Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy

CONGESTIVE

HEAR7 FAILURE

Dissociation of Sympathetic Responses to Baroreceptor Loading and Unloading in Compensated Congestive Heart Failure Secondary to Ischemic or Nonischemic Dilated Cardiomyopathy Steven R. Goldsmith, MD, and Gregory J. Hasking, MB, BS

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and headdown tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 f 45 to 413 f 60 pg/ml, p
From the Hennepin County Medical Center and the University of Minnesota, Minneapolis, Minnesota. This research was supported by a Grant-in-Aid from the American Heart Association, Dallas, Texas, and by Program Project Grant POlHL32427 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Goldsmith is an Established Investigator of the American Heart Association and CibaGeigy Corporation. Manuscript received August $1991; revised manuscript received and accepted November 12, 199 1. Address for reprints: Steven R. Goldsmith, MD, Hennepin County Medical Center, Cardiology Division, 701 Park Avenue, Minneapolis, Minnesota 55415.

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ncreasedactivity of the sympatheticnervoussystemis a hallmark of symptomatic congestiveheart failure (CHF).’ The mechanismresponsiblefor chronically increased sympathetic nervous system activity in CHF is not yet clear. Much speculation has been devoted to baroreceptor dysfunction as a possiblecontributing factor. Although several studies2J have shown abnormal sympathetic responsesto baroreceptorunloading - and demonstrated improvement with treatment4,5- much lessinformation is available concerning sympathetic responsesto baroreceptor loading, especially in compensated CHF in which increasedsympathetic activity persists. We therefore designedthe current investigation to assessthe responsesof the sympathetic nervous system to both baroreceptor unloading and loading in a group of patients with chronic compensatedCHF. METHODS

Eight patients with chronic CHF and 6 normal control subjects formed the study group: 6 patients were men aged 35 to 77, and the etiology of CHF was nonischemic (5 patients) or ischemic cardiomyopathy (3 patients). All patients had confirmed reductions of left ventricular systolic function (radionuclide ventriculographic ejection fraction <35% or echocardiogramwith moderately severeto severeleft ventricular dysfunction) and were in New York Heart Association functional class II (3 subjects) or III (5 subjects) at the time of study. All patients were taking diuretics, 7 of 8 were taking digitalis and angiotensin-converting enzyme inhibitor therapy. All drugs were withheld on the day of study. Normal subjects (5 men and 1 woman, aged 26 to 67 years) had no evidenceof cardiovascular disease, were not receiving any medication. Appropriate informed consent in accord with institutional guidelines was obtained from all subjects. On the day of study, subjectsreported to an outpatient study area and were positioned on a tilt table. Intravenous cannulas were inserted in each forearm and baseline heart rate and blood pressure were obtained. After thirty minutes of supine rest a 12 &i bolus of 3HNE (DuPont-New England Nuclear) was given followed by a 0.8 &i/min infusion. Blood samplesfor norepinephrine and 3HNE were obtained at 25, 30 and 60 minutes for normal subjects, and 50, 60, and 90 minutes for patients with CHF. Heart rate and mean arterial pressure were recorded at each time point. Subjectswere then tilted 60’ upright for 15 minutes with all variables reassessedat MARCH 1, 1992

TABLE II Summary Results in Patients with Congestive Heart

TABLE I Summary Results in Normal Subjects (n = 6)

Heart rate (beats/min) Mean arterial pressure (mm Hg) Plasma NE (pgiml) NEclearance (litersimin) NE spillover (ng/min)

Infusion

Head-Up Tilt

Head-Down Tilt

65 * 3.7 90 + 4.5

69 2 4.4 94 t 4.0

64 -t 3.0 88 r 3.7

270 e 45 2.0 +- 0.14 540 f 103

413 k 60* 1.8 f 0.12 781 2 124*

256 r 26t 1.8 i 0.08 466 it 400

Failure (n = 8)

Heart rate (beatsimin) Mean arterial pressure (mm Hg) Plasma NE (pgiml) NE clearance (liters/min) NE spillover (ngimin)

*p
Infusion

Head-Up Tilt

Head-Down Tilt

74 -t 5.7 90 t 4.2

78 t- 5.0 93 i: 2.9

75 + 5.8 92 2 3.1

436 + 105 1.7 2 0.18 802 t- 180

600 k 112* 1.5 2 0.14 1,037 -t 370’

456 +- 122t 1.8 + .19 949 f 338

*p CO.05, relativeto Infusion; tp ~0.05, relative to head-uptllt. Summary data for patients with congestive heartfallure. “lnfusion”values taken 90 minutes after the initiation of the 3HNE infusion. NE = norepinephrine.

that time. Finally, subjects were tilted 30’ head-down for 15 minutes at which point final assessmentof all the variables was obtained. Assays: All blood sampleswere obtained into chilled collection tubes, cold-centrifuged, and stored at -70” until assay.Plasma norepinephrine was measuredby radioenzymatic methods using the Cat-a-Kit (Amerschan Corporation, Kalamazoo, Michigan). Tritiated norepinephrine concentrations (dpm/ml) were measured by absorption of plasma catecholamineson to acid-washed alumina, elution with 0.2 N hydrochloric acid and direct scintillation counting of the eluates. Infusion rates were calculated from the activity of tritiated norepinephrine in the infusate and the volume rate of infusion. All samplesfrom an individual subject were assayedin duplicate in the same assay. In this group of subjects, recovery of tritiated norepinephrine added to plasma in the concentration range produced by the experiment was 61 f 7%. Variation between duplicate samplesin the same assay average 3% and in our laboratory, the interassay variation for duplicate sampleswas f 8%. Plasma norepinephrine kinetics: Norepinephrine kinetics were assayedby the method of Esler et a1.6The method uses a steady-state infusion of a radiolabeled form of norepinephrine (3HNE) in tracer quantities. The basic assumptions are that the amount of infused 3HNE has no direct impact on plasma norepinephrine levels, that there is no re-releaseof tracer in the body, and that the clearance (at steady state) of endogenous norepinephrine is equivalent to the clearance of infused 3HNE. If the clearance of endogenousand exogenous norepinephrine are equivalent, then the following relationship is implied. 3HNE infusion rate (dpm/min) Plasma3HNE (dpmiliter) = Norepinephrine spillover to plasma Plasmanorepinephrine concentration (pgiml) Therefore, norepinephrine spillover (ng/min) = plasma [norepinephrine] X clearance 3HNE. The key advantage of the technique is that one may make inferences about norepinephrine releaseand not rely solely on plasma norepinephrine concentration, which is affected independently by both release rates and clearance.This differentiation has been shown to be of importance in previous studies of clinical CHF.7,8 However, spillover is still an indirect reflection of sym-

are those

pathetic nervous system activity because it measures only that norepinephrine which appears in the blood.stream, not direct synaptic cleft norepinephrine concentrations or nerve traffic. Statistics: One-way analysis of variance with repeated measures compared the responses of each variable across time on each day for each subject group. A Mann-Whitney test was also used to compare the changes in each variable from head-up to head-down tilt between the 2 groups. RESULTS

Summary data from the investigation are listed in Tables I and II. There were no differences betweenthe 25-, 30- and 60-minute data in the normal subjects,or betweenthe 50-, 60- and 90-minute data in the patients with CHF. This stability indicates a steady state for the infused 3HNE. In Tables I and II, the immediate values before tilting are included as the “infusion” data. Figures 1, 2 and 3 show the individual data points for plasma norepinephrine, norepinephrine clearance, and norepinephrine spillover. During upright tilt plasma norepinephrine increased in both groups due largely to an increasein spillover, although nonsignificant reductions in clearance were also seen. During head-down tilt plasma norepinephrine declined in normal subjects becauseof a decreasein norepinephrine spillover, whereas clearance remained unchanged. Spillover suppressedto levels below control in the normal subjects. In patients with CHF, plasma norepinephrine also decreasedduring head-down tilt. However, there was no significant decrease in norepinephrine spillover in patients with CHF during head-down tilt, with values remaining elevated comparedwith those during both head-up tilt and at control before tilting. Mann-Whitney analysis indicated that the change in norepinephrine spillover during head-down tilt as a function of the head-up tilt values was different (p = 0.05) between normal subjects a.nd those with CHF. DISCUSSION

Upright tilt “unloads” both cardiopulmonary amd sinoaortic baroreceptors and reliably produces an increasein sympathetic activity in normal subjects.This has been demonstrated using both plasma norepinephrine and norepinephrine kinetics.2,8The current study confirmed these observationsby showing an increasein norepinephrine spillover during upright tilt due primari-

SYMPATHETIC RESPONSES IN CONGESTIVE HEART FAILURE 647

ly to an increase in norepinephrine spillover, although a nonsignificant decrease in clearance also occurred. Head-down tilt “loads” both cardiopulmonary and sinoaortic baroreceptors by means of central blood volume and pressureincreases.Whereas typically no change in heart rate or blood pressureoccurs, there is a hydrostatic effect on the sinoaortic baroreceptor as well. Headdown tilt in normal subjects has been reported to increaseforearm blood fl~w,~ an index of sympathetic release, and to decreaseplasma norepinephrine.10There are no published data that we are aware of on norepinephrine kinetics during head-down tilt. In the current study, the decreasein plasma norepinephrine in normal subjectsduring head-down tilt was due entirely to a reduction in norepinephrine spillover, indicating significant suppressionof sympathetic activity, actually to levels below baseline. In patients with severeCHF studied without medications, the sympathetic nervous system response to baroreceptor unloading during upright tilt, as assessed by plasma norepinephrine or norepinephrine spillover, is blunted.2,3,8Other reports have shown that the plasma norepinephrine responseto upright tilt in compensated CHF patients may be normalized at least in part by drug therapf15 or cardiac transplantation, l l suggesting that permanent baroreflex dysfunction is not present in

these patients. We also noted an increase in both plasma norepinephrine and norepinephrine spillover during upright tilt. This responsewould suggestthat the degree of sympathetic responsivenessto baroreceptorunloading was at least qualitatively normal in these stable, treated patients. In contrast, norepinephrine spillover to plasma failed to decline normally during head-down tilt in our patients with CHF. This observation suggests that although the degreeof clinical compensationachieved by therapy may have improved baroreflex function in responseto unloading stimuli, a defect in baroreflex function in responseto baroreceptorloading maneuverspersisted. These results may implicate failure of baroreflex suppressionof sympathetic activity as a contributor to the persistently increased level of sympathetic nervous system activity known to occur despite good symptomatic relief in CHF. Although there is heterogeneity in the responsesto both baroreceptor unloading and loading in CHF, it may be worth noting that patients with the highest values for norepinephrine spillover, i.e., those with the most activation of the sympathetic nervous system had the least tendency to decreasenorepinephrine spillover during head-down tilt (Figure 3). Thesedata do not prove that abnormal baroreflex function actually causesincreasedsympathetic nervous sys-

Normal

Normal

600

I 2.6 -

500 -

2.2 -

400 NE pg/ml

300

/A\

I

100I

I Infusion

NE Clearance ml/mln

Yi

-’

* , 6 ’

*

*

1.4 :kS

tpc.001 relative to Infusion ttp<.OOi relative to Tilt up I I Tilt Up Tilt Down

.Infusion

CHF

Tilt Up

Tilt bown

CHF

I

‘““I 7

3.5(

NE Clearance

50 -

ttpc.05 I Infusion

relative to Tilt up I I Tilt Down Tilt Up

“.I

Infu’sion

FIGURE 1. Response of plasma narepinephrine (NE) to up._ right and head-down tilt in normalsubjectsandpatienbwtth congestive heart failure (CHF). The “infusion” values are these measured at 60 minutes (normals) or SO minutes (CHF) after the initiation of %tNE. 648

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Tilt’Up

Tilt Down

FIGURE 2. Response of norepinephrine clearance __-- (NE clear_ ante) to upright and head-down titt in normal subjects and patients with congestive heart failure (CHF). The %fusion” values are those measured at 60 minutes (normals) or 90 minutes (CHF) after the initiation of ‘HNE. MARCH

1, 1992

-

cannot say whether the lack of sympathetic suppression in CHF is due to abnormalities in the cardiopulmonary baroreceptors, the sinoaortic baroreceptors, to central integration of afferent stimuli, or to abnormalities in efferent output from the central nervous system. We did not measure hemodynamics in the current study. We therefore do not know whether the afferent stimuli were exactly comparable in relative or absolute terms in the 2 groups. Hydrostatic stresson the sinoaortic baroreceptors should have been the same, and it is likely that there was at least a comparablecardiopulmonary baroreceptorloading stimulus sincepreload reserve is lost in CHF. This was the casein the report of Moe let a1,13where increasesin central pressureswere found ,in patients with CHF at least comparable to their control subjects. Cardiac output, however, did not increase in patients with CHF in the study of Moe, suggestingthat at least some of the failure of sympathetic activity to decline could have been due to a lack of input to the sinoaortic baroreceptor. Further study is obviously neededif the mechanism of the abnormal sympathetic responsesto baroreceptor loading in CHF is to be diefined.

Normal

4A

NE Spillover nglmin

+;.

ttpc.001 relative to Tilt up * pc.05 relative to Infusion I I I Tilt Down Tilt Up infusion

CHF 2500 -

Spillover nglmin NE

Acknowledgment: We thank Liz Miller, RN, for technical assistancein performing thesestudies,Ada !Simon, PhD, for the catecholamineassays,and Tina Otto for preparation of the manuscript.

*

Od

I Infusion

tpc.05 relative to Infusion I I Tilt Down Tilt Up

FIGURE 3. Response of norepinephrine spillover (NE spillover) to upright and head-down tilt in normal subjects and patients witb congestive heart failure (CHF). The %fusion” values are nermab) or 90 minutes (CHF) thosemeasuredat6Ominutes( after the in~itiatiun of WNE.

REFERENCES

tern activity in CHF, but failure of this suppressive mechanism could certainly have a permissive effect on sustainedincreasesin sympathetic nervous systemactivity, even if they were to have been initiated by other factors. We now have studied sympathetic responsesin 3 groups of patients with CHF during head-down tilt. In the first, with control values in the supine position, plasma norepinephrine levels did not decreaseduring headdown tilt.lO In the second(the current report), although plasma norepinephrine levels decreased,norepinephrine spillover did not decline after the additional stimulation of upright tilt. In a third group, reported as yet only in preliminary form, neither norepinephrine nor norepinephrine spillover decreased,again with control values in the supine position.l2 Moe et all3 also found that plasma norepinephrine levels failed to decline in patients with CHF during similar head-down tilt. The results in our 3 groups of patients together with those of Moe, when compared with those in our normal control subjects, strongly suggest that there is a problem with baroreceptor-mediated suppression of sympathetic activity in CHF. In experimental settings, abnormalities of both cardiopulmonary receptor function and sinoaortic baroreceptor function in CHF have been reported.14J5From the available human studies, however, we

1. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1666. 2. Levine TB, Francis GS, Goldsmith SR, Cohn JN. The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure. Circulation 1983;67:1070-1075. 3. Olivari MT, Levine TB, Cohn JN. Abnormal neurohumoral response to nitroprusside infusion in congestive heart failure. JArn CON Cardiol 1983;2:411-417. 4. 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 1982;66:135-142. 5. Timmis AD, Kenny JF, Smyth P, Campbell S, Kerkez SA, Jewitt DE. Restoration of normal reflex responses to orthostatic stress during felodipine therapy in heart failure. Cardiouasc Res 1984;18:613-619, 6. Esler M, Jackman G, Bobik A, Kelleher D, Jennings G, Leonard P, Skews H, Komer P. Determination of norepinephrine apparent spillover rate and clearance in humans. Life Sci 1979;25:1461-1470. 7. Hasking GJ, Esler MD, Jennings GL, Burton D, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nerve activity. Circulation 1986;73:615-621. 8. Davis D, Sinoway L, Robison J, Zelis R. Norepinephrine kinetics during orthostatic stress in congestive heart failure. Circ Res 1987;61(supplI):I-87-I-90. 9. Goldsmith SR, Cowley AW, Francis GS, Cohn JN. Effects of increased central venous and aortic pressure on plasma vasopressin in man. Am J Physiosiol 1984;246:H647-H651. LO. Goldsmith SR. Impaired suppression of plasma norepinephrine during headdown tilt in congestive heart failure. Am Heart J 1991;122:104-107. 11. Olivari MT, Levine TB, Ring WS, Simon A, Cohn JN. Normalization of sympathetic nervous system function after orthotopic cardiac transplantation in man. Circulation 1987;76(suppl V):V-62-V-69. 12. Goldsmith SR, Simon AB. Effect of digitalis on norepinephrine spillover in patierits with congestive heart failure (abstr). Circulation 1990;82(111):111-63 1, 13. Moe GW, Canepa-Anson CW, Armstrong PW, Howard R. Response of ANF to p&Ural change in patients with heart failureversus subjects with normal hemodynamics. J Am Coil Cardiol 199&l&599-600. 14. Zucker IH, Gilmore JP. Aspects of cardiovascular reflexes in pathologic status. Fed Proc 1985;44:24OL-2407. 15. Wang W, Chen Jwo-Sheng, Zucker I. Carotid sinus baroreceptor sensitivity in experimental heart failure. Circulation 1990;81:1959-1966.

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