Heart Rate Variability in Patients With Mild to Moderate Heart Failure: Effects of Neurohormonal Modulation by Digoxin and Ibopamine

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1 JACC Vol. 26, No October 1995: Heart Rate Varablty n Patents Wth Mld to Moderate Heart Falure: Effects of Neurohormonal Modulaton by Dgoxn and bopamne JAN BROUWER, MD, DRK J. VAN VELDHUSEN, MD, FACC, ARE J. MAN N 'T VELD, MD,* PETER H. J. M. DUNSELMAN, MD,t FRANS BOOMSMA, PHD,* JAAP HAAKSMA, BSc, K.. LE, MD, FOR THE DUTCH BOPAMNE MULTCENTER TRAL (DMT) STUDY GROUP Gronngen, Rotterdam and Breda, The Netherlands Objectves. Ths study assessed the effects of dgoxn and bopamne on varables of heart rate varablty n relaton to neurohormonal actvaton. Background. Analyss of heart rate varablty can be used to study the autonomc dysfuncton that characterzes chronc heart falure. n the Dutch bopamne Multcenter Tral, patents wth heart falure were found to have ncreased neurohormonal actvaton wth placebo therapy but not wth dgoxn and bopamne therapy. Methods. We studed 59 patents wth mld to moderate heart falure (mean [-+SEM] age 60-1 years, mean ejecton fracton 0.30 _+ 0.01). Patents were randomzed to double-blnd treatment wth dgoxn (0.25 mg [n = 22]), bopamne (100 mg three tmes a day [n = 19]) or placebo (n = 18); background therapy conssted of furosemde (up to 80 rag). Results. After 3 months, plasma norepnephrne levels had ncreased wth placebo, whereas they decreased wth dgoxn (+ 31 vs. -60 pg/ml, respectvely, p < 0.01). Wth bopamne, a nonsg- nfcant decrease was observed (-27 pg/ml, p = 0.10). All varables of heart rate varablty showed a deteroraton n the placebo group. Wth dgoxn, the percent dfferences between successve RR ntervals > 50 ms (pnn50) ncreased ( %, p < 0.01), along wth absolute and normalzed hgh frequency power (+40 _+ 33 ms 2, p < 0.05 and %, p < 0.01, respectvely). These changes were observed durng daytme hours only and were most pronounced n patents wth the most mpared baselne heart rate varablty. Wth bopamne, nonsgnfcant trends smlar to the changes wth dgoxn were observed. Conclusons. n patents wth early stages of heart falure, dgoxn may prevent a progressve deteroraton n heart rate varablty, whereas bopamne does not show statstcally sgnfcant effects. The changes n heart rate varablty wth dgoxn parallel an observed decrease n neurohormonal actvaton. Dgoxn apparently enhances cardac vagal tone n the settng of neuroendocrne actvaton. (J Am CoU Cardol 1995;26:983-90) t has been recognzed that neurohormonal actvaton s one of the hallmarks of chronc heart falure and that the degree of neurohormonal actvaton s strongly correlated wth the severty and prognoss of the syndrome (1,2). Furthermore, chronc heart falure s assocated wth autonomc dysfuncton that s characterzed by ncreased sympathetc and decreased parasympathetc actvty (3). Analyss of heart rate varablty can be used to study autonomc functon nonnvasvely (4-6), From the Department of Cardology,, Thoraxcenter, Unversty Hosptal. Gronngen; *Cardovascular Research nsttute COEUR, Department of nternal Medcne, Unversty Hosptal Djkzgt, Rotterdam: and gnatus Zekenhus, Breda, The Netherlands. Ths study was presented n part at the 66th Annual Scentfc Sessons of the Amercan Heart Assocaton, Atlanta, Georga, November t was fnancally supported by a grant from Zambon Nederland B.V., a Dvson of the Zarnbon Group, Bresso, Mlan, taly. A lst of the members of the DMT Study Group and ther afflatons appears n reference 18. Manuscrpt receved September 21, 1994; revsed manuscrpt receved May 16, 1995, accepted May 24, Address for correspondence: Dr. Drk J. van Veldhusen. Department of Cardology, Thoraxeenter, Unversty Hosptal Gronngen, Oostersnge159, 9713 EZ Gronngen, The Netherlands. and several studes have shown abnormaltes of heart rate varablty n patents wth heart falure (7-12). The mparment of heart rate varablty appears to be related to the degree of neurohormonal actvaton (7,10), whch may have prognostc value (13). Ths concept therefore suggests that analyss of heart rate varablty could be used to assess the severty of heart falure. At present, data on the effect of drug therapy on varables of heart rate varablty n patents wth heart falure are lmted (14-17). Moreover, although t has been suggested that neurohormonal modulaton by drug treatment may favorably affect heart rate varablty n patents wth heart falure, no placebo-controlled studes have compared the effects of pharmacologc treatment on both heart rate varablty and neurohormonal actvaton. n a recently reported double-blnd, placebo-controlled tral (18), we assessed the effcacy and safety of treatment wth dgoxn and the oral dopamne agonst bopamne n patents wth mld to moderate heart falure. The data showed that durng long-term follow-up, both dgoxn and bopamne prevented an ncrease n neurohormonal actvaton but placebo dd not. The purpose of the present study was to assess by lhc Amercan College ol ('aldolog} /95/$ (95)00285-C

2 984 BROUWER ET AL. JACC Vol. 26, No. 4 EFFECTS OF DGOXN AND BOPAMNE N HEART FALURE October 1995: effects of both drugs on varables of heart rate varablty and to nvestgate the relaton of these effects to changes n neurohormonal actvaton. Methods Study desgn. The Dutch bopamne Multcenter Tral (DMT) was a multcenter, double-blnd, randomzed, parallel-group comparson of bopamne (100 mg three tmes daly), dgoxn (0.25 mg once daly) and placebo n patents wth mld to moderate heart falure. After a placebo run-n perod of 7 to 10 days, patents receved double-blnd treatment. A double-dummy technque was used to ensure the blndng procedure. At the end of the placebo run-n perod, and after 3 months of treatment, 24-h ambulatory Holter montorng for analyss of heart rate varablty and blood samples for determnaton of neurohormonal actvaton were obtaned. The protocol was approved by the ethcs commttee of each partcpatng center and was conducted n accordance wth the revsed Declaraton of Helsnk. Before entry nto the study, all patents gave wrtten nformed consent. Study group. Patents 18 to 75 years old wth New York Heart Assocaton functonal class or heart falure and clncally stable for at least 2 weeks before the study were selected for ncluson n the tral. Chronc heart falure was characterzed by clncal sgns and symptoms and a radonuclde left ventrcular ejecton fracton -<0.45 (obtaned wthn the prevous 2 months). n addton, patents had to be able to exercse for at least 4 mn at 70 W on a bcycle ergometer. Durng the tral, furosemde (up to 80 mg/day) was allowed as background therapy, as well as short-actng ntrates. Tramterene was also permtted to control serum potassum levels. Other drugs for treatment of heart falure, ncludng vasodlators and angotensn-convertng en~me nhbtors, alpha- or beta-adrenergc blockng agents and calcum antagonsts were not allowed. Patents were excluded from partcpaton f they had heart falure due to hemodynamcally sgnfcant valvular or congental heart dsease, actve myocardts, thyrod dsease or hypertrophc obstructve cardomyopathy. Further excluson crtera were exercse-lmtng angna pectors; myocardal nfarcton or major operaton wthn the prevous 2 months; severe hypertenson; atral fbrllaton or flutter; pacemaker therapy; a hstory of sustaned ventrcular tachyarrhythmas, chronc obstructve lung dsease, severe hepatc or renal dsease, nsuln-dependent dabetes melltus, psychatrc llnesses and use of monoamne oxdase nhbtors or (ant-)dopamnergc agents. Neurohormonal levels. Venous blood for determnaton of plasma neurohormonal levels was drawn after 30 mn of supne rest. Plasma norepnephrne, aldosterone and renn concentratons were analyzed n a central core laboratory. Plasma norepnephrne (19) and plasma renn (20) were measured as descrbed prevously; aldosterone was measured by a commercally avalable radommunoassay kt (Aldokt, Labservce Benelux, Apeldoorn, The Netherlands). Table 1. Defntons of Varables of Heart Rate Varablty Varable Tme doman Mean NN (ms) SDNN (ms) cv(~) rmssd (ms) pnn50 (~) Frequency doman TP(abs) (ms 2) LF(abs) (ms:) HF(abs) (ms 2) LF(nu) (9~) HF(nu) (%) LF/HF rato Defnton Mean value of all normal RR ntervals durng 24 h Standard devaton of all normal RR ntervals durng 24 h Coelfcent of varance, calculated as (SDNN/mean NN) x 100% Root mean square of successve dfference; square root of mean value of squared dfferences between successve normal RR ntervals Percent dfferences between successve normal RR ntervals >50 ms Total power (absolute unts); energy n power spectrum between and z Low frequency power (absolute unts); energy n power spectrum between 0.04 and 0.15 Hz Hgh frequency power (absolute unts); energy n power spectrum between 0.15 and 0.40 Hz Low frequency power (normalzed unts); calculated as {LF(abs)/[TP(abs) - Power <0.03 Hz]} x 100% Hgh frequency power (normalzed unts); calculated as {HF(abs)/[TP(abs) - Power <0.03 l-z]} x 100% Rato of low to hgh frequency power Analyss of heart rate varablty. The 24-h ambulatory Holter recordngs were analyzed on a Marquette 8000 Holter system (Marquette Electroncs) by an experenced analyst (J.H.) and supervsed by a sngle physcan (J.B.). The analyses were performed wthout knowledge of the admnstered study medcaton. Recordngs wth >15% nose or ectopc beats were excluded from heart rate varablty analyss. For calculaton of varables of heart rate varablty, a data base of RR ntervals was transferred to a personal computer. Tme and frequency doman varables were calculated from the tme seres of RR ntervals (Table 1) and were computed over consecutve 5-mn segments. Segments wth >15% nose or ectopc beats were excluded from analyss. Before calculaton of the frequency doman varables n the other segments, epsodes wth nose and ectopc beats were substtuted by holdng the prevous normal RR nterval constant throughout the entre perod. Spectral analyss was performed usng the dscrete Fourer transform algorthm (21-23). Durng spectral analyss, the recordngs were controlled for dfferences n actual heart rate. Low and hgh frequency components of the power spectrum were calculated n absolute unts. Low and hgh frequency power were also expressed n normalzed unts analogous to calculatons used n autoregressve models. Furthermore, the rato of low to hgh frequency power whch s consdered a measure of sympathovagal balance, was calculated (6,23). Statstcal analyss. Statstcal analyss was performed usng SPSS-PC Verson Results are presented as mean value _+ SEM. Dfferences between treatment groups were analyzed by comparng the change from baselne wth use of

3 JACC Vol. 26, No. 4 BROUWER ET AL. 985 October 1995: t:ffe('ts OF DGOXN AND [BOPAMNE N HEART FALURE Table 2. Baselne Characterstcs of the Three Treatment Groups Placebo Dgoxn lbopamne (n :: 18) (n = 22) (n = 19) Age (yr) _ Gender (%) Male Female Left ventrcular ejecton fracton (! _ _ New York Heart Assocaton functonal class (%) ll Cause of heart fdlure ( :;) lschcmc dopathc Hemodynamc data Systolc blood pressure (ram Hg) 134 ~ % _+ 3 Dastolc blood pressure (mm Hg) 83 ~ Heart rate (beats/ran) _+ 2 Furosemde use (ms/day) Plasma neurohormonc levels* Norepnephrne (p~,ml) 391 ( ) 463 (75-999) 422 (119-1,321) Aldosterone (p~/ml) 911 (17-436) 104 (7-416) 97 (14-498) Renn (ngjml per h 22 (3-112) 28 (4-82) 23 (448) Hearl rate varablty Tme doman varables NN (ms) 762 _ SDNN (ms) CV (~b) rmssd (ms) pnn50 (C}) _ 0.9 Frequency, doman varablcs TP(abs) (ms el 2,14( , , LF(abs) (ms =) HF(abs) (ms-') 148 +_ 4( LF(nu) (%) ~ _ 2.( HF(nu) (~:,~) ltl.t + 1, _ _ 1.6 LF/HF rato 4.5 +: _+ 0.6 *Medan (range). Data presented are mean value _+ SEM, unless otherwse ndcated. Abbrevatons as n Table 1. analyss of varance and the Student t test. The Scheffd procedure was used n the analyss of varance to correct for multple comparsons. For nonnormally dstrbuted varables, the Kruskal-Walls and Wlcoxon sgned rank tests were used. All p values are reported for two-taled tests, and an alpha <0.05 was consdered statstcally sgnfcant. Mean values of varables of heart rate varablty were calculated for the entre 24-h perod. To assess the dfferental effects of drug treatment durng both daytme and nghttme, perods from mdnght to 8 AM (nghttme) and from 8 AM to noon (daytme) were analyzed separately. Lnear regresson analyss was used to test the relaton between values of varables of heart rate varablty at baselne and after treatment. Results Study patents. Of the orgnal DMT study patents (18), Holter recordngs for analyss of heart rate varablty were avalable n 71 at baselne and after 3-month follow-up. Holter recordngs could not be analyzed for heart rate varablty n 12 patents because ectopc beats or nose accounted for >15% of the sgnal at baselne (7 patents [placebo n 2, dgoxn n 2, bopamne n 3] or durng follow-up (5 patents [placebo n 3, bopamne n 2]). Therefore, the remanng 59 patents consttuted the study group and underwent heart rate varablty analyss both at baselne and after 3 months. There were no sgnfcant dfferences at baselne among the three treatment groups, wth respect to clncal characterstcs and varables of heart rate varablty (Table 2). Three patents had nonnsuln-dependent dabetes melltus (placebo n 1, dgoxn n 1, bopamne n 1). Heart falure was present for a medan of 7.5 months. Comparson of the baselne characterstcs of ths subgroup wth those of the orgnal DMT study cohort revealed no sgnfcant dfferences. Neurohormonal levels. After 3 months of treatment, plasma norepnephrne levels had ncreased n the placebo group (+31 pg/ml), whereas they had decreased n both the dgoxn ( 60 pg/ml, p < 0.01 vs. placebo) and bopamne

4 986 BROUWER ET AL. JACC Vol. 26, No. 4 EFFECTS OF DGOXN AND BOPAMNE N HEART FALURE October 1995: Norepnephrne Aldosterone Renn ; E o 20 4O / % Change after 3 months Fgure 1. Change n plasma neurohormone levels after 3 months of treatment, expressed as percent of baselne values. Sold bars = placebo; crosshatched bars = dgoxn; hatched bars = bopamne. **p < 0.01 versus placebo. Mean NN SDNN [ cv! rmssd[ pnn50 TP (abs) ~//////////////~ : % Change after 3 months! groups (-27 pg/ml, p = 0.10 vs. placebo). After dgoxn and bopamne therapy, a trend was observed for changes n aldosterone and renn opposte to those n the placebo group; however, these changes dd not reach statstcal sgnfcance (Fg. 1). Varables of heart rate varablty. After 3 months of treatment, all tme doman varables were decreased n the placebo group compared wth baselne values (Table 3, Fg. 2). n contrast, an overall ncrease was observed n the dgoxn group. Compared wth the placebo group, the mean value of normal RR ntervals ncreased sgnfcantly, as dd the standard devaton of normal RR ntervals (SDNN). The standard devaton adjusted for the change n mean value of normal RR ntervals (.e., coetfcent of varance) showed no sgnfcant change. The root mean square successve dfferences (rmssd) and percent dfference between successve normal RR ntervals >50 ms (pnn50) were sgnfcantly enhanced by dgoxn. n LF (abs) HF (abs) LF (nu) HF (nu) LF/HF rato: * J % Change after 3 months Fgure 2. Change n tme doman (top) and frequency doman varables (bottom) of heart rate varablty after 3 months of treatment, expressed as percent of baselne values, abs = absolute unts; CV = coelfcent of varance; HF = hgh frequency power; LF = low frequency power; NN = normal RR ntervals; nu = normalzed unts; pnn50 = percent dfference between successve normal RR ntervals >50 ms; rmssd = root mean square of successve dfference; SDNN - standard devaton of normal RR ntervals; TP = total power. Symbols as n Fgure 1. *p < 0.05, **p < 0.01 versus placebo. Table 3. Changes n Varables of Heart Rate Varablty After 3 Months of Treatment Placebo Dgoxn bopamne Varable (n = 18) (n = 22) (n = 19) Tme doman Mean NN (ms) * ' SDNN (ms) 10 _ _ CV (%) (.7 + (1.8 +(.4 _+ 1.1 rmssd (ms) 1 ± * - _+ 2 pnn50 (%) 1) t~ * +(}.6 + ().7 Frequency doman TP(abs) (ms 2) * ± 270 LF(abs) (ms 2) ± HF(abs) (ms 2) ~-40 -~ 33* LF(nu) (%) l. -2.[ HF(nu) (%) 0.2 ~ 0.9 ~2.4 ~ _+ 1.3 LF/HF rato t *p < 0.01, tp < 0.05 versus placebo. Data presented are mean change relatve to baselne _+ SEM. + = ncrease: - = decrease: abbrevatons as n Table 1. the bopamne group, smlar but nonsgnfcant trends opposte to the decrease n the placebo group were observed. Spectral analyss of heart rate varablty showed a decrease n all varables n the placebo group smlar to the change n tme doman varables, except for a small ncrease n the rato of low to hgh frequency power. n the dgoxn group, total power, and low and especally hgh frequency power showed a sgnfcant ncrease (absolute unts). Normalzed hgh frequency power also showed a sgnfcant ncrease, whereas normalzed low frequency power showed a nonsgnfcant trend to decrease. The rato of low to hgh frequency power was sgnfcantly reduced after dgoxn. n the bopamne group, agan, less pronounced and nonsgnfcant changes were observed. Comparson of the ndvdual changes n plasma neurohormone levels and varables of heart rate varablty revealed no sgnfcant correlatons, ether n the total group or n any of the three treatment groups.

5 JACC Vol. 26, No. 4 BROUWER ET AL. 987 October 1995: EFFECTS OF DGOXN AND BOPAMNE N HEART FALURE Table 4. Dfferental Effects of Dgoxn on Heart Rate Varablty Durng Nghttme and Daytme Nghttme Daytme Varable Baselne 3 mo Baselne 3 mo Tme doman Mean NN (ms) 842 _ _+ 25* 717 _ _+ 23~ rmssd (ms) * pnn50 (%) Frequency doman TP(abs) (ms 2) 2,736 _ ,906 _ , ,605 +_ 348* LF(abs) (ms 2) _ HF(abs) (ms 2) 186 _ _ _+ 34* LF(nu) (%) 52.9 _ t.0 _ _ _+ 1.8 HF(nu) (%) 22.3 _ _ _ _+ 1.8~ LF/HF rato _ _+ 0.3 *p < 0.01, tp < 0.001, :~p < 0.05 versus baselne. Data presented are mean value _+ SEM. Abbrevatons as n Table ~ The effects of dgoxn on varables of heart rate varablty durng nghttme and daytme are shown n Table 4. Compared wth that at baselne, the mean value of normal RR ntervals was sgnfcantly prolonged durng both nghttme and daytme. However, sgnfcant changes n varables of heart rate varablty were observed durng daytme hours only. The rmssd and pnn50 values, whch showed lower values at baselne durng the day than at nght, were sgnfcantly enhanced n the daytme hours durng dgoxn treatment. Smlar changes were observed n frequency doman varables. Both absolute and normalzed hgh frequency components were sgnfcantly enhanced wth dgoxn treatment durng the daytme, but changes n heart rate varablty after placebo and bopamne treatment were not sgnfcant durng ether nghttme or daytme. Comparson of the baselne values of heart rate varablty and the subsequent change durng treatment revealed an nverse relaton for several varables n the dgoxn-treated patents. A statstcally sgnfcant negatve correlaton was observed for rmssd, normalzed low frequency power, absolute and normalzed hgh frequency power and the rato of low to hgh frequency power (Table 5). n the bopamne-treated patents, a statstcally sgnfcant negatve correlaton was found for the rato of low to hgh frequency power only (r = Table 5. Correlaton Between Varables of Heart Rate Varablty, at Baselne and After 3 Months of Treatment n the Dgoxn Group (n = 22) r Value p Value rmssd (ms) ( HF(abs) (ms 2) LF(nu) (%) /117 HF(nu) (%) LFMF rato -(.68 < Only sgnfcant correlatons are lsted: r values obtaned usng least squares lnear regresson analyss. Abbrevatons as n Table , p = 0.045), not for the other varables. No sgnfcant trends were observed n the placebo group. Scatterplots of the correlaton between the rato of low to hgh frequency power and at baselne and after 3 months of treatment for the placebo, dgoxn and bopamne groups are shown n Fgure 3. Dscusson To our knowledge, the present study s the frst to report placebo-controlled data on the effects of treatment wth dgoxn and bopamne on varables of heart rate varablty n heart falure. n patents wth mld to moderate heart falure, treatment wth dgoxn was found to prevent the progressve deteroraton n varables of heart rate varablty that was observed n placebo-treated patents. n addton, dgoxn prevented the ncrease n neurohormonal actvaton that was observed n the placebo group. An mportant novel fndng n our study s that dgoxn treatment enhances varables of heart rate varablty assocated wth cardac vagal tone especally durng daytme, when sympathetc tone s known to be ncreased and parasympathetc tone s decreased (24). Furthermore, the treatment effect s nversely correlated wth a number of varables of heart rate varablty at baselne, and dgoxn therefore seems to exert ts effect on autonomc control, especally when these varables are mpared. As mentoned earler, there were no changes n exercse capacty and symptom scores after 3 months of dgoxn treatment, whch makes t unlkely that dfferences n actvty can explan the observed dfferences n heart rate varablty (18). These effects ndcate a modulatng nfluence on autonomc tone, whch agrees wth earler reports of the neurohormonalmodulatng effects of dgoxn (24-26). Furthermore, our results are concordant wth the recently publshed study of Krum et al. (17) n patents wth chronc heart falure. After treatment wth dgoxn, they also found a sgnfcant decrease n plasma norepnephrne levels combned wth a sgnfcant enhancement of parasympathetc actvty. However, a placebo control group was not ncluded n ther study. After bopamne,

6 988 BROUWER ET AL. JACC Vol. 26, No. 4 EFFECTS OF DGOXN AND BOPAMNE [N HEAR'[ FALURE October 1995: Placebo Change LF/HF rato after 3 months r= 0.33 p= Baselne Dgoxn LF/HF rato Change LF/HF rato after 3 months Baselne LF/HF rato bopamne Change LF/HF rato after 3 months _ = = r= p < 0, r = p= Baselne LF/HF rato Fgure 3. Scatterplot of correlaton between low frequency/hgh frequency (LF/HF) rato at baselne and change after 3 months of treatment n the placebo, dgoxn and bopamne groups. only nonsgnfcant trends opposte to the deteroraton n the placebo group were observed, both n varables of heart rate varablty and n neurohormonal actvaton. Varables of heart rate varablty. Compared wth the declne n the placebo group after 3 months n our study, dgoxn sgnfcantly mproved varables of heart rate varablty. bopamne dd not show a statstcally sgnfcant effect on these varables. The varables assocated wth cardac vagal control (rmssd, pnn50 and hgh frequency power) showed a sgnfcant ncrease wth dgoxn compared wth placebo. These results ndcate a parasympathommetc effect of dgoxn n patents wth heart falure, whch confrms the fndngs n expermental studes (26,27). Furthermore, our data are n agreement wth the fndngs of Kaufman et al. (28), who showed that short-term treatment wth dgoxn n healthy volunteers nduced ncreases n varables of heart rate varablty parameters up to 51%, partcularly n ndexes of vagal modulaton. Smlar to the fndngs of Ferguson et al. (27), we found a small but sgnfcant ncrease n the mean normal-tonormal nterval, that could be consdered a drect result of the shfted sympathovagal balance. The observed ncrease n absolute hgh frequency power may n part be explaned by ths ncrease n the mean normal-to-normal nterval and parallels the observed ncreases n SDNN and total power. Stll, hgh frequency power shows also a sgnfcant ncrease expressed n normalzed unts. Furthermore, the ncrease n absolute and normalzed hgh frequency power durng the day was sgnfcant. Absolute low frequency power also showed a sgnfcant ncrease, but normalzed low frequency power showed a trend to decrease. Because the rato of low to hgh frequency power showed a trend to decrease, the dgoxn-nduced changes n varables of heart rate varablty can be consdered to reflect a shft n sympathovagal balance toward enhanced cardac vagal tone (29). There are no prevous reports on the effects of bopamne on varables of heart rate varablty. n the present study, trends opposte to those n the placebo group were observed n bopamne-treated patents for both varables of heart rate varablty and neurohormonal actvaton. n the present study, none of these changes reached statstcal sgnfcance; but prevous data (18,30,32) suggest a sgnfcant decrease n neurohormone levels durng treatment wth bopamne compared wth placebo. Because ths study was carred out n patents wth mld dsease, and the sample sze was lmted, further studes wll be needed to better establsh the effects of bopamne on heart rate varablty. The effects of drug therapy on varables of heart rate varablty n patents wth heart falure have been addressed n three prevous studes (14-16). Angotensn-convertng enzyme nhbtors (14,15) were found to mprove overall heart rate varabl~ especally n assocaton wth vagal control. n a study by Coumel et al. (16), beta-blockers also mproved the mbalance of the autonomc nervous system, as was shown by changes n the heart rate varablty spectrum. However, the effect of treatment on neurohormonal actvaton was not evaluated n those prevous studes. Nevertheless, because

7 JACC Vol. 26, No. 4 BROUWER ET AL. 989 October 1995: EFFECTS OF DGOXN AND BOPAMNE N HEART FALURE both drugs have been shown to reduce neurohormonal actvaton (33), our results are bascally n accord wth the aforementoned studes (14-16). Neurohormonal actvaton. There s now accumulatng evdence that neurohormonal actvaton s not smply a marker of the severty of heart falure, but that t may actually contrbute to the progresson of the dsease and therefore may have prognostc sgnfcance (33,34). As a consequence, drugs that possess neurohormonal-nhbtng propertes, such as angotensnconvertng enzyme nhbtors (35,36), dgoxn (18,25), betablockers (37) and oral dopamnergc agents (18,30-32), have recently ganed ncreasng attenton. ndeed, the former two drugs appear to be benefcal n the long-term treatment of patents wth heart falure. t has been suggested (33,38) that a neurohormonal modulatng effect of these drugs may be more mportant than a benefcal hemodynamc nfluence. Neurohormonal actvaton may lead to progressve autonomc mparment and baroreceptor dysfuncton (39), and t may be hypotheszed that reversal of neurohormonal actvaton may correct these abnormaltes. Furthermore, t should be emphaszed that our study was performed n patents wth mld dsease. n these patents, treatment wth dgoxn mproved the progressve dsturbance n parasympathetc control of the heart that was observed n placebo-treated patents. n patents wth a roughly smlar, "early," degree of heart falure, Bnkley et al. (15) also showed augmentaton of cardac vagal tone after treatment wth an angotensn-convertng enzyme nhbtor. Both studes suggest that drug treatment may be benefcal early n the dsease process of heart falure, because t may restore the observed derangement n autonomc control. Other studes (7,10) have shown that mparment of heart rate varablty and autonomc functon n heart falure are correlated wth the degree of neurohormonal actvaton. Although our data suggest that ths neurohormona effect may be responsble for the observed mprovement n heart rate varablty, no drect correlatons between ndvdual changes n varables of heart rate varablty and plasma neurohormone levels were found. Ths result agrees wth a recent report from Adamopoulos et al. (11), who showed that n patents wth heart falure, an overall decrease n neurohormonal actvaton was related to an overall mprovement n varables of heart rate varablty but that no sgnfcant ndvdual correlatons were present. n fact, they concluded that specfc varables of autonomc functon reflect dfferent aspects of crculatory control (11). Clncal mplcatons. mprovement n heart rate varablty by drug treatment may be mportant rrespectve of changes n neurohormonal actvaton because recent studes (13) ndcate that mpared heart rate varablty s ndependently related to an adverse prognoss n patents wth heart falure. Although we dd not nvestgate the prognostc value of ths change n heart rate varablty, the drug-nduced mprovement n heart rate varablty n the present study may shed new lght on the value of dgoxn n ths syndrome. The beneft of dgoxn treatment has been questoned n patents wth heart falure who are n snus rhythm (40). Our fndng that dgoxn apparently affects heart rate varablty under crcumstances assocated wth neuroendocrne actvaton may well be compatble wth reports (40) ndcatng that patents wth more severe heart falure derve beneft from dgoxn treatment. The observed negatve correlaton between heart rate varablty at baselne and after treatment also suggests that analyss of heart rate varablty may be used to dentfy patents wth heart falure who wll beneft from drug treatment. Further studes wll be needed to evaluate the clncal consequences of these fndngs. We thank W. Arnold Djk, MSc, Bert J. M. Mulder, MSc, and Jan W. Versma, MD for ther techncal support and assstance n ths study. 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