aortic aneurysm in the patient cardiac transplantation

Transcription

1 Abdominal undergoing aortic aneurysm in the patient cardiac transplantation Joseph J. Piotrowski, MD, Kenneth E. McIntyre, MD, Glenn C. Hunter, MD, Gulshan K. Sethi, MD, Victor M. Bernhard, MD, and Jack C. Copeland, MD, Tucson, Ariz. In the past 3 years at our institution 130 patients have undergone cardiac transplantation for ischemic cardiomyopathy in 49 (38%), idiopathic cardiomyopathy in 42 (32%), viral cardiomyopathy in 9 (6.9%), pulmonary hypertension in 8 (6%), and graft atherosclerosis in 2 (1.5%). Routine preoperative abdominal ultrasonography was performed on 98 (75%) of these patients with specific visualization of the abdominal aorta in 93 (95%). Abdominal aortic aneurysms (all infrarenal) were found before operation in four patients and only in the subgroup undergoing transplantation for ischemic heart disease (10.5%). They measured 3.4, 4.5, 3.6, and 3.8 cm before transplantation. Periodic evaluation by ultrasonography was carried out after transplantation during the 3-year period of this study. One aneurysm that was initially 3.6 cm increased to 4.0 cm and ruptured 2 months after transplantation. The patient died despite emergent surgery. Aneurysms in three patients who demonstrated rapid aneurysm expansion after transplantation were successfully repaired at 5, 20, and 33 months after transplantation when the lesions reached 5.5, 5.9, and 4.8 cm. A fifth patient with an initially normal (1.5 cm) aorta developed a symptomatic aneurysm of 4.1 cm, which was repaired uneventfully. The average expansion rate of these aneurysms after transplantation was cm/year. This experience suggests that aneurysms are limited to patients undergoing transplantation for ischemic heart disease. Ultrasound examination may be appropriate for preoperative screening. Carefial aortic surveillance after transplantation is important in patients having transplantation for ischemic cardiomyopathy because of the apparent rapid expansion rate compared to aneurysms in the population not receiving transplants. (J VAse SvRa 1991;14:460-7.) Five-year survival rates for orthotopic cardiac transplantation reported from the registry of the International Heart Transplantation Society in 1988 averaged 73.5%, and long-term survivors are common, with 10-year survival reaching 72%.~ A third of these patients have had transplants for ischemic cardiomyopathy, and other manifestations of atherosclerosis can be expected to develop in this subgroup such as stroke, lower extremity occlusive disease, and aortic aneurysm. The first report of aortic aneurysms occurring in the population undergoing cardiac transplant was published in 1977 by Reitz et al. 2 In their experience From the Department of Surgery, Section of Vascular and Cardiothoracic Surgery, University of Arizona Health Sciences Center, Tucson. Presented at the Sixth Annual Meeting of the Western Vascular Society, Palm Springs, Calif., Jan , Reprint requests: Joseph J. Piotrowski, MD, Assistant Professor of Surgery, Case Western Reserve University, MetroHealth Medical Center, 3395 Scranton Rd., Cleveland, OH /6/30799 with 114 patients undergoing cardiac transplantation, symptomatic aortic aneurysms requiring repair developed in two. Subsequent case reports have documented three other cases. 3'4 In each of these five instances no clinical evidence of aneurysm was observed before transplantation, and the aortic lesion became evident 2 to 4 years later. Current 1- and 5-year survival rates for cardiac transplantation at the University of Arizona Health Sciences Center are 94% and 79%, respectively. Abdominal ultrasonography has been routinely used, during the preoperative evaluation of these patients undergoing transplantation during the past 3 years. The purpose of this retrospective report is to document the incidence, time of occurrence, and rate of expansion of abdominal aortic aneurysms in these patients. MATERIAL AND METHODS From October 1986 to February 1990, 130 patients received orthotopic cardiac transplants at the 460

2 Volume 14 Number 4 October 1991 Aortic aneurysms occurring in population undergoing transplantation 461 University of Arizona Health Sciences Center (UAHSC), Tucson, Ariz. Routine preoperative abdominal ultrasonography was performed on 98 (75 % ) of these patients, with specifc visualization of the abdominal aorta in 93 (95%). These patients comprise the study group. All ultrasound studies were reviewed by one author (J.J.P.), and the maximum anteroposterior diameter of the infrarenal aorta was measured in centimeters. Associated findings defined by ultrasonography were noted. Direct chart review and use of a computerized data base on all transplant recipients at UAHSC provided demographic data and pertinent data regarding immunosuppressive regimens used. Statistical analysis was performed on a microcomputer with use of TRUE EPISTAT (Epistat Services, Richardson, Texas). Fischer's exact retrospective case control analysis and Student's t test were used. RESULTS Demographics The average age of the study group (n = 93) was 46 years, and 83% were men. Indications for transplantation included ischemic heart disease in 38 (39%), idiopathic cardiomyopathy in 34 (35%), viral myopathy in 6 (6%), primary pulmonary hypertension in 5 (5%), transplant atherosclerosis in 2 (2%), and miscellaneous nonatherosclerotic cardiomyopathies in 8 (8%). The study group did not differ significantly from the entire population undergoing transplantation in age, sex, or indications for transplantation. Incidence Routine preoperative nltrasonography in the 93 patients of the study group revealed abdominal aortic aneurysms in 4 (4.3%) (Table I). These lesions were present only in the group of 38 patients with transplants for ischemic heart disease (4 (10.5%). This incidence was significantly increased when compared with the 55 patients with transplants for other indications (2o = 0.025; Fisher's exact test). If the fifth patient in whom an aneurysm developed after an initially normal study is included, aortic aneurysms developed in 13.2% of patients in the ischemic heart disease subgroup, which further increases the significance of the difference between groups (p = ; Fisher's exact test). All five were infrarenal and measured 3.4, 4.5, 3.6, 3.8, and 4.1 cm. Rate of expansion The four known aneurysms were repaired at 2, 5, 20, and 33 months after transplantation, therefore Table 1. Incidence of abdominal aortic aneurysms in the population undergoing transplantation Indications Aortic Aorta > 2.5 cm for treatment No. size (cm) No. (%) Ischemic heart (10.5%)*t disease Idiopathic cardiomy _ opathy Miscellaneous cardiomyopathy _ _ (4.3%) *p = 0.025; Fischer's exact test. tdoes not include an additional patient in whom aneurysmal disease developed despite an initially normal ultrasound finding. If included, the incidence would be 13.2% (p = ; Fischer's exact test). the true natural history of these lesions could not be evaluated. However, the time range of follow-up provided sufficient information to determine that the average expansion rate for aneurysms in these four patients was 0.70 _ era/year. A 4.1 cm abdominal aortic aneurysm developed in an additional patient 3 years after transplantation despite an initially normal (1.5 cm) aorta. Therefore the expansion rate for all five aneurysms was 0.74 _ era/year (Table II). Both the size of the aneurysms and the ejection fractions (EFs) increased significandy after transplantation (p = and p = 0.036; Student's t test). Statistical comparison of expansion rates has not been performed on patients from our institution who have aneurysms and have undergone transplantation and those with aneurysms who have not had transplantation. CASE REPORTS Case I. A 53-year-old physician underwent orthotopic cardiac transplantation for ischemic cardiomyopathy. Abdominal ultrasonography at the time of transplantation revealed an asymptomatic 3.4 cm infrarenal aortic aneurysm. Pretransplant EF by radionuclide scan (MUGA) was 19%. After transplantation mediastinal and sternal wound infections developed in the patient. The steroid dosage was reduced and eventually discontinued temporarily to permit wound healing. A chronic rejection syndrome occurred, and the patient had successful repeat transplantation 2 years later. The abdominal aneurysm was 4.8 cm at that time. After the second transplant the patient's EF was 66%, which has been sustained. Four months after the second transplant, ultrasonography revealed that the aneutysm diameter had increased to 5.5 cm. Elective abdominal aortic aneurysmectomy was performed without the use of pulmonary artery catheter monitoring. A large fusiform

3 462 Piotrowski et al. Journal of VASCULAR SURGERY Table II. Expansion rate and ejection fraction of abdominal aortic aneurysms in cardiac transplant recipients Aneurysm size* (cm) Ejection fraction Patient Pretreatment Posttreatment Growth rate Pretreatment Posttreatment N/A *Ultrasound. **Student's t test;p < tmuga ~* _ 5** infrarenal aortic aneurysm was replaced with a 16 mm woven Dacron tube graft. The patient tolerated aortic occlusion and demonstrated no declamping hypotension. His postoperative course was uneventful, and he was discharged from the hospital on the sixth postoperative day. He is doing well 36 months after aneurysmectomy. Case 2. A 64-year-old man received an orthotopic cardiac transplant for severe ischemic cardiomyopathy. At the time of transplantation, ultrasonography revealed he had an aortic aneurysm measuring 4.5 cm. His EF improved from 20% before transplantation to 61% after transplantation, which has been sustained. Two years after transplantation, he complained of a new onset of abdominal and back pain. Repeat sonography demonstrated that the aneurysm was 5.9 cm. The patient was operated on an emergency basis, and a large nonruptured infrarenal abdominal aortic aneurysm extending into the right common iliac artery was resected. A 20 x 10 mm woven Dacron bifurcation graft was used to replace the aorta with distal anastomoses to the left common iliac and the right external iliac arteries. He tolerated aortic occlusion and did not experience significant declamping hypotension. His postoperative course was unremarkable, and he was discharged from the hospital on the seventh postoperative day. He is doing well 30 months after operation. Case 3. A 60-year-old man underwent orthotopic cardiac transplantation for ischemic cardiomyopa~y, A 3.5 cm abdominal aorkic aneurysm was identified on ultras0nography. His pretransplant EF was 21%. He was readmitted 2 months later for evaluation of abdominal pain. Repeat ultrasound examination revealed a 4 cm aortic aneurysm not thought to be significantly increased from the previous study. On the sixty-second postoperative day the patient was found unconscious and hypotensive. Physical examination revealed a pulsatile mass in the midabdomen. An emergency celiotomy revealed free rupture of the aortic aneurysm. Replacement with a tube graft was performed. He died 16 hours later as a result of continued acidosis and cardiac arrhythmias. Case 4. A 55-year-old man underwent orthotopic cardiac transplantation for ischemic cardiomyopathy. Pre- operative ultrasound evaluation revealed a 3.5 cm infrarenal aortic aneurysm. His EF improved from 31% before transplantation to 54% after transplantation and has further improved to 67% currently. One year later his aneurysm was noted to have increased to 4 cm. At the 18-month follow-up, ultrasound examination revealed an increase to 4.8 cm. The aneurysm was resected uneventfully and replaced with a 16 x 8 woven Dacron graft with distal anastomosis to the common iliac vessels bilaterally. He is currently doing well 9 months after surgery. Case 5. A 52-year-old man receiving a cardiac transplant for ischemic cardiomyopathy was found to have a normal infrarenal aorta (1.5 cm diameter) on ultrasound examination performed 2 months before transplantation. His EF improved from 25% to 60%, which has been sustained. Three years later the patient was admitted for acute low back pain. Ukrasonography revealed a 4.1 cm abdominal aortic aneurysm that did not appear to be leaking when abdominal CT scanning was performed. However, laparotomy was performed shortly after admission for resection of a nonruptured infrarenal aneurysm with common iliac involvement. The postoperative course was uneventful. The patient continu~es~to do well 7 months after surgery. Incidental ultrasound findings The following incidental findings were noted in 23 (23..4%) of the 98 patients who had preoperative ultrasound evaluation of the abdomen. Gallstones were present in 11 (11.2%), gallbladder polyps in 3 (3.1%), simple renal cysts in 6 (6.1%), complex renal cysts in 2 (2.0%), and a hepatic hemangioma was noted in 1 (1.0%). All of these lesions were asymptomatic. DISCUSSION In the initial report of Reitz et al. 2 aneurysms occurred only in those patients who received their transplants for ischemic cardiomyopathy, for an incidence of 2.7% in this subgroup. Both patients

4 Volume 14 Number 4 October 1991 Aortic aneurysms occurring in population undergoing transplantation 463 recovered uneventfially. Oz et al.4 in a report on bacterial aortitis described a single patient 45 years old who had repair of a suprarenal aortic aneurysm after cardiac transplantation. It is unclear from the manuscript why this patient's aneurysm was considered mycotic since all cultures were negative, the patient had in situ Dacron graft repair, had only short-term antibiotic coverage after operation (2 weeks), was taking steroids, and did well for the 23 months of follow-up. Reichman et al.3 recently reported successful repair of symptomatic aortic aneurysms in two patients. In their total experience with 187 patients over 10 years, 56% had transplants for ischemic cardiomyopathy, and both aneurysms appeared in this subgroup, for an incidence of 2%. One might speculate that the true incidence of aneurysmal disease may have been higher because screening for asyrnptomatic aneurysms was not performed. Our report is unique because routine preoperative ultrasound examinations have been performed over a 3-year period on 75 % of the 130 patients undergoing transplantation during this period. Although preoperative evaluation did not involve all patients, we can estimate the incidence of aortic aneurysm disease in this population. Total incidence in the study group was 4.3%, but aneurysms were demonstrated only in patients with transplants for ischemic cardiomyopathy (10.5%) (Table I). This difference was statistically significant (p = 0.025; Fisher's exact test). In addition, the clinical course of these initially small ( cm) aneurysms was not benign in this group of patients who were all taking a cyclosporine, steroid, and azathioprine immunosuppressive regimen. One ancurysm ruptured, although it was only 4 cm, and the patient died. The other three all increased in size over time at a rate (0.70 _ cm/year), which is apparently greater than the commonly quoted figure of 0.4 cm/year, s However, some variability exists in aneurysm expansion rates, 6 and the small numbers in this study may reflect an anomaly. One patient became symptomatic and was repaired successfully. Two others were repaired electively. The case history of the fourth patient is particularly interesting because ultrasound studies for a year before transplantation and 2 years after transplantation are available. The expansion rate before transplantation was 0.3 cm/year but 0.67 cm/year after. A combination of steroid therapy and increased cardiac EF may be contributory. Similarly the aneurysm in patient 1 did not begin to increase markedly until after the second transplant where both steroid therapy and sustained increased EF by MUGA were concurrent. The expansion rate in this patient after the first transplant was 0.7 cm/year versus 1.4 cm/year after the second. Many studies have shown that increased arterial pressure may be a contributory factor in aneurysm rupture. 7'8 Cronenwett et al. 9 found that diastolic pressure was independently predictive of rupture. Sterpetti et al. 6 confirmed the relationship between arterial hypertension and risk of rupture for small aneurysms, but with use of multivariate analysis they were unable to show that this was independently predictive. The population undergoing cardiac transplantation is unique in that EF increases dramatically and therefore would be expected to be a test of hemodynamic theories of aneurysm formation. In addition, these patients are routinely hypertensive, which is usually well controlled with an angiotensin converting enzyme inhibitor. The importance of hypertension alone is not clear since all these patients are placed on steroid therapy as part of the immunosupprdssion regimen. Aortic aneurysm formation has been noted in hamsters and turkeys treated with steroids. ~ '11 In blotchy mice, where an x-linked trait produces fatal rupture of thoracic aneurysms in males, a2 steroids have been shown to induce similar rupture rates in heterozygous females. ~3 The population undergoing cardiac transplantation may be more susceptible to rapid aneurysm expansion and formation because of combined hemodynamic stress and steroid therapy. Cyclosporine has been shown to cause hypertension (blood pressure persistently above 150/95 mm Hg) in comparison to other immunosuppressive regimens. 14 The vasoconstrictive effects of cyclosporine are thought to be caused by an imbalance in the production of thromboxane A 2 (TXA2) and prostacyclin (PGI2)) s It has also been suggested that cyclosporine potentiates the effect of steroid therapy by reducing the hepatic clearance. ~6 Propranolol has been shown to increase the tensile strength of the aorta in aneurysm-prone turkeys, which appeared to be independent of reduction in heart rate and arterial pressure) 7 Higher doses of propranolol used in this study stimulated lysyl oxidase to produce greater amounts of reactive aldehydes for intermolecular crosslinks and stabilized intermolecular elastin crosslinks. Propranolol delayed the formation of aneurysms in the male blotchy mouse model) 8 In an uncontrolled retrospective review of 27 patients with abdominal aortic aneurysms greater than 3 cm followed by ultrasonogra-

5 464 Piotrowski et al. )'ournal of VASCULAR SURGERY phy, half of them placed on B-blockade, the average expansion rate was reduced from 0.44 cm/year to 0.17 cm/year in those patients under treatment. 19 Although a clear trend was suggested, these data did not reach statistical significance (p = 0.09). From a surgical standpoint patients undergoing heart transplantation present a unique challenge. After successful cardiac transplantation, ventricular function is generally normal. During intraoperative aortic occlusion, the left ventricle tolerates increased afterload without difficulty. In a similar manner, after aortic graft implantation, declamping hypotension has not been a significant factor because of suitable compensatory ventricular performance. For these reasons aortic aneurysm resection in successful cardiac transplant recipients seems well tolerated. However, certain special factors exist that should be emphasized in the preoperative evaluation and operative care of such patients. We routinely evaluate the patients undergoing cardiac transplantation with a yearly treadmill stress test, a MUGA scan to evaluate left ventricular function, and with coronary arteriography. If cardiac performance is deemed normal, then more invasive intraoperative monitoring, such as pulmonary artery catheterization, may not be necessary. If the use of a pulmonary artery catheter is indicated, it should be placed through the left internal jugular vein since the right internal jugular vein is the preferred route for heart biopsies. Careful scrutiny of the immunosuppressive regimen should be undertaken before operation. Patients who have been on long-term immunosuppression with prednisone will require increased steroid coverage in the perioperative period. We have used 100 mg hydrocortisone every 6 hours as the maximal dose during this period, with rapid tapering and reduction to the normal preoperative prednisone dose 4 to 5 days after the operation. Prophylactic measures for prevention of infections are of prime concern in these patients with suppressed immune systems. Reitz et al. 2 used suprapubic catheters to minimize the chance of urinary tract infection; however, we have used urethral catheters without any problems. A short course of prophylactic antibiotics was given to all patients. A concerted effort should be made for early postoperative removal of indwelling tubes (intravenous, arterial, gastric, and urinary). The basic operative technique for aneurysmectomy has not been modified in these patients. However, attention to detail with gentle tissue handling, adequate hemostasis, and tissue coverage of the aortic prosthesis must be meticulously accomplished. Midline longitudinal incisions were used in all patients. Large nonabsorbable sutures were used for abdominal closure, and retention sutures were used in one patient. After operation precise management of immunosuppressive therapy is mandatory. Both cyclosporine and azathioprine are administered through the nasogastric tube after operation after which the tube is clamped for 30 minutes. If the patient does not tolerate the administration of these drugs through a nasogastric tube, then cyclosporine may be cautiously given intravenously. Frequent monitoring for evidence of rejection is required and may include transvenous endomyocardial biopsy if indicated. CONCLUSION Before transplantation the incidence of abdominal aortic aneurysm in our population was 4.3%, and this was significantly increased in those with transplants for ischemic heart disease (10.5%). However, an initially normal ultrasound finding does not preclude further aneurysm formation (Case 5). Aneurysm expansion appears to be more rapid (0.74 _ cm/year) than in the population not undergoing transplantation and led to rupture or symptoms in three of five (60%) patients at a relatively small size ( cm). The factors that may promote aneurysm expansion in these patients include preexistent atherosclerosis, increased hemodynamic stress caused by improved cardiac output, and the effect of the immunosuppressive regimen. Ultrasonography appears to be a good screening tool, but the absence of aneurysmal disease before transplantation does not preclude subsequent development of this lesion. Low back pain in a patient undergoing cardiac transplantation whose indication was ischemic heart disease requires a prompt workup for aneurysmal disease. We currently believe that all aneurysms in the patient undergoing cardiac transplantation merit repair regardless of size. At the very least small aneurysms should be closely observed by objective (ultrasonography or CT scanning) methods with prompt intervention when expansion becomes evident or symptoms develop in the patient that may be related to this lesion. REFERENCES 1. Fragomeni LS, Kaye MP. The registry of the International Society for Heart Transplantation: fifth official report J Heart Trans 1988;7: Reitz BA, Baumga~ner WA, Oyer PE, Stinson EB. Abdominal aortic aneurysmectomy in long-term cardiac transplant survivors. Arch Surg 1977;112:

6 Volume 14 Number 4 October 1991 Aortic aneurysms occurring in population undergoing transplantation Reichman W, Dyke C, Lee HM, Hanralon J, Szentpetery S, Sobel M. Symptomatic abdominal aortic aneurysms in longterm survivors of cardiac transplantation. J Vasc Suite 1990; i 1: Oz MC, Brewer BJ, Bucla JA, et al. A ten-year experience with bacterial aortas. J VAse SuRc 1989;10: Bernstein ER, Chen EL. Abdominal aortic aneurysm in high-risk patients. Ann Surg 1984;200: Sterpetti AV, Schultz RD, Feldhaus RI, Chevy SE, Peety DJ. Factors finuencing enlargement rate of small abdominal aortic aneurysms. J Surg Res 1987;43: Szilagyi DE, Elliott JP, Smith RR. Chnical fate of the patient with asymptomatic abdominal aortic aneurysm and unfit for surgical treatment. Arch Surg 1972;104: Foster JH, Bolosky BL, Gobbel WG, Scott HW. Comparative study of elective resection and expectant treatment of abdominal aortic aneurysm. Surg Gynecol Obstet 1969;I29: Cronenwett JL, Murphy TF, Zelenack GB, et al. Actuarial analysis of variables associated with ruptures of small abdominal aortic aneurysms. Surgery 1985;98: Steffee CH, Snell KC. Dissecting aortic aneurysms in hamsters treated with cortisone acetate. Proc Soc Exp Biol Med 1955;90: Beall CW, Simpson CF, Pritchard WR, Horms RH. Aortic rupture in turkeys induced by diethylstilbestrol. Proc Soc Exp Biol Med 1971;Ii3: Brophy CM, Tilson JE, Broverman IM, Tilson MD. Age of onset, pattern of distribution and histology of aneurysm development in a genetically predisposed mouse model. J VAse SURG 1988;8: Reilly JM, Savage EB, Brophy CM, Tilson MD. Hydrocortisone rapidly induces aortic rupture in a genetically susceptible mouse. Arch Surg 1990;125: Ozdogan E, Bonner N, Fitzgerald M, Masumeci F, Khaghoni A, Yacoob M. Factors influencing the development of hypertension after heart transplantation, l Heart Transplant 1990;9: Forsterman U, Kuhn K, Vestergrist A. An increase in the ratio of thr0mboxane A2 to prostacycfin in association with increased blood pressure in patients on cyclosporin A. Prostaglandins 1989;37: Ost L. Effects of cyclosporin on prednisolone metabolism. Lancet 1984;1: Boucek RJ, Gunja-Smith Z, Noble NL, Simpson CF. Modulation by propranolol of the lysl cross-links in aortic elastin and collagen of the aneurysm-prone turkey. Biochem Pharmacol 1983;32: Brophy C, Ti/son JE, Tilson MD. Propranolol delays the formation of aneurysms in the male blotchy mouse. J Surg Res 1988;44: Leach SD, Toole AL, Stern H, DeNatale R, Tilson D. Effect of B-adrenergic blockade on the growth rate of abdominal aortic aneurysms. Arch Surg 1988;123: Submitted Feb. 7, 1991; accepted May 5, DISCUSSION Dr. Edward A. Stemmer (Long Beach, Calif.). The authors describe a 10% incidence of abdominal aortic aneurysms (AAAs) occurring in 38 patients undergoing cardiac transplantation for ischemic heart disease. An AAA developed in an additional patient after transplantation. The series is unique in several ways. First, no AAAs were discovered or developed in the 55 patients with transplants for indications other than ischemic heart disease; second, the initial 10% incidence of AAAs is greater than would be expected from data in other series of patients with coronary artery disease; third, all five aneurysms began to enlarge after transplantation and, in fact, grew at almost twice the rate that has come to be accepted as the norm (0.4 cm/year); fourth, all five aneurysms were small (3.4 cm to 4.5 cm) when they were initially discovered. One of the five patients died when his 4 cm aneurysm ruptured. The other four patients underwent successful repair of the aneurysm. The authors postulate that the aneurysmal growth was due to the hemodynamic stresses of an increased cardiac output after transplantation plus the effect of immunosuppressive agents. They conclude that all aneurysms in the patients undergoing cardiac transplantation merit repair regardless of size. Although clearly a significant relationship exists between cardiac transplantation and the growth of an AAA, the explanation may be more complex than that presented by the authors. It is noteworthy that the patients having transplants for indications other than ischemic heart disease did not develop aneurysms even though they also underwent the same immunosuppressive regime and hemodynamic stresses as did those with coronary artery disease. Moreover, we should not overlook the fact that cardiac transplantation changes not only the natural history of heart disease but also that of a coexisting AAA. In several series, myocardial infarction is responsible for at least 40% of deaths in patients with small aneurysms treated nonoperatively. In fact, death from cardiac disease is at least as common a cause of death in patients with AAAs as is rupture, regardless of the size of the aneurysm or whether the aneurysm is repaired or not. Successful cardiac transplantation removes this risk factor. Recent data from the University of Pittsburgh document that in the first 3 years after transplantation, only 4% of deaths are due to coronary artery disease. As a result, after transplantation the patient with an AAA suffers an even greater risk from complications of his aneurysm, primarily continued expansion and eventual rupture. The present series illustrates the problem very well. Only one of the authors' patients required operation for his aneurysm less than a year after transplantation. Had the end

7 466 Piotrowski et al. lournal of VASCULAR SURGERY stage cardiac disease been allowed to pursue its natural course in the other four patients, the presence of the AAA would have been a nonissue. Although some disagreement exists on the factors responsible for the enlargement and rupture of an AAA, it seems clear that initial size of the aneurysm, the presence of chronic obstructive pulmonary disease (COPD), the absence of peripheral vascular disease, and diastolic hypertension predict future problems with the aneurysm. The AAAs in the four patients who underwent aneurysmectomy more than a year after transplantation were subject not only to these factors but, in addition, were subject to additional factors related to the process of transplantation. The hemodynarnic stresses of an increased cardiac output and a higher dp/dt; the hypertensive effects of cyclosporine; the catabolic and hyperlipidemic effects of steroids, and possibly the effects of antivascular epithelial cell antibodies as a result of episodes of rejection would certainly be expected to accelerate growth of the aneurysm. The authors' conclusion that all AAAs in patients undergoing transplantation merit repair regardless of size is clearly correct. Because of the unpredictable behavior of the aneurysms, few vascular surgeons would choose to follow even small AAAs nonoperatively except in patients at high risk. By performing cardiac transplantation, the greatest component of the risk is eliminated. I have several questions for the authors. First, did any of the following correlate with expansion of the aneurysm: the level of increased dp/dt; the severity or frequency of rejection episodes; the dosage of cyclosporine or steroids; the level of hypertension, or the severity ofcopd? Second, were you able to measure the levels of elastase or collagenase in the patients with the AAAs? Dr. Joseph J. Piotrowski. I thank Dr. Stemmer for his kind comments. I agree with everything he said in the body of his commentary, and I have to say that all our comments about mechanisms in this particular group of patients are purely speculative. To answer your questions, we did not have specific data on the dp/dt in this group of patients. However, I would be very surprised if it was not increased in this group of patients. Their cardiac EFs increased dramatically. This group of patients were not subject to any additional rejection episodes compared to the other group of patients that had transplantations for ischemic cardiomyopathies. Cyclosporine and steroid doses are kept to a minimum. In fact, the steroid dose is usually tapered to the point where it is 5 mg or less of equivalent prednisone per day if at all possible. And this group of patients did not differ in that. All these patients have hypertension after cardiac transplantation. Most of those patients have a baseline tachycardia in addition because their vagus nerve has been completely transected. These patients, despite having systolic and diastolic hypertension, are well controlled on a single drug, and we have preferably used an angiotensin-converting inhibiter for this. All these patients have hyperlipidemia, specifically in their triglyceride levels. Many of the patients are quite debilitated by the time they come to cardiac transplantation and have low cholesterol and triglyceride levels. They routinely bounce back after transplantation, and these patients gain a lot of weight after transplantation. None of these patients had COPD. Chronic obstructive pulmonary disease is one of the contraindications to initial cardiac transplantation, and we do not routinely perform transplants in patients with COPD. And none of these specimens were analyzed for elastase or collagenase, so I do not have those data. Dr. Allan D. Callow (St. Louis, Mo.). This is a noteworthy paper for you have brought to our attention a very important problem. A major late cause of failure of the cardiac transplant is accelerated atherosclerosis in the coronary vessels of the transplanted heart. It is diffuse, extending throughout the small branches of the coronary circulation and thus is different in its distribution pattern from the nontransplant, nonaccelerated lesion. Although balloon angioplasty can be used in these failed transplants, it is primarily as a bridging procedure while waiting for retransplantation. A second observation is the increasing interest in the immune system involvement in atherosclerosis. A group of Swedish investigators has demonstrated the presence of complement, and many observations identify the presence of the T lymphocyte in the plaque as well. Inasmuch as there may be interference with the immune system of the patients you have studied, the possibility exists that some of them demonstrated recurrent coronary atherosclerosis, How many patients had failed immunosuppressive therapy and therefore were on the path to rejection? Finally, did you see any evidence of accelerated atherosclerosis or other degenerative changes in the arterial wall in vascular beds other than this one you have identified in the abdominal aneurysm? Dr. Piotrowski. Two of the patients in the group undergoing transplantation for ischemic cardiomyopathy had what we call transplant atherosclerosis and had had repeat transplantation for recurrent atherosclerosis. Neither of those two patients were patients in whom anenrysms developed. We currently have been looking at other manifestations of atherosclerosis in this group of patients. As far as the immunologic changes, the full case descriptions of these individual patients are in the manuscript. One of the patients is rather interesting in that a sternal wound infection developed after his original transplant. He subsequently had his steroid dose curtailed. He then rejected his transplanted heart, and his cardiac EF went down to 20%. However, his sternal wound did heal. The growth rate of his AAA was approximately 0.7 cm/year, which is the same as we have outlined here. However, he then had repeat retransplantation at that point, with standard prednisone and steroid doses, now that his sternum had healed sufficiently. At this point his EF was up to 60%, and the growth rate of his AAA was 1.4 cm/year. The fact that his cardiac EF came down may have led to the fact that his aneurysm did not grow quite as fast.

8 Volume 14 Number 4 October 1991 Aortic aneurysms occurring in population undergoing transplantation 467 As soon as we performed repeat transplantation and gave him immunosuppression, and he was able to increase his cardiac output again, he had a dramatic increase in the growth rate of his aneurysm. Dr. David B. Roos (Denver, Colo.). A few studies recently have emphasized an impressive familial incidence of patients in whom aortic aneurysms develop because of faculty elastase in the muscularis and overproduction of elastase. You said you had no predictive factors for patients in your series in whom the aneurysm developed. Was a familial history taken into account, and were elastase studies done? Dr. Piotrowski. We have not done that. We currently are planning to do similar studies, but we did not specifically look at familial history. Dr. Ralph B. Dilley (La Jolla, Calif.). Would you comment just a bit further on the timing of operation, particularly for those patients who were on the list for cardiac transplantation with abdominal aortic aneurysms. We currently have one patient on our list who has an aneurysm of 5.5 cm in diameter, and a 20% cardiac EF. Would you try to repair the aneurysm before the transplant? Dr. Joseph J. Piotrowski. That is an excellent question. I am not sure what the exact answer is. As a matter of fact, we have a patient just like that right now who has a terrible EF and a large aneurysm. We have not decided exactly what to do yet. Dr. Toshio Inahara (Portland, Ore.). I enjoyed this paper, but I want to ask the following: in view of the fact that this seems to point toward immunosuppression, did you make any comparison as to whether the incidence of abdominal aortic aneurysms is increased with other organ transplants, such as kidney transplants? Dr. Joseph J. Piotrowski. We have not made that comparison. However, my feeling is that, as you notice, the only group of patients it really showed up in was the patients who had had transplantation for ischemic heart disease. They were generally a little on the older side. In other words, the age range in this group of patients was about 50 to 60 years. The average age of the person undergoing cardiac transplantation was 40 years. I think if you look at the average age of the people undergoing renal transplantation, you might find they are also younger and have less evidence for ischemic or atherosclerotic disease, so I think you may be talking about different groups of patients. BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF VASCULAR SURGERY for 1991 are available to subscribers only. They may be purchased from the publisher at a cost of $59.00 for domestic, $79.13 for Canadian, and $75.00 for international subscribers for Vol. 13 (January to June) and Vol. 14 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Subscription Services, Mosby-Year Book, Inc., Westline Industrial Drive, St. Louis, MO , USA. In the United States call toll free: (800) , ext In Missouri call collect: (314) , ext Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.