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Coarctation of the Aorta and Hypertension
Coarctation of the Aorta and Hypertension Will C. Sealy, M.D.
C
oarctation of the aorta is a simple vascular obstruction that frequently causes arterial hypertension. However, the removal of the obstruction may elicit, paradoxically, two hypertensive responses [22]. T h e elevated pressure from the coarctation may be due simply to the resistance at the stenosis site and in the collaterals, though the manner in which it is sustained is still obscure. Since the coarctation is above the kidneys, the gastrointestinal organs, and large muscle masses yet below the baroreceptors in the aortic and carotid areas, this sets the stage for unusual responses from the autonomic nervous system, certain endocrine glands, and local blood flow control mechanisms. By the use of an experimental preparation [23] first used in our laboratory that mimics the disorder seen in man, it has been possible to observe the development of the hypertension. Its regression can be followed by watching the events that follow the removal of the coarctation in patients. This report will review the experimental and clinical observations made over the last 17 years on the nature of hypertension in coarctation. EXPE RIM E N TA L OBSERVATIONS
Coarctation of the aorta in dogs was first produced in our laboratory in 1949. Another series of more than 50 studies were repeated in 1963. With a Venturi tube of Lucite inserted in the thoracic aorta, as shown in Figure 1, it was possible to produce hypertension. The diameter of the tube at its narrowest point had to be less than 20% of the normal aortic size and a mean gradient across the constriction of more than 30 mm. Hg was required in order for hypertension to develop. The manner in which the rise of the femoral systolic and carotid systolic pressures occurred after experimental coarctation is represented in Figure 2. Between 7 and 21 days after aortic constriction, significant hypertension then occurred followed by developing hypertension in the femoral artery, These observations have been confirmed using other methods by Scott and Bahnson [21] and by Clatworthy et al. [51. Since the renal arteries originate from the aorta below the constriction and since the mean pressure reaches hypertensive levels in the femoral vessels, these From the Division of Thoracic Surgery, Duke University Medical Center, Durham, N.C. This study is supported in part by U.S. Public Health Service Grant HE-01782 and the John Klein Heart Research Fund. Presidential address delivered at the Thirteenth Annual Meeting of the Southern Thoracic Surgical Association, Asheville, N.C., Nov. 3-5, 1966.
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FIG. 1. ( A ) Method of producing experimental coarctation with Lucite sleeve inserted into the descending aorta. (B and C) Methods of transplantin renal arteries to aorta above the coarctation using either prosthetic or preservedg aortic homograf t. both point to the kidney as a possible source of a humoral substance maintaining generalized vasoconstriction. Young et al. [31] in 1949-1950 measured renal blood flow by indirect methods before and after induction of the coarctation. Except for slight increase in the filtration fraction, indicating some increase in arteriolar resistance, blood flows were unchanged. Recently Bounous et al. 121, in an ingenious study using direct flow measurements, confirmed these observations. Scott and Bahnson were the first to demonstrate that changing the origin of the renal arteries from below the coarctation to a site in the neck above the coarctation would revert the elevated pressure to normal. The period of observation of their animals was short, with only two animals being observed for 4 months and with all eventually dying from renal infection. In 1963 in our laboratory, Lesage and Koie approached this problem differently, transferring the origin of the kidney's blood supply to a point above EXPERIMENTAL COARCTATION OF THE AORTA
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FIG. 2. T h e blood pressure changes in a dog following aortic constriction as shown in Figure 1. C, carotid; F, femoral; D, diastolic; S, systolic. 16
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the coarctation as was shown in Figure 1. T h e kidney was left in situ with normal venous drainage, ureteral connections, and nerve supply. Altogether, 30 studies were carried out, and only six of our animals survived for 6 weeks to 7 months. T h e pressure changes in one dog are shown in Figure 3. I n three followed 2% months, 6 months, and 7 months, the blood pressure returned to levels equal those recorded before bypass. However, in all there was a decrease in pressure in the brachiocephalic region for a period of 30 to 60 days after transplantation. T h e gradual return of the hypertension in three animals after transplanting the blood supply of the kidneys to the aorta above the coarctation could indicate that mechanisms in addition to the renal ones play a role in the genesis of the hypertension, although this still needs further confirmation. Other organs must have some mechanism-either reflex or humoral-for satisfying their demands for increase in blood flow. Therefore, over a period ot time the combination of the latter plus the renal humoral mechanism may change the level of response of the baroreceptors to a point that the pressure is maintained at hypertensive levels. I n chronic experimental renal hypertension [41, angiotensin may be elevated early; but it returns to normal though the hypertension persists. T h e observations of iMcCubbin [17, 181 and Kezdi [I41 on the baroreceptors in hypertension indicate that the baroreceptors do change their responsiveness. I n this regard, Hawthorne and Mandal 1121 have produced hypertension by brachiocephalic and left subclavian artery stenosis. T h e resulting hypertension is not quite as severe as that noted in experimental coarctation of the aorta, though it does demonstrate that mechanisms other than the kidney may play a role in the development of arterial hypertension, presumably to increase flow, when there is a mechanical obstruction in an artery. I n summary, experimental coarctation of the aorta in the dog mimics the disorder occurring naturally in man. However, the hypertension is delayed in onset but is associated with hypertension below the coarctation. Evidence is available that the renal pressor system is one of the mechanisms involved in the genesis of the hypertension; this could explain the presence of hypertension below the coarctation. Our studies confirm those of Hawthorne and Mandal [121 and indicate that the reduced flow to organs other than the kidney may cause hypertension to occur. T h e hypertension in experimental coarctation may be a result of a combination of the humoral factors and reflex factors that permanently changes the "set" of the baroreceptors in carotid and aortic arch areas. VOI..
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CHARACTERISTICS OF T H E HYPERTENSION I N C O A R C T A T I O N OF T H E A O R T A I N M A N The clinical course of hypertension that occurs with coarctation of the aorta in man is different in some respects from the renal and essential types. The arterial pressure remains high throughout the patient’s life, but it rarely, if ever, progresses to the malignant stage. If the malignant stage does occur, then usually it can be explained on the basis of chronic nephritis or unrelated malignant hypertension. Admittedly the latter might be open to some question. Another characteristic of the hypertension in coarctation is the increase in mean arterial pressure below the coarctation, indicating, just as in experimental coarctation, that there is a generalized increase in vascular resistance. From experience with our patients, coronary artery disease does occur in the older patient with what may be an increased frequency, although surprisingly there is very little evidence of serious vascular disease elsewhere such as one might expect with long-standing essential hypertension. Local changes do occur around the coarctation site. This lack of associated small vessel disease clearly separates coarctation hypertension from other varieties, and actually raises the question of whether or not the vascular changes result from high arterial pressure alone. A series of studies by Harris et al. [ll] were performed in our clinic to determine whether or not a decrease in renal blood flow might be present that could explain the hypertension in man. The studies were similar to those in the dogs done by Young [311. Though there was some increase in the filtration fraction, no decrease in blood flow or kidney mass was found. The first was thought to be characteristic of the increased resistance everywhere. Subsequent to the work of Harris, other investigators made similar observations [6, 15, 281. Most agreed that there was no evidence of decreased renal blood flow. Kirkendall and his associates [I51 have done a particularly excellent group of studies in this regard. Not only did they study the kidney flow, but also they measured flows in the liver. They concluded that there was actually neither increased vascular resistance nor diminished flow anywhere. With recent improvements in methods for detection of renin activity, another approach to the evaluation of the renal factors has become possible. Gunnels et al. made angiotensin I1 determinations [lo1 on five of our patients with coarctation of the aorta. In two the levels were abnormally high, while in three, they were normal. Ueda et al. [301 found angiotensin to be normal in his patients with coarctation. One of our patients (H. J.) with a high angiotensin I1 level was 35 years of age and had complete interruption of his aorta at the level of the left subclavian artery. His blood pressure was recorded at times as high as 300 mm. Hg, although the pressure was unobtainable in his legs. About 12 years before an attempt to repair the coarctation was made at another hospital. Because of the location of the left carotid artery in relationship to the block, it was impossible to place a clamp across the aorta in such a way that the carotid could be avoided and so the operation was abandoned. One week before the first admission to Duke Hospital his arterial pressure was found to be 3001160 and was associated with an episode of hypertensive encephalopathy. Admission studies revealed a low normal creatinine clearance with a blood urea that varied from 30 to 40 mg. per 100 ml. The urine showed 4+ albumin. It was obvious that the patient had chronic nephritis. As shown in Figure 4, his angiotensin I1 levels were well into the abnormal range. His renal arteries were normal on angiography. Though it was realized that his hypertension could be entirely explained on the basis of nephritis, it was decided in view of the angiotensin I1 increase to repair his coarctation. Repair was carried out using a graft from the side of the ascending aorta to the end of the descending aorta. The angiotensin levels reverted to normal almost immediately after surgery and have remained so through the 3month follow-up period. His blood pressure, however, has remained high, though not as high as it was before surgery. He has a femoral systolic pressure only slightly 18
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The blood pressure recording of patient H . J . before and after surgery. Angiotensin IZ (A 11) levels before and after surgery are recorded.
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lower than the brachial one. His kidney status is similar to that noted before surgery. A second example of an unusual patient (H. L.) with coarctation and an elevated angiotensin I1 level was a 22-year-old woman (Fig. 5). This patient had an aneurysm in the transverse and first portion of the descending aorta removed 7 years before her second operation. Before the first operation there was a difference in pressure above and below the coarctation, but it was thought this was corrected when the aneurysm was removed and the kinking in the aorta corrected. As shown in Figure 5 , it is obvious that the pressure, although quite labile, still attained hypertensive levels. However, on bed rest it tended to come down. Angiotensin I1 levels were found to be elevated. At the second exploration there
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FIG. 5 . Blood pressure changes before and after surgery in patient H . L. Angiotensin I I (A 11) are recorded below.
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SEALY was a coarctation measuring about 3 or 4 mm. in diameter that was not evident on angiograms. A graft was used to replace a portion of the aorta. Following this, the patient’s angiotensin I1 levels were returned to normal as did her blood pressure. Studies of patients with coarctation indicate that the kidney is one source of a pressor substance in some instances. All do not have elevated levels of angiotensin, as 3 of our 5 patients did, nor is there indirect evidence of decrease in renal blood flow. Some patients have an increase in arteriolar resistance, as shown by the filtration fraction increase as well as increase in the mean arterial pressure below the coarctation. Though preoperative studies are conflicting concerning the presence or absence of differences between the vascular bed above and below the coarctation, events after surgery demonstrate conclusively that there are indeed striking differences. OBSERVATIONS O N PATIENTS AFTER REMOVAL OF T H E C O A R C T A T I O N I n previous reports [24, 251 our experiences were summarized for the years 1949 to 1958. From 1958 to 1964, 41 additional patients over 2 years of age were operated upon. There were no deaths. After discharge from the hospital, 31 had pressures below 140/90 mm. Hg within one month, and 2 more had pressures below 140/90 within a two-month period. Eight had pressures above this level, with only 1 still having pressures indicating severe hypertension. These figures are similar to the ones quoted by Sellors and Hobsley [261 and by Schuster and Gross [271. This is of significance, for it is an indication that anatomical changes in the small vessels rarely occur. This may be one of the important differences between the hypertension in coarctation and that in essential hypertension or even renal hypertension. I n 1951 a young Negro male had a repair of coarctation of the aorta at the Duke University Medical Center. After operation he did poorly. Soon it became evident that he had an acute abdominal disorder with intestinal obstruction, peritonitis, and shock. At laparotomy most of his small bowel was found to be gangrenous. Nothing could be done for him. Postmortem studies revealed a severe regional vasculitis involving the small arteries and arterioles that, strangely, were confined only to the area supplied by the coarcted aorta [l, 241. Figure 6 is a microscopic section from this patient’s mesenteric artery. About a year and a half later, this story was repeated again. This time the patient, who was 8 years of age, began to complain of abdominal pain about 4 or 5 days after surgery. There was evidence on x-ray of segmental small bowel dilatation. Because of an elevated white count to 35,000, he was explored and found to have two areas of gangrene of the small bowel with many small necrotic spots throughout the remainder. After resection of the gangrenous bowel, the patient made an uneventful recovery. Two months later, the blood pressure in the upper and lower extremities were within the limits of normal. Soon a third patient about the same age, with the same complaints as the second one, was encountered. This patient again had evidence of segmental small bowel obstruction and a 35,000 white count. He was found to have a diastolic pressure of 120 to 140 mm. Hg. In a review of the two preceding patients’ charts, they were also found to have had a diastolic hypertension following resection of their coarctation. On an entirely empirical basis, this patient was treated with hydralazine hydrochloride. This was followed by a rapid reduction in the diastolic pressure and a very prompt remission of the patient’s symptoms. Subsequently, another patient was treated, this time using reserpine with good results. This stimulated us to review further our experience with surgery for coarctation to see whether or not the development of hypertension after surgery for coarctation was common and to try to determine its relationship to the onset of abdominal pain [25].It soon became evident that there were actually two hypertensive responses that occurred after resection and restoration of the aortic lumen 20
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FIG. 6. Microscopic study ( ~ 7 4of) small branch of mesenteric artery from patient who died from postoperative paradoxical hypertension. T h e vessel is thrombosed; a portion of its muscular coat is destroyed, and there is a marked acute inflammatory exudate throughou.t the waJl. to normal. The first, which was sometimes associated with pressures as high as 260 mm. Hg systolic, occurred within the first 12 or 24 hours after surgery. A mild response in the first 24 hours is shown in Figures 7 and 8. The pressure often COARCTATION OF AORTA
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T h i s is blood pressure record on patient 12 years old who had a modest immediate elevation of blood pressure following coarctation operation. T h e n there was a second rise, 2 to 4 days later, of the diastolic pressure to 110 mm. Hg. H e experienced mild abdominal pain. T h e norepinephrine leuels were markedly elevated. VOL.
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would drop to a level below the patient’s preo erative level and then a second response, primarily diastolic, was noted 2 to 3 ays following surgery. The early hypertensive response in coarctation, though unexpected, could be explained on the “high set” of the baroreceptors. With the release of the obstruction, the stretch in the arch and carotid areas is decreased, thus releasing the buffering action of the pressor sensors. It will be remembered that hypertension in experimental coarctation is slow in developing, and this could be due to the time it takes for the baroreceptors to acquire a “high set.” A review of our recent experience (Table 1) indicates that all the patients who had the delayed postoperative diastolic hypertensive episode also had the immediate variety. The incidence of the hypertensive episodes was less, however, in the second series than in the first. The higher incidence of the immediate variety in the second series was due to preservation for review of the immediate postoperative blood pressure records. Thus, in two series of patients the presence of paradoxical hypertension has been confirmed. Observations of others 116, 19, 291 confirm that this is a definite syndrome.
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TABLE 1. INCIDENCE OF POSTOPERATIVE HYPERTENSION AFTER RESECTION OF COARCTATION OF T H E AORTA
Postoperative Hypertension 1949-1956: 50 patients First 24 hours
Delayed Abdominal pain
1956-1964: 41 patients First 24 hours
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Late or paradoxical hypertension following coarctation surgery has the following characteristics. First, it is preceded by an immediate postoperative pressure elevation of 12 to 24 hours' duration. T h e high level of the diastolic pressure is characteristic. T h e hypertension responds to sympatholytic and sympathetic blocking drugs. The pathological changes in the arteries and arterioles are confined to those supplied by the aorta below the coarctation. The clinical symptoms are related to ischemia and necrosis of the small bowel. The hypertension reverts to normal in 14 days or so, and a good result is obtained by the operation. An example was shown in Figure 8, where there was a good response to reserpine with disappearance of symptoms and a return of a normal blood pressure. Among the characteristics of this paradoxical hypertension, the response to sympatholytic drugs and the striking elevation in the diastolic pressure first suggested that this could be the result of excess norepinephrine secretion. Studies were begun several years ago to investigate this possibility. With the cooperation of Dr. McChesney Goodall, 12 patients with coarctation of the aorta had preoperative and postoperative catecholamine assays of 24-hour urine collections. Two patients with thoracotomy and 1 with an abdominal operation were used as controls. In all, the epinephrine and norepinephrine levels were elevated on the first postoperative day. Six of the 12 coarctation patients had abnormal levels of the norepinephrine for as long as followed, which was 5 to 7 days in most; in 1 it was elevated for 14 days. In the controls and other 6 coarctation patients, the excretion returned to normal in 3 days. Figures 7 and 9 demonstrate the levels of norepinephrine and epineph24C o !,.
24 HR CATECHOL AMINE EXCRETION IN URINE ~
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Control1 OP I I 2 3 4 5 6 7 8 FIG. 9 . Norepznephrzne and epinephrzne sccrctzon zn 21-year-old male following Tesectzon of coaictatzon of the aorta.
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rine after resection of the coarctation in 2 patients and demonstrate typical values, although in some patients levels of norepinephrine as high as 945 pg. per 24 hours were recorded. Franksson, Gemzell, and von Euler [81 have reported observations on postoperative patients similar to ours. How can this observation be related to the peculiarities of the paradoxical hypertension where there is the localization of the pathological changes to the vessels below the coarctation? It can only be explained by assuming that the vessels here are different from those above the coarctation. One explanation would be that they are more fragile and, therefore, are susceptible to increase in flow and pressure that follows removal of the obstruction; thus, they may break apart. However, high mean pressures already existed in the vessels below the coarctation, and flows through the vessels have always been great enough to meet normal demands. A more likely explanation for the postoperative localized vascular change would be the effect of the norepinephrine on the vessels below the coarctation, which are different from the ones above in that they might be either more reactive or already in a state of increased wall tone. Nolla-Panades' work [20] on the increased response to norepinephrine by the vessels in the lower extremities in experimental coarctation supports this thesis. T h e wall tension in the arterioles becomes so great that the critical closing pressure is now higher than the pressure level in the arterioles below the coarctation, and ischemia occurs in the vessel walls and in areas supplied by the vessels. Changes in the intestines similar to the ones noted in our patients have been reported in norepinephrine poisoning, shock, and aortic insufficiency [3, 7, 131. T h e difference between vessels below and above the coarctation may not be demonstrable by ordinary staining techniques, but physiologically the vessels are probably different as a result of the accommodation needed to meet the flow alterations necessitated by the block in the aorta. T h e significant elevation in diastolic pressure indicates the effect of the norepinephrine on the entire vascular tree. T h e increase in norepinephrine after any type of surgery is a stress phenomenon. Its continued high level in patients after resection and repair of a coarctation of the aorta is unusual, though the prolonged increased excretion of norepinephrine was noted by Goodall et al. after burns [9] and by Franksson, Gemzell, and von Euler [8] in some surgical patients. A feedback mechanism originating from the ischemic area produced by the peculiar vessels below the coarctation could be the mechanism for continuing the high level in the coarctation patients. Five of the 6 patients who had significant and prolonged postoperative elevation of norepinephrine had both the early and delayed paradoxical hypertension. Just how much of the norepinephrine response is the 24
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result of stimulation of the baroreceptor area in the first hours is not known. However, the relationship between the early and late varieties of hypertension as shown in the more recent group of our patients suggests this connection. T h e interesting finding of increased angiotensin I1 just after surgery in 2 patients who had had previously normal levels suggests an additional and perhaps augmenting factor in the hypertension. T h e renal artery constriction occurring from the high norepinephrine could have caused the renin production by the kidney. Thus, as one follows the genesis and regression of the hypertension in coarctation of the aorta, a variety of cardiovascular reactions occur, most seemingly related to maintaining adequate blood flow to organs below the constriction. T h e importance of the baroreceptor mechanism is evident both in the production and reversion of the hypertension and explains both the delay in its onset and its continuation after release of the aortic constriction. Humoral influences are exemplified by the preoperative elevation of angiotensin I1 noted in some patients. Norepinephrine levels may be increased and may persist for several days after surgical correction of the coarctation, and perhaps these levels are enhanced in the first day or so by the baroreceptor mechanism. Once the level of norepinephrine is increased, this then causes a diastolic hypertension. Because of differences in the vascular tree below the coarctation, serious consequences occasionally occur in this area that may lead to death. Though all these factors may lead to a life-threatening type of hypertension that, paradoxically, develops after removal of the coarctation, there is a dramatic response of the paradoxical hypertension to substances that block the action of norepinephrine. T h e reactions of the coarctation patient’s vascular tree to persistent hypertension is of interest. As the postoperative follow-up indicates, the hypertension is reversible. T h e natural history of the disorder is notable for the lack of development of small vessel degeneration such as one expects in renal or essential hypertension of long standing. This explains the ready reversibility of the hypertension. Where does this leave the original purpose of this review which was to define the nature of hypertension in coarctation? The descriptions given are related largely to acute events, which must be measured against hypertension that may be of a decade’s duration. T h e descriptions do, however, point out the complexity of blood pressure control which seems, in this situation, to be regulated by a need to get adequate blood flow beyond the simple obstruction in the aorta to areas of demand below. Thus there appear to be two mechanisms that explain the hypertension in coarctation. T h e first is the resistance to blood flow at the site of aortic constriction. T h e next factor or factors is an adaptation of VOL.
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the remainder of the blood pressure control mechanisms to assure flow to areas beyond the obstruction. This may be accomplished by a readjustment upward of the pressor sensing mechanism in the aortic arch and carotid bifurcation to a level that assures adequate flow by maintaining a high pressure. Experiments of McCubbin [18] have shown that such a readjustment of the baroreceptors occurs in experimental renal hypertension. In the absence of a continuously circulating humoral substance, increased vascular resistance could be present everywhere on the basis of the “high set” of the pressor sensors. T h e manner in which the baroreceptors change may be a combination of humoral and reflex change. As demands for blood flow to the kidneys increase, angiotensin levels may rise. Demands for blood to large muscle masses, liver, or gastrointestinal tract may incite other humoral or reflex mechanisms to raise pressure to increase flow through the fixed orifice of the coarctation. Both humoral and reflex factors, perhaps acting only intermittently or for short periods of time, may serve to set the baroreceptors at a hypertensive level, thus keeping the pressure above the coarctation high enough to assure adequate flow beyond the obstruction. SUMMARY
In coarctation of the aorta three varieties of arterial hypertension have been demonstrated. The first, the result of the obstruction, is relieved by the repair of the coarctation. An explanation for its genesis is offered. T h e second variety, which is limited to the first 24 hours after surgery, can be explained on the basis of a “high set” of the baroreceptors. T h e third variety, which occurs the second to fourth day after operation, may be life-threatening although it is self-limited. It very likely is due to a complex relationship of reflexes from the baroreceptor area, a norepinephrine increase, and local changes in blood vessels below the coarctation as a result of adaptation to the coarctation. REFERENCES
1. Benson, W. R., and Sealy, W. C. Arterial necrosis following resection of coarctation of the aorta. J . Lab. Invest. 5:359, 1956. 2. Bounous, G., Shumacker, H. B., Jr., and Hawtof, D. B. Experimental coarctation and supravalvular aortic stenosis. J . Thorac. Cardiov. Surg. 45: 210, 1963. 3. Brown, R. B., Rice, B. H., and Szakacs, J. E. Intestinal bleeding and perforation: Complication of treatment with vasoconstrictors. Ann. Surg. 150: 790, 1959. 4. Brown, T. C., Davis, J. D., Olichney, M. J., and Johnston, C. I. Relation of plasma renin to sodium balance and arterial pressure in experimental renal hypertension. Circ. Res. 18:475, 1966. 5. Clatworthy, H. W., Jr., Sako, Y., Chisholm, T. C., Culmer, C., and Varco, R. L. Thoracic aortic coarctation: Its experimental production in dogs, with 26
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SEALY 29. Trummer, M. J., and Mannix, E. P., Jr. Abdominal pain and necrotizing mesenteric arteritis following resection of coarctation of the aorta. J . Thorac. Cardiov. Surg. 45: 198, 1963.
30. Ueda, H., Kaneko, Y., and Takeda, T. Renal pressor system in hypertensive patients. Jap. Circ. J. 30: 167, 1966. 31. Young, W. G., Jr., Sealy, W. C., and Harris, J. S. The effects of chronic constriction of the thoracic aorta upon renal dynamics. Surg. Forum, pp. 200-205, 1950.
28
THE ANNALS OF THORACIC SURGERY
C
oarctation of the aorta is a simple vascular obstruction that frequently causes arterial hypertension. However, the removal of the obstruction may elicit, paradoxically, two hypertensive responses [22]. T h e elevated pressure from the coarctation may be due simply to the resistance at the stenosis site and in the collaterals, though the manner in which it is sustained is still obscure. Since the coarctation is above the kidneys, the gastrointestinal organs, and large muscle masses yet below the baroreceptors in the aortic and carotid areas, this sets the stage for unusual responses from the autonomic nervous system, certain endocrine glands, and local blood flow control mechanisms. By the use of an experimental preparation [23] first used in our laboratory that mimics the disorder seen in man, it has been possible to observe the development of the hypertension. Its regression can be followed by watching the events that follow the removal of the coarctation in patients. This report will review the experimental and clinical observations made over the last 17 years on the nature of hypertension in coarctation. EXPE RIM E N TA L OBSERVATIONS
Coarctation of the aorta in dogs was first produced in our laboratory in 1949. Another series of more than 50 studies were repeated in 1963. With a Venturi tube of Lucite inserted in the thoracic aorta, as shown in Figure 1, it was possible to produce hypertension. The diameter of the tube at its narrowest point had to be less than 20% of the normal aortic size and a mean gradient across the constriction of more than 30 mm. Hg was required in order for hypertension to develop. The manner in which the rise of the femoral systolic and carotid systolic pressures occurred after experimental coarctation is represented in Figure 2. Between 7 and 21 days after aortic constriction, significant hypertension then occurred followed by developing hypertension in the femoral artery, These observations have been confirmed using other methods by Scott and Bahnson [21] and by Clatworthy et al. [51. Since the renal arteries originate from the aorta below the constriction and since the mean pressure reaches hypertensive levels in the femoral vessels, these From the Division of Thoracic Surgery, Duke University Medical Center, Durham, N.C. This study is supported in part by U.S. Public Health Service Grant HE-01782 and the John Klein Heart Research Fund. Presidential address delivered at the Thirteenth Annual Meeting of the Southern Thoracic Surgical Association, Asheville, N.C., Nov. 3-5, 1966.
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FIG. 1. ( A ) Method of producing experimental coarctation with Lucite sleeve inserted into the descending aorta. (B and C) Methods of transplantin renal arteries to aorta above the coarctation using either prosthetic or preservedg aortic homograf t. both point to the kidney as a possible source of a humoral substance maintaining generalized vasoconstriction. Young et al. [31] in 1949-1950 measured renal blood flow by indirect methods before and after induction of the coarctation. Except for slight increase in the filtration fraction, indicating some increase in arteriolar resistance, blood flows were unchanged. Recently Bounous et al. 121, in an ingenious study using direct flow measurements, confirmed these observations. Scott and Bahnson were the first to demonstrate that changing the origin of the renal arteries from below the coarctation to a site in the neck above the coarctation would revert the elevated pressure to normal. The period of observation of their animals was short, with only two animals being observed for 4 months and with all eventually dying from renal infection. In 1963 in our laboratory, Lesage and Koie approached this problem differently, transferring the origin of the kidney's blood supply to a point above EXPERIMENTAL COARCTATION OF THE AORTA
F: s.
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FIG. 2. T h e blood pressure changes in a dog following aortic constriction as shown in Figure 1. C, carotid; F, femoral; D, diastolic; S, systolic. 16
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the coarctation as was shown in Figure 1. T h e kidney was left in situ with normal venous drainage, ureteral connections, and nerve supply. Altogether, 30 studies were carried out, and only six of our animals survived for 6 weeks to 7 months. T h e pressure changes in one dog are shown in Figure 3. I n three followed 2% months, 6 months, and 7 months, the blood pressure returned to levels equal those recorded before bypass. However, in all there was a decrease in pressure in the brachiocephalic region for a period of 30 to 60 days after transplantation. T h e gradual return of the hypertension in three animals after transplanting the blood supply of the kidneys to the aorta above the coarctation could indicate that mechanisms in addition to the renal ones play a role in the genesis of the hypertension, although this still needs further confirmation. Other organs must have some mechanism-either reflex or humoral-for satisfying their demands for increase in blood flow. Therefore, over a period ot time the combination of the latter plus the renal humoral mechanism may change the level of response of the baroreceptors to a point that the pressure is maintained at hypertensive levels. I n chronic experimental renal hypertension [41, angiotensin may be elevated early; but it returns to normal though the hypertension persists. T h e observations of iMcCubbin [17, 181 and Kezdi [I41 on the baroreceptors in hypertension indicate that the baroreceptors do change their responsiveness. I n this regard, Hawthorne and Mandal 1121 have produced hypertension by brachiocephalic and left subclavian artery stenosis. T h e resulting hypertension is not quite as severe as that noted in experimental coarctation of the aorta, though it does demonstrate that mechanisms other than the kidney may play a role in the development of arterial hypertension, presumably to increase flow, when there is a mechanical obstruction in an artery. I n summary, experimental coarctation of the aorta in the dog mimics the disorder occurring naturally in man. However, the hypertension is delayed in onset but is associated with hypertension below the coarctation. Evidence is available that the renal pressor system is one of the mechanisms involved in the genesis of the hypertension; this could explain the presence of hypertension below the coarctation. Our studies confirm those of Hawthorne and Mandal [121 and indicate that the reduced flow to organs other than the kidney may cause hypertension to occur. T h e hypertension in experimental coarctation may be a result of a combination of the humoral factors and reflex factors that permanently changes the "set" of the baroreceptors in carotid and aortic arch areas. VOI..
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CHARACTERISTICS OF T H E HYPERTENSION I N C O A R C T A T I O N OF T H E A O R T A I N M A N The clinical course of hypertension that occurs with coarctation of the aorta in man is different in some respects from the renal and essential types. The arterial pressure remains high throughout the patient’s life, but it rarely, if ever, progresses to the malignant stage. If the malignant stage does occur, then usually it can be explained on the basis of chronic nephritis or unrelated malignant hypertension. Admittedly the latter might be open to some question. Another characteristic of the hypertension in coarctation is the increase in mean arterial pressure below the coarctation, indicating, just as in experimental coarctation, that there is a generalized increase in vascular resistance. From experience with our patients, coronary artery disease does occur in the older patient with what may be an increased frequency, although surprisingly there is very little evidence of serious vascular disease elsewhere such as one might expect with long-standing essential hypertension. Local changes do occur around the coarctation site. This lack of associated small vessel disease clearly separates coarctation hypertension from other varieties, and actually raises the question of whether or not the vascular changes result from high arterial pressure alone. A series of studies by Harris et al. [ll] were performed in our clinic to determine whether or not a decrease in renal blood flow might be present that could explain the hypertension in man. The studies were similar to those in the dogs done by Young [311. Though there was some increase in the filtration fraction, no decrease in blood flow or kidney mass was found. The first was thought to be characteristic of the increased resistance everywhere. Subsequent to the work of Harris, other investigators made similar observations [6, 15, 281. Most agreed that there was no evidence of decreased renal blood flow. Kirkendall and his associates [I51 have done a particularly excellent group of studies in this regard. Not only did they study the kidney flow, but also they measured flows in the liver. They concluded that there was actually neither increased vascular resistance nor diminished flow anywhere. With recent improvements in methods for detection of renin activity, another approach to the evaluation of the renal factors has become possible. Gunnels et al. made angiotensin I1 determinations [lo1 on five of our patients with coarctation of the aorta. In two the levels were abnormally high, while in three, they were normal. Ueda et al. [301 found angiotensin to be normal in his patients with coarctation. One of our patients (H. J.) with a high angiotensin I1 level was 35 years of age and had complete interruption of his aorta at the level of the left subclavian artery. His blood pressure was recorded at times as high as 300 mm. Hg, although the pressure was unobtainable in his legs. About 12 years before an attempt to repair the coarctation was made at another hospital. Because of the location of the left carotid artery in relationship to the block, it was impossible to place a clamp across the aorta in such a way that the carotid could be avoided and so the operation was abandoned. One week before the first admission to Duke Hospital his arterial pressure was found to be 3001160 and was associated with an episode of hypertensive encephalopathy. Admission studies revealed a low normal creatinine clearance with a blood urea that varied from 30 to 40 mg. per 100 ml. The urine showed 4+ albumin. It was obvious that the patient had chronic nephritis. As shown in Figure 4, his angiotensin I1 levels were well into the abnormal range. His renal arteries were normal on angiography. Though it was realized that his hypertension could be entirely explained on the basis of nephritis, it was decided in view of the angiotensin I1 increase to repair his coarctation. Repair was carried out using a graft from the side of the ascending aorta to the end of the descending aorta. The angiotensin levels reverted to normal almost immediately after surgery and have remained so through the 3month follow-up period. His blood pressure, however, has remained high, though not as high as it was before surgery. He has a femoral systolic pressure only slightly 18
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240
Operation
I200
40
000 400 0
The blood pressure recording of patient H . J . before and after surgery. Angiotensin IZ (A 11) levels before and after surgery are recorded.
FIG. f .
lower than the brachial one. His kidney status is similar to that noted before surgery. A second example of an unusual patient (H. L.) with coarctation and an elevated angiotensin I1 level was a 22-year-old woman (Fig. 5). This patient had an aneurysm in the transverse and first portion of the descending aorta removed 7 years before her second operation. Before the first operation there was a difference in pressure above and below the coarctation, but it was thought this was corrected when the aneurysm was removed and the kinking in the aorta corrected. As shown in Figure 5 , it is obvious that the pressure, although quite labile, still attained hypertensive levels. However, on bed rest it tended to come down. Angiotensin I1 levels were found to be elevated. At the second exploration there
,A,d, f 600
401ya;;;,
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1020 April 1958
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FIG. 5 . Blood pressure changes before and after surgery in patient H . L. Angiotensin I I (A 11) are recorded below.
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SEALY was a coarctation measuring about 3 or 4 mm. in diameter that was not evident on angiograms. A graft was used to replace a portion of the aorta. Following this, the patient’s angiotensin I1 levels were returned to normal as did her blood pressure. Studies of patients with coarctation indicate that the kidney is one source of a pressor substance in some instances. All do not have elevated levels of angiotensin, as 3 of our 5 patients did, nor is there indirect evidence of decrease in renal blood flow. Some patients have an increase in arteriolar resistance, as shown by the filtration fraction increase as well as increase in the mean arterial pressure below the coarctation. Though preoperative studies are conflicting concerning the presence or absence of differences between the vascular bed above and below the coarctation, events after surgery demonstrate conclusively that there are indeed striking differences. OBSERVATIONS O N PATIENTS AFTER REMOVAL OF T H E C O A R C T A T I O N I n previous reports [24, 251 our experiences were summarized for the years 1949 to 1958. From 1958 to 1964, 41 additional patients over 2 years of age were operated upon. There were no deaths. After discharge from the hospital, 31 had pressures below 140/90 mm. Hg within one month, and 2 more had pressures below 140/90 within a two-month period. Eight had pressures above this level, with only 1 still having pressures indicating severe hypertension. These figures are similar to the ones quoted by Sellors and Hobsley [261 and by Schuster and Gross [271. This is of significance, for it is an indication that anatomical changes in the small vessels rarely occur. This may be one of the important differences between the hypertension in coarctation and that in essential hypertension or even renal hypertension. I n 1951 a young Negro male had a repair of coarctation of the aorta at the Duke University Medical Center. After operation he did poorly. Soon it became evident that he had an acute abdominal disorder with intestinal obstruction, peritonitis, and shock. At laparotomy most of his small bowel was found to be gangrenous. Nothing could be done for him. Postmortem studies revealed a severe regional vasculitis involving the small arteries and arterioles that, strangely, were confined only to the area supplied by the coarcted aorta [l, 241. Figure 6 is a microscopic section from this patient’s mesenteric artery. About a year and a half later, this story was repeated again. This time the patient, who was 8 years of age, began to complain of abdominal pain about 4 or 5 days after surgery. There was evidence on x-ray of segmental small bowel dilatation. Because of an elevated white count to 35,000, he was explored and found to have two areas of gangrene of the small bowel with many small necrotic spots throughout the remainder. After resection of the gangrenous bowel, the patient made an uneventful recovery. Two months later, the blood pressure in the upper and lower extremities were within the limits of normal. Soon a third patient about the same age, with the same complaints as the second one, was encountered. This patient again had evidence of segmental small bowel obstruction and a 35,000 white count. He was found to have a diastolic pressure of 120 to 140 mm. Hg. In a review of the two preceding patients’ charts, they were also found to have had a diastolic hypertension following resection of their coarctation. On an entirely empirical basis, this patient was treated with hydralazine hydrochloride. This was followed by a rapid reduction in the diastolic pressure and a very prompt remission of the patient’s symptoms. Subsequently, another patient was treated, this time using reserpine with good results. This stimulated us to review further our experience with surgery for coarctation to see whether or not the development of hypertension after surgery for coarctation was common and to try to determine its relationship to the onset of abdominal pain [25].It soon became evident that there were actually two hypertensive responses that occurred after resection and restoration of the aortic lumen 20
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FIG. 6. Microscopic study ( ~ 7 4of) small branch of mesenteric artery from patient who died from postoperative paradoxical hypertension. T h e vessel is thrombosed; a portion of its muscular coat is destroyed, and there is a marked acute inflammatory exudate throughou.t the waJl. to normal. The first, which was sometimes associated with pressures as high as 260 mm. Hg systolic, occurred within the first 12 or 24 hours after surgery. A mild response in the first 24 hours is shown in Figures 7 and 8. The pressure often COARCTATION OF AORTA
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FIG. 7.
T h i s is blood pressure record on patient 12 years old who had a modest immediate elevation of blood pressure following coarctation operation. T h e n there was a second rise, 2 to 4 days later, of the diastolic pressure to 110 mm. Hg. H e experienced mild abdominal pain. T h e norepinephrine leuels were markedly elevated. VOL.
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would drop to a level below the patient’s preo erative level and then a second response, primarily diastolic, was noted 2 to 3 ays following surgery. The early hypertensive response in coarctation, though unexpected, could be explained on the “high set” of the baroreceptors. With the release of the obstruction, the stretch in the arch and carotid areas is decreased, thus releasing the buffering action of the pressor sensors. It will be remembered that hypertension in experimental coarctation is slow in developing, and this could be due to the time it takes for the baroreceptors to acquire a “high set.” A review of our recent experience (Table 1) indicates that all the patients who had the delayed postoperative diastolic hypertensive episode also had the immediate variety. The incidence of the hypertensive episodes was less, however, in the second series than in the first. The higher incidence of the immediate variety in the second series was due to preservation for review of the immediate postoperative blood pressure records. Thus, in two series of patients the presence of paradoxical hypertension has been confirmed. Observations of others 116, 19, 291 confirm that this is a definite syndrome.
i
TABLE 1. INCIDENCE OF POSTOPERATIVE HYPERTENSION AFTER RESECTION OF COARCTATION OF T H E AORTA
Postoperative Hypertension 1949-1956: 50 patients First 24 hours
Delayed Abdominal pain
1956-1964: 41 patients First 24 hours
Delayed Abdominal pain
22
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No. of Pts.
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14
6
26 12 4
Coarctation of the Aorta and Hypertension
Late or paradoxical hypertension following coarctation surgery has the following characteristics. First, it is preceded by an immediate postoperative pressure elevation of 12 to 24 hours' duration. T h e high level of the diastolic pressure is characteristic. T h e hypertension responds to sympatholytic and sympathetic blocking drugs. The pathological changes in the arteries and arterioles are confined to those supplied by the aorta below the coarctation. The clinical symptoms are related to ischemia and necrosis of the small bowel. The hypertension reverts to normal in 14 days or so, and a good result is obtained by the operation. An example was shown in Figure 8, where there was a good response to reserpine with disappearance of symptoms and a return of a normal blood pressure. Among the characteristics of this paradoxical hypertension, the response to sympatholytic drugs and the striking elevation in the diastolic pressure first suggested that this could be the result of excess norepinephrine secretion. Studies were begun several years ago to investigate this possibility. With the cooperation of Dr. McChesney Goodall, 12 patients with coarctation of the aorta had preoperative and postoperative catecholamine assays of 24-hour urine collections. Two patients with thoracotomy and 1 with an abdominal operation were used as controls. In all, the epinephrine and norepinephrine levels were elevated on the first postoperative day. Six of the 12 coarctation patients had abnormal levels of the norepinephrine for as long as followed, which was 5 to 7 days in most; in 1 it was elevated for 14 days. In the controls and other 6 coarctation patients, the excretion returned to normal in 3 days. Figures 7 and 9 demonstrate the levels of norepinephrine and epineph24C o !,.
24 HR CATECHOL AMINE EXCRETION IN URINE ~
I Nor-Ep.
L
2
120
, m 100
*
80 60 40
20
0
Control1 OP I I 2 3 4 5 6 7 8 FIG. 9 . Norepznephrzne and epinephrzne sccrctzon zn 21-year-old male following Tesectzon of coaictatzon of the aorta.
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rine after resection of the coarctation in 2 patients and demonstrate typical values, although in some patients levels of norepinephrine as high as 945 pg. per 24 hours were recorded. Franksson, Gemzell, and von Euler [81 have reported observations on postoperative patients similar to ours. How can this observation be related to the peculiarities of the paradoxical hypertension where there is the localization of the pathological changes to the vessels below the coarctation? It can only be explained by assuming that the vessels here are different from those above the coarctation. One explanation would be that they are more fragile and, therefore, are susceptible to increase in flow and pressure that follows removal of the obstruction; thus, they may break apart. However, high mean pressures already existed in the vessels below the coarctation, and flows through the vessels have always been great enough to meet normal demands. A more likely explanation for the postoperative localized vascular change would be the effect of the norepinephrine on the vessels below the coarctation, which are different from the ones above in that they might be either more reactive or already in a state of increased wall tone. Nolla-Panades' work [20] on the increased response to norepinephrine by the vessels in the lower extremities in experimental coarctation supports this thesis. T h e wall tension in the arterioles becomes so great that the critical closing pressure is now higher than the pressure level in the arterioles below the coarctation, and ischemia occurs in the vessel walls and in areas supplied by the vessels. Changes in the intestines similar to the ones noted in our patients have been reported in norepinephrine poisoning, shock, and aortic insufficiency [3, 7, 131. T h e difference between vessels below and above the coarctation may not be demonstrable by ordinary staining techniques, but physiologically the vessels are probably different as a result of the accommodation needed to meet the flow alterations necessitated by the block in the aorta. T h e significant elevation in diastolic pressure indicates the effect of the norepinephrine on the entire vascular tree. T h e increase in norepinephrine after any type of surgery is a stress phenomenon. Its continued high level in patients after resection and repair of a coarctation of the aorta is unusual, though the prolonged increased excretion of norepinephrine was noted by Goodall et al. after burns [9] and by Franksson, Gemzell, and von Euler [8] in some surgical patients. A feedback mechanism originating from the ischemic area produced by the peculiar vessels below the coarctation could be the mechanism for continuing the high level in the coarctation patients. Five of the 6 patients who had significant and prolonged postoperative elevation of norepinephrine had both the early and delayed paradoxical hypertension. Just how much of the norepinephrine response is the 24
T H E ANNALS OF THORACIC SURGERY
Coarctation of the Aorta and Hypertension
result of stimulation of the baroreceptor area in the first hours is not known. However, the relationship between the early and late varieties of hypertension as shown in the more recent group of our patients suggests this connection. T h e interesting finding of increased angiotensin I1 just after surgery in 2 patients who had had previously normal levels suggests an additional and perhaps augmenting factor in the hypertension. T h e renal artery constriction occurring from the high norepinephrine could have caused the renin production by the kidney. Thus, as one follows the genesis and regression of the hypertension in coarctation of the aorta, a variety of cardiovascular reactions occur, most seemingly related to maintaining adequate blood flow to organs below the constriction. T h e importance of the baroreceptor mechanism is evident both in the production and reversion of the hypertension and explains both the delay in its onset and its continuation after release of the aortic constriction. Humoral influences are exemplified by the preoperative elevation of angiotensin I1 noted in some patients. Norepinephrine levels may be increased and may persist for several days after surgical correction of the coarctation, and perhaps these levels are enhanced in the first day or so by the baroreceptor mechanism. Once the level of norepinephrine is increased, this then causes a diastolic hypertension. Because of differences in the vascular tree below the coarctation, serious consequences occasionally occur in this area that may lead to death. Though all these factors may lead to a life-threatening type of hypertension that, paradoxically, develops after removal of the coarctation, there is a dramatic response of the paradoxical hypertension to substances that block the action of norepinephrine. T h e reactions of the coarctation patient’s vascular tree to persistent hypertension is of interest. As the postoperative follow-up indicates, the hypertension is reversible. T h e natural history of the disorder is notable for the lack of development of small vessel degeneration such as one expects in renal or essential hypertension of long standing. This explains the ready reversibility of the hypertension. Where does this leave the original purpose of this review which was to define the nature of hypertension in coarctation? The descriptions given are related largely to acute events, which must be measured against hypertension that may be of a decade’s duration. T h e descriptions do, however, point out the complexity of blood pressure control which seems, in this situation, to be regulated by a need to get adequate blood flow beyond the simple obstruction in the aorta to areas of demand below. Thus there appear to be two mechanisms that explain the hypertension in coarctation. T h e first is the resistance to blood flow at the site of aortic constriction. T h e next factor or factors is an adaptation of VOL.
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the remainder of the blood pressure control mechanisms to assure flow to areas beyond the obstruction. This may be accomplished by a readjustment upward of the pressor sensing mechanism in the aortic arch and carotid bifurcation to a level that assures adequate flow by maintaining a high pressure. Experiments of McCubbin [18] have shown that such a readjustment of the baroreceptors occurs in experimental renal hypertension. In the absence of a continuously circulating humoral substance, increased vascular resistance could be present everywhere on the basis of the “high set” of the pressor sensors. T h e manner in which the baroreceptors change may be a combination of humoral and reflex change. As demands for blood flow to the kidneys increase, angiotensin levels may rise. Demands for blood to large muscle masses, liver, or gastrointestinal tract may incite other humoral or reflex mechanisms to raise pressure to increase flow through the fixed orifice of the coarctation. Both humoral and reflex factors, perhaps acting only intermittently or for short periods of time, may serve to set the baroreceptors at a hypertensive level, thus keeping the pressure above the coarctation high enough to assure adequate flow beyond the obstruction. SUMMARY
In coarctation of the aorta three varieties of arterial hypertension have been demonstrated. The first, the result of the obstruction, is relieved by the repair of the coarctation. An explanation for its genesis is offered. T h e second variety, which is limited to the first 24 hours after surgery, can be explained on the basis of a “high set” of the baroreceptors. T h e third variety, which occurs the second to fourth day after operation, may be life-threatening although it is self-limited. It very likely is due to a complex relationship of reflexes from the baroreceptor area, a norepinephrine increase, and local changes in blood vessels below the coarctation as a result of adaptation to the coarctation. REFERENCES
1. Benson, W. R., and Sealy, W. C. Arterial necrosis following resection of coarctation of the aorta. J . Lab. Invest. 5:359, 1956. 2. Bounous, G., Shumacker, H. B., Jr., and Hawtof, D. B. Experimental coarctation and supravalvular aortic stenosis. J . Thorac. Cardiov. Surg. 45: 210, 1963. 3. Brown, R. B., Rice, B. H., and Szakacs, J. E. Intestinal bleeding and perforation: Complication of treatment with vasoconstrictors. Ann. Surg. 150: 790, 1959. 4. Brown, T. C., Davis, J. D., Olichney, M. J., and Johnston, C. I. Relation of plasma renin to sodium balance and arterial pressure in experimental renal hypertension. Circ. Res. 18:475, 1966. 5. Clatworthy, H. W., Jr., Sako, Y., Chisholm, T. C., Culmer, C., and Varco, R. L. Thoracic aortic coarctation: Its experimental production in dogs, with 26
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Coarctation of the Aortn and Hypertension
G. 7. 8. 9. 10. 11.
12. 13. 14. 15. 16. 17. 18.
19.
20. 21. 22. 23. 24. 25. 26. 27. 28.
special reference to technical methods capable of inducing significant intraluminal stenosis. Surgery 28:245, 1950. Culbertson, J. W., Eckstein, J. W., Kirkendall, W. M., and Bendell, G. N. General hemodynamics and splanchnic circulation in patients with coarctation of the aorta. J. Clin. Invest. 36:1537, 1957. Ende, N. Infarction of the bowel in cardiac failure. N e w Eng. J. Med. 258:879, 1958. Franksson, C., Gemzell, C. A., and von Euler, U. S. Cortical and medullary adrenal activity in surgical and allied conditions. J. Clin. Endocr. 14:608, 1954. Goodall, M., Stone, C., and Haynes, B. W., Jr. Urinary output of adrenaline and noradrenaline in severe thermal burns. Ann. Surg. 145:479, 1957. Gunnels, J. C., Jr., Grim, C. E., and Robinson, R. R. A technique for the measurement of human plasma renin activity: Preliminary experiences in healthy subjects and hypertensive patients. Ann. Intern. Med., in press. Harris, J., Sealy, W. C., and DeMaria, W. Renal dynamics and hypertension in aortic coarctation. Amer. J. Med. Sci. 9:734, 1950. Hawthorne, E. W., and Mandal, A. K. Chronic experimental hypertension in dogs after constriction of brachiocephalic and left subclavian arteries. Circ. Res. 11:155, 1962. Hoffman, F. G., Zimmerman, S. L., and Cardwell, E. S. Massive intestinal infarction without vascular occlusion associated with aortic insufficiency. New Eng. J. M e d . 263:436, 1960. Kezdi, P. Sinoaortic regulatory system. A.M.A. Arch. Intern. Med. 91:26, 1953. Kirkendall, W. M., Culbertson, J. W., and Eckstein, J. W. Renal hemodynamics in patients with coarctation of the aorta. J . Lab. Clin. Med. 53:6, 1959. Lober, P. H., and Lillehei, C. W. Necrotizing panarteritis €allowing repair of coarctation of aorta. Surgery 35:950, 1954. McCubbin, J. W., Green, J. H., and Page, I. H. Baroceptor function in chronic renal hypertension. Circ. Res. 4:205, 1956. McCubbin, J. W. Carotid sinus participation in experimental renal hypertension. Circulation 17:791, 1958. Mays, E. T., and Sergeant, C. K. Postcoarctectomy syndrome. Arch. Surg. (Chicago)91:59, 1965. Nolla-Panades, J. Hypertension and increased hindlimb vascular reactivity in experimental coarctation of the aorta. Circ. Res. 12:3, 1963. Scott, H. W., Jr., and Bahnson, H. T. Evidence for a renal factor in the hypertension of experimental coarctation ol the aorta. Surgery 30:206, 1951. Sealy, W. C. Indications for surgical treatment of coarctation of the aorta. Surg. Gynec. Obstet. 97:301, 1953. Sealy, W. C., and McSwain, G. H. A method for producing coarctation of the aorta in dogs. Surgery 25:451, 1949. Sealy, W. C., DeMaria, W., and Harris, J . Studies of the development and nature of the hypertension in experimental coarctation of the aorta. Surg. Gynec. Obstet. 90: 193, 1950. Sealy, W. C., Harris, J. S., Young, W. G., Jr., and Callaway, H. H., Jr. Paradoxical hypertension following resection of coarctation of the aorta. Surgery 42: 135, 1957. Sellors, T. H., and Hobsley, M. Coarctation of the aorta: Effect of operation on blood pressure. Lancet 1:1387, 1963. Schuster, S. R., and Gross, R. E. Surgery for coarctation of the aorta. J. Thorac. Cardiov. Surg. 43:54, 1962. Tonelli, F. B., and Malizia, E. Pre- and postoperative renal function in coarctation of the aorta and its relationship to the genesis of hypertension. Acta Med. Scand. 148:35, 1954. VOL.3,
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1967
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SEALY 29. Trummer, M. J., and Mannix, E. P., Jr. Abdominal pain and necrotizing mesenteric arteritis following resection of coarctation of the aorta. J . Thorac. Cardiov. Surg. 45: 198, 1963.
30. Ueda, H., Kaneko, Y., and Takeda, T. Renal pressor system in hypertensive patients. Jap. Circ. J. 30: 167, 1966. 31. Young, W. G., Jr., Sealy, W. C., and Harris, J. S. The effects of chronic constriction of the thoracic aorta upon renal dynamics. Surg. Forum, pp. 200-205, 1950.
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THE ANNALS OF THORACIC SURGERY