonidine. However, CI remained unchanged and dP/dt decreased significantly after the first dose and remained depressed at 1 week. These changes are graphically depicted in Figs 1 and 2.
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Table 2 presents the hormonal responses to the first dose of clonidine and 1 week of treatment. As expected, circulating catecholamine levels were significantly suppressed after a single dose and decreased further after 1 week, whereas PRA remained unchanged and AVP had a small tendency to rise. These results are also depicted in Fig 3. There was a significant inverse correlation between the postclonidine levels of plasma norepinephrine and AVP (r=-.48, P<.03). Furthermore, the decreased norepinephrine levels after clonidine correlated significantly with the decreased RAP (r=.51, P<.03) and the epinephrine levels with the PVR (r=.52, P<.03).
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Since the normal range of plasma norepinephrine is 0.150 to 0.350 ng/mL, patients were separated into two groups: those with baseline norepinephrine >0.400 ng/mL (n=9) and those with norepinephrine <0.400 ng/mL (n=11). The former group had significantly higher average norepinephrine levels than the latter (0.57±0.18 versus 0.27±0.06 ng/mL, P<.001) and worse values in several hemodynamic parameters, ie, CI, 2.10±0.3 versus 2.59±0.3 L · min-1 · m-2, P<.006; SVI, 25.2±6 versus 32.7±6 mL/m2, P<.02; and LVSWI, 26.1±10 versus 36.1±10 g · m · m-2, P<.04. Their differences continued to be significant after the first dose of clonidine, though somewhat minimized: norepinephrine, 0.40±0.18 versus 0.22±0.10 ng/mL, P<.01; CI, 2.18±0.4 versus 2.56±0.3 L · min-1 · m-2, P<.03; SVI, 31.0±6 versus 37.0±7 mL/m2, P<.04; and LVSWI, 30.4±13 versus 38.5±11 g · m · m-2, P=NS. These values represent a change in norepinephrine by -30% versus -14%, respectively; in CI by 3.5% versus -0.25%; in SVI by 21% versus 14%; and in LVSWI by 17.5% versus 7.2%. In addition, RAP changed by -30% versus -8%, respectively. Although these percentages did not differ significantly between the two groups, the data suggested a tendency to more pronounced improvement in the sicker patients.
Clinical side effects from acute clonidine administration were nausea and somnolence in one patient each. During the week of clonidine treatment, all patients tended to lose weight, with an average loss of 1.2 kg, evidently as a result of diminished edema. The dose of digitalis remained unchanged, but 5 of 8 subjects required a decrease in the dose of diuretic to half the original dose, and none complained of side effects.
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Discussion |
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Several hemodynamic characteristics of CHF and attendant compensatory reactions are attributable to sympathetic activation. These include increased HR and arrhythmias as well as peripheral venous and arterial constriction with elevated PAP and SVR, leading to diminished forward flow and to backward congestion despite a positive inotropic action. Clonidine, used as an antihypertensive for more than 25 years,25 is a highly lipophilic
2-adrenergic receptor agonist acting
mostly on sympathoinhibitory neurons of the central
nervous system.26 In this study of 20 patients who were
already past the phase of acute pulmonary edema and in stable
CHF, we found that a single oral dose of 0.15 mg clonidine produced,
within 2 to 3 hours, a significant reduction of the still elevated
sympathetic outflow (as inferred by the 28% reduction of circulating
norepinephrine levels), followed by a further reduction to
38% of the original levels after 1 week of treatment. There was also a
concurrent drop in epinephrine levels to one third of the
original values. These changes were accompanied by significant and
sustained improvement in a number of hemodynamic
indexes, such as a decrease in RAP by 23%, in PCWP by 21%, in PVR by
16%, and in HR by 12%, associated with increases in SVI by 17% and
LVSWI by 12%. Arterial blood pressure in these
normotensive patients (with the exception of one hypertensive
individual) decreased by an average of 8%, which, though statistically
significant, posed no clinical problems while contributing to the
reduction of the double product. Since higher plasma
norepinephrine levels are an index of more severe CHF,
patients were also separated into two groups. Eleven had
norepinephrine levels <0.400 ng/mL, and 9 had levels
beyond that cutoff point. The latter group had significantly worse
hemodynamic parameters (CI, SVI, and LVSWI)
at baseline and a tendency toward greater improvement with clonidine,
as shown by the somewhat smaller, though still significant, differences
between the two groups in these parameters during
treatment. These findings indicate that sympathetic suppression was
well tolerated even by the more severely decompensated patients. There was a tendency toward increased plasma AVP levels, which were inversely correlated to the suppressed norepinephrine levels after clonidine. In other words, suppression of norepinephrine in CHF enhanced the release of AVP, as has been repeatedly shown in the past in hypertensive patients with or without CHF,27 28 and AVP may counteract the fall in SVR and partly account for the lack of significant increase in CO. It could be anticipated that concurrent inhibition of AVP might further improve these parameters, as indicated by previous experimental and clinical evidence.11 12 13 14 The decrease in dP/dt was almost commensurate with the decreased left ventricular systolic pressure and therefore should not necessarily be taken as an index of diminished contractility. Interestingly, the increase in SVI occurred in the absence of an increase in CO; it is tempting to speculate that along with the diminished heart rate, there may have been an improvement in diastolic capacity of the left ventricle and that the increase in stroke volume reflected this improvement. Of course, only measurement of left ventricular geometry with simultaneous measurement of left ventricular pressures could directly demonstrate ameliorated left ventricular diastolic function. Nevertheless, an increase in stroke volume as PCWP decreases has been demonstrated in CHF patients in the past29 and attributed, among other mechanisms, to increased left ventricular compliance following a decrease in right atrial and right ventricular filling pressures with an associated decrease in left ventricular pericardial constraint. Our results are consistent with such a mechanism, which could account for the increased stroke volume at a lower PCWP.
Despite the lack of significant overall change in SVR and CO, the patients who continued on clonidine treatment for 1 week had substantial subjective and objective clinical improvement. Actually, half of them required diminished doses of diuretic during that period, a finding consistent with previous experience in animals.30 Repeat hemodynamic measurements at that time (after 12 hours from the last dose of clonidine) indicated mostly persistent amelioration in values in the seven subjects who agreed to repeat testing. It is notable that in two of them, who underwent these measurements again at 2 hours after another oral dose of clonidine, there was additional hemodynamic improvement from the new baseline (data not shown), suggesting that maintenance treatment on at least a twice-daily basis can confer additional benefit.
These findings suggest that chronic suppression of the activated sympathoadrenal system in CHF can alleviate the hemodynamic burden to the myocardium by reducing primarily the preload and the double product (blood pressure times HR) and hence the energy expenditure, a feature particularly helpful in ischemic cardiomyopathy. In a recent study of sympathetic status in severe CHF, the authors found evidence of activation of noradrenergic neurons in the central nervous system, with increased rates of cardiac norepinephrine spillover.31 The degree of sympathetic activation was unrelated to the cause of heart failure but was closely correlated to PAP and PCWP, ie, the parameters that showed the greatest improvement with clonidine in our study. Our present data are in agreement with earlier acute studies with methyldopa and clonidine that demonstrated dramatic improvement in preload parameters and overall left ventricular functional capacity but only modest or absent changes in afterload and CO.19 20 21 This finding, attributed to a presumed negative inotropic effect of clonidine (or, most likely, of sympathetic withdrawal) apparently acted as a deterrent to long-term use of this treatment by previous investigators.19 20 21 However, the data do not suggest significantly diminished contractile capacity of the myocardium. The lack of a significant fall in SVR may also be in part attributable to enhancement of AVP as mentioned above, and hence correctable by AVP inhibitors, which are now becoming available for oral use in humans.32 In contrast to central sympathetic inhibition, peripheral arterial dilation with a variety of drugs over the years,33 34 including angiotensin II antagonists and ACE inhibitors,7 8 was shown to produce a dramatic fall in SVR and increase in CO. Peripheral dilators such as hydralazine achieve this at a cost of increased neurohormonal activation and augmented energy expenditure as a result of reflex tachycardia, which may account for the lesser overall improvement of long-term performance compared with ACE inhibitors.35 ACE inhibition, in addition to immediate hemodynamic amelioration, presents the advantage of direct or indirect reversal of neurohumoral abnormalities and is the only therapy shown to prolong life in CHF.9 10 However, certain patients are unable to tolerate ACE inhibitors because of side effects such as cough, renal functional deterioration, or orthostatic hypotension, and for them, alternatives to the current inotropes and diuretics are needed.
In conclusion, there is ample evidence that rational therapy of CHF should include suppression of activated neurohormones, which account for a number of complications and/or treatment failures by the standard therapeutic approaches. In this pilot study, we demonstrated the effects of sympathetic suppression with clonidine in the short-term and after 1 week of follow-up. The study was limited by the open-label design, small number of patients, and lack of placebo control subjects, and its findings will have to be confirmed by a more rigorous design and a longer observation period. Nevertheless, on the basis of our present findings, we propose that chronic oral treatment with clonidine alone or in combination with a peripheral vasodilator might be considered as an alternative or an adjunct to ACE inhibition. In the not too distant future, a combination of chronic clonidine treatment with an AVP antagonist may be another etiologically sound therapeutic strategy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to thank Dr Carl Apstein for critical review of the manuscript.
Received May 11, 1995; first decision June 6, 1995; accepted August 14, 1995.
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References |
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K. Swedberg, C.-H.a. Bergh, K. Dickstein, J. McNay, M. Steinberg, and Moxonidine Investigators The effects of moxonidine, a novel imidazoline, on plasma norepinephrine in patients with congestive heart failure J. Am. Coll. Cardiol., February 1, 2000; 35(2): 398 - 404. [Abstract] [Full Text] [PDF]
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E. R. Azevedo, G. E. Newton, and J. D. Parker Cardiac and systemic sympathetic activity in response to clonidine in human heart failure J. Am. Coll. Cardiol., January 1, 1999; 33(1): 186 - 191. [Abstract] [Full Text] [PDF]
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C. C. Lang, C. M. Stein, R. A. Nelson, H. B. He, F. J. Belas, I. A. Blair, M. Wood, and A. J. J. Wood Sympathoinhibitory Response to Clonidine Is Blunted in Patients With Heart Failure Hypertension, September 1, 1997; 30(3): 392 - 397. [Abstract] [Full Text]
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A. J. Manolis, C. Olympios, M. Sifaki, S. Handanis, D. Cokkinos, M. Bresnahan, I. Gavras, and H. Gavras Combined Sympathetic Suppression and Angiotensin-Converting Enzyme Inhibition in Congestive Heart Failure Hypertension, January 1, 1997; 29(1): 525 - 530. [Abstract] [Full Text] [PDF]
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K. Swedberg, M. R. Bristow, J. N. Cohn, H. Dargie, M. Straub, C. Wiltse, T. J. Wright, and for the Moxonidine Safety and Efficacy (MOXSE) Inv Effects of Sustained-Release Moxonidine, an Imidazoline Agonist, on Plasma Norepinephrine in Patients With Chronic Heart Failure Circulation, April 16, 2002; 105(15): 1797 - 1803. [Abstract] [Full Text] [PDF]
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