CONGENITAL HEART DISEASE

Atenolol Therapy for Exercise-Induced Hypertension After Aortic Coarctation Repair

Rae-Ellen W. Kavey, MD, John L. Cotton, DAD, and Marie S. Blackman, MD

After successful repair of coarctation of the aorta in childhood, exercise-induced upper body systolic hypertension is well documented. Beta blockade has been shown to reduce the arm/leg gradient in untreated coarctation of the aorta; treatment be- fore coarctation repair has decreased paradoxical hypertension after repair. Ten patients with suc- cessful surgical repair of coarctation, defined as a resting arm/leg gradient of I18 mm Hg, were eval- uated by treadmill exercise before and after fi blockade with atenolol. Mean age was 5.5 years at repair and 18 at study. At baseline evaluation, sys- tolic blood pressures at termination of exercise ranged from 201 to 270 mm Hg (mean 229 mm Hg). Arm/leg gradients at exercise termination ranged from 30 to 143 mm Hg (mean 64). Follow- up treadmill exercise studies were performed after fi blockade. Upper extremity systolic pressures at exercise termination were normalized in 9 of 10 patients. Maximal systolic blood pressure recorded at exercise termination ranged from 163 to 223 mm Hg (mean 196 mm Hg, p 50.005). Arm/leg gradient at termination of exercise also decreased significantly to a mean of 51 mm Hg (p 50.05). No patient had symptoms on atenolol and exercise en- durance times were unchanged.

The study results in this small series suggest that cardioselective B blockade can be used to treat exercise-induced upper body hypertension effec- tively after surgical repair of coarctation. Because a high incidence of premature cardiovascular dis- ease has been well documented after satisfactory surgical repair, the findings are of importance for this group Qf postoperative patients.

(Am J Cardiol 1990;66:1233-X236)

From the Division of Pediatric Cardiology, State University of New York Health Science Center at Syracuse, Syracuse, New York. Manu- script received January 1, 1990; revised manuscript received and ac- cepted July 9, 1990.

Address for reprints: Rae-Ellen W. Kavey, MD, Division of Pediat- ric Cardiology, SUNY Health Science Center at Syracuse, 725 Irving Avenue, Room 804, Syracuse, New York 13210.

A n exaggerated upper body hypertensive response to exercise after repair of coarctation of the aor- ta has been well described.les Such hypertension

theoretically leaves patients at an accelerated risk for acquired cardiovascular disease despite satisfactory sur- gical repair with elimination of resting upper extremity hypertension and arm/leg pressure gradients. Long- term follow-up studies have documented significant car- diovascular morbidity and premature mortality in pa- tients who have undergone satisfactory surgical repair of coarctation.6-9 Persistent systolic hypertension in the context of increased cardiac output, such as with exer- cise, would be anticipated to contribute to this. Pharma- cologic treatment with /3 blockade has been shown to reduce upper limb hypertension and arm/leg gradient before coarctation repair.iO Treatment with 0 blockade before coarctation repair has resulted in a significant decrease in acute paradoxical hypertension postopera- tively.” This study was undertaken to evaluate the ef- fect ‘of cardioselective /3 blockade on exercise-induced upper extremity hypertension and arm/leg gradient af- ter coarctation repair.

METHODS The records of the Division of Pediatric Cardiology

were reviewed for patients >lO years of age who had undergone previous repair of isolated coarctation of the aorta. To exclude residual coarctation of the aorta as the cause of hypertension, only patients with resting arm/leg systolic blood pressure difference I1 8 mm Hg were considered for inclusion. Those who had under- gone previous treadmill testing with exercise-induced upper extremity systolic blood pressure ,220 mm Hg, or arm/leg gradient 230 mm Hg, or both, were con- tacted, of these, 13 agreed to undergo evaluation.

Treadmill exercise: Initial blood pressure measure- ments were taken in the supine position. Right arm blood pressure was determined with an oscillometric de- vice (Dinamapp Model 1846SX) using a cuff of appro- priate size. Blood pressures taken in this way have been shown to correlate well with direct central aortic and radial artery pressures.12J3 Right leg systolic blood pressure was determined using a standard leg cuff on the thigh with a Doppler probe over the popliteal artery. Heart rate and rhythm were monitored continuously us- ing leads Vi, V5 and aVF. Patients were exercised using the modified Bruce protocol. Right arm and leg blood pressures were recorded immediately after termination of exercise, as were heart rate and electrocardiogram. These determinations were repeated every 2 minutes throughout the IO-minute recovery period.

THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 15. 1990

TABLE I Characteristics of Study Group

Age at Years of Pts. Repair (yr) Follow-Up

Surgical Baseline BP Technique A/L Grad

Exercise BP A/L Grad

Atenolol BP A/L Grad

1 9 2 7 3 17 4 14 5 l/12 6 l/12 7 12 8 7 9 9

10 7/12

11 9 1 3

19 20

5 4

11 19

R/E 126/76,14 249/69,109 209/63,79 WE 120/70,3 260/80,122 185/70,28 PA 132/70,0 210/80,30 191/61.39 SFA 136/60,18 270/65,69 214/72.18

R/E 118/50,0 220/60,91 163/65,51

R/E 144/80,9 220/70,143 203/76,60

R/E 140/78,15 240/60,73 196/61,66 PA 126/82,0 201/68,63 165/57,30

R/E 147/77,0 216/84,74 203/60,33 R/E 126/62,0 207/67,65 223/68,109

A/L Grad = systolic blood pressure difference in mm Hg between right arm and either leg; BP = blood pressure; PA = patch angioplasty; R/E = resection and end-to-end anastomosis; SFA = sub&&n flap angioplasty.

Of the 13 potential patients, 10 demonstrated upper extremity systolic blood pressure 2220 mm Hg, or arm/leg gradient 230 mm Hg, or both, with treadmill evaluation. Each patient was begun on atenolol 50 mg once in the morning. Patients were reevaluated within 4 weeks. Resting and exercise heart rates were not de- creased by 25% in 6 patients, so the dose of atenolol was increased until effective ,f3 blockade was achieved. Treadmill blood pressure results on this final dosage are those reported. Of the 10 patients, 4 were receiving atenolol 50 mg, 1 was receiving 75 mg and 5 were re- ceiving 100 mg at the time of this report.

RESULTS Study results are listed in Table I. On pretesting

evaluation (before exercise testing), systolic blood pres- sures ranged from 106 to 140 mm Hg (mean 128). While all pressures were within the normal range, the systolic blood pressure was above the 80th percentile in 8 of 10 patients when compared with age- and gender- specific normal subjects. I4 Diastolic blood pressures were normal in all subjects. Resting arm/leg gradients were only present in 5 patients and ranged from 3 to 18 mm Hg (mean 7).

At baseline treadmill evaluation, resting systolic blood pressures in the upper extremity were higher, ranging from 117 to 153 mm Hg; systolic blood pres- sures in 9 of 10 patients were above the 95th percentile compared with age- and gender-specific normal sub- jects. Diastolic blood pressures were unchanged. Arm/ leg gradients were present in 8 patients, ranging from 7 to 36 mm Hg (mean 13). The increase in systolic blood pressure and in arm/leg gradient before treadmill test- ing was attributed to anticipatory anxiety. Peak exercise heart rates reached the predicted maximum in all pa- tients, ranging from 186 to 202 per minute. Upper ex- tremity systolic blood pressures at exercise termination ranged from 201 to 270 mm Hg (mean 229). Arm/leg gradients increased in all patients with a range of 30 to 143 mm Hg and a mean of 84.

After /3 blockade with atenolol, resting heart rates significantly decreased to a mean of 62 per minute (range 47 to 75 p lO.005). Resting upper extremity blood pressures also significantly decreased to 115 to 143 mm Hg (mean 129). Although this did not reach

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statistical significance, systolic blood pressures did fall into the normal range in 7 of 10 patients. Arm/leg gra- dients persisted at rest with atenolol in 7 patients, rang- ing from 7 to 19 mm Hg. With atenolol, peak exercise heart rates were significantly reduced to a mean of 154 per minute (p CO.005). Upper extremity systolic blood pressures at exercise termination normalized in 9 of 10 patients, as shown in Figure 1. The maximal systolic blood pressure recorded at peak exercise ranged from 163 to 223 mm Hg (mean 196), a significant decrease compared with baseline reading (p SO.005). Exercise arm/leg gradients also significantly decreased to a mean of 51 mm Hg (p 50.05). In 1 patient, effective /3 blockade did not decrease systolic hypertension with ex- ercise and treatment was discontinued. No patient had symptoms related to atenolol therapy. Endurance times after ,L3 blockade did not differ significantly from times before treatment (Figure 2).

DISCUSSION In this group of patients, studied after satisfactory

surgical repair of coarctation of the aorta, severe exer- cise-induced upper extremity systolic hypertension was effectively treated by cardioselective /? blockade. Blood pressure response to exercise normalized, and arm/leg gradients were reduced. Patients had no symptoms re- lated to atenolol either during the study or on follow-up (now of 24 months), and treadmill endurance times were unchanged. Cardioselective @ blockade would ap- pear to be a safe and effective way to treat exercise- induced upper limb hypertension in this context.

Many mechanisms have been proposed as the etiolo- gy of this hypertensive response. Beekman et alI5 dem- onstrated altered baroreceptor function in patients who remain hypertensive after satisfactory coarctation re- pair; this mechanism may contribute to the hypertensive response to exercise even when resting blood pressures are normal. Histologically, the aortic wall before coarc- tation has been shown to be more rigid than the wall below coarctation and this difference may well persist after surgical repair. l6 Increased vascular resistance and abnormal reactivity in the upper extremities, with nor- mal resistance and reactivity in the lower extremities, has been demonstrated long after coarctation repairi7Js; this could certainly contribute to the hypertensive re-

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THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 15, 1990

FIGURE il. Systolic bleed pressure (BP) at exercise terfflina- tion in the 10 study patients before (1) and after (2) fi block- de with atenokd.

sponse to exercise. A minimal residual anatomic nar- rowing may result in no significant systolic gradient at rest as well; however, with the increased cardiac output with exercise, the same mild degree of narrowing can result in a significant gradient and in upper extremity hypertension.3J9 It seems likely that some combination of these mechanisms represents the etiology of exercise- induced upper extremity hypertension after satisfactory surgical repair of coarctation.

Beta blockade is known to produce a powerful sup- pression of the cardiac chronotropic response to exer- cise. Concurrently, systolic blood pressure is reduced at rest and at all levels of exercise. Cumming and Mir,lO in a catheterization study of patients with coarctation, used propranolol to demonstrate that the decrease in

Change in Endurance with Atenolol Treatment

1 2 3 4 5 6 7 8 9 10 .

Patlent Number

FIGURE 2. Treadmill exercise endurance times in the 10 study patients before and after @ blmkade with atenolol.

blood pressure after p blockade is due to a decrease in cardiac output mediated almost entirely by the decrease in heart rate, with little if any decrease in stroke vol- ume. Cardioselective @ blockade with atenolol has been shown to produce the same hemodynamic response as nonselective 0 blockade with propranolol.20 Potentially important humoral and metabolic effects of nonselective p blockade are avoided by using atenolol.

Late follow-up studies after coarctation repair dem- onstrate important residual problems. In particular, a high incidence of premature cardiovascular disease has been well documented, with a significant risk for early mortality even with apparently satisfactory surgical re- pair.6m9 The duration of preoperative hypertension has been identified as a significant risk factor for persistent hypertension and early cardiovascular disease.6j9 IHow- ever, even in patients who have undergone surgery at an early age with a satisfactory resting result, severe upper extremity hypertension with exercise is common. Exer- cise is used as an analogue for the wide variety of physi- ologic stresses resulting in increased cardiac output that occur in everyday life. Systolic hypertension is known to be a powerful predictor of cardiovascular morbidity in adults.21,22 There would therefore appear to be a good rationale for treatment of an exaggerated systolic hy- pertensive response to exercise in patients after coarcta- tion repair, most of whom had considerable systolic hy- pertension of variable duration before their operations. The results in this small series suggest that cardioselec- tive p blockage can be used to achieve this result safely and effectively.

t: We gratefully ac~owledge the secretarial assistance of Terry Howe and Cindy Shear- er.

. James FW, Kaplan S. Systolic hypertension during submaximal exercise after correction of coarctaticn of the aorta. Circulation 1974;5O(suppl 11):11-27-1X-34. 2. Connor TM. Evaluation of persistent coarctation of aorta after surgery with blood pressure measurement and exercise testing. Am .I Car&l 1979;43:74-- 78. 3. Freed MD, Rocchini A, Rosenthal A, Nadas AS, Castaneda AR. Exercise- induced hypertension after surgical repair of coarctation of the aorta. urn J Car&d 1979;43:253-258. 4. Pelech AN, Kartodihardjo W, Balfe JA, Balfe JW, Olley PM, Leenen FHH.

Exercise in children before and after coarctectomy: hemodynamic, echocardio- graphic and biochemical assessment. Am Heart J 1986;112:1263-1270. 5. Daniels SR, James FW, Loggie JMH, Kaplan S. Correlates of resting and maximal exercise systolic blood pressure after repair of coarctation of the aorta: a multivariate analysis. Am Heart J 1987;113:349-353. 6. Maron BJ, Humphries JO, Rowe RD, Mellits ED. Prognosis of surgically corrected coarctation of the aorta: a 20-year postoperative appraisal. Circulation 1973;47:119-126. 7. Simon AB, Zloto AE. Coarctation of the aorta. Longitudinal assessment of operated patients. Circulation 1974;50:456-464. 6. Liberthson RR, Pennington DG, Jacobs ML, Daggett WM. Coarctation of the aorta: review of 234 patients and clarification of management problems. Am J Cardiol 1979;43:835-840. 9. Cohen M, Fuster V, Sttde PM, Driscoll D, McGoon DC. Coarctation of the aorta. Long-term follow-up and prediction of outcome after surgical correction. Circulation 1989;80:840-845. 10. Cumming GR, Mir GH. Exercise hemodynamics of coarctation of the aorta: acute effects of propranolol. Anz Heart J 1970;32:365-369. 11. Gidding SS, Rocchini AP, Be&man R, Szpunar CA, Moorehead C, Beh- rendt D. Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta. N Engl J Med 1985;312:1224-1229. 12. Borrow KM, Newburger JW, Rosenthal A. Noninvasive estimation of central aortic pressure using the oscillometric method for analysis of systemic artery pulsatile flow: comparative study of indirect systolic, diastolic and mean brachial artery pressure with simultaneous direct ascending aortic pressure measurements. Am Heart J 1982;103:879-886. 13. Park MK, Menard SM. Accuracy of blood pressure measurement by the

Dinamapp monitor in infants and children. Pediatrics 1987;79:907-914 14. Report of task force on blood pressure control in children. Pediatrics 1977;59(suppl):797-820. 15. Beckman RN, Katz BP, Moorehead-Steffens C, Rocchini AP. Altered baro- receptor function in children with systolic hypertension after coarctation repair. Am J Cardiol 1983;52:112-117. 16. Sehested J, Baandrup U, Mikkelsen E. Different reactivity and structure of the prestenotic and poststenotic aorta in human coarctation. Implications for baroreceptor function. Circulation 1982;65:1060-1066. 17. Samanek M, Goetzova J, Liserova J, Skovranek J. Differences in muscle blood flow in upper and lower extremities of patients after correction of coarcta- tion of the aorta. Circulation 197654377-381. 16. Gidding SS, Rocchini AP, Moorehead C, Schork MA, Rosenthal A. ln- creased forearm vascular reactivity in patients with hypertension after repair of coarctation. Circulation 1985;71:495-499, 19. Markel H, Rocchini AP, B&man RH, Martin J, Palmisano J, Moorehead C, Rosenthal A. Exercise-induced hypertension after repair of coarctation of the aorta: arm versus leg exercise. J Am Coil Cardiol 1986;8:165-171. 20. McLeod AA, Brown JE, Kuhn C, Kitchell BB, Seder FA, William RS, Shand DG. Differentiation of hemodynamic, humoral and metabolic responses to beta-l and beta-2 adrenergic stimulation in man using atenolol and propranolol. Circulation 1983;67:1076-1084. 21. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk of coronary heart disease: the Framingham study. Am J Curdiol 1971;27:335-346. 22. Weissman DN. Systolic or diastolic blood pressure significance. Pediatrics 1988;82:112-114.

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