CURRENT REVIEW
Paradoxical Hypertension After Repair of Coarctation of the Aorta: A Review of Its Causes Will C. Sealy, MD Department of Surgery, Mercer University School of Medicine, and the Medical Center of Central Georgia, Macon, Georgia
Correction of a coarctation of the aorta, an apparent simple cause of hypertension, paradoxically can provoke two hypertensive responses, one of which is potentially fatal. The first, limited to the first 24 hours, occurs in nearly one half of the patients. This is likely due to the high set of the carotid baroreceptors. The second, which may be associated with abdominal pain and, in some, with necrosis of the small bowel as a result of severe arteritis confined to arteries arising from the aorta below the coarctation, develops in about one half of the first responders. Norepinephrine excretion greatly increases
for several days, whereas angiotensin levels are elevated for 3 to 4 days. The hypertension responds to pblockers, to arterial smooth muscle relaxants, and to angiotensin converting enzymes. A theory is advanced to explain the second response. It is the adaptation gone awry that ensures adequate flow to exercising muscles below the coarctation, above and beyond that delivered by increasing the systolic pressure. It could be a regionally controlled mechanism similar to the rationing of blood flow in diving mammals. (Ann Thoruc Surg 2990;50:323-9)
T
jejunum for necrosis. At autopsy, severe acute arteritis was found in the arterial system connected to the aorta by the vessels originating from below the coarctation [ 3 ] .The changes noted were a disruption of the walls of the vessels associated with fibrinoid necrosis and intense acute inflammatory exudate. The pathologist described the change as resembling periarteritis nodosa. Lober and Lillehei [4] made a similar comparison in their study. The second patient, a 4-year-old boy, was admitted a little more than a year later. His blood pressure was 150/80 mm Hg in his arms and 90/65 mm Hg in his legs. The coarctation of the aorta was resected, and a large patent ductus arteriosus was divided. On the fourth postoperative day, he complained of abdominal pain. His blood pressure at this time was 150/125mm Hg in both arms and legs. The white blood cell count ranged from 24 to 48 x lO’/L. On the 14th postoperative day at laparotomy, there were punctate serosal hemorrhagic areas throughout the small bowel. In the ileum, there were three perforations and many scattered areas of spotty gangrene. Seventy centimeters of the ileum had to be removed. Microscopic sections of the mesenteric vessels and of the mediumsized and small arteries in the abdominal wall showed findings similar to those noted in the first patient. The patient recovered satisfactorily. Ten days after he was operated on, the blood pressure was 118/74 mm Hg in his arms and 124/84 mm Hg in his legs. Severe hypertension and arteritis suggested that overactivity of the sympathetic nervous system was the cause of these remarkable changes. Soon after, the same abdominal complaint developed in a third patient, a 6-year-old girl, following removal of her coarctation. Preoperative blood pressures in her arms and legs were 190/40 mm Hg and 10472 mm Hg, respectively. A moderate-sized ventricular septa1 defect was present. Forty-eight hours after the operation, the blood pressure
hat the correction of a coarctation of the aorta, an apparently simple cause of hypertension, can provoke two different hypertensive responses, one of which is life threatening, is unexpected and illogical; thus, the name paradoxical hypertension [ 11. The first response occurs immediately and subsides in most patients within 24 hours. The second response, which is more pronounced in diastole, appears within 48 to 72 hours (Fig 1). The striking finding in the second response is the severe acute inflammatory changes that may occur in arteries and arterioles that originate from the aorta below the coarctation [24]. In this review, I will give an account of how these postoperative hypertensive events were first recognized and how a therapeutic program was then devised that has virtually eliminated them as serious clinical problems. This will be followed by a review of current thoughts about the physiological adaptations occuring in coarctation that maintain homeostasis. Then I will propose a theory to explain the pathogenesis of the two paradoxical responses based on a disruption of these cardiovascular adaptations. This story [3]began in 1952 after a 22-year-old man was operated on for coarctation of the aorta. Before operation, the blood pressure in his arms varied from 190 to 215/60 to 0 mm Hg and in his legs, from 140/80 to 0 mm Hg. He had a pronounced aortic valvar insufficiency. In the immediate postoperative period, his blood pressure increased in his arms and legs from 140180 mm Hg on the first day to 224194 mm Hg on the third day. At this time, he complained of moderately severe abdominal pain. He died 13 days later during removal of most of the ileum and Address reprint requests to Dr Sealy, Department of Surgery, Hospital Box No. 140, The Medical Center of Central Georgia, 777 Hemlock St, Macon, GA 31208. 0 1990 by The
Society of Thoracic Surgeons
0003-4975/90/$3.50
324
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
230
I
21 0
.
10
0
I
2
'
I
0
t , . '
I
2
'
I
4
'
I
6
.
1
8
'
1
10
'
+30dayr+
DAYS
Fig I . Blood pressure (BP) record of a patient showing a marked elevation of the blood pressure immediately after operation. The second hypertensive response begins on the fourth day, and blood pressure approaches normal on the 30th day.
in the arms was 190/140 mm Hg. At 72 hours, abdominal pain developed and she had a white blood cell count of 25 x lo9 L [3]. On the assumption that overactivity of the sympathetic nervous system was present, intravenous hydralazine hydrochloride was given. The abdominal pain promptly disappeared, the white blood cell count decreased to normal, and the blood pressure decreased from 190/140 mm Hg to 150/70 mm Hg. Medication was continued for 10 days. She was discharged from the hospital with a blood pressure of 140/80 mm Hg in her arms and without symptoms. Very soon after this experience, 3 more patients were found to have the same signs and symptoms. In these patients, reserpine was used with equally good results. The records of all patients with coarctation of the aorta on whom we had operated were then reviewed [l]. Postoperative hypertension was considered to be present when it was found to be higher than the preoperative level of the arm pressure. Although the blood pressure records in some patients were incomplete, 7 of 30 patients (23%)were found to have had marked elevation of blood pressure in the first 24 hours. In 1 patient, the systolic pressure was recorded as high as 230 mm Hg. One of the 7 patients progressed to the second response. Fourteen patients (47%)had a delayed hypertensive response 12 to 72 hours after operation. When a prospectively observed group of patients was studied after removal of the coarctation [5], 26 of the 41 patients (63%)had the immediate hypertensive response. The second hypertensive response was found in 12 of the 41 patients (29%)but all 12 patients had the first response. These two studies clearly separated the two postoperative hypertensive responses (Fig 1). The first response, occurring in more than one half of the patients, was not usually of more than 24-hours' duration. The second hypertensive response was frequently associated with abdominal pain. The two postoperative hypertensive responses were not described in early reports of the surgical treatment of coarctation, but most detailed accounts since then have
Ann Thorac Surg 1990;50:323-9
noted paradoxical hypertension [6-191. One patient had the diagnosis made 3 months after repair [20]. Along with abdominal pain, paralysis developed in the lower half of his body secondary to arteritis of a spinal artery. Vasculitis including splenic and mesenteric artery rupture [4, 9, 211 and gastrointestinal bleeding have been reported [22]. Intestinal stricture developed in another patient 4 weeks after operation [lo]. Although there are reports of arteritis in the mesenteric vessels (4, 8, 2CL261, only two autopsy reports aside from the one outlined here describe the vascular lesions in areas other than the intestines [4, 201. The cause of the first hypertensive response can be explained by the release of the stretch on the baroceptors in the carotid arteries and aortic arch after removal of the aortic obstruction. The best evidence for this is the marked increase in sympathetic activity indicated by elevations in norepinephrine level after operation greater than those found after other operations of similar magnitude [12, 26, 271. The norepinephrine level remained elevated for up to 13 days in the Duke series (Fig 2) and for 6 months in the Benedict, Graham-Smith, and Fisher study [28]. The latter observers noted that only 2 of the 6 patients had the early hypertensive response, whereas 5 of the 6 patients had the second response. In the Duke series, 6 of 12 patients had elevated levels of norepinephrine with 5 of the 6 having the first and second responses. Studies of baroreceptor sensitivity have been done only on postoperative coarctation patients who have chronic hypertension. As expected, they had a high set of the baroreceptors [29]. Baroreceptor activity in experimental coarctation investigated by Bonchek and Rees [30] showed only normal sensitivity. Experimental observations of Igler, Boerboom, and associates [31] indicated that the baroreceptor reset occurred after induction of coarctation, only to return to normal after coarctation repair. The reason for the second hypertensive response is not clearly understood. The following facts are known. Pa240 220
200 I80 a
160 140
P. 120 e = 100 e
'
N
80
60
40 20
0 Control0
I
2
3
4
5
6 7 DAYS
8
91011
121314
Fig 2 . Great increase in excretion of norepinephrine (Nor-Ep) in a 12-year-old patient after operation. This was associated with the two hypertensive responses and abdominal (ABD) pain.
Ann Thorac Surg 1990;5032>9
REVIEW SEALY PARADOXICAI. HYPERTENSION, COARCTATION AORTA
normal. The pressure continues to rise over the next 3 weeks or so, when one would expect collateral circulation to be increasing. The pressure below the coarctation reaches its precoarctation level in 14 to 21 days (Fig 3). Added evidence that the kidneys play a role in hypertension of coarctation were the experiments of Scott and Bahnson [45, 461, who showed that moving a single remaining kidney above the experimental thoracic coarctation relieved the hypertension. Studies of renal dynamics in dogs with experimental coarctation have shown only an increase in the filtration fraction [55-571. Svane and Jensen [58] reported microscopic evidence of juxtaglomerular hyperplasia.
EXPERIMENTAL COARCTATION OF THE AORTA
cs
24 22
?--,,,-,,,,-.---------~---*
325
CD
FS FD 120
Hypertension and Coarctation in Humans 0
20
40
60
80
100
120
140
J
DAYS
Fig 3. Coarctation of the aorta on the adult dog shows that the initial postcoarctation blood pressure is not elevated. Only at 14 days after operation do the pressures reach hypertensive level. Note that femoral pressures are stabilized slightly above the preoperative levels. (CS = carotid systolic; CD = carotid diastolic; FD = femoral diastolic; FS = femoral systolic.)
tients have increased sympathetic activity that continues well after the expected baroreceptor reset. The norepinephrine levels encountered indicate extreme levels of sympathetic activity, judged by the studies of Floras and associates [32]. In addition, the second hypertensive response can be reversed by reserpine, which causes a depletion of the adrenergic transmitter; by @blocking agents [33]; by hydralazine hydrochloride, a smooth muscle relaxant; and by angotensin converting enzyme inhibitors. Giddings and co-workers [34] showed that preoperatively administered propranolol prevented a hypertensive response in 7 patients, whereas hypertension developed in 4 of 7 patients of the control group. That plasma renin activity would increase for 3 to 5 days after removal of the coarctation and that angiotensin I1 enzyme blocking agents will reverse the hypertensive responses is, to say the least, illogical [35-381. The relationship between norepinephrine and angiotensin 11, both potent vasoconstrictors, is complex [3943]. None of these considerations explains exactly why blocking the action of one or the other hormone are equally effective in controlling paradoxical hypertension.
Experimental Coarctation of the Aorta Coarctation of the aorta has been produced in adult dogs [4448], puppies [30], and rats [49, 501. The development of the hypertension resembles the pattern of the onekidney, one-clip Goldblatt preparation [51] (Fig 3). Plasma renin activity increases immediately and remains elevated for 3 to 5 days [52-541. The blood pressure above and below the coarctation site begins to increase in 3 to 5 days, at the time the plasma renin activity is returning to
The hypertension in coarctation of the aorta in humans has been the subject of both intense study and much speculation [59-651. Sir Thomas Lewis [62] showed that the femoral pulse wave occurred later than the radial, opposite to the normal. He found normal blood flows in the legs. Direct arterial pressure measurements, notably those of Steele and Cohn [63], indicated that mean pressures below the coarctation were frequently at hypertensive levels and equal to the resting mean pressures above the coarctation. Wakim, Slaughter, and Clagett [64] found blood flows to be unchanged in the arms and legs before and after operation for coarctation. Patterson, Shepherd, and Whelan [65] found flows to be the same in the arms and legs, but the resistances in the arms were greater than those in the legs. The cross-sectional area of the coarctation and collateral circulation vary tremendously from patient to patient. In an occasional neonate, congestive failure occurs, supposedly due to failure of collaterals to develop before birth [66-681. Examples of heart failure corrected by repair of the coarctation in patients who have intracardiac lesions have also been reported [69]. In an attempt to supply blood flow demands to strictures below the coarctation, unusually high arterial pressures occur above the coarctation with exercise [70-721. In one study [70], the systolic levels in 6 of 20 patients reached 300 to 360 mm Hg. Dahlback, Dahn, and Westling [71] found that in the femoral artery, mean pressures recorded during exercise did not change despite great increases above the coarctation, but cardiac output recorded during strenuous exercise increased from 5 to 10 L. In a study of 20 patients with coarctation, Taylor and Donald [70] found 6 patients with clinically significant elevations of resting cardiac output. Nine of the 20 patients showed an increase in the pulmonary wedge pressure during exercise. Seven of 8 patients examined after operation were found to have a reversion of the pressure to normal levels. Three patients had an increase in the pulmonary artery pressure during exercise. The left ventricular work before operation was increased in all 20 patients over that of the normal control group. Do these observations indicate that the left ventricle may be stressed to its limits to supply blood flow to structures below the coarctation?
326
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
The great interest in 1930 to 1940 in the Goldblatt experiments [73, 741 led to several studies in humans trying to relate the hypertension in coarctation to the kidney [75-771. Harris, Sealy, and DeMaria [77] reviewed the information then available on renal hemodynamics in coarctation and reported their observations on patients before and after operation. They concluded that there was no decrease in renal blood flow in coarctation and speculated that some other mechanism was a factor in causing the hypertension, in addition to the resistances at the coarctation site and in the collaterals. When it became possible to determine more easily the plasma renin activity, this was measured in patients with coarctation [7%81]. Most showed no elevation in plasma renin activity before operation. Alpert and co-workers [80], in an excellent study on patients with coarctation, found that when furosemide was added to a low-sodium diet, marked elevations in plasma renin activity occurred. In addition, they found that plasma volume and extracellular fluid volume were increased, as was the cardiac output, and noted the similarity between coarctation and Goldblatt hypertension. In a recent discussion of the hypertension in coarctation of the aorta, Schaffer [82] called attention to ”the bipedal exercise triad.” During exercise, an increase occurred in systolic pressure in the arms. The pressures in the legs were unchanged despite an increase in the systolic gradient across the coarctation. The response to exercise caused a shunting of blood to muscle from the kidney, which increased plasma renin activity.
Comment The cardiovascular adaptations to a coarctation of the aorta are more complex than merely an elevated blood pressure above the coarctation and the development of collateral arterial channels around it. As the removal of the coarctation may cause two hypertensive responses, it is reasonable to assume that interruption of the need for the adaptations is related to these unexpected events. That such responses do not occur in every postoperative patient speaks of the wide variation among patients in the coarctation cross-sectional area and in the number and size of the collaterals. Thus in some patients, collateral development alone ensures blood flow to the structures below the coarctation. The high set of the baroreceptors explains the first postoperative hypertensive response. The decrease in the stretch of the carotid and aortic baroreceptors by removal of the aortic obstruction causes greatly increased sympathetic activity that could be a factor in initiating a second response. The high set could be the result of the next adaptation noted below. The adaptation that by increasing the pressure above the coarctation maintains normal renal blood flow has been compared with Goldblatt hypertension. There is one important difference between the two hypertensions. The kidneys have to share the blood flow getting through the coarctation. For example, the great flow demand that suddenly arises from strenuous muscle activity can in-
Ann Thorac Surg 1990;50:32>9
crease the need from less than 800 mL/min to as much as 5,000 to 8,000 mL/min (831. To meet this need during exercise in a tight stenosis, a great increase in the systolic blood pressure occurs above the coarctation to as much as 360 mm Hg. If the pressure increase above the coarctation fails to meet the flow needs of the exercising muscles below, are there other adaptations present that can ration the volume of blood that gets through the coarctation and through the collaterals to supply this demand? A part of this needed diversion to the muscle occurs directly to the muscles of the trunk and upper abdomen by the large collaterals, which may further reduce the blood volume available for the distal aorta. Shunting of blood to structures of great need is a mechanism found in both physiological and pathological states. During exercise, there is a shift of blood to muscles to meet short-term needs. In heart failure and low-volume shock, blood may be shunted to the heart and brain from the kidney, the gastrointestinal tract, and the extremities. One of the most interesting examples of physiological shunting of blood to the site of greatest need is found among diving animals, in which blood flow to muscle, gut, and kidney is nearly all shunted to the heart-brain axis [84-86.. Weddell seals can actively search for food while submerged for as long as an hour. Folkow and co-workers [84] showed that in diving ducks, the arteries leading to the muscles but outside of them had high concentrations of adrenergic receptors. He believed that this mechanism permits the duck to reduce muscle blood flow by constriction of the large arteries despite the autoregulatory dilatation of the muscle’s arteriolar bed. One of the adaptations in coarctation during exercise could be a regional mechanism that would shunt blood to muscle from the kidney and gastrointestinal tract. Over the past several years, an array of substances have been found in the endothelium and the smooth muscle of the vessel walls that dilate and constrict the vessels and could play a role in this adaptation [87-913. These include norepinephrine, angiotensin I and 11, renin, and angiotensin converting enzyme. Prostaglandin and both relaxing and constricting endothelial substances are among the other paracrines and autocrines noted. These substances could be used for regulating regional flow by some mechanisms not yet understood. As an indicator of activity of these substances, plasma renin activity in some patients is elevated for 3 to 5 days after correction of the coarctation, whereas norepinephrine levels are increased well above those found after other operations of the same magnitude. The hypertension continues after the angiotensin level returns to normal, although the angiotensin converting enzyme inhibitors are still effective in controlling the blood pressure and preventing the arteritis. The dramatic morphological change in the arteries below the coarctation after operation may reflect another adaptation of these arteries to the coarctation. Theories explaining the pathogenesis of the arteritis in malignant and experimental hypertension fit the circumstances present after removal of the coarctation [92-1011. The sudden great increase in blood pressure in malignant
Ann Thorac Surg 1990;50322-9
hypertension is thought to cause the marked arteritis. In patients with coarctation, the arterial bed below the coarctation has been protected from high systolic pressures. This suddenly changes when the pressure is greatly elevated. The vessels below the coarctation perhaps respond as the entire arterial system does in malignant hypertension. This explanation leaves one with a degree of uncertainty. The increase in arterial muscle spasm is the principal cause of the hypertension. The spasm then becomes intense and persistent enough to cause ischemia of the arterial wall, followed by the severe changes. In coarctation, the destructive spasm only occurs below the coarctation in vessels conditioned or adapted to a greater capacity to respond. The adaptation needed to make certain that distal exercise muscle flows are adequate could be activated by the removal of the coarctation in those patients with the second hypertensive response. If the theory is correct, the persistently elevated norepinephrine level and transiently elevated angiotensin I1 level may be indicators of this response. This mechanism can be shut down by substances that relax spasm of the arterial muscle and block the action of norepinephrine and angiotensin 11. That this response is self-limited is shown by failure of the hypertension to recur after medication is stopped and the limited course that it runs in other patients not given specific medication.
Conclusion Coarctation of the aorta can cause a series of complex cardiovascular responses, all adapted to maintaining the needed blood flow to organs below the stricture. Operation disrupts these adaptations and may cause two paradoxical hypertensive responses. The presence of collaterals around the coarctation is the first adaptation. This may be all that is needed in many patients. The second adaptation, similar to Goldblatt hypertension, causes an increase in the blood pressure above the coarctation to a level that maintains blood flow adequate for optimal kidney function. The third adaptation is the high set of the carotid and aortic baroreceptors. An increase in blood pressure occurs for a few hours after operation until the baroreceptors are set at a lower level. The fourth adaptation is a theoretical one. The arterial system contains a regional mechanism that during exercise shunts most or all of the blood reaching the distal aorta to the muscle. When the coarctation is removed, a signal is read indicating the start of exercise. After operation, the mechanism does not shut off and remains in effect until the arterial system below the resected coarctation virtually destroys itself. Despite the still large gaps in our knowledge about these illogical hypertensive responses, an empirical approach to them years ago led to their near-absolute control. This has eliminated the chance for more detailed study of its most interesting aspect, the severe regional arteritis.
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
327
References 1. Sealy WC, Harris JS, Young WG Jr, Callaway HA Jr. Paradoxical hypertension following resection of coarctation of aorta. Surgery 1957;42:135-47. 2. Sealy WC. Indications for surgical treatment of coarctation of the aorta. Surg Gynecol Obstet 1953;97301-6. 3. Benson WR, Sealy WC. Arterial necrosis following resection of coarctation of the aorta. Lab Invest 1956;5:359-76. 4. Lober PH, Lillehei CW. Necrotizing panarteritis following repair of coarctation of aorta. Surgery 1954;35:950-6. 5. Sealy WC. Coarctation of the aorta and hypertension. Ann Thorac Surg 1967;3:15-28. 6. Gross RE. Coarctation of the aorta. Circulation 1953;7 757-68. 7. Counihan TB. Changes in the blood pressure following resection of coarctation of the aortic arch. Clin Sci 1956;15: 149-59. 8. Landtman 8, Tuuteri L. Vascular complications in coarctation of the aorta. Acta Paediatr 1959;48:329-34. 9. Ring DM, Lewis FJ. Abdominal pain following surgical correction of coarctation of the aorta: a syndrome. J Thorac Surg 1956;31:71%23. 10. Mays ET, Sergeant CK. Postcoarctectomy syndrome. Arch Surg 1965;91:58-66. 11. Trummer MJ, Mannix ET. Experimental coarctation and aortic stenosis. J Thorac Cardiovasc Surg 1963;45:19%209. 12. Verska JJ, Quattro VD, Woolley MM. Coarctation of the aorta: the abdominal pain syndrome and paradoxical hypertension. J Thorac Cardiovasc Surg 1969;58:746. 13. Tawes RL Jr, Bull JC, Roe BB. Hypertension and abdominal pain after resection of aortic coarctation. Ann Surg 1970;171: 409-12. 14. Ho ECK, Moss AJ. The syndrome of ”mesenteric arteritis” following surgical repair of aortic coarctation. Pediatrics 1972;49:4&5. 15. Stansel HC, Tabry IF, Poirier RA, Berman MA, Hellenbrand WE. One hundred consecutive coarctation resections followed from one to thirteen years. J Pediatr Surg 1977;12: 279-86. 16. Ibarra-Perez C, Lillehei CW. Treatment of mesenteric arteritis following resection of coarctation of the aorta. J Thorac Cardiovasc Surg 1969;58:135-9. 17. Fox S, Pierce WS, Waldhausen JA. Pathogenesis of paradoxical hypertension after coarctation repair. Ann Thorac Surg 1980;29:135-41. 18. Lerberg DB, Hardesty RL, Siewers RD, Zuberbuhler JR, Bahnson HT. Coarctation of the aorta in infants and children: 25 years of experience. Ann Thorac Surg 1982;33: 159-70. 19. Clarkson PM, Nicholson MR, Barratt-Boyes BG, Neutze JM, Whitlock RM. Results after repair of coarctation of the aorta beyond infancy: A 10 to 28 year follow-up with particular reference to late systemic hypertension. Am J Cardiol 1983; 51:1481-8. 20. Singleton A 0 Jr, McGinnis LS, Eason HR. Arteritis following correction of coarctation of the aorta. Surgery 1959;45: 665-73. 21. Hurt RL, Hanbury WJ. Intestinal vascular lesions simulating polyarteritis nodosa after resection of coarctation of the aorta. Thorax 1957;12:258-63. 22. Downing DF, Grotzinger PJ, Weller RW. Coarctation of the aorta. Am J Dis Child 1958;96:711-9. 23. Perez-Alvarez JJ, Oudkerk S. Necrotizing arteriolitis of the abdominal organs as a postoperative complication following
328
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
correction of the coarctation of the aorta. Surgery 1955;37: 833-7. 24. Kounis NG. Postcoarctectomy mesenteric arteritis presenting as neonatal appendicitis. J Cardiovasc Surg 1979;20: 503-5. 25. Gammelgaard A, Friis-Hansen 8. Acute abdominal reactions following operation for coarctation of the aorta. Acta Chir Scand 1960;119:361-8. 26. Reid HC, Dallachy R. Infarction of ileum following resection of coarctation of the aorta. Br J Surg 1958;45:625-33. 27. Goodall McC, Sealy WC. Increased sympathetic nerve activity following resection of coarctation of the thoracic aorta. Circulation 1969;39:345-51. 28. Benedict CR, Phil D, Grahame-Smith DG, Fisher A. Changes in plasma catecholamines and dopamine betahydroxylase after corrective surgery for coarctation of the aorta. Circulation 1978;57597-602. 29. Beekman RH, Katz BP, Moorehead-Steffens C, Rocchini AP. Altered baroreceptor function in children with systolic hypertension after coarctation repair. Am J Cardiol 1983;52: 112-7. 30. Bonchek LI, Rees PM. Baroreflex sensitivity and carotid sinus dimensions in dogs with coarctation. J Appl Physiol 1976;41:3640. 31. Igler FO, Boerboom LE, Werner PH, et al. Coarctation of the aorta and baroreceptor resetting. Circ Res 1981;48:365-71. 32. Floras J, Jones JV, Hassan MO, Osikowska BA, Sever PS, Sleight P. Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans. Hypertension 1986; 8:641-9. 33. Will RJ, Walker OM, Traugott RC, Treasure RL. Sodium nitroprusside and propranolol therapy for management of postcoarctectomy hypertension. J Cardiovasc Surg 1978;75: 7224. 34. Gidding SS, Rocchini AP, Beekman R, et al. Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta. N Engl J Med 1985;312: 1224-8. 35. Strong WB, Botti RE, Silbert DR, Liebman J. Peripheral and renal vein plasma renin activity in coarctation of the aorta. Pediatrics 1970;45:2549. 36. Rocchini AP, Rosenthal A, Barger C, Castaneda AR, Nadas AS. Pathogenesis of paradoxical hypertension after coarctation resection. Circulation 1976;54:382-7. 37. Ribeiro AB, Krakoff LR. Angiotensin blockade in coarctation of the aorta. N Engl J Med 1976;295:148-50. 38. Casta A, Conti VR, Talabi A, Brouhard BH. Effective use of captopril in postoperative paradoxical hypertension of coarctation of the aorta. Clin Cardiol 1982;5:551-3. 39. Davis JO, Freeman RH. Mechanisms regulating renin release. Physiol Rev 1976;56:34-41. 40. Buhler FR, Laragh JH, Baer L, Vaughan ED Jr, Brunner HR. Propranolol inhibition of renin secretion. N Engl J Med 1972;287:1209-14. 41. Corwin EJ, Seaton JF, Hamaji M, Harrison TS. Central role ' for angiotensin in control of adrenal catecholamine secretion. Am J Physiol 1985;248:R363-70. 42. Cowley AW Jr, Skelton MM, Merrill DC. Are hypertensive effects of aldosterone, angiotensin, vasopressin, and norepinephrine chronically additive? Hypertension 1986;8:332-43. 43. Zimmerman BG. Adrenergic facilitation by angiotensin: does it serve a physiological function? Clin Sci 1981;60: 343-8. 44. Sealy WC, McSwain GH. A method for producing coarctation of the thoracic aorta in dogs. Surgery 1949;25:451-5.
Ann Thorac Surg 1990;50323-9
45. Scott HW Jr, Bahnson HT. Evidence for a renal factor in the hypertension of experimental coarctation of the aorta. Surgery 1951;30:206-17. 46. Scott HW Jr, Collins HA, Langa AM, Olsen NS. Additional observations concerning the physiology of the hypertension associated with experimental coarctation of the aorta. Surgery 1954;36:445-9. 47. Habib WK, Nanson EM. The causes of hypertension in coarctation of the aorta. Ann Surg 1968;168:771-8. 48. Ferguson JC, Barrie WN, Schenk WG Jr. Hypertension of coarctation: the role of renal and other factors. Ann Surg 1977;185:423-8. 49. Rytand DA. The renal factor in arterial hypertension with coarctation of the aorta. J Clin Invest 1938;17:391-9. 50. Nolla-Panades J. Hypertension and increased hindlimb vascular reactivity in experimental coarctation of the aorta. Circ Res 1963;12:3-9. 51. Guyton AC. Arterial pressure and hypertension. Philadelphia: W.B. Saunders, 1980. 52. Yagi S, Kramsch DM, Madoff IM, Hollander W. Plasma renin activity in hypertension associated with coarctation of the aorta. Am J Physiol 1968;215:605-10. 53. Van Way CW 111, Michelakis AM, Anderson WJ, Manlove A, Oates JA. Studies of plasma renin activity in coarctation of the aorta. Ann Surg 1976;183:229-38. 54. Sealy WC, Panijayanond P, Alexander J, Seaber AV. Activity of plasma angiotensin I1 in experimental coarctation of the aorta. J Thorac Cardiovasc Surg 1973;65:283-91. 55. Sealy WC, DeMaria W, Harris J. Studies of the development and nature of the hypertension in experimental coarctation of the aorta. Surg Gynecol Obstet 1950;90:193-8. 56. Schenk WG Jr, Menno AD, Martin JW. Hemodynamics of experimental coarctation of the aorta. Ann Surg 1961;153: 163-72. 57. Bagby SP, Mass RD, Gray DK. Abnormality of the reninl body-fluid-volume relationship in serially studied inbred dogs with neonatally induced coarctation hypertension. Hypertension 1980;2:63142. 58. Svane H, Jensen OM. Structure of the juxtaglomerular apparatus in kidneys situated centrally and peripherally to an experimental coarctation of the aorta in dogs. Acta Pathol 1967;70:501-11. 59. Grollman A, Ferrigan JP Jr. Cardiac output: its related functions in a case of coarctation of the aorta. Arch Intern Med 1934;53:358. 60. Wilson PM. The nature of the peripheral resistance in arterial hypertension with special reference to the vasomotor system. J Clin Invest 1936;15:63-88. 61. Stewart HJ, Bailey RL Jr. The cardiac output and other measurements of the circulation in coarctation of the aorta. J Clin Invest 1941;20:145-52. 62. Lewis T. Material relating to coarctation of the aorta of the adult type. Heart 1933;16:20561. 63. Steele JM, Cohn AE. The nature of hypertension in coarctation of the aorta. J Clin Invest 1938;17514. 64. Wakim KG, Slaughter 0, Clagett OT. Studies on the blood flow in the extremities in cases of coarctation of the aorta: determinations before and after excision of the coarctate region. Proc Staff Meetings Mayo Clin 1948;23:347-51. 65. Patterson GC, Shepherd JT, Whelan RF. The resistance to blood flow in the upper and lower limb vessels in patients with coarctation of the aorta. Clin Sci 1957;16:627-32. 66. Lang HT Jr, Nadas AS. Coarctation of the aorta with congestive heart failure in infancy-medical treatment. Pediatrics 1956;1745-57.
Ann Thorac Surg 1990;50:32?-9
67. Tawes RL Jr, Aberdeen E, Waterston DJ, Carter REB. Coarctation of the aorta in infants and children. Cardiovasc Surg 1968;l:172-84. 68. Shinebourne EA, Tam ASY, Elseed AM, et al. Coarctation of the aorta in infancy and childhood. Br Heart J 1976;38: 375-80. 69. Sealy WC. Indications for surgical treatment of coarctation of the aorta. Surg Gynecol Obstet 1953;97301-6. 70. Taylor SH, Donald KW. Circulatory studies at rest and during exercise in coarctation of the aorta before and after operation. Br Heart J 1960;22:117-39. 71. Dahlback 0, Dahn I, Westling H. Hemodynamic observations in coarctation of the aorta with special reference to the blood pressure above and below the stenosis at rest and during exercise. Scand J Clin Lab Invest 1964;16:33946. 72. Sehested J, Kornerup HJ, Pedersen EB, Christensen NJ. Effects of exercise on plasma renin, aldosterone, and catecholamines before and after surgery for aortic coarctation. Eur Heart J 1983;4:52-8. 73. Goldblatt H, Lynch J, Hanzal RF, Summerville WW. The production of presistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934;59:347-79. 74. Blalock A, Levy SE. Studies on the etiology of renal hypertension. Ann Surg 1937;105:826-47. 75. Friedman M, Selzer A, Rosenblum H, McLean P, Picard W. The renal blood flow in coarctation of the aorta. J Clin Invest 1941;20:107-11. 76. Kirkendall WM, Culbertson JW, Eckstein JW. Renal hemodynamics in patients with coarctation of the aorta. J Lab Clin Med 1959;53:6-21. 77. Harris JS, Sealy WC, DeMaria W. Hypertension and renal dynamics in aortic coarctation. Am J Med 1950;9:734-46. 78. Werning C, Schonbeck M, Weidmann P, et al. Plasma renin activity in patients with coarctation of the aorta: a comment on the pathogenesis of prestenotic hypertension. Circulation 1969;40:731-7. 79. Amsterdam EA, Albers WH, Christlieb AR, Morgan CL, Nadas AS, Hickler RB. Plasma renin activity in children with coarctation of the aorta. Am J Cardiol 1969;23:396-9. 80. Alpert BS, Bain HH, Balfe JW, Kidd BSL, Olley PM. Role of the renin-angiotensin-aldosterone system in hypertensive children with coarctation of the aorta. Am J Cardiol 1979;43: 828-34. 81. Parker FB Jr, Streeten DHP, Farrell B, Blackman MS, Sondheimer HM, Anderson GH Jr. Preoperative and postoperative renin levels in coarctation of the aorta. Circulation 1982;66:513-4. 82. Schaffer AI. Coarctation hypertension is renovascular, modified by ambulation: coarctation hypertension renovascular variant. J Clin Hypertens 1986;1:69-78. 83. Pickering GW. The nature of essential hypertension. New York: Grune and Stratton, 1961:117.
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
329
84. Folkow B, Fuxe K, Sonnenschein RR. Responses of skeletal musculature and its vasculature during "diving" in the duck: pecularities of the adrenergic vasoconstrictor innervation. Acta Physiol Scand 1966;67:327-42. 85. Blix AS, Elsner R, Kjekshus JK. Cardiac output and its distribution through capillaries and A-V shunts in diving seals. Acta Physiol Scand 1983;118:109-16. 86. Gooden BA, Elsner R. What diving animals might tell us about blood flow regulation. Perspect Biol Med 1985;28: 465-75. 87. Gould AB, Skeggs LT, Kahn JR. The presence of renin activity in blood vessel walls. J Exp Med 1964;119:389-99. 88. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987;59:59A-65A. 89. Dzau VJ, Gibbons GH. Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension. Am J Cardiol 1987;60:99-103. 90. Vanhoutte PM. The endothelium-modulator of vascular smooth-muscle tone. N Engl J Med 1988;319:512-3. 91. Luscher TF, Cooke JP, Houston DS, Neves RJ, Vanhoutte I'M. Endothelium-dependent relaxations in human arteries. Mayo Clin Proc 1987;62:601-6. 92. Wilson C, Pickering GW. Acute arterial lesions in rabbits with experimental renal hypertension. Clin Sci 1938;3:W55. 93. Goldblatt H. The renal origin of hypertension. Physiol Rev 1947;27:120-65. 94. Byrom FB, Dodson LF. The causation of acute arterial necrosis in hypertensive disease. J Pathol Bacteriol 1948;60: 35748. 95. Giese J. Acute hypertensive vascular disease. Acta Pathol 1964;62:481-96. 96. Byrom FB. The hypertensive vascular crisis: an experimental study. London: William Heinemann Medical Books, 1969. 97. Kojimahara M. Healing and exacerbation of arterial lesions in rats with experimental hypertension, with special reference to effects of antihypertensive drugs on arterial lesions. Gunma J Med Sci 1967;16:142. 98. McQueen EG, Hodge JV. Modification of secondary lesions in renal hypertensive rats by control of the blood pressure with reserpine. Q J Med 1961;118:213-31. 99. Beilin LJ, Goldby FS. High arterial pressure versus humoral factors in the pathogenesis of the vascular lesions of malignant hypertension. Clin Sci Mol Med 1977;52:111-3. 100. Mohring J. The case for humoral factors as well as pressure. Clin Sci Mol Med 1977;52:113-7. 101. Nemes Z, Dietz R, Mann JFE, Luth JB, Gross F. Vasoconstriction and increased blood pressure in the development of accelerated vascular disease. Virchows Arch [A] 1980;386: 161-73.
Paradoxical Hypertension After Repair of Coarctation of the Aorta: A Review of Its Causes Will C. Sealy, MD Department of Surgery, Mercer University School of Medicine, and the Medical Center of Central Georgia, Macon, Georgia
Correction of a coarctation of the aorta, an apparent simple cause of hypertension, paradoxically can provoke two hypertensive responses, one of which is potentially fatal. The first, limited to the first 24 hours, occurs in nearly one half of the patients. This is likely due to the high set of the carotid baroreceptors. The second, which may be associated with abdominal pain and, in some, with necrosis of the small bowel as a result of severe arteritis confined to arteries arising from the aorta below the coarctation, develops in about one half of the first responders. Norepinephrine excretion greatly increases
for several days, whereas angiotensin levels are elevated for 3 to 4 days. The hypertension responds to pblockers, to arterial smooth muscle relaxants, and to angiotensin converting enzymes. A theory is advanced to explain the second response. It is the adaptation gone awry that ensures adequate flow to exercising muscles below the coarctation, above and beyond that delivered by increasing the systolic pressure. It could be a regionally controlled mechanism similar to the rationing of blood flow in diving mammals. (Ann Thoruc Surg 2990;50:323-9)
T
jejunum for necrosis. At autopsy, severe acute arteritis was found in the arterial system connected to the aorta by the vessels originating from below the coarctation [ 3 ] .The changes noted were a disruption of the walls of the vessels associated with fibrinoid necrosis and intense acute inflammatory exudate. The pathologist described the change as resembling periarteritis nodosa. Lober and Lillehei [4] made a similar comparison in their study. The second patient, a 4-year-old boy, was admitted a little more than a year later. His blood pressure was 150/80 mm Hg in his arms and 90/65 mm Hg in his legs. The coarctation of the aorta was resected, and a large patent ductus arteriosus was divided. On the fourth postoperative day, he complained of abdominal pain. His blood pressure at this time was 150/125mm Hg in both arms and legs. The white blood cell count ranged from 24 to 48 x lO’/L. On the 14th postoperative day at laparotomy, there were punctate serosal hemorrhagic areas throughout the small bowel. In the ileum, there were three perforations and many scattered areas of spotty gangrene. Seventy centimeters of the ileum had to be removed. Microscopic sections of the mesenteric vessels and of the mediumsized and small arteries in the abdominal wall showed findings similar to those noted in the first patient. The patient recovered satisfactorily. Ten days after he was operated on, the blood pressure was 118/74 mm Hg in his arms and 124/84 mm Hg in his legs. Severe hypertension and arteritis suggested that overactivity of the sympathetic nervous system was the cause of these remarkable changes. Soon after, the same abdominal complaint developed in a third patient, a 6-year-old girl, following removal of her coarctation. Preoperative blood pressures in her arms and legs were 190/40 mm Hg and 10472 mm Hg, respectively. A moderate-sized ventricular septa1 defect was present. Forty-eight hours after the operation, the blood pressure
hat the correction of a coarctation of the aorta, an apparently simple cause of hypertension, can provoke two different hypertensive responses, one of which is life threatening, is unexpected and illogical; thus, the name paradoxical hypertension [ 11. The first response occurs immediately and subsides in most patients within 24 hours. The second response, which is more pronounced in diastole, appears within 48 to 72 hours (Fig 1). The striking finding in the second response is the severe acute inflammatory changes that may occur in arteries and arterioles that originate from the aorta below the coarctation [24]. In this review, I will give an account of how these postoperative hypertensive events were first recognized and how a therapeutic program was then devised that has virtually eliminated them as serious clinical problems. This will be followed by a review of current thoughts about the physiological adaptations occuring in coarctation that maintain homeostasis. Then I will propose a theory to explain the pathogenesis of the two paradoxical responses based on a disruption of these cardiovascular adaptations. This story [3]began in 1952 after a 22-year-old man was operated on for coarctation of the aorta. Before operation, the blood pressure in his arms varied from 190 to 215/60 to 0 mm Hg and in his legs, from 140/80 to 0 mm Hg. He had a pronounced aortic valvar insufficiency. In the immediate postoperative period, his blood pressure increased in his arms and legs from 140180 mm Hg on the first day to 224194 mm Hg on the third day. At this time, he complained of moderately severe abdominal pain. He died 13 days later during removal of most of the ileum and Address reprint requests to Dr Sealy, Department of Surgery, Hospital Box No. 140, The Medical Center of Central Georgia, 777 Hemlock St, Macon, GA 31208. 0 1990 by The
Society of Thoracic Surgeons
0003-4975/90/$3.50
324
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
230
I
21 0
.
10
0
I
2
'
I
0
t , . '
I
2
'
I
4
'
I
6
.
1
8
'
1
10
'
+30dayr+
DAYS
Fig I . Blood pressure (BP) record of a patient showing a marked elevation of the blood pressure immediately after operation. The second hypertensive response begins on the fourth day, and blood pressure approaches normal on the 30th day.
in the arms was 190/140 mm Hg. At 72 hours, abdominal pain developed and she had a white blood cell count of 25 x lo9 L [3]. On the assumption that overactivity of the sympathetic nervous system was present, intravenous hydralazine hydrochloride was given. The abdominal pain promptly disappeared, the white blood cell count decreased to normal, and the blood pressure decreased from 190/140 mm Hg to 150/70 mm Hg. Medication was continued for 10 days. She was discharged from the hospital with a blood pressure of 140/80 mm Hg in her arms and without symptoms. Very soon after this experience, 3 more patients were found to have the same signs and symptoms. In these patients, reserpine was used with equally good results. The records of all patients with coarctation of the aorta on whom we had operated were then reviewed [l]. Postoperative hypertension was considered to be present when it was found to be higher than the preoperative level of the arm pressure. Although the blood pressure records in some patients were incomplete, 7 of 30 patients (23%)were found to have had marked elevation of blood pressure in the first 24 hours. In 1 patient, the systolic pressure was recorded as high as 230 mm Hg. One of the 7 patients progressed to the second response. Fourteen patients (47%)had a delayed hypertensive response 12 to 72 hours after operation. When a prospectively observed group of patients was studied after removal of the coarctation [5], 26 of the 41 patients (63%)had the immediate hypertensive response. The second hypertensive response was found in 12 of the 41 patients (29%)but all 12 patients had the first response. These two studies clearly separated the two postoperative hypertensive responses (Fig 1). The first response, occurring in more than one half of the patients, was not usually of more than 24-hours' duration. The second hypertensive response was frequently associated with abdominal pain. The two postoperative hypertensive responses were not described in early reports of the surgical treatment of coarctation, but most detailed accounts since then have
Ann Thorac Surg 1990;50:323-9
noted paradoxical hypertension [6-191. One patient had the diagnosis made 3 months after repair [20]. Along with abdominal pain, paralysis developed in the lower half of his body secondary to arteritis of a spinal artery. Vasculitis including splenic and mesenteric artery rupture [4, 9, 211 and gastrointestinal bleeding have been reported [22]. Intestinal stricture developed in another patient 4 weeks after operation [lo]. Although there are reports of arteritis in the mesenteric vessels (4, 8, 2CL261, only two autopsy reports aside from the one outlined here describe the vascular lesions in areas other than the intestines [4, 201. The cause of the first hypertensive response can be explained by the release of the stretch on the baroceptors in the carotid arteries and aortic arch after removal of the aortic obstruction. The best evidence for this is the marked increase in sympathetic activity indicated by elevations in norepinephrine level after operation greater than those found after other operations of similar magnitude [12, 26, 271. The norepinephrine level remained elevated for up to 13 days in the Duke series (Fig 2) and for 6 months in the Benedict, Graham-Smith, and Fisher study [28]. The latter observers noted that only 2 of the 6 patients had the early hypertensive response, whereas 5 of the 6 patients had the second response. In the Duke series, 6 of 12 patients had elevated levels of norepinephrine with 5 of the 6 having the first and second responses. Studies of baroreceptor sensitivity have been done only on postoperative coarctation patients who have chronic hypertension. As expected, they had a high set of the baroreceptors [29]. Baroreceptor activity in experimental coarctation investigated by Bonchek and Rees [30] showed only normal sensitivity. Experimental observations of Igler, Boerboom, and associates [31] indicated that the baroreceptor reset occurred after induction of coarctation, only to return to normal after coarctation repair. The reason for the second hypertensive response is not clearly understood. The following facts are known. Pa240 220
200 I80 a
160 140
P. 120 e = 100 e
'
N
80
60
40 20
0 Control0
I
2
3
4
5
6 7 DAYS
8
91011
121314
Fig 2 . Great increase in excretion of norepinephrine (Nor-Ep) in a 12-year-old patient after operation. This was associated with the two hypertensive responses and abdominal (ABD) pain.
Ann Thorac Surg 1990;5032>9
REVIEW SEALY PARADOXICAI. HYPERTENSION, COARCTATION AORTA
normal. The pressure continues to rise over the next 3 weeks or so, when one would expect collateral circulation to be increasing. The pressure below the coarctation reaches its precoarctation level in 14 to 21 days (Fig 3). Added evidence that the kidneys play a role in hypertension of coarctation were the experiments of Scott and Bahnson [45, 461, who showed that moving a single remaining kidney above the experimental thoracic coarctation relieved the hypertension. Studies of renal dynamics in dogs with experimental coarctation have shown only an increase in the filtration fraction [55-571. Svane and Jensen [58] reported microscopic evidence of juxtaglomerular hyperplasia.
EXPERIMENTAL COARCTATION OF THE AORTA
cs
24 22
?--,,,-,,,,-.---------~---*
325
CD
FS FD 120
Hypertension and Coarctation in Humans 0
20
40
60
80
100
120
140
J
DAYS
Fig 3. Coarctation of the aorta on the adult dog shows that the initial postcoarctation blood pressure is not elevated. Only at 14 days after operation do the pressures reach hypertensive level. Note that femoral pressures are stabilized slightly above the preoperative levels. (CS = carotid systolic; CD = carotid diastolic; FD = femoral diastolic; FS = femoral systolic.)
tients have increased sympathetic activity that continues well after the expected baroreceptor reset. The norepinephrine levels encountered indicate extreme levels of sympathetic activity, judged by the studies of Floras and associates [32]. In addition, the second hypertensive response can be reversed by reserpine, which causes a depletion of the adrenergic transmitter; by @blocking agents [33]; by hydralazine hydrochloride, a smooth muscle relaxant; and by angotensin converting enzyme inhibitors. Giddings and co-workers [34] showed that preoperatively administered propranolol prevented a hypertensive response in 7 patients, whereas hypertension developed in 4 of 7 patients of the control group. That plasma renin activity would increase for 3 to 5 days after removal of the coarctation and that angiotensin I1 enzyme blocking agents will reverse the hypertensive responses is, to say the least, illogical [35-381. The relationship between norepinephrine and angiotensin 11, both potent vasoconstrictors, is complex [3943]. None of these considerations explains exactly why blocking the action of one or the other hormone are equally effective in controlling paradoxical hypertension.
Experimental Coarctation of the Aorta Coarctation of the aorta has been produced in adult dogs [4448], puppies [30], and rats [49, 501. The development of the hypertension resembles the pattern of the onekidney, one-clip Goldblatt preparation [51] (Fig 3). Plasma renin activity increases immediately and remains elevated for 3 to 5 days [52-541. The blood pressure above and below the coarctation site begins to increase in 3 to 5 days, at the time the plasma renin activity is returning to
The hypertension in coarctation of the aorta in humans has been the subject of both intense study and much speculation [59-651. Sir Thomas Lewis [62] showed that the femoral pulse wave occurred later than the radial, opposite to the normal. He found normal blood flows in the legs. Direct arterial pressure measurements, notably those of Steele and Cohn [63], indicated that mean pressures below the coarctation were frequently at hypertensive levels and equal to the resting mean pressures above the coarctation. Wakim, Slaughter, and Clagett [64] found blood flows to be unchanged in the arms and legs before and after operation for coarctation. Patterson, Shepherd, and Whelan [65] found flows to be the same in the arms and legs, but the resistances in the arms were greater than those in the legs. The cross-sectional area of the coarctation and collateral circulation vary tremendously from patient to patient. In an occasional neonate, congestive failure occurs, supposedly due to failure of collaterals to develop before birth [66-681. Examples of heart failure corrected by repair of the coarctation in patients who have intracardiac lesions have also been reported [69]. In an attempt to supply blood flow demands to strictures below the coarctation, unusually high arterial pressures occur above the coarctation with exercise [70-721. In one study [70], the systolic levels in 6 of 20 patients reached 300 to 360 mm Hg. Dahlback, Dahn, and Westling [71] found that in the femoral artery, mean pressures recorded during exercise did not change despite great increases above the coarctation, but cardiac output recorded during strenuous exercise increased from 5 to 10 L. In a study of 20 patients with coarctation, Taylor and Donald [70] found 6 patients with clinically significant elevations of resting cardiac output. Nine of the 20 patients showed an increase in the pulmonary wedge pressure during exercise. Seven of 8 patients examined after operation were found to have a reversion of the pressure to normal levels. Three patients had an increase in the pulmonary artery pressure during exercise. The left ventricular work before operation was increased in all 20 patients over that of the normal control group. Do these observations indicate that the left ventricle may be stressed to its limits to supply blood flow to structures below the coarctation?
326
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
The great interest in 1930 to 1940 in the Goldblatt experiments [73, 741 led to several studies in humans trying to relate the hypertension in coarctation to the kidney [75-771. Harris, Sealy, and DeMaria [77] reviewed the information then available on renal hemodynamics in coarctation and reported their observations on patients before and after operation. They concluded that there was no decrease in renal blood flow in coarctation and speculated that some other mechanism was a factor in causing the hypertension, in addition to the resistances at the coarctation site and in the collaterals. When it became possible to determine more easily the plasma renin activity, this was measured in patients with coarctation [7%81]. Most showed no elevation in plasma renin activity before operation. Alpert and co-workers [80], in an excellent study on patients with coarctation, found that when furosemide was added to a low-sodium diet, marked elevations in plasma renin activity occurred. In addition, they found that plasma volume and extracellular fluid volume were increased, as was the cardiac output, and noted the similarity between coarctation and Goldblatt hypertension. In a recent discussion of the hypertension in coarctation of the aorta, Schaffer [82] called attention to ”the bipedal exercise triad.” During exercise, an increase occurred in systolic pressure in the arms. The pressures in the legs were unchanged despite an increase in the systolic gradient across the coarctation. The response to exercise caused a shunting of blood to muscle from the kidney, which increased plasma renin activity.
Comment The cardiovascular adaptations to a coarctation of the aorta are more complex than merely an elevated blood pressure above the coarctation and the development of collateral arterial channels around it. As the removal of the coarctation may cause two hypertensive responses, it is reasonable to assume that interruption of the need for the adaptations is related to these unexpected events. That such responses do not occur in every postoperative patient speaks of the wide variation among patients in the coarctation cross-sectional area and in the number and size of the collaterals. Thus in some patients, collateral development alone ensures blood flow to the structures below the coarctation. The high set of the baroreceptors explains the first postoperative hypertensive response. The decrease in the stretch of the carotid and aortic baroreceptors by removal of the aortic obstruction causes greatly increased sympathetic activity that could be a factor in initiating a second response. The high set could be the result of the next adaptation noted below. The adaptation that by increasing the pressure above the coarctation maintains normal renal blood flow has been compared with Goldblatt hypertension. There is one important difference between the two hypertensions. The kidneys have to share the blood flow getting through the coarctation. For example, the great flow demand that suddenly arises from strenuous muscle activity can in-
Ann Thorac Surg 1990;50:32>9
crease the need from less than 800 mL/min to as much as 5,000 to 8,000 mL/min (831. To meet this need during exercise in a tight stenosis, a great increase in the systolic blood pressure occurs above the coarctation to as much as 360 mm Hg. If the pressure increase above the coarctation fails to meet the flow needs of the exercising muscles below, are there other adaptations present that can ration the volume of blood that gets through the coarctation and through the collaterals to supply this demand? A part of this needed diversion to the muscle occurs directly to the muscles of the trunk and upper abdomen by the large collaterals, which may further reduce the blood volume available for the distal aorta. Shunting of blood to structures of great need is a mechanism found in both physiological and pathological states. During exercise, there is a shift of blood to muscles to meet short-term needs. In heart failure and low-volume shock, blood may be shunted to the heart and brain from the kidney, the gastrointestinal tract, and the extremities. One of the most interesting examples of physiological shunting of blood to the site of greatest need is found among diving animals, in which blood flow to muscle, gut, and kidney is nearly all shunted to the heart-brain axis [84-86.. Weddell seals can actively search for food while submerged for as long as an hour. Folkow and co-workers [84] showed that in diving ducks, the arteries leading to the muscles but outside of them had high concentrations of adrenergic receptors. He believed that this mechanism permits the duck to reduce muscle blood flow by constriction of the large arteries despite the autoregulatory dilatation of the muscle’s arteriolar bed. One of the adaptations in coarctation during exercise could be a regional mechanism that would shunt blood to muscle from the kidney and gastrointestinal tract. Over the past several years, an array of substances have been found in the endothelium and the smooth muscle of the vessel walls that dilate and constrict the vessels and could play a role in this adaptation [87-913. These include norepinephrine, angiotensin I and 11, renin, and angiotensin converting enzyme. Prostaglandin and both relaxing and constricting endothelial substances are among the other paracrines and autocrines noted. These substances could be used for regulating regional flow by some mechanisms not yet understood. As an indicator of activity of these substances, plasma renin activity in some patients is elevated for 3 to 5 days after correction of the coarctation, whereas norepinephrine levels are increased well above those found after other operations of the same magnitude. The hypertension continues after the angiotensin level returns to normal, although the angiotensin converting enzyme inhibitors are still effective in controlling the blood pressure and preventing the arteritis. The dramatic morphological change in the arteries below the coarctation after operation may reflect another adaptation of these arteries to the coarctation. Theories explaining the pathogenesis of the arteritis in malignant and experimental hypertension fit the circumstances present after removal of the coarctation [92-1011. The sudden great increase in blood pressure in malignant
Ann Thorac Surg 1990;50322-9
hypertension is thought to cause the marked arteritis. In patients with coarctation, the arterial bed below the coarctation has been protected from high systolic pressures. This suddenly changes when the pressure is greatly elevated. The vessels below the coarctation perhaps respond as the entire arterial system does in malignant hypertension. This explanation leaves one with a degree of uncertainty. The increase in arterial muscle spasm is the principal cause of the hypertension. The spasm then becomes intense and persistent enough to cause ischemia of the arterial wall, followed by the severe changes. In coarctation, the destructive spasm only occurs below the coarctation in vessels conditioned or adapted to a greater capacity to respond. The adaptation needed to make certain that distal exercise muscle flows are adequate could be activated by the removal of the coarctation in those patients with the second hypertensive response. If the theory is correct, the persistently elevated norepinephrine level and transiently elevated angiotensin I1 level may be indicators of this response. This mechanism can be shut down by substances that relax spasm of the arterial muscle and block the action of norepinephrine and angiotensin 11. That this response is self-limited is shown by failure of the hypertension to recur after medication is stopped and the limited course that it runs in other patients not given specific medication.
Conclusion Coarctation of the aorta can cause a series of complex cardiovascular responses, all adapted to maintaining the needed blood flow to organs below the stricture. Operation disrupts these adaptations and may cause two paradoxical hypertensive responses. The presence of collaterals around the coarctation is the first adaptation. This may be all that is needed in many patients. The second adaptation, similar to Goldblatt hypertension, causes an increase in the blood pressure above the coarctation to a level that maintains blood flow adequate for optimal kidney function. The third adaptation is the high set of the carotid and aortic baroreceptors. An increase in blood pressure occurs for a few hours after operation until the baroreceptors are set at a lower level. The fourth adaptation is a theoretical one. The arterial system contains a regional mechanism that during exercise shunts most or all of the blood reaching the distal aorta to the muscle. When the coarctation is removed, a signal is read indicating the start of exercise. After operation, the mechanism does not shut off and remains in effect until the arterial system below the resected coarctation virtually destroys itself. Despite the still large gaps in our knowledge about these illogical hypertensive responses, an empirical approach to them years ago led to their near-absolute control. This has eliminated the chance for more detailed study of its most interesting aspect, the severe regional arteritis.
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
327
References 1. Sealy WC, Harris JS, Young WG Jr, Callaway HA Jr. Paradoxical hypertension following resection of coarctation of aorta. Surgery 1957;42:135-47. 2. Sealy WC. Indications for surgical treatment of coarctation of the aorta. Surg Gynecol Obstet 1953;97301-6. 3. Benson WR, Sealy WC. Arterial necrosis following resection of coarctation of the aorta. Lab Invest 1956;5:359-76. 4. Lober PH, Lillehei CW. Necrotizing panarteritis following repair of coarctation of aorta. Surgery 1954;35:950-6. 5. Sealy WC. Coarctation of the aorta and hypertension. Ann Thorac Surg 1967;3:15-28. 6. Gross RE. Coarctation of the aorta. Circulation 1953;7 757-68. 7. Counihan TB. Changes in the blood pressure following resection of coarctation of the aortic arch. Clin Sci 1956;15: 149-59. 8. Landtman 8, Tuuteri L. Vascular complications in coarctation of the aorta. Acta Paediatr 1959;48:329-34. 9. Ring DM, Lewis FJ. Abdominal pain following surgical correction of coarctation of the aorta: a syndrome. J Thorac Surg 1956;31:71%23. 10. Mays ET, Sergeant CK. Postcoarctectomy syndrome. Arch Surg 1965;91:58-66. 11. Trummer MJ, Mannix ET. Experimental coarctation and aortic stenosis. J Thorac Cardiovasc Surg 1963;45:19%209. 12. Verska JJ, Quattro VD, Woolley MM. Coarctation of the aorta: the abdominal pain syndrome and paradoxical hypertension. J Thorac Cardiovasc Surg 1969;58:746. 13. Tawes RL Jr, Bull JC, Roe BB. Hypertension and abdominal pain after resection of aortic coarctation. Ann Surg 1970;171: 409-12. 14. Ho ECK, Moss AJ. The syndrome of ”mesenteric arteritis” following surgical repair of aortic coarctation. Pediatrics 1972;49:4&5. 15. Stansel HC, Tabry IF, Poirier RA, Berman MA, Hellenbrand WE. One hundred consecutive coarctation resections followed from one to thirteen years. J Pediatr Surg 1977;12: 279-86. 16. Ibarra-Perez C, Lillehei CW. Treatment of mesenteric arteritis following resection of coarctation of the aorta. J Thorac Cardiovasc Surg 1969;58:135-9. 17. Fox S, Pierce WS, Waldhausen JA. Pathogenesis of paradoxical hypertension after coarctation repair. Ann Thorac Surg 1980;29:135-41. 18. Lerberg DB, Hardesty RL, Siewers RD, Zuberbuhler JR, Bahnson HT. Coarctation of the aorta in infants and children: 25 years of experience. Ann Thorac Surg 1982;33: 159-70. 19. Clarkson PM, Nicholson MR, Barratt-Boyes BG, Neutze JM, Whitlock RM. Results after repair of coarctation of the aorta beyond infancy: A 10 to 28 year follow-up with particular reference to late systemic hypertension. Am J Cardiol 1983; 51:1481-8. 20. Singleton A 0 Jr, McGinnis LS, Eason HR. Arteritis following correction of coarctation of the aorta. Surgery 1959;45: 665-73. 21. Hurt RL, Hanbury WJ. Intestinal vascular lesions simulating polyarteritis nodosa after resection of coarctation of the aorta. Thorax 1957;12:258-63. 22. Downing DF, Grotzinger PJ, Weller RW. Coarctation of the aorta. Am J Dis Child 1958;96:711-9. 23. Perez-Alvarez JJ, Oudkerk S. Necrotizing arteriolitis of the abdominal organs as a postoperative complication following
328
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
correction of the coarctation of the aorta. Surgery 1955;37: 833-7. 24. Kounis NG. Postcoarctectomy mesenteric arteritis presenting as neonatal appendicitis. J Cardiovasc Surg 1979;20: 503-5. 25. Gammelgaard A, Friis-Hansen 8. Acute abdominal reactions following operation for coarctation of the aorta. Acta Chir Scand 1960;119:361-8. 26. Reid HC, Dallachy R. Infarction of ileum following resection of coarctation of the aorta. Br J Surg 1958;45:625-33. 27. Goodall McC, Sealy WC. Increased sympathetic nerve activity following resection of coarctation of the thoracic aorta. Circulation 1969;39:345-51. 28. Benedict CR, Phil D, Grahame-Smith DG, Fisher A. Changes in plasma catecholamines and dopamine betahydroxylase after corrective surgery for coarctation of the aorta. Circulation 1978;57597-602. 29. Beekman RH, Katz BP, Moorehead-Steffens C, Rocchini AP. Altered baroreceptor function in children with systolic hypertension after coarctation repair. Am J Cardiol 1983;52: 112-7. 30. Bonchek LI, Rees PM. Baroreflex sensitivity and carotid sinus dimensions in dogs with coarctation. J Appl Physiol 1976;41:3640. 31. Igler FO, Boerboom LE, Werner PH, et al. Coarctation of the aorta and baroreceptor resetting. Circ Res 1981;48:365-71. 32. Floras J, Jones JV, Hassan MO, Osikowska BA, Sever PS, Sleight P. Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans. Hypertension 1986; 8:641-9. 33. Will RJ, Walker OM, Traugott RC, Treasure RL. Sodium nitroprusside and propranolol therapy for management of postcoarctectomy hypertension. J Cardiovasc Surg 1978;75: 7224. 34. Gidding SS, Rocchini AP, Beekman R, et al. Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta. N Engl J Med 1985;312: 1224-8. 35. Strong WB, Botti RE, Silbert DR, Liebman J. Peripheral and renal vein plasma renin activity in coarctation of the aorta. Pediatrics 1970;45:2549. 36. Rocchini AP, Rosenthal A, Barger C, Castaneda AR, Nadas AS. Pathogenesis of paradoxical hypertension after coarctation resection. Circulation 1976;54:382-7. 37. Ribeiro AB, Krakoff LR. Angiotensin blockade in coarctation of the aorta. N Engl J Med 1976;295:148-50. 38. Casta A, Conti VR, Talabi A, Brouhard BH. Effective use of captopril in postoperative paradoxical hypertension of coarctation of the aorta. Clin Cardiol 1982;5:551-3. 39. Davis JO, Freeman RH. Mechanisms regulating renin release. Physiol Rev 1976;56:34-41. 40. Buhler FR, Laragh JH, Baer L, Vaughan ED Jr, Brunner HR. Propranolol inhibition of renin secretion. N Engl J Med 1972;287:1209-14. 41. Corwin EJ, Seaton JF, Hamaji M, Harrison TS. Central role ' for angiotensin in control of adrenal catecholamine secretion. Am J Physiol 1985;248:R363-70. 42. Cowley AW Jr, Skelton MM, Merrill DC. Are hypertensive effects of aldosterone, angiotensin, vasopressin, and norepinephrine chronically additive? Hypertension 1986;8:332-43. 43. Zimmerman BG. Adrenergic facilitation by angiotensin: does it serve a physiological function? Clin Sci 1981;60: 343-8. 44. Sealy WC, McSwain GH. A method for producing coarctation of the thoracic aorta in dogs. Surgery 1949;25:451-5.
Ann Thorac Surg 1990;50323-9
45. Scott HW Jr, Bahnson HT. Evidence for a renal factor in the hypertension of experimental coarctation of the aorta. Surgery 1951;30:206-17. 46. Scott HW Jr, Collins HA, Langa AM, Olsen NS. Additional observations concerning the physiology of the hypertension associated with experimental coarctation of the aorta. Surgery 1954;36:445-9. 47. Habib WK, Nanson EM. The causes of hypertension in coarctation of the aorta. Ann Surg 1968;168:771-8. 48. Ferguson JC, Barrie WN, Schenk WG Jr. Hypertension of coarctation: the role of renal and other factors. Ann Surg 1977;185:423-8. 49. Rytand DA. The renal factor in arterial hypertension with coarctation of the aorta. J Clin Invest 1938;17:391-9. 50. Nolla-Panades J. Hypertension and increased hindlimb vascular reactivity in experimental coarctation of the aorta. Circ Res 1963;12:3-9. 51. Guyton AC. Arterial pressure and hypertension. Philadelphia: W.B. Saunders, 1980. 52. Yagi S, Kramsch DM, Madoff IM, Hollander W. Plasma renin activity in hypertension associated with coarctation of the aorta. Am J Physiol 1968;215:605-10. 53. Van Way CW 111, Michelakis AM, Anderson WJ, Manlove A, Oates JA. Studies of plasma renin activity in coarctation of the aorta. Ann Surg 1976;183:229-38. 54. Sealy WC, Panijayanond P, Alexander J, Seaber AV. Activity of plasma angiotensin I1 in experimental coarctation of the aorta. J Thorac Cardiovasc Surg 1973;65:283-91. 55. Sealy WC, DeMaria W, Harris J. Studies of the development and nature of the hypertension in experimental coarctation of the aorta. Surg Gynecol Obstet 1950;90:193-8. 56. Schenk WG Jr, Menno AD, Martin JW. Hemodynamics of experimental coarctation of the aorta. Ann Surg 1961;153: 163-72. 57. Bagby SP, Mass RD, Gray DK. Abnormality of the reninl body-fluid-volume relationship in serially studied inbred dogs with neonatally induced coarctation hypertension. Hypertension 1980;2:63142. 58. Svane H, Jensen OM. Structure of the juxtaglomerular apparatus in kidneys situated centrally and peripherally to an experimental coarctation of the aorta in dogs. Acta Pathol 1967;70:501-11. 59. Grollman A, Ferrigan JP Jr. Cardiac output: its related functions in a case of coarctation of the aorta. Arch Intern Med 1934;53:358. 60. Wilson PM. The nature of the peripheral resistance in arterial hypertension with special reference to the vasomotor system. J Clin Invest 1936;15:63-88. 61. Stewart HJ, Bailey RL Jr. The cardiac output and other measurements of the circulation in coarctation of the aorta. J Clin Invest 1941;20:145-52. 62. Lewis T. Material relating to coarctation of the aorta of the adult type. Heart 1933;16:20561. 63. Steele JM, Cohn AE. The nature of hypertension in coarctation of the aorta. J Clin Invest 1938;17514. 64. Wakim KG, Slaughter 0, Clagett OT. Studies on the blood flow in the extremities in cases of coarctation of the aorta: determinations before and after excision of the coarctate region. Proc Staff Meetings Mayo Clin 1948;23:347-51. 65. Patterson GC, Shepherd JT, Whelan RF. The resistance to blood flow in the upper and lower limb vessels in patients with coarctation of the aorta. Clin Sci 1957;16:627-32. 66. Lang HT Jr, Nadas AS. Coarctation of the aorta with congestive heart failure in infancy-medical treatment. Pediatrics 1956;1745-57.
Ann Thorac Surg 1990;50:32?-9
67. Tawes RL Jr, Aberdeen E, Waterston DJ, Carter REB. Coarctation of the aorta in infants and children. Cardiovasc Surg 1968;l:172-84. 68. Shinebourne EA, Tam ASY, Elseed AM, et al. Coarctation of the aorta in infancy and childhood. Br Heart J 1976;38: 375-80. 69. Sealy WC. Indications for surgical treatment of coarctation of the aorta. Surg Gynecol Obstet 1953;97301-6. 70. Taylor SH, Donald KW. Circulatory studies at rest and during exercise in coarctation of the aorta before and after operation. Br Heart J 1960;22:117-39. 71. Dahlback 0, Dahn I, Westling H. Hemodynamic observations in coarctation of the aorta with special reference to the blood pressure above and below the stenosis at rest and during exercise. Scand J Clin Lab Invest 1964;16:33946. 72. Sehested J, Kornerup HJ, Pedersen EB, Christensen NJ. Effects of exercise on plasma renin, aldosterone, and catecholamines before and after surgery for aortic coarctation. Eur Heart J 1983;4:52-8. 73. Goldblatt H, Lynch J, Hanzal RF, Summerville WW. The production of presistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934;59:347-79. 74. Blalock A, Levy SE. Studies on the etiology of renal hypertension. Ann Surg 1937;105:826-47. 75. Friedman M, Selzer A, Rosenblum H, McLean P, Picard W. The renal blood flow in coarctation of the aorta. J Clin Invest 1941;20:107-11. 76. Kirkendall WM, Culbertson JW, Eckstein JW. Renal hemodynamics in patients with coarctation of the aorta. J Lab Clin Med 1959;53:6-21. 77. Harris JS, Sealy WC, DeMaria W. Hypertension and renal dynamics in aortic coarctation. Am J Med 1950;9:734-46. 78. Werning C, Schonbeck M, Weidmann P, et al. Plasma renin activity in patients with coarctation of the aorta: a comment on the pathogenesis of prestenotic hypertension. Circulation 1969;40:731-7. 79. Amsterdam EA, Albers WH, Christlieb AR, Morgan CL, Nadas AS, Hickler RB. Plasma renin activity in children with coarctation of the aorta. Am J Cardiol 1969;23:396-9. 80. Alpert BS, Bain HH, Balfe JW, Kidd BSL, Olley PM. Role of the renin-angiotensin-aldosterone system in hypertensive children with coarctation of the aorta. Am J Cardiol 1979;43: 828-34. 81. Parker FB Jr, Streeten DHP, Farrell B, Blackman MS, Sondheimer HM, Anderson GH Jr. Preoperative and postoperative renin levels in coarctation of the aorta. Circulation 1982;66:513-4. 82. Schaffer AI. Coarctation hypertension is renovascular, modified by ambulation: coarctation hypertension renovascular variant. J Clin Hypertens 1986;1:69-78. 83. Pickering GW. The nature of essential hypertension. New York: Grune and Stratton, 1961:117.
REVIEW SEALY PARADOXICAL HYPERTENSION, COARCTATION AORTA
329
84. Folkow B, Fuxe K, Sonnenschein RR. Responses of skeletal musculature and its vasculature during "diving" in the duck: pecularities of the adrenergic vasoconstrictor innervation. Acta Physiol Scand 1966;67:327-42. 85. Blix AS, Elsner R, Kjekshus JK. Cardiac output and its distribution through capillaries and A-V shunts in diving seals. Acta Physiol Scand 1983;118:109-16. 86. Gooden BA, Elsner R. What diving animals might tell us about blood flow regulation. Perspect Biol Med 1985;28: 465-75. 87. Gould AB, Skeggs LT, Kahn JR. The presence of renin activity in blood vessel walls. J Exp Med 1964;119:389-99. 88. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987;59:59A-65A. 89. Dzau VJ, Gibbons GH. Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension. Am J Cardiol 1987;60:99-103. 90. Vanhoutte PM. The endothelium-modulator of vascular smooth-muscle tone. N Engl J Med 1988;319:512-3. 91. Luscher TF, Cooke JP, Houston DS, Neves RJ, Vanhoutte I'M. Endothelium-dependent relaxations in human arteries. Mayo Clin Proc 1987;62:601-6. 92. Wilson C, Pickering GW. Acute arterial lesions in rabbits with experimental renal hypertension. Clin Sci 1938;3:W55. 93. Goldblatt H. The renal origin of hypertension. Physiol Rev 1947;27:120-65. 94. Byrom FB, Dodson LF. The causation of acute arterial necrosis in hypertensive disease. J Pathol Bacteriol 1948;60: 35748. 95. Giese J. Acute hypertensive vascular disease. Acta Pathol 1964;62:481-96. 96. Byrom FB. The hypertensive vascular crisis: an experimental study. London: William Heinemann Medical Books, 1969. 97. Kojimahara M. Healing and exacerbation of arterial lesions in rats with experimental hypertension, with special reference to effects of antihypertensive drugs on arterial lesions. Gunma J Med Sci 1967;16:142. 98. McQueen EG, Hodge JV. Modification of secondary lesions in renal hypertensive rats by control of the blood pressure with reserpine. Q J Med 1961;118:213-31. 99. Beilin LJ, Goldby FS. High arterial pressure versus humoral factors in the pathogenesis of the vascular lesions of malignant hypertension. Clin Sci Mol Med 1977;52:111-3. 100. Mohring J. The case for humoral factors as well as pressure. Clin Sci Mol Med 1977;52:113-7. 101. Nemes Z, Dietz R, Mann JFE, Luth JB, Gross F. Vasoconstriction and increased blood pressure in the development of accelerated vascular disease. Virchows Arch [A] 1980;386: 161-73.
