- Email: [email protected]
Baroreceptor-mediated release of vasopressin in patients with chronic congestive heart failure and defective sympathetic responsiveness
COHGEWIVE HEART FAILURE
Baroreceptor-Mediated Release of Vasopressin in Patients with Chronic Congestive Heart Failure and Defective Sympathetic Responsiveness Joachim Manthey, MD, Rainer Dietz, MD, Dieter Opherk, MD, Karl J. Osterziel, MD, Hans Leinberger, MD, and Wolfgang KUbler, MD he autonomic nervous system has a major role in the maintenance of arterial blood pressure. Furthermore, other neurohormonal systemssuch as the renin-angiotensin system and nonosmolarrelease of vasopressinappear to be important backup mechanisms in blood pressure regulation.rJ In patients with congestive heart failure (CHF) these vasopressorsystems may be activated to maintain circulatory homeo stasi~.~~~ When blood pressure is reduced in these patients due to vasodilation, a reflex increase in sympathetic nervous activity is not usually present, indicating an impairment of reflex responsivenessto baroreceptor unloading.5-8Prior investigations comparing reflex responses of neurohormonal vasopressor systems with baroreceptor unloading in CHF yielded conflicting re~ults.~~~-~* Thus, the reflex responsesof neurohormonal systemsin patients with CHF were studied. A high dose of hydralazine was used to unload arterial barorecep tors, and the drug-induced decreasein arterial blood pressure was related to the reflex responsesof plasma norepinephrine, renin activity and vasopressin in patients with severeleft ventricular dysfunction. Hydralazine was selected becauseit acts on arteriolar smooth muscle without directly affecting neurohormonal systems.
T
In patients with congestive heart failure (CHF), overactivity of the sympathetic nervous system may be accompanfed by an impairment of the barorefiex control mechanism. To evaluate the reflex responses of the sympathetk nervous system, the renin-anglotensbt system and vasopreuln release to baroreceptor unloading, 38 patients with kft ventrkubr dysfunction were studied. Hemodynamic data, and plasma noreptnephrine, rentn actMty and vasopres& concentrations were measured before and 60 minutes after administration of high-dose hydralazbte (0.4 mg/kg itiravenously). On the bask of blood pressure response to vasodilator administration, patients were divided arbitrarily into those wfth a decrease in mean arterfal bleed pressure 115 mm Hg (group A; n = 12) and those with a decrease <15 mm Hg (group B; n = 26) compared with control values. In response to hydrafazine, heart rate decreased in group A from 100 to 92 beats/min (p
MerHO
Patkntu This study comprised 38 consecutive patients (36 men and 2 women, age range 26 to 78 years, mean 52) undergoing cardiac catheterization and core nary angiography for evaluation of chest pain or CHF, or both. All patients had class III or IV CHF (New York Heart Association criteria)” due to severely impaired left ventricular function (ejection fraction 0.35). The causesof CHF were idiopathic dilated cardiomyop athy (n = 30) or coronary artery disease(n = 8). Left ventricular ejection fraction was calculated using the area-length method.14Patients with mitral incomp tence exceeding grade l+ of regurgitation (as determined angiographically)15 were excluded. Twelve patients with atypical angina, but with normal coronary angiogramsand left ventricular function and no detectable congenital or valvular heart diseaseserved as conHeidelberg, Abteilung Innere
From Mediihe Univeri&&linik Medizin III (Kardiologie), Heidelberg, Germany. This study was sup ported by the DeutscheForschungsgemeinschaft, SFB 320, Herzfunktion und ihre Regulation, Universitit Heidelberg, Heidelberg, Germany. Manuscript receivedJanuary 12,1992,revisedmanuscript received March 241992, and acceptedMarch 23. Address for reprints: Joachim Manthey, MD, Kreiilrrankenhaus am Plattenwald, Abteilung Imxre Medikin (Kardiologie), W 7107Bad Friedrichshall, Germany. 224
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
tiOlS.
~%~w&wB and W The protocol was approved by the ethical committee of the University of Heidelberg, and all patients gave informed consent. Measurementsbefore and after hydralazine administration were obtained in the postabsorptivestate without premeditations between 2 and 4 P.M. at a special re-
JULY 15, 1992
TABLE
I Hemodynamic Data of Study Patients Before and After Hydralazine Administration
Mean arterial blood pressure (mm Hg) Heart rate (beats/min) Cardiac index (Liminlm2) Stroke volume index (ml/m*) Left ventricular filling pressure (mm Hg) Mean right atrial pressure (mm Hg) Systemic vascular resistance (dynes. s. cmA5)
C H C H C H C H C H C H C H
All Patients (n = 38)
Group A (n = 12)
98 + 12 86 f 11* 93 _t 15 952 14 2.3 -+ 0.6 3.7 2 0.4* 25 k 8 39 2 8* 27 + 8 23 + 8$ 824 7*4 1,911 ‘- 599 984 +- 287*
105 r 15 76 k 10 100 + 13 92 + 12* 2.0 5 0.4 3.3 2 0.4* 21 -t 6 36 zk 8* 30 + 8 19 + 6* 923 6 f 2* 2,220 2 653 970 2 238*
*p
Group B (n = 26) 95 + 90 r 90 t 96 + 2.4 +3.9 2 26 + 40 + 26 + 24 ? 824 8*4 1 ,768 -t 991 3
9* 7* 16 15t 0.6 0.8* 8 8* 7 7
529 311*
p Value (A vs B) NS
NS = not significant.
search laboratory. Patients continued to receivedosesof diuretics and digitalis. Most patients had no maintenance therapy with vasodilators before the study. In 3 patients receiving captopril and in 5 receiving nitrates or dihydralazine, or both, vasodilators were withheld for 23 days. No patient had evidenceof deterioration during vasodilator withdrawal. Right-sided heart catheterization was performed in all patients using a triple-lumen Swan-Ganz catheter through which measurementsof right atrial, and pulmonary arterial and capillary wedge pressureswere ob tained. Cardiac output was determined by the thermodilution method. Arterial pressureswere monitored by the standard cuff method. Derived hemodynamic variables were calculated as follows: mean arterial pressure = % (systolic + 2 X diastolic pressure);cardiac index = cardiac output/body surface area; stroke volume index = cardiac index/heart rate; and systemicvascular resistance= 80 X (mean arterial pressure- mean right atria1 pressure)/cardiac output. Blood specimensfor plasma hormone analysis were obtained from the pulmonary artery. Sampleswere collected in heparinized tubes and immediately placed on ice. Plasma was then separated by centrifugation at 4OCwithin 5 minutes and stored at -8OOC for analysis. Plasma norepinephrine was measured radioenzymatically,16 and plasma renin activity and arginine vasopressin were determined by radioimmunoassays.“J* Plasma osmolality was measured using the freezing point method. Before control hemodynamic data and plasma hormone values were obtained, patients rested in a supine position for 30 minutes. After control measurements were obtained, patients were given 0.4 mg/kg hydralazine intravenously over a period of 15 minutes with constant monitoring of blood pressureand heart rate. Measurements of hemodynamic values and plasma hormones were repeated 45 minutes later. All results are expressed as StdStk8imean f SD. Intergroup differenceswere analyzed using Student’s t or Wilcoxon’s test for unpaired data, or by the chi-square method for categorical data. The signifi-
cance of the responsesto hydralazine administration was assessedwith Student’s t or Wilcoxon’s test for paired observations. When multiple comparisons were obtained in the samegroup of data, the critical value of t was corrected using the Bonferroni method.19Relations between different variables were calculated by means of least-squarelinear regressionanalysis. RESULTS Ciassifieation of patio&
and baseline hemodynrm-
its: Patients were divided arbitrarily on the basis of blood pressure responsesto hydralazine administration into those with a decreasein mean arterial blood pressure 2 15 mm Hg (group A) and those with a decrease <15 mm Hg or no decrease(group B) compared with control values. There was no significant difference between group A and B patients regarding age, sex, underlying heart diseaseor functional class.Left ventricular ejection fraction was lower in group A than in B (0.19 f 0.06 vs 0.24 f 0.07; p <0.05). Hemodynamic data before and after hydralazine administration are listed in Table I. Initial mean arterial blood pressure, heart rate, left ventricular filling pressureand systemic vascular resistancetended to be higher, and cardiac and stroke volume indexes tended to be lower in group A than in B, but the differences were not significant. Hemodyna& =w to hydralazine: By definition, the drug-induced reduction in mean arterial blood pressure was greater in group A than in B (-28 vs -5%). However, a reflex increase in heart rate after hydralazine was observedonly in group B. In contrast, group A patients had a significant decreasein heart rate after hydralazine, despite the marked reduction in systemic blood pressure.However, if group A and B patients are considered together, there is no significant change in heart rate after hydralazine administration. Systemicvascular resistancedecreasedmore in group A than in B (-56 vs -44%; p <0.05). The increasesin cardiac output and stroke volume after hydralazine were similar in both groups. Left ventricular filling and mean right atria1 pressuresdecreasedsignificantly in group A, but not in B. BARORECEF’TOR-MEDIATED RELEASE OF VASOPRESSIN
225
TABLE II Plasma Hormones in Study Patients Before and After Hydralazine Administration All Patients (n = 38) Plasma norepinephrine @g/ml) Plasma renin activity (ng/ml/hr) Plasma vasopressin (pg/ml)
C H C H C H
538 469 9.6 16.1 8.4 20.2
+ ‘+ + r +
Group A (n = 1.2)
348 238 19.4 21.17 6.6 23.3t
822 518 20.0 23.2 8.4 45.2
++ 2 + + k
406 276* 34.2 33.8 7.5 26.3$
Group B (II = 26) 407 447 5.3 13.1 8.4 83.
+ k 2 + k c
226 220 5.0 13.2$ 6.2 6.0
p Value (A vs B)
*p
honnolwn: Values for plasma hormonesbefore and after hydralazine are listed in Table II. Baseline plasma norepinephrine levels in group A were sub stantially higher than in B. Baselineplasma renin activity also tended to be higher in group A than in B. There was a large amount of heterogeneityin the renin values, ranging from very suppressedto markedly elevated levels. No significant difference was found with respectto plasma vasopressinbaselinevalues between the groups. Baselinevalues for all plasma hormonestestedin groups A and B were significantly higher (p X0.05) than those of control patients (norepinephrine 199 f 26 pg/ml, plasma renin activity 1.3 f 0.34 rig/ml/hour, and plasma vasopressin4.7 f 0.4 pg/ml). In group A, the hemodynamic changes induced by hydralazine were accompaniedby a marked decreasein plasma norepinephrine levels (-37%; p
tem and vasopressin release in patients with severe CHF. Ovwactivity of va soeon&Mor msms: Virtually all patients in the present investigation had elevated baseline plasma norepinephrine concentrations compared with thoseof control subjects.Thesefindings conFirm previous observationssuggestingoveractivity of the sympathetic nervoussystemin CHF and a direct correlation betweenplasma norepinephrine and the degreeof hemodynamicdeterioration.20,21 Similarly, plasma renin activity and vasopressinconcentrations were increased in a large proportion of patients studied, but no significant differences were noted between groups A and B regarding these hormones.Therefore, our data are consistent with those of previous studiesdescribing elevated plasma levels of renin and vasopressinwithout corre lation with hemodynamic variables in patients with CHF.21,22 Reflexresponsesofefferedsympab6cacti~
Although the mechanism that causesactivation of the sympathetic nervous systemin CHF is not fully understood, excitatory sympathetic reflexes initiated by peripheral hypoperfusion appear to have a major role.23 Therefore, improved tissue perfusion due to vascdilator therapy can be expectedto reduce sympathetic outflow. However, unloading of arterial baroreceptorsmay result in reflex activation of the sympathetic nervous system. Therefore, the responseof the sympathetic nervous system to hydralazine-induced vasodilation in patients with CHF is the result of the following 2 opposing mechanisms: (1) reduction of excitatory influences of sympathetic outflow due to hemodynamic improvement, and (2) reflex stimulation of efferent sympathetic activity mediated by arterial baroreceptors. This concept is supported by the data of the present study. In group A patients (those with the most severe degreeof CHF), plasma norepinephrine decreasedconsistently, whereas norepinephrine levels tended to increasein the remaining patients. In group A, a marked defect in baroreceptor control mechanismscould be expecte~L~~ It may be postulated that the excitatory influence of unloading of arterial baroreceptorson sympathetic outflow is overridden by the inhibition of efferent DISCUSSION sympathetic activity resulting from hemodynamic imThis study presents the first evidence that arterial provement in group A patients. These findings corrobobaroreceptor unloading may induce a dissociation be- rate numerous investigations suggestingimpaired barotween reflex responsesof the sympathetic nervous sys- receptor control of systemic circulation in CHF.5-7y25
226
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15, 1992
The substantial decreasein mean arterial blood pressure observedin group A may be due to this abnormal neurohormonal response. In contrast, most group B patients had an essentially normal increase in heart rate and a trend toward increased norepinephrine levels in response to hydralazinc. In these patients, the baroreceptor reflex can be assumedto be less impaired than in group A patients. This reflex activation of the sympathetic nervoussystem due to vasodilator therapy in group B patients is consistent with the findings of Packer et al* who observed rebound hemodynamic eventsafter withdrawal of nitroprusside in patients with severeCHF. Plasmavasopmssin
baroreceptors,whereasvasopressinreleasewas not impaired in comparison with that in healthy subjects.Because vasopressincan exert direct vasoconstrictor actions at plasma concentrations observedafter hydrala-
tvspomotovtnridbaroracap-
tar m In healthy humans, a reduction in mean arterial blood pressureof 10 to 15%produceslittle or no increase in plasma vasopressinlevels, whereas a more marked hypotension increasesvasopressinin an expo nential fashion.26A similar relation betweendecreasein mean arterial blood pressureand increasein vasopressin levels is shown in this study. Therefore, the results indicate that the releaseof vasopressinin responseto a significant decreasein blood pressure appears not to be impaired in patients with CHF. Our data confirm and extend some observationsof Uretsky et a127and Borghi et a1.28These investigators reported only a weak correlation between changes in mean arterial pressure and plasma vasopressinafter a drug-induced vasodilation. In a similar study, Francis et al9 could not find any significant changesin vasopressin levels after nitoprusside and captopril administration in patients with CHF. In their study, the drug-induced re duction in mean arterial blood pressure was not > 12 mm Hg. The results of these studies are in agreement with our findings. The drug-induced decreasein blood pressurewas too small to induce major changesin vasopressin releasein these previous studies. The increaseof plasma vasopressinin group A after vasodilation appearsto be largely mediated by afferents originating from arterial baroreceptors.This assumption is supported by the close relation between decreasein mean arterial pressureand increasein vasopressin.Unloading of cardiopulmonary receptors may have an additional role in vasopressin release after hydralazine. However, the correlation between the changes in left ventricular filling pressuresand plasma vasopressinlevels is rather weak. Plasma renin activity in group A patients did not change significantly after hydralazine administration. The increase in plasma vasopressin in these patients is evidently not mediated by the reninangiotensin system. Posdbkroleofvasopredninbbodpresswemgu-
ktionr The autonomic nervous system has a significant role in the regulation of arterial blood pressure.Alterations in blood pressure control are known to occur in patients with CHF.3*5-7During tilting, some patients with CHF have a major reduction in arterial pressure similar to that in idiopathic orthostatic hypotension.25 In group A, the reflex responseof heart rate was blunted, and plasma norepinephrine concentrations did not increase in responseto a marked unloading of arterial
. 0
10
A
A
20
-20
-10
MEAN
ARTERIAL
-30
-50
-40
PRESSURE
-60
[mm&a]
.
10 0-s
l* l . . .
: .
.
‘..T .
-10
..
.
.
l *
.
-
a
B
10
A
0
-20
-10
MEAN
ARTERIAL
-30
-50
-40
bb 1
PRESSURE
‘00 [
/ I
.
z Ei B 3 2
%.,; C
+ 1.1
y = 0.03x2
20 .
.
r’
‘:
-60
.
4o2 .
l
0
. r = 0.85
.
l
p- 0.001
*g
.
. 10
0
dx
MEAN
-10 ARTERIAL
-20 PRESSURE
-30
-40
-50 [mm%
-60 ]
BARORECEPTOR-MEDIATED RELEASE OF VASOPRESSIN 227
zine in group A,2gendogenousvasopressinmay have an important role in maintaining systemic pressurein this subgroup of patients with CHF. This view is supported by M6hring et a130who observedgreatly enhancedpressure responsesto vasopressinin patients with idiopathic orthostatic hypotension. Ipnpliecltianr: The results of this study suggestthat the b&roreceptor-mediatedreleaseof vasopressinis unimpaired in patients with CHF and defective sympathetic nervous reflex control mechanisms. Therefore, baroreceptor unloading may induce a substantial increasein plasma vasopressinwithout a reflex increasein sympathetic activity in these patients. Thus, the vasopressin systemmay have a protective role in the maintenance of arterial blood pressurein severeCHF. AdcnowWgme& We are indebted to Dr. Hartmut Kirchheim for helpful criticism, and to Dr. Eberhard Hackenthal for measuring plasma renin activity.
andsodiumnitroprussideon plasmacatecholaminesand heart rate. ChinPharmaco1 Ther 1983;34:474-480. 11. Elkayam U, Roth A, Hsueh W, W&r L, FreidenbergerL, Rahimtoola SH. Neurohumoral consequences of vasodilator therapy with hydralazine and nifedipine in severecongestiveheart failure. Am Hem? J 1986;111:1130-1138. 12. Kubo SH. Neurohormonal activation and the responseto convertingenzyme inhibitors in congestiveheart failure. Circularion 1990;81(suppl111):107-l14. 13. Criteria Committeeof the New York Heart Association.Nomenclature and Criteria for Diagnosis of the Heart and Great Vessels.Boston: Little, Brown, 1979:290. 14. KasserIS, KennedyJW. Measurementof left ventricular volumesin man by singleplane cineangicxxdiography. Irwest Radio1 1969;4:83-90. IS. Dalen JE, Alpert JS. Valvular Heart Disease. Boston: Little, Brown, 1981:119. 16. De Prada M, Ziiroher G. Simultaneousradioenzymatic determination of plasmaand tissueadrenaline,noradrenaline,and dopaminewithin the femtomole range. Fiji Sci 1976;19:1161-1174. 17. Hackenthal E, Hackenthal R, Hilgenfeldt U. Iso-renin,pseudo-renin,cathep sin D and renin. A comparativeenzymaticstudy to angiotensinforming enzymes. Biochem Biophys Acto 1978;522:574-588.
18. Manthey J, Dietz R, Hackenthal E, Leinberger H, R6hrig N, Schmidt-Gayk H, sCh6migA, Schwarz F, Kiibler W. Linksventrikul8re Fur&ion und Aktivitit vasopressorischer Systemehei Patientenmit chronischerHerzinsuffienz. Z Kardial 198+73x279-288.
19. Sachs L. Angewandte Statist&. Berlin, Heidelberg, New York: SpringerVerlag, 198494. 20. Goldstein DS. Plasmanorepinephrineas an indicator of sympatheticneural activity in clinical cardiology. Am J Cardiol 1981;48:1147-1154. 21. Levine BT, FrancisGS, Goldsmith SR, SimonAB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensinsystem assessedby plasma REFERENCES 1. GavrasH, Hatzinikolaou P, North WG, BresnahanM, Gavras1.Interaction of hormone levels and their relation to hemodynamicabnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1660. the sympatheticnervoussystemwith vasopressinand renin in the maintenanceof blood pressure. Hypertension 1982;4:400-405. 22. Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN. Increased 2. Ebert TJ. Cowley AW, Skelton M. Vasopressinreducescardiac function and plasmaarginine vasopressinin patientswith congestiveheart failure. J Am Co11 augmentscardiopulmonary barorellex resistance.increasesin man. J Clin Imst Gzrdiol 1983;1:1385-1390. 1986;77:1136-1142. 23. Malliani A, PaganiM. The role of the sympatheticnervoussystemin conges3. Abboud FM, S&mid PG. Circulatory adjustmentsto heart failure. In: Fish- tive heart failure. Eur Heart J 1983;4(supplA):49-54. 24. Braunwald E. Pathophysiologyof heart failure. In: Braunwald E, ed. Heart man AP, cd. Heart Failure. New York McGraw-Hill, 1978:249-260. A Textbook of CardiovascularMedicine. Philadelphia,London,Toronto: 4. Cohn JN, Ma&o J, Levine TB, Mehta J. Role of vasxxonstrictormechanisms Dii. in the control of left ventricular performanceof the normal and damagedheart. Saunders,1988:426-448. Am J Cardiol 1979;44:1019-1022. 21. Kubo SH, Cody RJ. Circulatory autoregulation in chronic congestiveheart 5. Levine TB, Francis GS, Goldsmith SR, Cohn NJ. The neurohumoral and failure: responsesto head-uptilt in 41 patients.Am J Cordial 1983;52:512-518. hemodynamicresponseto orthostatic tilt in patientswith congestiveheart failure. 26. RobertsonGL. Osmoticand hemodynamiccontrol of vasopressin:functional and anatomical relationships.In: Takacs L, ed. Advance in Physiological SciCircularion 1983;67:1070-1075. 6. Goldstein RE, Beiier GD, Stampfer M, EpsteinSE. Impairment of autonomi- ences 11: Kidney and Body Fluids. Budapest:Pergamon, 1981:537. cally mediated heart rate control in patients with cardiac dysfunction. Circ Res 27. Uretsky BF, Verbalis JG, Generalovich T, Valdes A, Reddy PS. Plasma 1975;36:571-578. vasopressinresponse.to osmoticand hemodynamicstimuli in heart failure. Am J Physio/ 1985;248:H396-H402. 7. Olivari MT, Levine TB, Cohn JN. Abnormal neurohumoralresponseto nitroprusside infusion in congestive heart failure. J Am Co11 Cardiof 19832: 28. Borghi C, Magelli C, BoschiS, Costa FV, Capelli M, Varani E, Magnani B, Ambrosioni E. Peripheral hemodynamicand humoral effects of oral zofenopril 411-417. 8. Packer M, Mella J, Medina N, Yushak M, Gorlm R. Determinantsof drug calcium (SQ 26,991)in patientswith congestiveheart failure. J Clin Phurmacol responsein severechmnic heart failure. 1. Activation of vasoconstrictorforces 1989;29:1077-1082. 29. Liard JF. Vasopressinin cardiovascularcontrol: role of circulating vaspressin. during vasodilator therapy. Circulolion 1981;64:506-511. Clin Sci 1984;67:473-481. 9. FrancisGS, Olivari MT, GoldsmithSR, Levine TB, Pierpxtt G, Cohn JN. The acute responseof plasmanorepinephrine,renin activity, and arginine vasopressin 30. M6hring J, Gl&nzerK, Maciel JA, Diising R, Kramer HJ, Arbogast R, Kochto short-term nitroprussideand nitroprussidewithdrawal in patientswith conges- Weser J. Greatly enhancedpressorresponseto antidiuretic hormonein patients tive heart failure. Am Heart J 1963;106:1315-1320. with impaired cardiovascularreflexesdue to idiopathic orthostatic hypotension.J 10. Lin MS, McNay JL, ShepherdAMM, K&on TK. Effects of hydralazine Cardiwasc Phormacol 1980;2:367-376.
228
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15, 1992
Baroreceptor-Mediated Release of Vasopressin in Patients with Chronic Congestive Heart Failure and Defective Sympathetic Responsiveness Joachim Manthey, MD, Rainer Dietz, MD, Dieter Opherk, MD, Karl J. Osterziel, MD, Hans Leinberger, MD, and Wolfgang KUbler, MD he autonomic nervous system has a major role in the maintenance of arterial blood pressure. Furthermore, other neurohormonal systemssuch as the renin-angiotensin system and nonosmolarrelease of vasopressinappear to be important backup mechanisms in blood pressure regulation.rJ In patients with congestive heart failure (CHF) these vasopressorsystems may be activated to maintain circulatory homeo stasi~.~~~ When blood pressure is reduced in these patients due to vasodilation, a reflex increase in sympathetic nervous activity is not usually present, indicating an impairment of reflex responsivenessto baroreceptor unloading.5-8Prior investigations comparing reflex responses of neurohormonal vasopressor systems with baroreceptor unloading in CHF yielded conflicting re~ults.~~~-~* Thus, the reflex responsesof neurohormonal systemsin patients with CHF were studied. A high dose of hydralazine was used to unload arterial barorecep tors, and the drug-induced decreasein arterial blood pressure was related to the reflex responsesof plasma norepinephrine, renin activity and vasopressin in patients with severeleft ventricular dysfunction. Hydralazine was selected becauseit acts on arteriolar smooth muscle without directly affecting neurohormonal systems.
T
In patients with congestive heart failure (CHF), overactivity of the sympathetic nervous system may be accompanfed by an impairment of the barorefiex control mechanism. To evaluate the reflex responses of the sympathetk nervous system, the renin-anglotensbt system and vasopreuln release to baroreceptor unloading, 38 patients with kft ventrkubr dysfunction were studied. Hemodynamic data, and plasma noreptnephrine, rentn actMty and vasopres& concentrations were measured before and 60 minutes after administration of high-dose hydralazbte (0.4 mg/kg itiravenously). On the bask of blood pressure response to vasodilator administration, patients were divided arbitrarily into those wfth a decrease in mean arterfal bleed pressure 115 mm Hg (group A; n = 12) and those with a decrease <15 mm Hg (group B; n = 26) compared with control values. In response to hydrafazine, heart rate decreased in group A from 100 to 92 beats/min (p
MerHO
Patkntu This study comprised 38 consecutive patients (36 men and 2 women, age range 26 to 78 years, mean 52) undergoing cardiac catheterization and core nary angiography for evaluation of chest pain or CHF, or both. All patients had class III or IV CHF (New York Heart Association criteria)” due to severely impaired left ventricular function (ejection fraction 0.35). The causesof CHF were idiopathic dilated cardiomyop athy (n = 30) or coronary artery disease(n = 8). Left ventricular ejection fraction was calculated using the area-length method.14Patients with mitral incomp tence exceeding grade l+ of regurgitation (as determined angiographically)15 were excluded. Twelve patients with atypical angina, but with normal coronary angiogramsand left ventricular function and no detectable congenital or valvular heart diseaseserved as conHeidelberg, Abteilung Innere
From Mediihe Univeri&&linik Medizin III (Kardiologie), Heidelberg, Germany. This study was sup ported by the DeutscheForschungsgemeinschaft, SFB 320, Herzfunktion und ihre Regulation, Universitit Heidelberg, Heidelberg, Germany. Manuscript receivedJanuary 12,1992,revisedmanuscript received March 241992, and acceptedMarch 23. Address for reprints: Joachim Manthey, MD, Kreiilrrankenhaus am Plattenwald, Abteilung Imxre Medikin (Kardiologie), W 7107Bad Friedrichshall, Germany. 224
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
tiOlS.
~%~w&wB and W The protocol was approved by the ethical committee of the University of Heidelberg, and all patients gave informed consent. Measurementsbefore and after hydralazine administration were obtained in the postabsorptivestate without premeditations between 2 and 4 P.M. at a special re-
JULY 15, 1992
TABLE
I Hemodynamic Data of Study Patients Before and After Hydralazine Administration
Mean arterial blood pressure (mm Hg) Heart rate (beats/min) Cardiac index (Liminlm2) Stroke volume index (ml/m*) Left ventricular filling pressure (mm Hg) Mean right atrial pressure (mm Hg) Systemic vascular resistance (dynes. s. cmA5)
C H C H C H C H C H C H C H
All Patients (n = 38)
Group A (n = 12)
98 + 12 86 f 11* 93 _t 15 952 14 2.3 -+ 0.6 3.7 2 0.4* 25 k 8 39 2 8* 27 + 8 23 + 8$ 824 7*4 1,911 ‘- 599 984 +- 287*
105 r 15 76 k 10 100 + 13 92 + 12* 2.0 5 0.4 3.3 2 0.4* 21 -t 6 36 zk 8* 30 + 8 19 + 6* 923 6 f 2* 2,220 2 653 970 2 238*
*p
Group B (n = 26) 95 + 90 r 90 t 96 + 2.4 +3.9 2 26 + 40 + 26 + 24 ? 824 8*4 1 ,768 -t 991 3
9* 7* 16 15t 0.6 0.8* 8 8* 7 7
529 311*
p Value (A vs B) NS
NS = not significant.
search laboratory. Patients continued to receivedosesof diuretics and digitalis. Most patients had no maintenance therapy with vasodilators before the study. In 3 patients receiving captopril and in 5 receiving nitrates or dihydralazine, or both, vasodilators were withheld for 23 days. No patient had evidenceof deterioration during vasodilator withdrawal. Right-sided heart catheterization was performed in all patients using a triple-lumen Swan-Ganz catheter through which measurementsof right atrial, and pulmonary arterial and capillary wedge pressureswere ob tained. Cardiac output was determined by the thermodilution method. Arterial pressureswere monitored by the standard cuff method. Derived hemodynamic variables were calculated as follows: mean arterial pressure = % (systolic + 2 X diastolic pressure);cardiac index = cardiac output/body surface area; stroke volume index = cardiac index/heart rate; and systemicvascular resistance= 80 X (mean arterial pressure- mean right atria1 pressure)/cardiac output. Blood specimensfor plasma hormone analysis were obtained from the pulmonary artery. Sampleswere collected in heparinized tubes and immediately placed on ice. Plasma was then separated by centrifugation at 4OCwithin 5 minutes and stored at -8OOC for analysis. Plasma norepinephrine was measured radioenzymatically,16 and plasma renin activity and arginine vasopressin were determined by radioimmunoassays.“J* Plasma osmolality was measured using the freezing point method. Before control hemodynamic data and plasma hormone values were obtained, patients rested in a supine position for 30 minutes. After control measurements were obtained, patients were given 0.4 mg/kg hydralazine intravenously over a period of 15 minutes with constant monitoring of blood pressureand heart rate. Measurements of hemodynamic values and plasma hormones were repeated 45 minutes later. All results are expressed as StdStk8imean f SD. Intergroup differenceswere analyzed using Student’s t or Wilcoxon’s test for unpaired data, or by the chi-square method for categorical data. The signifi-
cance of the responsesto hydralazine administration was assessedwith Student’s t or Wilcoxon’s test for paired observations. When multiple comparisons were obtained in the samegroup of data, the critical value of t was corrected using the Bonferroni method.19Relations between different variables were calculated by means of least-squarelinear regressionanalysis. RESULTS Ciassifieation of patio&
and baseline hemodynrm-
its: Patients were divided arbitrarily on the basis of blood pressure responsesto hydralazine administration into those with a decreasein mean arterial blood pressure 2 15 mm Hg (group A) and those with a decrease <15 mm Hg or no decrease(group B) compared with control values. There was no significant difference between group A and B patients regarding age, sex, underlying heart diseaseor functional class.Left ventricular ejection fraction was lower in group A than in B (0.19 f 0.06 vs 0.24 f 0.07; p <0.05). Hemodynamic data before and after hydralazine administration are listed in Table I. Initial mean arterial blood pressure, heart rate, left ventricular filling pressureand systemic vascular resistancetended to be higher, and cardiac and stroke volume indexes tended to be lower in group A than in B, but the differences were not significant. Hemodyna& =w to hydralazine: By definition, the drug-induced reduction in mean arterial blood pressure was greater in group A than in B (-28 vs -5%). However, a reflex increase in heart rate after hydralazine was observedonly in group B. In contrast, group A patients had a significant decreasein heart rate after hydralazine, despite the marked reduction in systemic blood pressure.However, if group A and B patients are considered together, there is no significant change in heart rate after hydralazine administration. Systemicvascular resistancedecreasedmore in group A than in B (-56 vs -44%; p <0.05). The increasesin cardiac output and stroke volume after hydralazine were similar in both groups. Left ventricular filling and mean right atria1 pressuresdecreasedsignificantly in group A, but not in B. BARORECEF’TOR-MEDIATED RELEASE OF VASOPRESSIN
225
TABLE II Plasma Hormones in Study Patients Before and After Hydralazine Administration All Patients (n = 38) Plasma norepinephrine @g/ml) Plasma renin activity (ng/ml/hr) Plasma vasopressin (pg/ml)
C H C H C H
538 469 9.6 16.1 8.4 20.2
+ ‘+ + r +
Group A (n = 1.2)
348 238 19.4 21.17 6.6 23.3t
822 518 20.0 23.2 8.4 45.2
++ 2 + + k
406 276* 34.2 33.8 7.5 26.3$
Group B (II = 26) 407 447 5.3 13.1 8.4 83.
+ k 2 + k c
226 220 5.0 13.2$ 6.2 6.0
p Value (A vs B)
*p
honnolwn: Values for plasma hormonesbefore and after hydralazine are listed in Table II. Baseline plasma norepinephrine levels in group A were sub stantially higher than in B. Baselineplasma renin activity also tended to be higher in group A than in B. There was a large amount of heterogeneityin the renin values, ranging from very suppressedto markedly elevated levels. No significant difference was found with respectto plasma vasopressinbaselinevalues between the groups. Baselinevalues for all plasma hormonestestedin groups A and B were significantly higher (p X0.05) than those of control patients (norepinephrine 199 f 26 pg/ml, plasma renin activity 1.3 f 0.34 rig/ml/hour, and plasma vasopressin4.7 f 0.4 pg/ml). In group A, the hemodynamic changes induced by hydralazine were accompaniedby a marked decreasein plasma norepinephrine levels (-37%; p
tem and vasopressin release in patients with severe CHF. Ovwactivity of va soeon&Mor msms: Virtually all patients in the present investigation had elevated baseline plasma norepinephrine concentrations compared with thoseof control subjects.Thesefindings conFirm previous observationssuggestingoveractivity of the sympathetic nervoussystemin CHF and a direct correlation betweenplasma norepinephrine and the degreeof hemodynamicdeterioration.20,21 Similarly, plasma renin activity and vasopressinconcentrations were increased in a large proportion of patients studied, but no significant differences were noted between groups A and B regarding these hormones.Therefore, our data are consistent with those of previous studiesdescribing elevated plasma levels of renin and vasopressinwithout corre lation with hemodynamic variables in patients with CHF.21,22 Reflexresponsesofefferedsympab6cacti~
Although the mechanism that causesactivation of the sympathetic nervous systemin CHF is not fully understood, excitatory sympathetic reflexes initiated by peripheral hypoperfusion appear to have a major role.23 Therefore, improved tissue perfusion due to vascdilator therapy can be expectedto reduce sympathetic outflow. However, unloading of arterial baroreceptorsmay result in reflex activation of the sympathetic nervous system. Therefore, the responseof the sympathetic nervous system to hydralazine-induced vasodilation in patients with CHF is the result of the following 2 opposing mechanisms: (1) reduction of excitatory influences of sympathetic outflow due to hemodynamic improvement, and (2) reflex stimulation of efferent sympathetic activity mediated by arterial baroreceptors. This concept is supported by the data of the present study. In group A patients (those with the most severe degreeof CHF), plasma norepinephrine decreasedconsistently, whereas norepinephrine levels tended to increasein the remaining patients. In group A, a marked defect in baroreceptor control mechanismscould be expecte~L~~ It may be postulated that the excitatory influence of unloading of arterial baroreceptorson sympathetic outflow is overridden by the inhibition of efferent DISCUSSION sympathetic activity resulting from hemodynamic imThis study presents the first evidence that arterial provement in group A patients. These findings corrobobaroreceptor unloading may induce a dissociation be- rate numerous investigations suggestingimpaired barotween reflex responsesof the sympathetic nervous sys- receptor control of systemic circulation in CHF.5-7y25
226
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15, 1992
The substantial decreasein mean arterial blood pressure observedin group A may be due to this abnormal neurohormonal response. In contrast, most group B patients had an essentially normal increase in heart rate and a trend toward increased norepinephrine levels in response to hydralazinc. In these patients, the baroreceptor reflex can be assumedto be less impaired than in group A patients. This reflex activation of the sympathetic nervoussystem due to vasodilator therapy in group B patients is consistent with the findings of Packer et al* who observed rebound hemodynamic eventsafter withdrawal of nitroprusside in patients with severeCHF. Plasmavasopmssin
baroreceptors,whereasvasopressinreleasewas not impaired in comparison with that in healthy subjects.Because vasopressincan exert direct vasoconstrictor actions at plasma concentrations observedafter hydrala-
tvspomotovtnridbaroracap-
tar m In healthy humans, a reduction in mean arterial blood pressureof 10 to 15%produceslittle or no increase in plasma vasopressinlevels, whereas a more marked hypotension increasesvasopressinin an expo nential fashion.26A similar relation betweendecreasein mean arterial blood pressureand increasein vasopressin levels is shown in this study. Therefore, the results indicate that the releaseof vasopressinin responseto a significant decreasein blood pressure appears not to be impaired in patients with CHF. Our data confirm and extend some observationsof Uretsky et a127and Borghi et a1.28These investigators reported only a weak correlation between changes in mean arterial pressure and plasma vasopressinafter a drug-induced vasodilation. In a similar study, Francis et al9 could not find any significant changesin vasopressin levels after nitoprusside and captopril administration in patients with CHF. In their study, the drug-induced re duction in mean arterial blood pressure was not > 12 mm Hg. The results of these studies are in agreement with our findings. The drug-induced decreasein blood pressurewas too small to induce major changesin vasopressin releasein these previous studies. The increaseof plasma vasopressinin group A after vasodilation appearsto be largely mediated by afferents originating from arterial baroreceptors.This assumption is supported by the close relation between decreasein mean arterial pressureand increasein vasopressin.Unloading of cardiopulmonary receptors may have an additional role in vasopressin release after hydralazine. However, the correlation between the changes in left ventricular filling pressuresand plasma vasopressinlevels is rather weak. Plasma renin activity in group A patients did not change significantly after hydralazine administration. The increase in plasma vasopressin in these patients is evidently not mediated by the reninangiotensin system. Posdbkroleofvasopredninbbodpresswemgu-
ktionr The autonomic nervous system has a significant role in the regulation of arterial blood pressure.Alterations in blood pressure control are known to occur in patients with CHF.3*5-7During tilting, some patients with CHF have a major reduction in arterial pressure similar to that in idiopathic orthostatic hypotension.25 In group A, the reflex responseof heart rate was blunted, and plasma norepinephrine concentrations did not increase in responseto a marked unloading of arterial
. 0
10
A
A
20
-20
-10
MEAN
ARTERIAL
-30
-50
-40
PRESSURE
-60
[mm&a]
.
10 0-s
l* l . . .
: .
.
‘..T .
-10
..
.
.
l *
.
-
a
B
10
A
0
-20
-10
MEAN
ARTERIAL
-30
-50
-40
bb 1
PRESSURE
‘00 [
/ I
.
z Ei B 3 2
%.,; C
+ 1.1
y = 0.03x2
20 .
.
r’
‘:
-60
.
4o2 .
l
0
. r = 0.85
.
l
p- 0.001
*g
.
. 10
0
dx
MEAN
-10 ARTERIAL
-20 PRESSURE
-30
-40
-50 [mm%
-60 ]
BARORECEPTOR-MEDIATED RELEASE OF VASOPRESSIN 227
zine in group A,2gendogenousvasopressinmay have an important role in maintaining systemic pressurein this subgroup of patients with CHF. This view is supported by M6hring et a130who observedgreatly enhancedpressure responsesto vasopressinin patients with idiopathic orthostatic hypotension. Ipnpliecltianr: The results of this study suggestthat the b&roreceptor-mediatedreleaseof vasopressinis unimpaired in patients with CHF and defective sympathetic nervous reflex control mechanisms. Therefore, baroreceptor unloading may induce a substantial increasein plasma vasopressinwithout a reflex increasein sympathetic activity in these patients. Thus, the vasopressin systemmay have a protective role in the maintenance of arterial blood pressurein severeCHF. AdcnowWgme& We are indebted to Dr. Hartmut Kirchheim for helpful criticism, and to Dr. Eberhard Hackenthal for measuring plasma renin activity.
andsodiumnitroprussideon plasmacatecholaminesand heart rate. ChinPharmaco1 Ther 1983;34:474-480. 11. Elkayam U, Roth A, Hsueh W, W&r L, FreidenbergerL, Rahimtoola SH. Neurohumoral consequences of vasodilator therapy with hydralazine and nifedipine in severecongestiveheart failure. Am Hem? J 1986;111:1130-1138. 12. Kubo SH. Neurohormonal activation and the responseto convertingenzyme inhibitors in congestiveheart failure. Circularion 1990;81(suppl111):107-l14. 13. Criteria Committeeof the New York Heart Association.Nomenclature and Criteria for Diagnosis of the Heart and Great Vessels.Boston: Little, Brown, 1979:290. 14. KasserIS, KennedyJW. Measurementof left ventricular volumesin man by singleplane cineangicxxdiography. Irwest Radio1 1969;4:83-90. IS. Dalen JE, Alpert JS. Valvular Heart Disease. Boston: Little, Brown, 1981:119. 16. De Prada M, Ziiroher G. Simultaneousradioenzymatic determination of plasmaand tissueadrenaline,noradrenaline,and dopaminewithin the femtomole range. Fiji Sci 1976;19:1161-1174. 17. Hackenthal E, Hackenthal R, Hilgenfeldt U. Iso-renin,pseudo-renin,cathep sin D and renin. A comparativeenzymaticstudy to angiotensinforming enzymes. Biochem Biophys Acto 1978;522:574-588.
18. Manthey J, Dietz R, Hackenthal E, Leinberger H, R6hrig N, Schmidt-Gayk H, sCh6migA, Schwarz F, Kiibler W. Linksventrikul8re Fur&ion und Aktivitit vasopressorischer Systemehei Patientenmit chronischerHerzinsuffienz. Z Kardial 198+73x279-288.
19. Sachs L. Angewandte Statist&. Berlin, Heidelberg, New York: SpringerVerlag, 198494. 20. Goldstein DS. Plasmanorepinephrineas an indicator of sympatheticneural activity in clinical cardiology. Am J Cardiol 1981;48:1147-1154. 21. Levine BT, FrancisGS, Goldsmith SR, SimonAB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensinsystem assessedby plasma REFERENCES 1. GavrasH, Hatzinikolaou P, North WG, BresnahanM, Gavras1.Interaction of hormone levels and their relation to hemodynamicabnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1660. the sympatheticnervoussystemwith vasopressinand renin in the maintenanceof blood pressure. Hypertension 1982;4:400-405. 22. Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN. Increased 2. Ebert TJ. Cowley AW, Skelton M. Vasopressinreducescardiac function and plasmaarginine vasopressinin patientswith congestiveheart failure. J Am Co11 augmentscardiopulmonary barorellex resistance.increasesin man. J Clin Imst Gzrdiol 1983;1:1385-1390. 1986;77:1136-1142. 23. Malliani A, PaganiM. The role of the sympatheticnervoussystemin conges3. Abboud FM, S&mid PG. Circulatory adjustmentsto heart failure. In: Fish- tive heart failure. Eur Heart J 1983;4(supplA):49-54. 24. Braunwald E. Pathophysiologyof heart failure. In: Braunwald E, ed. Heart man AP, cd. Heart Failure. New York McGraw-Hill, 1978:249-260. A Textbook of CardiovascularMedicine. Philadelphia,London,Toronto: 4. Cohn JN, Ma&o J, Levine TB, Mehta J. Role of vasxxonstrictormechanisms Dii. in the control of left ventricular performanceof the normal and damagedheart. Saunders,1988:426-448. Am J Cardiol 1979;44:1019-1022. 21. Kubo SH, Cody RJ. Circulatory autoregulation in chronic congestiveheart 5. Levine TB, Francis GS, Goldsmith SR, Cohn NJ. The neurohumoral and failure: responsesto head-uptilt in 41 patients.Am J Cordial 1983;52:512-518. hemodynamicresponseto orthostatic tilt in patientswith congestiveheart failure. 26. RobertsonGL. Osmoticand hemodynamiccontrol of vasopressin:functional and anatomical relationships.In: Takacs L, ed. Advance in Physiological SciCircularion 1983;67:1070-1075. 6. Goldstein RE, Beiier GD, Stampfer M, EpsteinSE. Impairment of autonomi- ences 11: Kidney and Body Fluids. Budapest:Pergamon, 1981:537. cally mediated heart rate control in patients with cardiac dysfunction. Circ Res 27. Uretsky BF, Verbalis JG, Generalovich T, Valdes A, Reddy PS. Plasma 1975;36:571-578. vasopressinresponse.to osmoticand hemodynamicstimuli in heart failure. Am J Physio/ 1985;248:H396-H402. 7. Olivari MT, Levine TB, Cohn JN. Abnormal neurohumoralresponseto nitroprusside infusion in congestive heart failure. J Am Co11 Cardiof 19832: 28. Borghi C, Magelli C, BoschiS, Costa FV, Capelli M, Varani E, Magnani B, Ambrosioni E. Peripheral hemodynamicand humoral effects of oral zofenopril 411-417. 8. Packer M, Mella J, Medina N, Yushak M, Gorlm R. Determinantsof drug calcium (SQ 26,991)in patientswith congestiveheart failure. J Clin Phurmacol responsein severechmnic heart failure. 1. Activation of vasoconstrictorforces 1989;29:1077-1082. 29. Liard JF. Vasopressinin cardiovascularcontrol: role of circulating vaspressin. during vasodilator therapy. Circulolion 1981;64:506-511. Clin Sci 1984;67:473-481. 9. FrancisGS, Olivari MT, GoldsmithSR, Levine TB, Pierpxtt G, Cohn JN. The acute responseof plasmanorepinephrine,renin activity, and arginine vasopressin 30. M6hring J, Gl&nzerK, Maciel JA, Diising R, Kramer HJ, Arbogast R, Kochto short-term nitroprussideand nitroprussidewithdrawal in patientswith conges- Weser J. Greatly enhancedpressorresponseto antidiuretic hormonein patients tive heart failure. Am Heart J 1963;106:1315-1320. with impaired cardiovascularreflexesdue to idiopathic orthostatic hypotension.J 10. Lin MS, McNay JL, ShepherdAMM, K&on TK. Effects of hydralazine Cardiwasc Phormacol 1980;2:367-376.
228
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15, 1992