The effects of improved hemodynamics on aortic dimensions in patients undergoing heart transplantation

Transcription

1 The effects of improved hemodynamics on aortic dimeio in patients undergoing heart traplantation David A. Bull, MD, Leigh A. Neumayer, MD, Bryan J. Venerus, MD, Charles W. Putnam, MD, Luis Rosado, MD, Pamela Lund, MD, Kenneth E. MeIntyre, MD, Victor M. Bernhard, MD, Jack G. Copeland, MD, Gulshan K. Sethi, MD, and Glenn C. Hunter, MD, Salt Lake City, Utah, Tucson, Ariz., and Galveston, Texas Purpose: Retrospective studies have demotrated an accelerated growth rate of abdominal aortic aneurysms in heart traplant patients. This prospective study was undertaken to define the relatiohip between cardiac hemodynamics and posttraplant aortic dilation. Methods: Sixty-eight patients undergoing heart (n = 60) or heart-lung (n = 8) traplantation were prospectively evaluated with abdominal ultrasonography before traplantation and annually after traplantation. Risk factors implicated in aneurysm growth, including age, indication for traplantation, immunosuppression, posttraplantation hyperteion, and abdominal aortic dimeion before traplantation were recorded. All patients underwent annual coronary artery catheterization and multiple gated acquisition scanning. Results: Thirty-seven patients (54%) had no change in aortic diameter after traplantation (pretraplantation and posttraplantatlon diameter = cm), over a mean follow-up period of months. In the remaining 31 (46%) patients, aortic diameter increased by cm over months (p < 0.05). Four (6%) of these 31 patients had abdominal aortic aneurysms (mean aortic diameter = cm). The mean increase in aortic diameter among these 4 patients was cm (annual rate of growth = cm/year). Patients experiencing an increase in aortic dimeion after traplantation had significantly lower (p < 0.005) pretraplantation ejection fractio (17.1% % vs 28.6% %) and, as a coequence, significantly greater (to < 0.05) increases in their ejection fractio after traplantation compared with patients with stable aortic dimeio (42.7O/o % vs 31.8% ± 18.0%). Conclusio: Of 68 heart traplant patients prospectively evaluated, aortic diameter increased in 31 (46%); new aneurysms developed in four of these patients. Greater incremental increases in cardiac ejection fraction were significant correlates with aortic enlargement. (J VASC SURG 1994;20: ) The rate at which abdominal aortic aneurysms From the Department of Surgery (Drs. Bull and Neumayer), University of Utah, Salt Lake City, the Departments of Surgery (Drs. Venerus, Putnam, Rosado, Bernhard, Copeland, Sethi, and Hunter) Pharmacology (Dr. Putnam), and Radiology (Dr. Lund), University of Arizona, Tucson; and the Department of Surgery (Dr. McIntyre), University of Texas Medical Branch, Galveston. Presented at the Ninth Annual Meeting of the Western Vascular Society, Santa Barbara, Calif., Jan. 9-13, Reprint requests: Glenn C. Hunter, MD, Department of Surgery, University Medical Center, 1501 N. Campbell, Tucson, AZ Copyright 1994 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /94/S /6./58334 (AAA) enlarge increases after heart traplantation. 1 We have previously &scribed a subgroup of heart traplant patients at increased risk for development of peripheral vascular disease, including AAA, after traplantation: those with a pretraplantation history of ischemic cardiomyopathy, and those in whom hyperteion or hyperlipidemia develops after traplantation. 2 In this report, we l exarnine the contributio of altered hemodynamic stress resulting from improved cardiac performance after traplantation versus the effects of immunosuppression, particularly cyclosporine and steroids, on aortic dilation after heart traplantation. 539

2 540 Bull et al. JOURNAL OF VASCULAR SURGERY October 1994 Table I. Indicatio for traplantation Indication No. (%) Ischemic cardiomyopathy 34 (50) Idiopathic cardiomyopathy 18 (26) Heart lung 8 (12) Valvular heart disease 3 (4) Congenital heart disease 2 (3) Viral cardiomyopathy 2 (3) Doxorubicin hydrochloride cardiomyopathy 1 (1) MATERIAL AND METHODS To define the relatiohip between cardiac hemodynamics after traplantation and aortic dilation, we prospectively evaluated patients undergoing heart traplantation at our ititution between 1987 and Abdominal ultrasonography was performed before traplantation and then yearly after traplantation. All ultrasound studies were reviewed by two of the authors (P.L. and B.V.), independently blinded, with the maximum anteroposterior diameter of the infrarenal aorta measured in millimeters with calipers. The two independent readings were then averaged for each study. In addition, indication for traplantation, age at the time of traplantation, the immunosuppressive regimen, presence of posttraplantation hyperteion, and the pretraplantation aortic dimeio were recorded for each patient. All patients undergoing heart traplantation were studied annually by coronary artery catheterization. Systemic vascular resistance was calculated at the time of cardiac catheterization. Annual multiple gated acquisition scanning evaluated left ventricular function. Statistical analysis. The data are expressed as mean + SD. Student t tests were used to determine whether improved hemodynamics (as measured by ejection fraction and change in ejection fraction) and the patient's immunosuppressive regimen were significant contributors to an increase in aortic dimeio and abdominal aortic aneurysm formation. Measures of association were tested with chi-squared analysis. RESULTS Between 1987 and 1991, we prospectively evaluated 68 patients with abdominal ultrasonography before traplantation and yearly after traplantation. Indicatio for traplantation are listed in Table I. Among the patients in the study group, 50 (74%) were men, and the mean age was years at the time of traplantation. Of the 68 patients in the study group, 37 (54%) had no significant change in aortic diameter after traplantation compared with before traplantation (pretraplant diameter = posttraplant diameter cm). In the remaining 31 (46%) patients, the aortic diameter increased from a mean of 2.0 _+ 0.6 cm before traplantation to 2.5 _+ 1.0 cm after traplantation, a mean increase of cm per patient (p < 0.05). The follow-up periods were not statistically different between the two groups ( months and 31 _+ 15 months, respectively). The incidence of posttraplantation hyperteion, antihyperteive and antirejection medicatio, and the almual rate of change in aortic diameters are fisted in Table II. Patients experiencing an increase in aortic dimeion after traplantation had significantly lower (p ) ejection fractio before traplantation (17.1% _+ 10.5% vs 28.6% %), and, as a coequence, significantly greater (p < 0.05) increases in their ejection fractio after traplantation compared with those patients with stable aortic dimeio (42.7% % vs 31.8% %). These data appear in Table III and Figs. i and 2. The patients whose aortic diameters increased over the study period were not significantly older at the time of traplantation than those with stable aortic diameters, (51.0 _ vs 46.1 _ years, p = 0.066). Neither did the two groups differ significantly with regard to sex, cyclosporine or steroid dosages, or the presence of hyperteion after traplantation. There was also no difference between the two groups with respect to the percentage taking calcium channel blockers, angiotein converting enzyme inhibitors, or beta blockers. Systemic vascular resistance was not significantly different between the two groups. To determine whether initial aortic diameter contributed to aortic dilation after traplantation, we divided the patients into two groups: those with initial aortic diameters less than 2.0 cm and those with initial aortic diameters 2.0 cm or greater. When compared in this fashion, there was no difference in ejection fractio before traplantation (Table IV). The age of the patients in these two groups was almost identical. Among the 31 patients with an increase in aortic dimeio after traplantation, four had AAA. Analysis of this subgroup of four patients showed that all patients in whom aneurysms developed had a pretraplantation history of ischemic cardiomyopathy. Their mean age at traplantation was 61.3 _+ 5.9 years (p < 0.05 compared with those with no change in aortic dimeion). The mean aortic diam-

3 JOURNAL OF VASCULAR SURGERY Volume 20, Number 4 Bull et al. 54][ Table II. Risk factors Factor Group i: no change in aortic diameter (n = 37) Group 2: increase in aortic diameter (n = 27) Group 3: aneurysm formation (n = 4) p Value r Age at traplant (years) Sex (male) 81% Percent with hyperteion after traplantation (> 150/90) 27% Cyclosporine daily dose (nag) Prednisone daily dose (mg) Calcium channel blocker (percent receiving the drug) 44% ACE inhibitor (percent taking the drug) 41% Beta blocker (percent taking the drug) 6% Rate of growth (cm/year) % 33% _ % 61% 10% % 75% % 50% 0% US us ACE, Angiotein converting enzyme. ~Student t test comparing groups 1 and 2. 1-p < 0.05 when compared with group 1. Sp < 0.05 when compared with group 2. Table III. Changes in ejection fraction and aortic dimeio Group I* Group 2-/- Group 35 Pretraplantation ejection fraction (%) Post traplantation ejection fraction (%) Change in ejection fraction (%) ]] ~No change in aortic diameter. tlncrease in aortic diameter. SAneurysm formation. p = compared with group 1. ][0 = compared with group 1. eter among these patients before traplantation was 3.2 _+ 1.0 cm, whereas the mean aortic diameter after traplantation was cm, a mean increase of 1.8 +_ 0.2 cm over the months of follow-up (annual growth rate = cm). DISCUSSION Previously, in a retrospective study, we reported accelerated enlargement ofaneurysms in recipients of heart traplants for ischemic heart disease) We suggested that ultrasonography be used to screen this subgroup of patients before traplantation, because the incidence of AAA was 10.5%. We also proposed routine screening for AAA after traplantation in patients with a history of ischemic cardiomyopathy because of the apparent rapid expaion rate of aneurysms in this group of patients: cm/year. 1 In our earlier report, we suggested that the increased growth rate of aneurysms in this group of patients might be the coequence of increased hemodynamic stress on the infrarenal aorta engendered by the improved hemodynamics of the new cardiac allograft or of the patient's immunosuppressive medicatio, in particular cyclosporine or steroids. This report addresses these questio. In this series, patients experiencing an increase in aortic diameter after traplantation had a significantly lower ejection fraction before traplantation and, coequently, a significantly greater increase in their ejection fractio after traplantation. These changes did not appear to correlate with initial aortic diameter, and there was no correlation with cyclosporine or steroid dose. These observatio suggest, but do not establish, a relatiohip of improvement in the patient's hemodynamics, as measured by ejection fraction, after traplantation to the development of an increased aortic diameter after traplantation. In patients with coexistent risk factors, including a pretraplantation history of ischemic cardiomyopathy, age at traplantation greater than 55 years, and posttraplantation hyperteion, the aortic dilation may progress to the development of an AAA. Heart traplant patients represent an unique biologic model in which to test whether an improvement in hemodynamics influences the diameter of the infrarenal aorta. Our results suggest that at least in heart traplant patients, increases in ejection fraction of greater than 35% may play a role in aortic dilation and aneurysm formation. The patients in whom an

4 542 Bull et al. JOURNAL OF VASCULAR SURGERY October ) o 60 - O.-- "~ 6@ -.9_ o [1_ ~ 40 - _9.+-, o 80 - LIJ +..o m co E ~- I 10-2 n 0 I 1, 2. I GROUP Fig. 1. Box plot of ejection fraction (in percent) by group. Group 1 represents patients with no change in aortic diameter; group 2 represents patients with change in aortic diameter. increase in aortic diameter was noted after traplantation had significantly lower ejection fractio before traplantation and thus had significantly greater increases in their ejection fractio after traplantation. This change in hemodynamics is rather sudden with the placement of the traplanted heart. The infrarenal aorta is particularly susceptible to the wall stress of the pressure wave generated by the left ventricle. 3 Thus the improvement in contractility generated by the left ventricle of the cardiac allograft may paradoxically manifest itself as dilation, and in some cases aneurysm development, in the infrarenal aorta. Hyperteion predisposes to the development of aneurysms, 4"6 likely by increasing stress on the infrarenal aortic wall. 4,5 Previously, we have demotrated that hyperteion after traplantation is a significant risk factor for the development of peripheral vascular disease, including aneurysms, after heart traplantation} We found older age at the time of traplantation to be associated with aneurysm formation, as it is in the nontraplantafion population. 7,8 Coincident with an increase in wall stiffness and decrease in compliance is a decline in the fractional widening of the aorta during the cardiac cycle, or strain, with increasing age.8 Traplantation of a dynamic cardiac allografr into a patient 55 years or older therefore may result in the tramission of an increased arterial pressure pulse to the infrarenal aorta, increasing the pulsatile load on a vessel that has become stiffer and less compliant with age. Dilation of the infrarenal aorta can occur, and, if hyperteion is also present, frank aneurysm formation may result. A number of factors may potentially influence the pressure/diameter relatiohips of the aorta. Increasing age, blood pressure, variation during the cardiac cycle, sympathetic and smooth muscle tone, individual differences in aortic geometry, antihyperteive medicatio, and immunosuppressive medicatio may all contribute to aortic enlargement, although the latter two did not appear to contribute in our study. The validity of use of B-mode ultrasonography to determine aortic size has been well documented, with a less than 5% variance in aortic dimeion measurements achievable with experienced examiners. 9 Our data suggest that patients who at the time of

5 JOURNAL OF VASCULAR SURGERY Volume 20, Number 4 Bull et al I I (1) o 60 0._ t- t-. o 40 kl O 0 _~ w 2O T / o r I I 1, 2. GROUP Fig. 2. Box plot of change in ejection fraction (in percent) after traplantation. Group 1 represents patients with no change in aortic diameter;gr0up 2 represents patients with change in aortic diameter. Table IV. Comparison between before and after traplantation ejection fraction in patients with aortic diameter < 2 cm and _> 2 cm Initial diameter < 2.0 cm Initial diameter >-2.0 cm p Value Age (years) Pretraplantation ejection fraction (%) Post traplantation ejection fraction (%) Change in ejection fraction (%) traplantation are over the age of 55, who have ischemic cardiomyopathy, or who have an ejection fraction of less than 20% (and thus are likely to experience an increase of 35% or greater in their ejection fractio after traplantation) are at increased risk for the development of aortic dilation and, possibly, aneurysm formation after traplantation. Such patients should undergo annual ultrasonography or computed tomography scanning to detect aneurysm formation: as we have previously reported, aneurysms in heart traplant patients have a significant predisposition to rupture. 1 Our recommendation is to resect AAA of 4 cm or greater in diameter in heart traplant patients. This can be performed with low morbidity and mortality rates. 1 REFERENCES 1. Piotrowski JJ, McIntyre ICE, Hunter GC, Sethi GK, Bernhard VM, Copeland JG. Abdominal aortic aneurysm in the patient undergoing cardiac traplantation. J VAse SURG 1991;14:: Bull DA, Hunter GC, Copeland JG, et al. Peripheral vascular disease in heart traplant recipients. J VASC SUV, G 1992;16: Dobrin PB. Pathophysiology and pathogenesis of aortic aneurysms. Current concepts. Surg Clin North Am 1989;69: Szilagyi DE, Elliot JP, Smith RF. Clinical fate of the patient with asymptomaric abdominal aortic aneurysm

6 544 Bull et al. JOURNAL OF VASCULAR SURGERY October 1994 and unfit for surgical treatment. Arch Surg 1972;104: Cronenwett JL, Murphy TF, Zelenock GB, et al. Actuarial analysis of variables associated with rupture of small aortic aneurysms. Surgery 1985;98: Taylor LM, Porter JM. Basic data related to clinical decisionmaking in abdominal aortic aneurysms. Ann Vasc Surg i990; 1: Liddington MI, Heather BP. The relatiohip between aortic diameter and body habitus. Eur J Vasc Surg 1992;6: Lanne T, Sonesson B, Bergqvist D, Bengtsson H, Gustafsson D. Diameter and compliance in the male human abdominal aorta: Influence of age and aortic aneurysm. Eur J Vasc Surg 1992;6: Lanne T, Stale H, Bengtssan H, et al. Non-invasive measurement of diameter changes in the distal aorta in man. Ultrasound Med Biol 1992;18: Submitted Feb. 15, 1994; accepted June li, DISCUSSION Dr. R. Scott Mitchell (Stanford, Calif.). The group from Tucson has once again defined some interesting relatiohips for aneurysm formation among patients undergoing heart traplantation. In a group of 68 patients prospectively evaluated for changes in infrarenal aortic dimeio, 37 patients had no significant change in aortic dimeion over a mean follow-up period of 28 months. In 31 patients (46%), however, the aortic dimeion increased by 0.5 cm mean over a 31-month mean follow-up. Four patients (6%) had development of a frank aneurysm with a mean increase of 1.8 cm in aortic diameter. Two factors were noted to be significantly different for this subgroup in which the aortic diameter had increased: older age, and lower ejection fraction before traplantation. As previously noted, aneurysm formation occurred only in those patients diagnosed with ischemic cardiomyopathy. While this change in hemodynamics is an appealing concept, one wonders what might have been missed in the multivariate analysis if the variable entered was history of hyperteion. Those patients with the most depressed ventricles are almost invariably treated with aggressive afterload reduction, and may have hypoteion at the time of traplantation. The absolute difference in systolic blood pressure before and after traplantation would thus be greatest in this subgroup of patients, and quite likely would be expected to produce the greatest change in aortic diameter. If this potentially confounding variable can be eliminated through a rigorous multivate analysis, then we can investigate the exciting possibilities of flow-mediated mechanisms for this increase in aortic diameter. In our own experience of more than 600 traplants, we have discovered anetu~csm formation in only eight patients, significantly fewer than the authors' experience. Most aneurysms developed in patients with an ischemic cause. Not enough pretraplantation ejection fractio were available to allow analysis. Did you analyze the data with use of pretraplantation systolic blood pressure as a variable? If not, do you think that would affect your findings? Have you attempted to correlate aortic blood flow, perhaps as measured with magnetic resonance imaging, with this propeity for aneurysm formation? Dr. Glenn C. Hunter. As you may be aware, a number of these patients have hypoteion before traplantation and require medical or mechanical support of their blood pressure and cardiac output. For this study, we used the preoperative blood pressure and the blood pressures recorded at their annual visits. About one third of all the patients had hyperteion within a short time after commencing their immunosuppressive regime. I believe one of the important questio we have to address is whether the increase in aortic diameter is real. We have not used magnetic flow imaging studies. We plan to measure aortic impedance at various levels along the aorta to more clearly define the hemodynamic changes within the aorta and their influence on aortic dimeio. The effect ofimmunosuppression on aortic dimeio is a critical question. Dr. Baxter and others have demotrated that patients with atherosclerotic aneurysms demotrate gene expression for type I collagen. However, four of the five patients we have studied have no mrna for type I collagen. There are only preliminary data, and we have to confirm these results with quantitative measurements. We believe that the changes in aortic dimeio are multifactorial and that hemodynamic changes merely represent one of the factors that may be involved and amenable to therapy. Dr. F. William Blaisdell (Sacramento, Calif.). You mentioned immunosuppression, but what about steroids? How many of these patients received steroids as part of their immunosuppression? Wouldn't that be a potent factor that would tend to encourage enlargement of these aortas? Dr. Hunter. The mean daily steroid dose for the entire group was about 5 mg per day, which is a fairly low dose. Our traplant surgeo make a big effort to keep the prednisone dose as low as possible. The steroid dose necessary to suppress type I collagen is presently unknown. These patients do receive larger doses of steroids within the first 6 to 12 months of traplantation. Whether this process starts early in the posttraplantation period remai to be determined. Dr. Christopher K. Zari (Stanford, Calif.). Most of your patients had no change in terms of enlargement of the

7 JOURNAL OF VASCULAR SURGERY Volume 20, Number 4 Bull et al. 545 aorta. Some had a small change, and then you had several that had fairly large changes. What is causing this? The indication for traplantation was ischemic cardiomyopathy. So obviously the patients had atherosclerosis and severe coronary artery disease, and they had a lot of atherosclerosis. My question relates to the atherosclerosis. Experimentally we have been able to show that with regression of atherosclerosis in animals you can produce aneurysms. What were the cholesterol levels in these patients? As part of their treatment for ischemic cardiomyopathy, were they given vigorous cholesterol lowering drugs? What were their serum cholesterol levels? Was the vigorous cholesterol-lowering regime, flit was there, potentially a factor in the enlargement of these aortas? Dr. Hunter. A number of these patients have cardiac cachexia with cholesterol levels between 100 and 150 mg/dl before traplantation. Within the first year after traplantation, the mean total cholesterol levels are about 250 mg/dl and triglyceride levels are 200 mg/dl There is a problem with treating hyperlipidemia in these patients too enthusiastically because severe myopathy may develop when lipid lowering drugs such as lovastatin (Mevacor) are used in combination with cyclosporine. One of my frustratio has been that many of these patients have not been as vigorously treated as one would have expected. Of the present group, only three or four patients were given lipid lowering drugs. Dr. Jerry Goldstone (San Francisco, Calif.). If the immunosuppression regime were an important factor, it: seems we would see these patients more often in other circumstances. We have at UCSF, I think, the largest: kidney traplantation experience of any center in the,, world, and I can't remember more than one patient from that group with an aortic aneurysm. This perhaps lends some support to the concept of a hemodynamic factor or at least something other than imrnunosuppression in the cause of these aneurysms. Dr. Hunter. The kidney traplant patients have not been as well studied as heart traplant patients. The group at Houston has done a lot of work on atherosclerosis in kidney traplant patients. I agree with your observation that aneurysms are uncommon in kidney traplant recipients. We have treated a number of patients with occlusive disease, but none with aneurysms. Perhaps the reason for this difference is the marked improvement in ejection fraction in the heart traplant patients. BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF VASCULAR SURGERY for 1994 are available to subscribers only. They may be purchased from the publisher at a cost of $76.00 for domestic, $97.32 for Canadian, and $92.00 for international subscribers for Vol. 19 (January to June) and Vol. 20 (July to December). Price includes shipping charges. Each bound volume contai 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 Dr., St. Louis, MO , USA. In the United States call toll free (800) , ext In Missouri or foreign countries call (314) Subscriptio must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.