Influence of transdermal scopolamine on cardiac sympathovagal interaction after acute myocardial infarction

Influence of Transdermal Scopolamine on Cardiac Sympathovagal Interaction After

Acute Myocardial Infarction Roberto Pedretti, MD, Enrica Colombo, MD, Simona Sarzi Braga, MD, and Bruno Carti, MD

In 41 survivors of acute myocardial hfaletion (AM) a prospe&ive study was pehnned in 2 se quent&lphase9.Inphasel,theroleofbrvoreflex sensitivtty imId bealt rate variability as predktors of indudbk and spontaneous sustained ventticu- lar Wthyanhytbmks was evaluated. In phase 2, tbeeffectsof- scopokmineonbarore flexsensitivtty,specbUandnonspeckalmea sums of heart rate variability were investi@ed. Atameanfollovwpof10+3monthsafterAMI, 5of4lpatknts(l2%)devekpedalateanh* mic event. of these, all (100%) had indudbility of sustained monomorphic ventrkular h&ycafdia at wmmad stimulatkn compared with 3 of 35 patii (5%) witbout events (p 4.0001). At muC tivaiate anatysis, -XWWiWvityhadthe strongest relation to both indudbllity of sustained monomorphic ventdcular tachycardia (p ~0.0001) and occurrence of anhythmic events (p *O.OOOl). of4lpatkntq2s(55%) wnwnted to undergo plume 2 of the inve8tigation. Baromnexwwithri- ty !Bigniicantly (p <O.OOOOl) increased aftertrams- dennal8copolamine as well as heart rate variabi% tyindexea.ofthese,themeanofSDsofnonnal RR intervals for &Mute - (P *O-0001) and the total power (p ~0.0001) had the most sig- Meant improvement after scopolamine. The present investigation confirmsthat B of &onomk function is an essential part of aMyth mic rkk evaluation after AM. Transdemral 8~0 polamine, administered to survivors of a recent AM, reversea the autonomic indexes that inde pendeNy predkt mmk event occuwence. ontbebasisoftbsedata,-IscopoC amlne could be a potential useful tool in the pi PhylaxkofI -ingventriculararrhytk miss after AMI.

(Am J CaWol l-72:35&352)

From the Division of Cardiology, Clinica de1 Lavoro Foundation, IRCCS, Medical Center of Rehabilitation, Tradate, Italy. Manuscript received November 4, 1992; revised manuscript received March 10, 1993, and accepted March 18.

Address for reprints: Bruno Caru, MD, Division of Cardiology, Clinica de1 Lavoro Foundation, IRCCS, Medical Center of Rehabilita- tion, Tradate, Via Roncaccio 16/H, 21049, Tradate (VA), Italy.

A nalysis of the autonomic control of the heart, by means of indirect markers, may represent a new approach for identifying patients at higher risk

for sudden cardiac death after acute myocardial infarction (AMI). In previous studies,1-5 depressed baroreflex sensitivity and heart rate variability (markers of reflex and tonic cardiac vagal activity, respectively) were found to be strong and independent predictors of both total death and sudden death in patients after AMJ. There- fore, pharmacologic manipulation of sympatbovagal balance could have a favorable effect on electrical heart stability. Usefulness of p blockers in the prophylaxis of post-AMI arrhythmic events is well known,6 but little information is available on pharmacologic vagomimetic interventions in humans. In 2 studies, transdermal scopolamine was found to increase cardiac vagal activity in normal subjects?s These tindings may have therapeutic implications, as suggested by 2 abstracts on effects of scopolamine on cardiac vagal outtlow in patients after AMJ9,10 Recently, in the study of Farrell et ak3 baroreflex sensitivity was found to be the most significant predictor of inducibility of sustained monomorphic ventricular tachycardia in post-AMI patients, and the use of alternative indexes proved inferior. Because inducibility of sustained monomorphic ventricular tachycardia seems to be a strong marker of arrhytbmic propensity after AMJ, w’s this tinding may have clinical relevance. At present, only Farrell’s data3 are available and further investigations may give a useful contri- bution. We performed a prospective study of patients surviving a recent AMJ to assess 4 factors: (1) the relation between indicators of depressed autonomic function and inducibility of sustained monomorphic ventricular tachycardia at programmed ventricular stimulation; (2) the prognostic power of markers of impaired autonomic balance in predicting arrhythmic outcome; (3) the intluence of transdermal scopolamine on vagal cardiac nervous activity, evaluated by baroreflex sensitivity and heart rate variability; and (4) the influence of transdermal scopolamine on cardiac electrical properties, assessed by measurement of refractoriness of right atrium, atrioventricular node, and right ventricle during electrophysiologic study.

%u@ desl#~ This study was conducted in 2 sequen- tial phases. In phase 1, we evaluated the role of baroreflex sensitivity and heart rate variability as predictors of inducible sustained monomorphic ventricular tachycardia. From September 1991 to July 1992, from a total of 131 patients surviving an AMJ and admitted to our in- stitute within 30 days of the infarction for cardiac reha-

384 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 AUGUST 15,1993

bilitation, 116 (88%) were eligible for the present investigation and were asked to give written consent to both programmed ventricular stimulation and baroreflex sensitivity testing. Patients aged >70 years, with arterial blood pressure >160/90 mm Hg, insulin-dependent dia- betes, flutter or atrial fibrillation (or both), abnormal sinus node function, ventricular-paced rhythm, heart fail- ure, and unstable angina were excluded from the study. Of eligible patients, 41 (35%) gave their consent to electrophysiologic study and baroreflex sensitivity testing, and were enrolled in the present study. Clinical and demographic characteristics of both the study population and the 75 patients who refused to participate in the investigation are listed in Table I. All patients underwent measurement of left ventricular ejection fraction by 2- dimensional echocardiography, exercise testing, Holter monitor analysis for ventricular ectopic beats and heart rate variability baroreflex sensitivity testing, and electrophysiologic study. During electrophysiologic study, after evaluation of the right atrium, atrioventricular node and right ventricle refractoriness, programmed ventricular stimulation was performed. Baroreflex sensitivity measurement and electrophysiologic study were performed on the same day; in each case all patients underwent programmed ventricular stimulation 1 to 2 hours after baroreflex sensitivity testing. All tests were performed between 15 and 21 days after AMI, and no patient received B blockers, calcium antagonists, digi- talis or ant&rhythmic drugs at the time of the investigation. In phase 2, we determined the effects of transdermal scopolamine on baroreflex sensitivity, heart rate variability, and cardiac refractory periods. Of patients enrolled in the study, 28 (68%) consented to undergo this phase of the investigation. After electrophysiologic study, all patients wore 1 patch of transdermal scopolamine behind an ear for 48 hours. The therapeutic system (TranscopB, Recordati, Italy) used in the present study delivers low-dose scopolamine (total dose 0.5 mg) at a continuous rate over 3 days. After 24 hours of treatment, baroreflex sensitivity was tested in all patients; atrial, atrioventricular and ventricular refractoriness were evaluated in 20 patients. In the second 24-hour interval, all patients underwent 24-hour Holter monitoring for heart rate variability assessment. To compare responses of baroreflex sensitivity and heart rate variability to 1 scopolamine patch with those to 1 placebo patch, a further group of 20 consecutive patients was enrolled in the present investigation from July 1992 to September 1992; their clinical and demographic characteristics are listed in Table I. In the third week after AMI and after written consent, all patients underwent 2-dimensional echocardiography, exercise testing, Holter monitoring, and baroreflex sensitivity testing in pharmacologic washout; electrophysiologic study was not performed. After baseline evaluation, a single-blind experiment was begun and all patients wore 1 placebo patch behind an ear for 48 hours. As in the scopolamine-treated group, after 24 hours baroreflex sensitivity was again assessed, and in the second 24-hour interval all patients underwent a further Holter monitor analysis for heart rate variability. Follow-up data of patients who underwent phase 1 to 2 of the investigation were analyzed; all patients had

TABLE I Placebo-Treated Group and Patients Who Did and Did Not Consent to Investigation: Comparison of Clinical and Demographic Characteristics

Age (years) 54 L 8 55 2 9 57k 11 Men/women (no.) 66/9 3912 16/4 Past AMI (%) 13 (17) 4 (10) 4 (20) VF O-5 days after AMI (%I 8 (111 3 (7) 1 (5) Anterior AMI (%) 36 (48) 24 (58) 12 (60) Inferior AMI (%I 39 (52) 17 (42) 8 (40) Q-wave AMI (%I 58 (77) 28 (68) 12 (60) Thrombolysis (%) 36/58 (62) 18/36 (50) 10/13 (77) Maximal work capacity (METS) 8?3 8?3 8+4 LVEF (%) 47 +- 8 45 + 13 48 f 10 Dyskinesia (%) 11 (15) 8 (19) 0 (0)

Nontested (n = 75)

Tested Placebo (n = 41) (n = 20)

Continuous variables are expressed as mean + 1 SD. Unless stated otherwise, statistical comparisons were not significant.

AMI = acute myocardial infarction; LVEF = left ventricular ejection fraction; VF = ventricular fibrillation.

follow-up contact by phone. A “late arrhythmic event” was delined as sudden death or the occurrence of symp- tomatic or sustained ventricular arrhythmia 15 days after AMI. Sudden death was delined as a witnessed, unex- pected death occurring within 1 hour of the onset of symptoms or during sleep. Sustained ventricular arrhythmia was delined as spontaneous ventricular fibrillation or tachycardia lasting >30 seconds or necessitating cardioversion because of hemodynamic collapse. This deli&ion was also used to include patients who subse- quently had syncope and were found to have inducible sustained ventricular tachycardia at electrophysiologic study, in the absence of other identifiable causes for syncope. Neither B blockers nor other antiarrhythmic drugs were prescribed routinely to patients with or without inducible ventricular tachycardia or high-grade ventricular ectopic activity.

Bauordbx sedUvt@ amesme& Arterial baroreceptor function was evaluated by the administration of phenyle hrine scribed. !

according to a method previously de- ,16 Studies were performed with subjects in the

supine position and in the fasting state. Brachial or radi- al arterial pressure was obtained through a Teflon@ can- nula (Arrow, 18 G) connected to a Spectramed Statham P23X2 transducer. One electrocardiographic lead and systolic arterial pressure signal were continuously sam- pled, digitally converted and fed into an Epson 286 AX2 computer system. After a period of rest, when blood pressure and heart rate were stable, phenylephrine hy- drochloride (2 l.@kg) was injected into an antecubital vein. Patients received a bolus injection to raise systolic arterial pressure >15 and ~40 mm Hg. If blood pressure did not increase as desired, additional injections were given, increasing the dosage of phenylephrine by increments of 25 pg to reach a maximum of 3.5 pg/kg. The bolus injection was repeated 23 times at the dosage found to induce the required blood pressure increase; intervals between each bolus were >lO minutes. A computer analysis provided accurate detection of all sinus QRS complexes (premature complexes and the 3 subse- quent sinus beats were excluded). Systolic blood pressure and RR intervals were calculated as increments in respect to the baseline condition. The RR intervals were

TRANSDERMAL SCOPOLAMINE AFTER AMI 385

plotted against the preceding arterial pulse, and a linear regression analysis was performed for points included between the beginning and the end of the first significant increase in systolic arterial pressure. Only regression lines with a correlation coefficient either 9.80 or statistically significant (p ~0.05) were accepted for the analysis. A final slope was obtained by calculating the mean value of 23 determinations. This value was then considered as representing the baroreflex sensitivity (ms/rnm Hg). As suggested by La Rovere et aL2 a baroreflex sensitivity 13 ms/mm Hg in post-AMI patients was considered markedly depressed.

Holter monitorl~ A 24-hour Holter monitoring was available in all patients. A 3-channel electrocardio- gram was analyzed with a Marquette Electronics Holter 8000 T system. Frequency of ventricular ectopic beats, presence of multiform or paired ventricular ectopic beats (or both), and presence of unsustained ventricular tachycardia (run of 23 consecutive ventricular ectopic beats lasting ~30 seconds) were assessed for each tape.

Heart rate variaMllty nrsarpment: Heart rate variability was evaluated over the 24-hour Holter recording in ah 41 patients. Each beat was targeted as normal or aberrant according to its recognition by the algorithm for tape analysis and after investigator’s control. To measure heart rate variability, we used a Marquette Electronics Software program, and spectral and nonspectral measures of heart period variability were computed. The following time domain variables were used in this study: (1) SD of all normal RR intervals for 24 hours, (2) SD of the mean of normal RR intervals for 5-minute segments, (3) the mean of the SDS of normal RR intervals for 5minute segments, (4) the root-mean-square of successive differences of the normal RR intervals, and (5) the proportion of adjacent normal RR intervals difTerent by >50 ms. In each recording, the mean heart period was also calculated. The heart period power spectrum was computed by a fast Fourier transform algorithm. Power spectra were quantified in 3 frequency bands: (1) total power between 0.00 and 0.40 Hz, (2) low-frequency power between 0.04 and 0.15 Hz, and (3) high- frequency power between 0.15 and 0.40 Hz. To have a normal distribution of the power spectrum data, the nat- ural logarithm of the original units of measurement (ms2) was used.

Ektrophysiologk study: Ah patients underwent electrophysiologic testing in the fasting and nonsedated state. After electrode catheters had been placed in the high right atrium and His bundle area, the patients were allowed to rest for 15 to 20 minutes during which time heart rate was continuously monitored. When stable values were present for 210 minutes, effective refractory periods of right atrium and atrioventricular node were measured. Then 1 catheter had been advanced from the high right atrium to right ventricle apex, and ventricular effective refractory period was measured. After measurement of cardiac refractoriness, programmed ventricular stimulation was performed using a protocol reported in a previous study of OUTS.*~ Up to 3 extrastimuli were introduced at the right ventricular apex after 8 ventricular paced beats at 3 drive cycle lengths (600-

500-400 ms). The protocol was discontinued on the induction of a sustained ventricular arrhythmia, but only the induction of sustained monomorphic ventricular tachycardia at a rate ~270 beats/min was regarded as a positive result. Polymorphic ventricular tachycardia (i.e., ventricular tachycardia with a continuously varying QRS complex configuration in any recorded electrocardiographic lead), ventricular fibrillation, and unsustained arrhythmias were each regarded as a nonspecitic response.

Other w procmhres: A 2dimensional echo- cardiogram, using a Ving Med CFM 750 unit, was obtained. Evaluation of left ventricular ejection fraction by Simpson’s formula, and detection of left ventricular dyskinesia were performed. A symptom-limited exercise test according to Bruce’s protocol was performed on a Marquette Electronics Case 12 treadmill. Among the er- gometric variables, only maximal work capacity was considered.

SWWcal analysis: Continuous variables were tested for normal distribution with the Kohnogorov-Smir- nov goodness-of-fit test for normality. When a normal distribution was observed, continuous variables were expressed as mean + 1 SD and were compared using Stu- dent’s paired or unpaired t test, where appropriate. When observed frequencies were significantly different from the expected normal distribution, continuous variables were expressed as median, lower and upper quartiles, and were compared using the nonparametric Mann-Whitney test. Discrete variables were compared by &i-square analysis with Yates’ correction for continuity or Fischer’s exact test. McNemar’s test with Yates’ correction for continuity was used to compare propor- tions of patients with inducible atrial tachyarrhythmias during assessment of right atrial refractoriness before and after scopolamine. When 3 groups were compared, l-way analysis of variance and &i-square analysis were used where appropriate. A p value co.05 was considered statistically significant. To assess the strength of the association between baseline and placebo measurements, the intraclass correlation coefficient was calculated for both baroreflex sensitivity and heart rate variability using results of a l-way random-effect analysis of variance.17 To identify patients who were “responders” to scopolamine, the variable with the highest intraclass correlation coefficient was used to calculate the 95% fiducial limits of baseline-to-placebo variation. For 20 observed values, the required limits concerning 95% of the population were mean + 2.7 SD.‘* In the scopolamine-treated group, variations between baseline and scopolamine measurements were evaluated: a change exceeding fiducial limits was considered a “real change.” Using the BMDP LR program (BMDP Statistical Software, Inc., 1988), stepwise logistic regression analysis was performed to determine which variables contributed independent information to (1) the inducibility of sustained monomorphic ventricular tachycardia at a rate ~270 beats/mm, and (2) the prediction of late arrhythmic event occurrence. Selections were based on the maximal like- lihood ratio method. The p values used for entry and re- moval of variables were set at 0.05 and 0.10, respectively.

366 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 AUGUST 151993

TABLE II Characteristics of Patients With and Without Inducible Sustained Monomorphic Ventricular Tachycardia

No SMVT SMVT at PVS at PVS

(n = 8) (n = 33) p Value

Clinical data Age (years) 60 -+ 10 54 + 9 NS Men/women (no.) 7/l 32/l NS Past AMI (%) l(12) 3 (9) NS VF O-5 days after AMI (%) 2 (25) 1 (3) NS Anterior AMI (%) 8 (100) 16 (48) < 0.05 Q-wave AMI (%I 8 (100) 20 (61) <0.05 Thrombolysis (%) 3/a (37) 15/28 (53) NS

Echocardiographic data LVEF (%) 31+4 482 12 <O.OOl Dyskinesia (%) 6 (75) 2 16) < 0.001

Holter monitoring data VPCs/hour (no.)* 2.2; 0.3; 11.5 0.8; 0.1; 12.0 NS Multiform VPCs (%) 7 (87) 19 (57) NS Paired VPCs (%I 4 (50) 11 (33) NS Unsustained VT (%) 2 (25) 5 (15) NS

Heart rate variability data Mean heart period (ms) 731 * 75 a72 e 122 <O.Ol SD of RR intervals/24 hours (ms) 81 -t40 122 2 43 -co.05 SD of mean of RR intervals for 78 2 39 110 + 42 NS

5-minute segments (ms) Mean of SDS of RR intervals 26 f 14 55 f 23 <O.Ol

for 5-minute segments (msl Root-mean-square of successive 17 + 7 31 + 16 NS

differences in RR intervals (ms) Proportion of adjacent RR intervals 2.3 k 3.3 9.2 2 10.1 NS

different by > 50 ms (%) Total power (log units) 5.33 2 1.08 7.01 * 0.97 < 0.001 Low-frequency power (log units) 3.75 + 1.62 5.98 ‘- 1.25 <O.OOl High-frequency power (log units) 3.09 ic 0.83 4.66 2 1.14 <O.Ol

Continuous variables are expressed as mean + 1 SD or (*) median, lower and upper quartiles. PVS = programmed ventricular stimulation: SMVT = sustained monomorphic ventricular tachycardia; VPCs = ventricular

premature complexes; Vl = ventricular tachycardia; other abbreviations as in Table I.

petient mstk~ We compared clinical and demographic characteristics of patients who refused to participate in the investigation with those of patients who underwent phase 1 to 2 of the study or placebo treatment. Among the 3 groups of patients, there were no signilicant differences in variables listed in Table I.

bmweilex~,heartrateva+ fJhig?Z~~tOpogarmwd~ IarA Of 41 patients tested, 8 (19%) had a positive electrophysiologic study. Of the variables listed in Table II, the following had a signilicant relation to inducibility of sustained monomorphic ventricular tachycar&a: anterior AMI (p <O.OS), Q-wave AMI (p <0.05), left ventricular dyslcinesia (p <O.OOl) and ejection fraction (p <O.OOl), and most of heart rate variability measures. In Figure 1, baroreflex sensitivity of patients with and without inducible sustained monomorphic ventricular tachycardia is shown: baroreflex sensitivity was significantly reduced in patients with a positive electrophysiologic study (2.9 f 2.6 vs 9.8 f 6.8 ms/mm Hg; p ~0.01). In particular, of 8 patients with inducible sustained monomorphic ventricular tachycardia, 7 (87%) had a profoundly depressed baroreflex sensitivity (13 ms/mm Hg) compared with 3 of 33 patients (9%) with a negative electrophysiologic study (p <O.OOOl). To determine which variables contributed independent information, a stepwise logistic regression analysis was per-


TABLE III Characteristics of Patients With and Without Arrhythmic Events

Events No Events (n = 5) (n = 36)

Clinical data Age (years) 63 2 7 54 + 9 Men/women (no.) 4/l 35/l Past AMI (%) 1 (20) 3 (8) VF O-5 days after AMI (%) 1 (20) 2 (5) Anterior AMI (%I 5 (100) 19 (53) Q-wave AMI (%I 5 (100) 23 (64) Thrombolysis (%) l/5 (20) 17/31 (55)

Echocardiographic data LVEF (%) 20 2 3 47 k 12 Dyskinesia (%) 4 (80) 4 (11)

Holter monitoring data VPCs/hour (no.)* 0.4; 0.3; 7.4 1.0; 0.3; 12.8 Multiform VPCs (%) 5 (100) 21 (58) Paired VPCs (%) 3 (60) 12 (33) Unsustained VT (%I 1 (20) 6 (17)

Heart rate variability data Mean heart period (ms.1 729 * 91 864 f 122 SD of RR intervals/24 hours (ms) 69 2 27 122 2 42 SD of mean of RR intervals 66 2 27 111 r 41

for 5-minute segments (ms) Mean of SDS of RR intervals 22 -t 10 55 f 23

for 5-minute segments (ms) Root-mean-square of successive 15 2 4 31 2 16

differences in RR intervals (ms) Proportion of adjacent RR intervals 1.0 f 1.4 9.2 f 9.9

different by > 50 ms f%) Total power flog units) 5.04 2 0.89 7.01 f 0.95 Low-frequency power (log units) 3.32 2 1.37 5.98 + 1.23 High-frequency power (log units) 2.81 + 0.52 4.65 k 1.12

Continuous variables are expressad as mean + 1 SD or (9 median. lower and upper quartiles. Abbreviations as in Tables I and II.

p Value

10.05 NS NS NS NS NS NS

<O.Ol co.01

NS NS NS NS

-co.05 <O.Ol -co.05

<O.Ol

10.05

NS

<O.OOl <0.0001 <O.Ol

formed: baroreflex sensitivity (improvement, &i-square = 17.6; p <0.0001) and anterior AML (improvement, &i-square = 5.1; p = 0.02) had a signiticant relation to inducible sustained monomorphic ventricular tachycardia.

Followup data: At a mean follow-up of 10 f 3 months after AMI, 5 of 41 patients (12%) who underwent phase 1 to 2 of the study developed a late arrhythmic event; of 5 events, 4 (80%) occurred in the thst 2 months after AMI (mean 36 zb 22 days). Only 1 event (20%) was observed 5 months after AMI. Sudden death occurred in 1 patient, 2 had aborted sudden death with evidence of ventricular fibrillation at the time of cardioversion, and 2 had sustained ventricular tachycardia.

VofBW#theraly:of5 arrhythmic events, 3 (60%) occurred during the in-hospital period, during this period patients both with and without events were in pharmacologic washout. At hospital discharge, empiric antiarrhythmic therapy, was administered by the attending physician to 4 of 38 asymptomatic patients (10%) (amiodarone in 2; mexiletine in the other 2) because of inducible sustained ventricular arrhythmias. At hospital discharge, p blockers were prescribed to 9 of 38 asymptomatic patients (24%). None of the 9 patients with p blockers developed arrhythmic events compared with 2 of 29 (7%) without p blockers (p = NS).

-of--, hemtratevd aJutty,mdothwpmzmmtm~o~mlete &yUmdc events Age (p <0.05), left ventricular dys-

388 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 AU( SST 15,1993

kinesia (p 4.01) and ejection fraction (p ~0.01) had a signiticant relation to late arrhythmic events (Table III). Of heart rate variability measures, all were significantly reduced in patients with events except the proportion of adjacent normal RR intervals ditferent by >50 ms (Table III). Figure 2 shows baroreflex sensitivity of patients with and without arrhythmic events: baroreflex sensitivity was significantly reduced in patients who developed arrhythmic events (1.6 f 0.9 vs 9.4 + 6.7 ms/mm Hg; p ~0.01). Of 5 patients with events, all (100%) had a markedly depressed baroreflex sensitivity of 13 ms/mm Hg compared with 5 of 36 patients (14%) without post- AMI malignant ventricular arrhythmias (p ~0.001). When stepwise logistic regression analysis was used to determine the independent prognostic power of 19 variables (see Appendix), baroreflex sensitivity (improvement, &i-square = 16.4; p cO.OOOl), left ventricular dyskinesia (improvement, chi-square = 6.9; p = 0.008) and ejection fraction (improvement, &i-square = 5.9; p = 0.01) had a significant relation to occurrence of arrhythmic events. The clinical meaning of inducible sustained monomorphic ventricular tachycardia at a rate R70 beats/nun was even analyzed. Late arrhythmic events occurred in 5 of 8 patients (62%) with inducibility of sustained monomorphic ventricular tachycardia compared with none of 33 patients with negative pro- dollar stimulation (p cO.0001).

banwefleXtMJdlM@andheartrste

varlabil& dter irmsdmd smpohdm In patients who underwent phase 2 of the investigation, baroreflex

higher variations than those observed after placebo ad-

sensitivity increased from 9.9 + 7.4 to 16.5 f 9.2 ms/mm Hg (p <O.OOOOl) after wearing 1 patch of transdermal scopolamine for 24 hours (Figure 3). Even infiuence of transdermal scopolamine on heart rate variability was assessed. Of heart rate variability measures, all increased signiticantly after scopolamine except the SD of all normal RR intervals for 24 hours and the SD of the mean of normal RR intervals for 5minute segments (Table TV). We compared responses of baroreflex sensitivity and heart rate variability to scopolamine with those to placebo treatment. After transdermal scopolamine, baroreflex sensitivity (p <O.OOOOl) and all heart rate variability measures, except the SD of all normal RR intervals for 24 hours and the SD of the mean of normal RR intervals for kninute segments, revealed significantly

ministration (Table V). Baseline measurements of baroreflex sensitivity and heart rate variability in both the scopolamine and placebo-treated groups were also compared, and no signiticant ditferences were found (Table V).

(p ~0.~~).

chmgesinuudlac- -mati ter lsmsdmd scopolamhe: Effective refractory periods of right atrium, atrioventricular node, and right ventricle were assessed before and after scopolamine in 20 of 28 patients (71%) who underwent phase 2 of the investigation. After wearing 1 patch of transdermal scopolamine for 24 hours, right atrium refractory period de- creased from 242 rt: 44 to 223 + 41 ms (p <O.Ol), atrioventricular node refractory period increased from 320 k 65 to 357 f 77 ms (p <O.OS), and right ventricle refractory period increased from 224 + 14 to 235 + 16 ms

TABLE IV Changes in Heart Rate Variability Measurement After Transdermal Scopolamine in 28 Survivors of Acute Myocardial Infarction

Mean heart period (ms)

SD of RR intervals/24 hours (ms)

SD of mean of RR intervals for 5-minute segments (ms)

Mean of SDS of RR intervals for 5-minute segments (ms)

Root-mean-square of successive differences in RR intervals (ms)

Proportion of adjacent RR intervals different by > 50 ms (%)

Total (log units) power

Low-frequency power (log units) High-frequency power (log units)

Baseline

a75 f 144 119 + 50 110 2 47

53 f 26

31 2 16

9.2 2 9.9

6.87 f 1.23

5.77 f 1.66 4.61 +- 1.22

Scopolamine

912 + 146 123 f 46 1112 40

62 f 29

36 2 22

12.9 + 12.0

7.18 + 1.10 6.16 2 1.31 4.90 + 1.27

p Value

<O.Ol NS NS

<0.0001

<0.05

<O.OOl

10.0001 co.01 <O.OOl

0

8

EVENTS NO EVE&-l-S (n=S) (n = 36)

nllRE2.8cdmgmmef-~(8R8)~ cerdingte-acportinfactknanhythmiceventr:

4s

40.

35.

30.

G 25

1 20.

8 15.

10.

5.

v- ~~

BASELINE scoFQLAMlNE

lWRE3.Eff@CtOftWSfMH~Oll-X bpsslnsa~efacatelnyocalidinfactkn.-

fkXdOpSWSShOWltb6fiU9snd24hOUISdtiUappllcakn oflsmpdamhpatcheachln28~mesnvdue,~ 180aroalsodkpkyed,mdfhe&ttedlinerepmmtsa arteffpdntata bamdlex seinavQ (888) a ms/lml Hg. -Xmk- (p ~0.oooo1) incmased after sctwdmh a&ninlstmUon.


t

TABLE V Variations of Baroreflex Sensitivity and Heart Rate Variability in Scopolamine- and Placebo-Treated Patients, and Comparison of Baseline Measurements

Scopolamine (n = 28) Placebo tn = 20)

Baseline Baseline Value A A Value

Baroreflex sensitivity (ms/mm Hg) 9.8 2 7.4 6.6 + 5.7 -0.2 2 1.5 8.8 k 6.0 l-p <0.00001-_1

Mean heart period (ms) 875 5 144 37 f 62 -25 t 70 856 + 130 L-p <o.o1r

SD of RR intervals/24 hours tms) 119 -t 50 4 r 24 3 f 24 118 t 42 SD of mean of RR intervals for 110 k 47 1 f 27 4 f 25 106 ‘- 43

5-minute segments (ms) Mean of SDS of RR intervals for 53 A 26 9*8 -2 f 10 50 + 22

5-minute segments (ms) Lp <O.OOl- Root-mean-square of successive 31 2 16 529 -2.5 _c 9 31 f 22

differences in RR intervals (ms) Lp <o.o1r Proportion of adjacent RR intervals 9.2 f 9.9 3.7 f 4.6 -0.7 2 4.7 8.3 of: 10.8

different by > 50 ms (%) -p <0.01r Total (log units) power 6.87 2 1.23 0.31 f 0.39 -0.13 f 0.52 6.78 t 0.91

1p <o.o1r Low-frequency power (log units) 5.77 f 1.66 0.39 + 0.61 -0.15 + 0.63 5.70 + 1.06

1p <o.o1r High-frequency power (log units) 4.61 2 1.22 0.29 k 0.36 -0.18 + 0.69 4.49 ? 1.25

-p <o.o1r

Unless stated otherwise, statistical comparisons were not significant. A = difference from baseline values.

. ers~tsm@mmw For autonomic variables, intraclass correlation coefficients between placebo and baseline measurement had the following values: 0.94 for baroreflex sensitivity, 0.90 for the root-mean-square of successive differences of the normal RR intervals, 0.89 for the proportion of adjacent normal RR intervals different by >50 ms, 0.86 for the mean of the SDS of normal RR intervals for 5minute segments, 0.84 for total and high- frequency power, 0.83 for low-frequency power and mean heart period, and 0.81 for the SD of all normal RR intervals for 24 hours and the SD of the mean of normal RR intervals for 5minute segments. For baroreflex sensitivity the 95% fiducial limits of basehne-to- placebo variation ranged from -4 to +4 ms/rnm Hg, therefore a baroreflex sensitivity increase >4 ms/mm Hg was considered a “real change.” After wearing 1 patch of transdermal scopolamine for 24 hours, 19 of 28 patients tested (68%) had a baroreflex sensitivity variation YI ms/mm Hg and were defined as responders to scopolamine. The remaining 9 (32%) had a variation 14 ms/mm Hg and were considered nonresponders to scopolamine. Of the 19 responder patients, 12 (63%) had a Q-wave AMI and 9 (47%) an anterior AMI, mean age was 54 I!I 8 years, left ventricular ejection fraction was 48 + 12% and maximal work capacity was 9 & 3 METS. In the 9 nonresponder patients, the distributions of Q waves and AMI location were similar (5 of 9 patients [55%] with Q-wave Ah4l and 4 of 9 [44%] with anterior AM& p = NS); mean age was 56 f 12 years, ejection fraction was 47 f 13% and maximal work capacity was 10 f 3 METS, neither of which ditfered significantly from those of the responder group. Regarding

baroreflex sensitivity, no significant difference was observed between responders and nonresponders (8.8 + 7.2 vs 11.7 + 8.1 ms/rnm Hg; p = NS).

syqanlsanl~in~vu-itydur- ingsopobninebwtmenk After receiving a placebo patch none of 20 patients experienced adverse effects, whereas 3 of 28 patients treated with scopolamine (11%) reported adverse effects (blurred vision, nausea) (p = NS). During baseline evaluation of right atrial refractoriness, none of the 20 patients tested had inducible atrial tachycardia. On the contrary, after wearing 1 patch of transdermal scopolamine for 24 hours, 4 (20%) had inducibility of sustained or unsustained (or both) atrial flutter (p = NS).

DISCUSSION Me of autonamic tone evaluation in anhythmic

risk stratiRcation after acute myocdial infwcth: In agreement with previous reports,11-15 in the present study inducibility of sustained monomorphic ventricular tachycardia appeared to be strongly related to occurrence of arrhythmic events after AMT. Nevertheless, electrophysiologic testing is an invasive procedure and therefore not ideally suited as a screening test in a large nurn- ber of patients: it would be preferable to limit electrophysiologic study to a high risk group of patients. A combined use of low left ventricular ejection fraction, ventricular late potentials and ventricular ectopic beats on Holter monitoring has been proposed as a method of selecting post-AMI patients suitable for further investigation.15Jg,20 Interestingly, in a recent study, Farrell et al3 found a markedly reduced baroreflex sensitivity in Ah4I survivors who developed sustained monomorphic ventricular tachycardia at programmed stimulation. In our investigation, at multivariate analysis, left ventricular


ejection fraction and ventricular ectopic beats on Holter monitoring did not add any information to that provided by baroreflex sensitivity in predicting results of electrophysiologic study. Therefore baroreflex sensitivity seems to be superior to other risk markers in selecting patients for programmed ventricular stimulation. Previ- ously, La Revere* and Farrell3 and co-workers found a strikingly lower baroreflex sensitivity in AMI survivors who had arrhythmic events during follow-up. Even time and frequency domain measures of heart rate variability predict at-rhythmic events after AMI.1,s-5 In accor- dance with the results of Farrell et al,3 our data showed that baroreflex sensitivity was a better predictor of arrhythmic events than heart rate variability. Nevertheless, measurement of baroreflex sensitivity is an invasive procedure requiring both phenylephrine administration and arterial cannulation, whereas heart rate variability assessment is noninvasive and easier. Therefore, as Farrell et al suggest, heart rate variability may be of more value in larger populations. A large prospective study is need- ed in which both measures are determined in post-AMI patients and their prognostic correlation is independent- ly assessed; this is currently ongoing.*l

llmuenced- !3u@mlmonuleauto- nomkcontroloftheheartaftwacutemyocdiali~ farctson: Because of the correlation between impaired autonomic function and susceptibility to life-threatening ventricular arrhythmias, improvement of both baroreflex sensitivity and heart rate variability may be a powerful means of reducing the risk of post-AMI at-rhythmic events. In theory, this could be achieved either by increasing vagal efferent activity or, to a lesser extent, by antagonizing sympathetic activity. Although the benefits of B blockers have received much attention6 compara- tively little is known about the therapeutic potential of vagomimetic agents, such as transdermal scopolamine. Similar to an-opine, scopolamine acts as a peripheral vagolytic agent at high dosages but exerts an opposite, presumably central vagotonic effect at lower dosages.* Dibner-Dunlap et al7 and Vybiral et al8 found that transdermal scopolamine increases baroreceptor-cardiac reflex responsiveness and heart rate variability in normal subjects. Since vagal activity influences heart electrical stability,22,23 these findings could have therapeutic implications if confinned in post-M patients. In our study transdennal scopolamine significantly improved baroreflex sensitivity, and spectral and nonspectral measures of heart rate variability in AMI survivors. More- over, we evaluated cardiac electrical properties before and after scopolamine by measurement of cardiac effective refractory periods. Right atrium, atrioventricular node and right ventricular refractoriness significantly changed, reflecting an increase in cardiac vagal outflow. Because of the striking increase in baroreflex sensitivity values, we can hypothesize a beneficial effect of scopolamine on the capacity to sustain ventricular tachycardia. In our study, as in others,3 a baroreflex sensitivity <3 ms/mm Hg was a powerful marker of ventricular electrical instability. In 4 of 5 patients (80%) with a markedly depressed value at baseline measurement,

baroreflex sensitivity increased from 13 to 25 mslmm Hg, a level often associated with a lower risk of events (Figure 3). This finding suggests that an increase in cardiac parasympathetic outflow by transdermal scopolamine may have clinical implications in the prophylaxis of post-AMI arrhythmic events. With regard to spectral and nonspectral measures of heart rate variability, all except the SD of all normal RR intervals for 24 hours and the SD of the mean of normal RR intervals for 5minute segments had a significant improvement after scopolamine. Why scopolamine did not increase these 2 variables is not clear. One can speculate that the effect of scopolamine is almost completely on vagal tone, and does not extend to the more prognostically important heart rate variability indexes. Nevertheless, in heart rate variability measurements, the mean of the SDS of normal RR intervals for 5minute segments showed the most significant improvement after scopolamine. This time domain variable has a very high correlation with both the very low and the low-frequency power.5 Big- ger et al4 found very low frequency power as the strongest predictor of arrhythmic death; therefore, a specific antiarrhythmic effect of scopolamine cannot be excluded. Several factors (i.e., age, physical training, left ventricular ejection fraction, development of Q waves, site of AMI) may interact with autonomic function.2,3,2b27 We evaluated whether clinical and demographic variables, or baseline level of vagal activity in- fluenced responsiveness to scopolamine. We did not tind any significant difference between responders and nonresponders. In particular, both age and left ventricular ejection fraction were similar in the 2 groups of patients. Interestingly, a qualitative difference was appreciable: baroreflex sensitivity was lower in responders that in nonresponders indicating a relative major effect of scopolamine in patients who had a more reduced parasympathetic activity. Although this fact could be a simple reflection of “regression towards the mean,” a possible wide use of scopolamine in patients with a greater autonomic dysfunction after AMI may be suggested. Transdennal scopolamine was well tolerated; in fact, few patients experienced adverse effects. A trend toward a higher rate of inducible atria1 tachyarrhythmias was observed, but the difference did not reach statistical significance.

Study limitations: In the present study we evaluated the prognostic power of baroreflex sensitivity, and spectral and nonspectral measures of heart rate variability. Results were attractive, but the small number of arrhythmic events and the short follow-up prevent us from advancing conclusions. Only a proportion (35%) of the patients suitable for this investigation gave their consent to electrophysiologic study and baroreflex sensitivity testing, and were enrolled in the study. Therefore, doubt must exist as to the applicability of these results to our population as a whole. This was an uncontrolled study: although all patients were tested in a drug-free state, it is impossible at present to exclude the effects of drug therapy on arrhythmic event occurrence during follow- up. Concerning scopolamine effect evaluation, this was


neither a randomized nor a double-blind study; even this fact may represent a possible bias of our investigation.

Acknowledgmmk We thank Luigi Ballardini, MS, and Mario Cornelli, PhD, for statistical assistance, and Cinzia Guicciardi for her expert technical assistance.

APPENDIX The variables used in the stepwise logistic regression

analysis were 9 spectral and nonspectral measures of heart rate variability, baroreflex sensitivity, age, prior AMI, site of AMI, Q-wave AMI, left ventricular dyskinesia and ejection fraction, ventricular ectopic beat fie- quency, ventricular couplets, and unsustained ventricular tachycardia.

1. Kleiger RE, Miller JP, Bigger JT, Moss AJ, and the Multicenter Post-Infaxtion Research Group. Dtmeasd heatt rate variability and its asswiation with increased mortality after acute myocatdial infarction. Am J Cardiol 1987;59:256-262. 2. La Revere MT, Spxchia G, Mortara A, Schwartz PJ. Bamreflex sensitivity, clinical correlates, and catdiovawular mortality among patients with a lirst myocardial infarction. A prospective smdy. Circulation 1988;78:816-824. 3. Farrell TG, Paul V, Cripps TR, Malik M, Bennett ED, Ward D, Camm AJ. Bamteflex sensitivity and electmphysiological correlates in patients after acute myocardial infarction. Circulation 1991;83:94.5-952. 4. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman IN. Frequency domain measures of heart period variabihty and mortality after myo- cat&l infarction. Circulation 1992;85:16&171. 5. Bigger IT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rot&mm JN. Correlations among time and frequency domain measures of hezut period vatiabil- ity two weeks after acute myocatdial infarction. Am J Cardiol 1992;69:891-898. 6. Yusuf S, Pete R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. frog Cardiovasc Dis 1985;27:335-371. 7. Dibner-DunIap ME, Eckberg DL, Magid NM, Cintin-Treviiio NM. The long- term increase of baseline and reflexly augmented levels of human vagal-cardiac nervous activity induced by scopolamine. Circulation 1985;71:797-804. 8. Vybiral T, Btyg RJ, Maddens ME, Bhasin SS, Cmti S, B&n WE, Lehmaon MH. Effects of transdetmal scopolamine on he;ut rate variability in normal subjects. Am J Cardiol 1990,65:604-608. 0. Casadei B, PipiIis A, Sessa F, Flather M, Conway J, Sleight P. Transdermal scopolamine: a potential tool in preventing sudden death in myocardial infarction (absu). Ew Heart J 1991;12 (suppl):366. 10. De Ferrxi GM, Mantica M, Curcuroto P, Vanoli E, Schwartz PJ. Tmnsdermal scopolamine modifies autonomic balance after myocardial infarction (abstr). Cir- cularion 1991;84 (suppl II):lI-266. ll. Den&s AR, Richards DA, Cody DV, Russell PA, Young AA, Cooper MJ, Ross DL, Utber JB. Prognostic significance of ventricular tachycardia and fibril-

lation induced at programmed stimulation and delayed potentials detected on the signal-averaged electmcardiogram of smvivors of acute myocatdial infarction. Cir- culation 198674731-745. II. Cripps T, Bemxtt ED, Camm AJ, Ward DE. Inducibility of sustained monomer- phic vennicular tachycatdia BS a pmgnostic indicator in survivors of recent myocardial infarction: a prospective evaluation in relation to other prognostic variables. J Am Co11 Cardiol 1989;14328%296. la Iesaka Y, Nogami A, Aonuma K, Nitta I, Chon Y, Fujiwam H, Himoka M. Rognostic significance of sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation using up to triple extrastimuli in survivors of acute myocardial infarction. Am J Cardiol 1990;65:1057-1063. U. Bourke JP, Richards DA, Ross DL, Wallace EM, McGuite MA, Uther JB. Routine programmed electrical stimulation in survivors of acute mywardial infarction for prediction of spontaneous ventricular tachyarrhythmias during follow- up: results, optimal stimulation protwol and cost-effective screening. J Am CON Cordial 1991;18:780-788. 1s. Pedretti R, Etm MD, Laporta A, Sarzi Braga S, Ca& B. Prediction of late arrhythmic events after acute myocardial infarction from combined use of noninvasive variables and inducibility of sustained monomorphic venhictdar tachycardia Am J cur&J1 1993;71:1131-1141. 16. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man. Circ Res 1%9;~109-121. 17. Fleiss JL. Design and Analysis of Clinical Experiments. New York: John Wiley, 19863. 18. Weissberg A, Beatty GH. Tables of tolerance&nit factors for normal distributions. Technometrics 1960$483-500. 1% Kuchar DL, Thorbum CW, Sammel NL. Prediction of serious arrhythmic events after myocardial infarction: signal-averaged electrocudiogmm, Halter monitoring and radionuclide venhiculogmphy. J Am CON Cardiot 1987;9:531-538. 20. Games JA, Winters SL, Stewart D, Homwitz S, Mihter M, Barreca P. A new noninvasive index to predict sustained ventricular tachycardia and sudden death in the fmt year after myowdial infarction: based on signal-averaged electmxdio gram, radionuclide ejection fraction and Halter monitoring. J Am CotI Cardiol1987; l&349-357. 21. Schwartz PJ, La Revere MT, Vanoli E. Autonomic nervous system and sod- den cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 1992;85 (suppl 1):1-177-I-191. 22. Lawn B, Venier RL. Neural activity and ventricular fibrillation. N Engt J Med 1976;294:116~1170. 22. Vanoli E, De Ferrari GM, Stmmba-Badiale M, Hull SS, Foreman RD. Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471-1481. 24. Bigger JT, La Revere MT, Steimnan RC, Fleiss JL, Rottman JN, Rolnitzky LM, Schwartz PJ. Comparison of bamreflex sensitivity and heaa period variabihty after myocardiaJ infarction. J Am Co11 Car&o1 1989;14:1511-1518. 21. Pipilis A, Flather M, Ormemd 0, Sleight P. Heart rate variability in acute my- ocardiaI infarction and its association with infarct site and clinical course. Am J Cardiol 1991;67:1137-1139. 26. M@lgaard H, Swensen KE, Bjenegaard P. Circadian variation and influence of 3 risk factom on heart rate variability in healthy subjects. Am J Cardiol 1991; 68~777-784. 27. &solo GC, Stmdez P, Signorini C, Calmlari F, Zuc&ini M, Balli E, Sulla A, Lamhi S. Heart rate variability during the acute phase of myocadial infarction. Circulation 1992;85:2073-2079.


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Influence of transdermal scopolamine on cardiac sympathovagal interaction after acute myocardial infarction