CARDIOMYOPATHY

Adrenergic Hypersensitivity After Beta-Blocker Withdrawal in Hypertrophic Cardiomyopathy David M. Gilligan, MRCPI, Wan L. Chan, MB, Ralph Stewart, MB, and Celia M. Oakley, FRCP, with the technical assistance of Shirley Krikler, and Jayshree Joshi, BSc

Withdrawal of &blocker therapy has been associated with the development of adrenergic hypersensitivity and adverse clinical effects in patients with coronary artery disease and hypertension. The aim of this study was to establish the occurrence and clinical significance of adrenergic hypersensitivity after abrupt withdrawal of longterm /? blockade in hypertrophic cardlomyopathy. Beta-adrenergic sensitivity was measured using the isoprenaline chronotropic dose~s. Symptom assessment chronotropic doses caleulation, bicycle exercise, echocardiography and Holter monitoring were performed while the patient received &bloeker therapy and repeated on days 2,4,6,8 (acute withdrawal perlod) and on day 21 after abrupt withdrawal. The study was terminated after 7 patients had been studied because all patients experienced a marked deterioration in symptoms and several clinical events had occurred. The chronotropic doses (mean f standard deviation) demonstrated /31-adrenergic hypersensitivity with a minimal value of 1.6 f 0.8 H during the acute withdrawal period compared with 3.8 f 1.7 # on day 21 (p = 0.003). Heart rates during rest and exercise showed an overshoot increase during the acute withdrawal period. The maximal 24-hour ventricular ectopic count was higher during the acute withdrawal period than during day 21 (p = 0.04). Df 3 patients with inducible outflow tract gradients, 2 developed resting gradients >30 mm Hg during the acute withdrawal period. There was an increase in peak late tilling velocity of mltral inflow after /Iblocker withdrawal. In conclusion, transient padrenergic hypersensitivity occurs after & blocker withdrawal in hypertrophic cardiomyopFrom Clinical Cardiology (Department of Medicine), Royal Postgraduate Medical School, Hammersmith Hospital, London, United Ringdom. This study was supported in part by grants from Nissan, United Kingdom. Manuscript received April 1, 1991; revised manuscript received and accepted May 20,199 1. Address for reprints: David M. Gilligan, MD, Clinical Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W 12 ONN, United Kingdom.

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68

athy and is associated with significant physiologic changes and adverse clinical consequences. (Am J Cardiol 1691;68:766-772)

n patients with coronary artery disease,adverseeffects of abrupt @-adrenergicblocker withdrawal were first reported in 1973,’ and since then several case reports and clinical trials have reported the development of unstable angina, myocardial infarction and even suddendeath when P-blocker therapy was stopped suddenly.2-4Hypertensive patients who discontinue p blockers may also have increased cardiovascular mortality and morbidity in the withdrawal period,5,6and a P-blocker withdrawal syndrome, manifested by palpitation, anxiety and hypertension above pretreatment levels may occur in some patients.5 These adverseeffects may be due to transient adrenergic hypersensitivity after P-blocker withdrawal. In normal subjectsand in patients with hypertension, hypersensitivity to catecholamine stimulation has been shown to begin 24 to 48 hours after ,Bblockers are withdrawn and may last for up to 14 days.7-9This hypersensitivity has been attributed to an increasein P-receptor numbers or sensitivity (up-regulation) during therapy that persiststemporarily after the elimination of a P-blocking drug. l”yl l Although p blockers are widely used in hypertrophic cardiomyopathy,i2,13the question of whether adrenergic hypersensitivity occurs after @-blockerwithdrawal has not been investigated in this condition. Since patients with hypertrophic cardiomyopathy have a substrate for the development of arrhythmia14 ischemia15 and labile outflow tract obstruction,16P-blocker withdrawal may be especiallyhazardous.Additionally it has been suggestedthat inherent adrenergic hypersensitivity may be a feature of the developmentof this condition. l7 The aim of this study was to determine the occurrence and significance of adrenergic hypersensitivity after abrupt withdrawal of p blockade in hypertrophic cardiomyopathy.

I

METHODS Patients: The diagnosis of hypertrophic cardiomyopathy was basedon typical clinical and electrocardio-

SEPTEMBER 15, 1991

TABLE I Clinical Features and Beta-Blocker Therapy (n=7) 8 Blocker Case No.

Age (yr)

NYHA Class

IVS

PW

& Sex

ASH

(mm)

(mm)

1 2 3 4 5 6 7

32M 68F 57F 70F 36M 37F 53M

II II II Ill I Ill III

+ + + + + +

15 16 20 17 16 32

10 14 12 13

*Long-acting preparation of propranolol. ASH = asymmetric septal hypertrophy; present; - = ASH absent; 0 = none.

15

10 17 11

ISMN = isosorbide

Drug Therapy

Dose

Duration

(mg)

Ws)

Atenolol Atenolol Atenolol Atenolol Propranolol Propranolol* Propranolol

100 100

1.5 4

100

2

200 360 320 240

5 14 3 20

mononitrate;

IVS = intraventricular

graphic findings in association with a hypertrophied, nondilated left ventricle on 2-dimensional echocardiography, in the absenceof a cardiac or systemic causeof such hypertrophy. Patients were consideredsuitable for study if they had been treated with p blockers for 13 months and if there was a clinical indication to stop pblocker therapy. Exclusion criteria were ( 1) a resting left ventricular outflow tract gradient >30 mm Hg (at cardiac catheterization or derived from Doppler flow velocity) since isoprenaline was to be used to test adrenergic sensitivity; (2) atria1 fibrillation or permanent pacemaker; (3) congestive heart failure; (4) a history of serious deterioration on previous withdrawal of /3 blockers; and (5) a history of cardiac surgery, coronary artery diseaseor other concurrent disease.The clinical features, drug therapy and indication for P-blocker withdrawal in the 7 patients studied are listed in Table I. Four patients were receiving cardioactive medication other than p blockers (Table I). To avoid confounding effects, these drugs were maintained unchanged throughout the study period even though they were likely to mitigate the effects of adrenergic hypersensitivity. Study protocok The study was approvedby the hospital ethics committee. All patients gave written, informed consent. Patients were admitted to the hospital and assessedon day 0 (with p blocker) and on days 2, 4, 6 and 8 after abrupt cessationof a p blocker. If well, patients were discharged on day 9 and restudied on day 21, when adrenergic hypersensitivity would be expected to have resolvecL8 Methods: Six tests were performed on each study day. Tests were always performed in the following order and begun in the early afternoon: 1. HEARTRATEANDBLOODPRESSURE: Heart rate and blood pressure were measured after 5 minutes supine rest. ~.ECHOCARDIOGRAPHYANDDOPPLER: All studieswere performed with a Toshiba Sonolayer SSH 65A phasedarray ultrasound system using a 3.75MHz transducer

septum;

Indication for Withdrawal

Concomitant Drug Therapy (m&!/day)

Fatigue Fatigue Resistant symptoms Resistant symptoms Fatigue, depression Resistant symptoms Reduced systolic function

0 Amiodarone (200) Verapamil(240) 0 Amiodarone (200) 0 ISMN (30)

NYHA = New York Heart Association:

PW = posterior wall;

+ = ASH

for 2-dimensional echocardiography and a 2.5MHz transducer for Doppler. Left ventricular end-systolic and end-diastolic dimensions were measured from the parasternal short-axis view at the level of the tips of the mitral leaflets. Transmitral early (E wave) and late (A wave) peak inflow velocities were measured by sampling with pulsed Doppler proximal to the mitral leaflet tips and recording in midexpiration. An average of 3 values was taken. The left ventricular outflow tract velocity was measuredby continuous-wave Doppler from the apical 5-chamber window. On 1 occasion in the withdrawal period (usually day 4), Doppler was performed during the isoprenaline sensitivity test (see later) to determine the maximal inducible left ventricular outflow tract velocity and derived pressure gradient. Where possible,all studies in an individual patient were performed by 1 operator. All echocardiographic measurements were obtained by 1 experienced observer (RS). 3. ISOPRENALINE SENSITIVITY TEST: The heart rate changesproduced by small incremental bolus dosesof isoprenaline were measured as an index of cardiac piadrenergic sensitivity.8~18 Baselineheart rate was calculated as the mean of 10 RR intervals before each isoprenaline dose. An initial bolus of isoprenaline 0.1 pg was given into a rapidly running intravenous infusion of 5% dextrose. A 3-lead electrocardiogram was recorded continuously for the next 3 minutes. If the heart rate did not increase,the next doseof 0.25 pg was given and the dosethereafter doubled (maximal dose256 pg) until an increasein heart rate of 30 to 35 beats resulted. A linear regression analysis was performed between the logarithms of each isoprenaline dose and the resulting maximal increase in heart rate. From this regression equation the isoprenaline dose required to raise the heart rate by 25 beats/min was calculated (“chronotropit dosezs” [CD2s], Figure 1). 4. EXERCISE TEST: Symptom-limited exercise tests were performed on an electrically braked bicycle ergometer (ERG 55I, Bosch) in the upright position in 3-

BETA-BLOCKER WITHDRAWAL IN HYPERTROPHIC CARDIOMYOPATHY

767

minute increment was 20 f 7 W. Heart rate and blood pressureat each work load and at peak work load were recorded together with the time to chest pain or ST Heart Rate 30_ depression,or both. 5. TWENTY-FOUR-HOUR HOLTER MONITOR: Two-channel Holter monitoring was performed using “Tracker” recorders(Reynold’s Medical). Tapeswere analyzed by a technician on a Pathfinder 3 high-speed analyzer 0 I * I ‘II * I - 1 (Reynold’s Medical) and reviewed by 1 of the investi0.0 0.2 0.4 0.6 0.6 1.0 gators (DG). Minimal and maximal heart rates, the Log dose of lsoprenaline number of supraventricular and ventricular extrasysltoles in 24 hours and the Occurrenceof supraventricular FIGURE 1. Method of cakulation of the dose of kprenaline required to increase hearl rate by 26 beats/n& = chronotroor ventricular tachycardia (23 extrasystolesat a rate of pit dose= (CD26). In this example logarithms (Log) of 4 isoL 120 beats/min) were recorded. prendino dosoa are plotled against resulting changes in heart 6. SYMPTOMS: Patients scoredchest pain, breathlessrate, a regregsion line is plotted between these points, and CD25 Is &rived from the rogrosd etplatii. ness,palpitation and presyncopeor lightheadednesson a 0 to 4 scale of severity. The 4 individual symptom minute incremental stages.Patients performed at least scoreswere combined to give a total symptom score. Statistical analysis: A “summary measures” tech1 exercisetest before the study, so that they were familiar with the test and individualized work load protocols nique was used to determine if hypersensitivity occould be determined. The mean ( f standard deviation) curred: the minimal or maximal value (e.g., minimum starting work load was 26 f 12 W and the mean 3- for CD25 and maximum for heart rate) demonstrated

0 LOG

3

Ioy:j

L

:

I

I

1

I

I

I

I

I

I

I

I

,

654321o-1

,

0

,

24

,

,

68

,

I

21

024

68

Days following Beta-Blocker Withdrawal 768

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68

SEPTEMBER 15. 1991

,

21

FIGURE 2. Logarithms (LOG) of the chronotropic doso~ (CD26) of isoprenaline in each patient while receiving b-blocker therapy (day 0) and afler withdrawal. Patient 6 did not undergo se&l testing because of chest pain with isqrenaline. In all patients except patient 2, CD25 decreases to a nadir in the first week and than hncrosaos on day 21, imliiting transient &-adrenergic hype-.

r

TABLE II Rest and Exercise Hemodynamics During Beta-Blocker Withdrawal in Hypertrophic Cardiomyopathy Peak

Days After Withdrawal

(or nadir*) on Day 2,

B Blocker

(day 0) Supine rest Heart rate (beats/min) Systolic BP (mm/Hg) Diastolic BP (mm/Hg) Rate-pressure product (0.000) 3-Minute exercise Heart rate (beats/min) Systolic BP (mm/Hg) Diastolic BP (mm/Hg) Rate-pressure product (0.000) Peak exercise Heart rate (beats/min) Systolic BP (mm/Hg) Diastolic BP (mm/Hg) Rate-pressure product CO.0001 Duration exercise W *Minimal value. All values are mean k standard

Day 2

Day 4

Day 6

Day 8

4,6or8

80(13)

59 (10)

70 (16)

70 (12)

72 (11)

76 (9)

127 (26)

126 (20)

133 (201

123 (23)

130 (23)

79 (5) 7.3 (1.6)

79 (7) 8.8 (1.2)

a3 (10) 9.2 (1.2)

79 (5) 8.9 (2.4)

a2 (4) 9.8 (1.7)

a4 (15) 139 (36) 93 (9)

11.5 (2.8) 98 (26) 152 93 15 394

(32) (13) (3) (211)

101 147 91 14.9

(17) (26) (8) (3.6)

109 148 91 16.2

Day 21 71 (7)

134 (20)

75 (6)* 10.7 (2.1)

Peak vs 0

Peak vs21

p Value

p Value

133 (24)

0.16

0.002

88 (9) 9.3 (1.3)

0.18 0.002

0.02 0.89 0.004 0.12

(20) (29) (9) (4.5)

112 146 93 16.4

(25) (28) (9) (5.3)

iii 144 a9 16.0

(ia) (24) (9) (3.7)

116 152 a7 17.6

(21) (29) (lo)* (4.8)

103 153 96 15.9

(17) (33) (10) (5.2)

0.004 0.15 0.14 0.01

0.025 0.84 0.006 0.06

130 (22)

133 (33)

165 (23)

163 (33)

139 168 92 23

(28) (31) (9) (6)

144 167 94 24

(26) (24) (8) (5)

148 174 a7 26

(26) (27) (7)* (6)

133 169 98 23

(25) (291 (ii) (6)

30 mm Hg. Post = after. BETA-BLOCKER WITHDRAWAL IN HYPERTROPHIC CARDIOMYOPATHY

771

sures could explain the change in filling pattern,23and this would fit with the described lusitropic effect of @adrenergic stimulation in hypertrophic cardiomyopathy.24Alternatively, the increasedatria1 contribution to filling could represent a deterioration in myocardial relaxation and early filling without p blockers. In the setting of abrupt ,&blocker withdrawal, an increase in myocardial ischemia and other factors may adversely affect diastolic function and, interestingly, one of the main studies to show improvement in diastolic function with /?-blockadewas performed with treatment and 7 days after abrupt withdrawal.25 Implications

for clinical

practice

and research:

rebound phenomenon:exacerbationof coronary eventsafter abrupt cessationof antianginal therapy. N Engl J Med 1975;293:416-418. 4. EgstrupK. Transient myocardial ischemiaafter abrupt withdrawal of antianginal therapy in chronic stable angina. Am J Cardiol 1988;61:1219-1222. 5. Houston MC, Hedge R. Beta-adrenergicblocker withdrawal syndromesin hypertensionand other cardiovasculardiseases.Am Heart J 1988;116:515-523. 6. PsatyBM, KoepsellTD, WagnerEH, LoGerfo JP, lnui TS. The relative risk of incident coronary heart diseaseassociatedwith recently stopping the use of @Blockers. JAM.4 1990;263:1653-1657. 7. BoudoulasH, Lewis RP, Kates RE, DalamangasG. Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects.Ann Intern Med 1977;87:433-436. 8. Nattel S, Rangno RE, Van Loon G. Mechanism of propranolol withdrawal phenomena.Circulation 1979$9:1158-l 164. 9.R angnoRE, Langlois S. Comparisonof withdrawal phenomenaafter propran0101,metoprolol and pindolol. f3r J Clin Pharmacol 1982;13:3458-351s. 10. Aarons RD, Nies AS, Gal J, Hegstrand L, Molinoff PB. Elevation of betaadrenergicreceptor density in human lymphocytesafter propranolol administration. J Clin Invest 1980;65:949-957. 11. FraserJ, NadeauJ, RobertsonD, WoodAJJ. Regulationof humanleukocyte beta receptorsby endogenouscatecholamines:relationship of leukocyte beta receptor density to the cardiac sensitivity to isoproterenol. J Clin Invest 1981;

First, most research studies are performed after the temporary omission of therapy. From our results it is clear that this will be a time of adrenergic hypersensitivity, and the hemodynamic state and its responseswill 67:1777-1784. 12. Frank MJ, Abdulla AM, Watkins LO, Prisant L, Stefadouros MA. Longbe different from those in the truly basal state. Studies term medical managementof hypertrophic cardiomyopathy: usefulnessof proshould be performed 3 weeksafter discontinuing thera- pranolol. Eur Heart d 1983;4(supplF):lSS-164. py. Second,our study suggeststhat abrupt discontinua- 13. Maron BJ, Bonow RO, Canon RO, Leon MB, Epstein SE. Hypertrophic cardiomyopathy: interrelation of clinical manifestations, pathophysiology and tion of fi blockers is potentially deleteriousbut the opti- therapy. N Engl J Med 1987;316:780-789and 844-852. ma1 method of withdrawing long-term p blockade has 14. McKenna WJ, England D, Doi YL, Deanfield JE, Oakley CM, Goodwin JF. in hypertrophic cardiomyopathy. 1.Influence on prognosis.Br Heart not been established.Rango and Langlois showedthat JArrhythmia 1981.46:168-172, gradual dose reduction and subsequentmaintenance of 15.0 Gara ’ PT, Bonow RO, Maron BJ, DamskeBA, Van Lingen A, Bacharach low-dose p blockers for 3 weekswill prevent adrenergic SL, Larson SM, EpsteinSE. Myocardial perfusionabnormalitiesin patients with hypertrophic cardiomyopathy:assessmentwith thallium-201 emissioncomputed hypersensitivity. Finally, although fi blockers produce tomography. Circulation 1987;76:1214-1223. symptomatic benefit in hypertrophic cardiomyopathy, 16. Wigle ED, SassonZ, Henderson MA, Ruddy TD, Fulop J, Rakowski H, Williams WG. Hypertrophic cardiomyopathy.The importanceof the site and the their use has not been associatedwith improved surviv- extent of hypertophy: a review. Prog Cardiovasc Dis 1985;28:1-83. a1.14y26 Temporary omission of @blockers may have led 17. Perloff JK. Pathogenesisof hypertrophic cardiomyopathy: hypothesesand to periods of excessrisk, negating any beneficial effect speculations.Am Heart J 1981;101:219-226. 18. CleavelandCR, Rangno RE, ShandDG. A standardizedisoproterenolsensiof p blockers on survival. tivity test. The effects of sinusarrhythmia, atropine and propranolol. Arch Intern Conclusion: Transient /3-adrenergichypersensitivity Med 1972;130:47-53. 19. Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial occurs after abrupt withdrawal of P-blocker therapy in measurement in medical research.Br Med J 1990,300:230-235. hypz-trophic cardiomyopathy and iS associated With 20, Al-QassabH, &eves LA, FrancisPL, Al-Sereiti MR, Findley L, HedgesA, important physiologic changes and clinical deteriora- Silman R, Turner P. Is there a central nervouswithdrawal syndromeassociated with discontinuing long-term treatment with propranolol? Human Toxicol tion. Physicians and patients should avoid abrupt with- 1988;7:249-254, drawal of p blockers in hypertrophic cardiomyopathy. 21. FrishmanWH, Christcdoulou J, Weksler B, SmithenC, Killip T, ScheidtS. Clinical research studies performed during the tempo- Abrupt propranolol withdrawal in angina pectoris:effects on platelet aggregation and exercise tolerance. Am Heart J 1978;95:I69- 179. rary omission of /3 blockers may be affected by the 22. Appelton CP. Influence of incremental changesin heart rate on mitral flow velocity: assessmentin lightly sedated, consciousdogs. J Am CON Cardiol presenceof adrenergic hypersensitivity. We are grateful to John G. F. Cleland, MD, for his advice and comments. Acknowledgment:

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1991;17:227-236. 23. St. Goar FG, GiggonsR, Schnittger I, Valantine H, PoppRL. Left ventricular diastolic function. Doppler echocardiograpbicchanges soon after cardiac transplantation. Circulation 1990;82:872-878. 24. Udelson JE, Cannon RO, Bacharach SL, Rumble TF, Bonow RO. Betaadrenergicstimulation with isoproterenolenhancesleft ventricular diastolic performance in hypertrophic cardiomyopathy despite potentiation of myocardial ischemia.Circulation 1989;79:371-382. 25. Alvares RF, Goodwin JF. Non-invasive assessmentof diastolic function in hypertrophiccardiomyopathyon and off betaadrenergicblockingdrugs.Br Heart J 1982;48:204-212. 26. Maron BJ, Roberts WC, EpsteinSE. Suddendeath in hypertrophic cardiomyopathy: a profile of 78 patients. Circulation 1982;65:1388-1394.

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