Are Heart-Lung Transplant Recipients Protected From Developing Transplant Coronary Artery Disease?
A Case-Matched Intracoronary Ultrasound Study
Background Accelerated coronary artery disease is a major cause of mortality in heart transplant recipients; however, it does not appear to play a major role in the clinical outcome of heart-lung transplant recipients. The purpose of this study was to determine whether the incidence and severity of transplant coronary artery disease as detected by intracoronary ultrasound in heart-lung transplant recipients are less than those encountered in heart transplant recipients.
Methods and Results We studied the left anterior descending coronary artery with the use of intracoronary ultrasound imaging in 22 heart-lung transplant recipients at the time of their routine annual coronary angiogram. Twenty-two heart transplant recipients were case matched for number of years after transplant at ultrasound study, recipient age, donor age, and diagnosis of nonischemic cardiomyopathy. Mean intimal area, intimal index, Stanford class, and incidence of at least moderate disease (Stanford class ≥3) were measured and calculated in each group and then compared between the two groups. Mean intimal area (1.6±2.5 versus 3.8±2.8 mm2), mean intimal index (0.07±0.10 versus 0.22±0.14), mean Stanford class (1.7±1.0 versus 2.7±1.2), and incidence of Stanford class ≥3 (14% versus 45%) were significantly lower in the heart-lung transplant recipient group.
Conclusions The incidence and severity of transplant coronary artery disease are much less in patients receiving heart-lung transplants than in those receiving heart transplants alone.
Accelerated coronary atherosclerosis is a major cause of morbidity and mortality in cardiac transplant recipients.1 Coronary artery disease accounts for 36% of deaths in patients who survive 1 year beyond transplantation and for 60% of the retransplantation procedures performed at our institution.2 The etiology of transplant coronary artery disease is probably immune in nature and may be related to the frequency and severity of myocardial rejection.3 The incidence of myocardial rejection is known to be less in patients with heart-lung transplantation.4 5 6 Furthermore, recent reports have indicated that the development of transplant coronary artery disease, as detected by angiography, appears to be attenuated in heart-lung compared with heart-only transplant recipients.7 8 9
Heart and heart-lung transplant recipients undergo an early baseline angiogram before hospital discharge and return annually for surveillance angiograms. Intracoronary ultrasound (ICUS) imaging has been part of this surveillance for heart transplant recipients since 1991 and for heart-lung transplant recipients since 1993. The purpose of this study was to determine whether the incidence and severity of transplant coronary artery disease in heart-lung transplant recipients are less in heart transplant recipients as assessed by ICUS.
From July 1993 until December 1994, we studied the left anterior descending coronary artery of 22 consecutive heart-lung transplant recipients (at 88 sites) using ICUS during routine annual surveillance coronary angiography. With the Stanford Transplant Intracoronary Ultrasound Database, 22 heart transplant recipients were case matched for number of years after transplantation at the ultrasound study, recipient age, donor age, and original diagnosis of nonischemic cardiomyopathy. Nonischemic cardiomyopathy patients were selected to minimize possible confounding risk factors of atherosclerosis. In addition, the following clinical characteristics for each patient were obtained: (1) cardiac risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, and smoking; (2) cytomegalovirus infections; (3) number of treated cellular rejection episodes of the heart; and (4) mean dosage of the immunosuppressive drugs at 3 months, 1 year, and 2 years after transplantation. Both patient groups received a triple immunosuppression maintenance regimen of cyclosporine, azathioprine, and prednisone. All transplant patients received induction therapy with OKT-3, and heart-lung recipients received rabbit antithymocyte globulin (RATG). Moderate rejection episodes were treated with increased or pulse steroids or with either OKT-3 or RATG.
The study protocol was approved by the Committee for the Protection of Human Subjects in Research at Stanford University Medical Center, and written informed consent was obtained from all subjects.
Ultrasound Imaging Procedure and Analysis
In both the heart-lung and heart transplant recipient groups, ICUS imaging was accomplished with a 30-MHz ultrasound transducer and rotating mirror enclosed within an acoustic housing at the tip of a 2.9F or 4.3F rapid-exchange catheter (Cardiovascular Imaging Systems Inc). Two hundred micrograms of nitroglycerin IC and 0.4 mg of sublingual nitroglycerin SL were given before ultrasound imaging to prevent vasospasm and to minimize variations in vessel tone. After anticoagulation was achieved with heparin, the imaging catheter was introduced through a guiding catheter over a 0.014-in guide wire, and the left main and proximal to mid portions of the left anterior descending coronary artery were then imaged. Coronary segments of <2 mm in diameter were avoided. In addition to continuous scanning of the artery, four distinct arterial sites per patient were chosen for precise ultrasound measurements. Both ICUS and concomitant angiography of these sites were obtained.
Ultrasound studies were recorded on 0.5-in videotape and analyzed off-line. Gain settings were adjusted for optimal visualization of the vessel-lumen interface, and images were digitized as previously described.10 The frame with the largest lumen from the cardiac cycle immediately before contrast injection was selected for measurements. Measurements included the luminal cross-sectional area and, if intimal thickening was present, the total cross-sectional area and, if intimal thickening was present, the total cross-sectional area or area within the media layer (Fig 1).⇓ The intimal area was calculated by subtracting the luminal cross-sectional area from the total cross-sectional area. The values were entered into a customized database that calculated an intimal index, a measure of plaque area: II=(TA−LA)TA, where LA is luminal cross-sectional area, TA is total cross-sectional area, and IA is intimal area. We have previously shown good reproducibility and low interobserver and intraobserver variability for the above intravascular parameters.10
The Stanford classification was used to further categorize the degree of coronary disease.11 All segments studied were classified according to the severity of intimal thickening and degree of circumferential involvement: class 0 (none), no evidence of intimal layer by ultrasound and homogeneous wall; class 1 (minimal), intimal layer <300 μm thick involving <180° of the vessel circumference; class 2 (mild), intimal layer <300 μm thick involving >180° of the vessel circumference; class 3 (moderate), intimal layer 300 to 500 μm thick but involving <180° of the vessel circumference or >500 μm thick at any point of the vessel cross section; and class 4 (severe), intimal layer >500 μm thick involving >180° of the vessel circumference or intima >1 mm in any point of the vessel cross section.
Mean values of the intimal area, intimal index, Stanford class, and incidence of Stanford class ≥3 of the four sites in each patient were calculated.
Comparisons between differences in mean values of intracoronary ultrasound parameters and clinical parameters were determined with a Student's t test. All data are expressed as mean±1 SD. Statistical significance was defined as a two-sided value of P<.05. The statistical model used to compare the ICUS outcomes incorporated matching.
The heart-lung transplant recipient group included 12 men and 10 women, with a mean age of 38.3±8.0 years at the time of transplantation. The heart transplant recipient group included 15 men and 7 women with a mean age of 36.5±9.1 years. Mean ages of the donors in both groups were 27.4±10.7 years in the heart-lung and 25.9±8.5 years in the heart transplant recipient group, respectively. Patients were studied at a mean of 4.8±2.3 years after transplantation in the heart-lung and 4.7±2.2 years in the heart transplant recipient group. The pretransplantation diagnoses in the heart-lung transplant group were primary pulmonary hypertension (n=8), cystic fibrosis (n=5), Eisenmenger syndrome (n=8), and emphysema (n=1). In the heart transplant group, the pretransplant diagnoses were idiopathic cardiomyopathy (n=16), viral cardiomyopathy (n=4), postpartum cardiomyopathy (n=1), and heart failure secondary to valve disease (n=1). Both patient groups had comparable coronary atherosclerosis risk factors (hypertension, diabetes, smoking) (Table 1).⇓ Cytomegalovirus (CMV) infection was defined as either having a clinical CMV infection, laboratory evidence of a new CMV infection (a new positive IgM titer), or a reactivation of a CMV infection defined as a fourfold increase in IgG titer. Donor seropositivity and recipient CMV infections were comparable in both groups. The mean dose of cyclosporine in the heart-lung transplant recipient group was significantly higher at 3, 12, and 24 months after-transplantation than in the heart transplant recipient group. However, cyclosporine plasma levels taken at these time points did not show any significant difference between the groups. The mean doses of prednisone and azathioprine in both groups were comparable. There were significantly more patients receiving oral diltiazem in the heart-transplant recipient group than in the heart-lung transplant recipient group. In comparing the clinical parameters of the two groups, heart-lung transplant patients had significantly fewer treated myocardial rejection episodes, a higher mean cyclosporine dose (mean of dose at 3, 12, and 24 months), and a higher cholesterol level. Multivariate analysis, with the use of a stepwise regression model, did not identify any variable predicting less intimal thickening.
Four sites in the left anterior descending coronary artery were scanned in every patient. A total of 88 segments were analyzed by ICUS in the 22 patients in the heart-lung group, and a total of 88 sites were analyzed in 22 patients in the heart transplant group. Mean intimal index (Fig 2A)⇓, intimal area (Fig 2B)⇓, Stanford class (Fig 2C)⇓, and incidence of Stanford class ≥3 (Fig 2D)⇓ were compared between the two groups. Mean intimal area was significantly smaller, and mean intimal index, mean Stanford class, and incidence of Stanford class ≥3 were significantly lower in the heart-lung transplant recipient group (Table 2)⇓. These results show that the incidence and severity of transplant coronary artery disease are much less in heart-lung than in heart transplant recipients.
This is the first study to compare the incidence and severity of transplant coronary artery disease in heart-lung and heart transplant recipients with the use of ICUS. The results of this study show that the incidence and severity of transplant coronary artery disease are less in heart-lung transplant recipients than in heart transplant recipients.
A major cause of mortality, and the main cause of retransplantation in heart transplant recipients, is transplant coronary artery disease. As many as 50% of the patients will develop significant angiographic disease by 5 years after transplantation. The majority of the heart-lung transplant recipients who survive the first year do not die as the result of cardiac disease or event.8 9 12 The present study confirms earlier reports that indicate that transplant coronary artery disease, as assessed by quantitative coronary angiography, does not play a major role in the morbidity and mortality of heart-lung transplant recipients. Richardson et al8 observed that only 11.8% of a group of heart-lung transplant recipients had angiographic evidence of coronary artery disease 4 years after heart-lung transplantation. Sarris et al9 reported similar findings and found that only 11% of their group of heart-lung transplant recipients had angiographically detectable coronary artery disease at 5 years after transplantation. Despite its accuracy in detecting late changes, quantitative angiography is unable to detect the earliest stages of transplant coronary artery disease.11 With ICUS, which is a more sensitive technique with which to detect transplant coronary artery disease, the incidence and severity of transplant coronary disease can be assessed at an earlier stage and can be better quantified.10 13 14 15 16 17
It is unclear why heart-lung transplant recipients have less coronary artery disease than those with cardiac allografts only. Both groups were comparable regarding traditional coronary atherosclerosis risk factors. There were more women in the heart-lung transplant recipient group. Although women may have a lower incidence of coronary artery disease in the general population, the incidence of transplant coronary artery disease in heart transplant recipients appears to be equal among men and women.19 The incidence of primary and secondary CMV infections were similar in the two groups. When the immunosuppressive regimens were compared, it was noted that the mean cyclosporine dose was significantly higher in the heart-lung transplant recipient group. However, cyclosporine plasma levels taken at several time points did not show any significant difference in plasma level. One of the reasons for the discrepancy between dosage and plasma levels could be that twice as many heart transplant patients (n=11) than heart-lung transplant recipients (n=6) received oral diltiazem, which has been shown to change the pharmacokinetics of cyclosporine. A recent report shows that oral diltiazem may play a role in attenuating the progression of transplant coronary artery disease in heart transplant recipients.20 The heart-lung recipients have less transplant coronary disease despite this bias toward the heart-only recipients. The mean doses of prednisone and azathioprine in both groups were comparable.
Little is known regarding the etiology of transplant coronary artery disease.3 It is generally believed to be an immune-mediated process, mainly because the disease is limited to the vascular bed of the allograft and affects it diffusely. However, clinical studies assessing the relation of cellular rejection and transplant coronary disease in heart transplant recipients yielded conflicting results. Recently, a multicenter database has shown that smoldering low-grade rejection correlates with the development of intimal thickening as detected by intravascular ultrasound.21 The lower incidence of transplant coronary artery disease in heart-lung transplant recipients may well be linked to their lower incidence of cardiac allograft rejection.4 5 6 Different immunosuppressive protocols have not been able to decrease the incidence and severity of transplant coronary artery disease. Kutlu et al22 and Westra et al23 demonstrated in a rat transplant model that combined heart-lung transplantation would prolong heart graft survival compared with heart transplantation alone. Histological studies demonstrated more rejection of the heart in the heart-only transplant group than in the heart-lung transplant group. Kutlu et al22 further observed in the heart-only transplant group, with a severe degree of rejection, that there was a significant degree of vasculitis in large- and medium-sized coronary arteries with subendothelial proliferation, resembling an atherosclerotic process. In a similar experiment, Ueki et al24 demonstrated that the degree of atherosclerosis in a heart-lung transplanted group of rats was less than that in a heart-only transplanted group. The degree of rejection of the heart in the heart-lung group was also less than that of the heart-only transplanted group. The conclusion was that the lung suppresses but does not abolish immunologically induced coronary atherosclerosis–like lesions after heart-lung transplantation. Westra et al23 observed in rats in which hearts were transplanted in combination with lungs or spleen that there was an impressive reduction in myocardial rejection. This phenomenon of reduction in myocardial rejection after combined transplantation with the lung is termed the combi-effect. The authors hypothesized that the mechanism of the combi-effect had to be immunological because transplantation of a syngeneic lung or third-party spleen did not have an effect on graft survival. Cyclosporine immunosuppression appeared to be essential to get a strong combi-effect. Without cyclosporine treatment, there was no improved graft survival. Westra et al23 suggested that there could be two possible mechanisms: (1) the pulmonary lymphoid framework may filter anti–graft-reactive lymphocytes out of the blood circulation so that these cells do not reach the myocardium; or (2) donor lymphocytes in the bronchus-associated lymphoid tissue massively activate graft-reactive T cells as well as suppressor cells. Cyclosporine inhibits the graft-reactive T cells, whereas it does not inhibit the stimulation of suppressor cells. Therefore, the rejection response will be shifted toward suppression.22 23 24 Elucidation of the mechanisms of this phenomenon may lead to new treatment methods for transplant coronary artery disease.
Several limitations of this study should be noted when interpreting the results. First, this is a cross-sectional rather than a longitudinal study. Second, this is a selected group of heart-lung transplant recipients. Heart-lung transplant recipients who die of obliterative bronchiolitis are not represented in this study. Therefore, patients who may have coexistent transplant coronary artery disease were omitted from this study. However, data from our institute indicate that none of the 39 patients who died of obliterative bronchiolitis (3.3±1.9 years) after transplantation had significant disease (≥50%) on postmortem examination. Lesions of 20% to 50% were seen in 12.5% of these patients. No significant difference was seen in a comparison of the incidence of coronary artery disease, on either annual angiograms or postmortem examinations, between heart-lung transplant recipients with and without obliterative bronchiolitis.
Compared with heart transplant recipients, heart-lung transplant recipients develop less transplant coronary artery disease as detected by ICUS. These observations support the observation that only a minority of heart-lung transplant recipients die as the result of cardiac disease or event. Elucidation of the mechanisms of this phenomenon may lead to new treatment methods for transplant coronary artery disease.
This work was supported by the NIH CIDA grant K08-HL-02787 (Dr Yeung). We thank Dr Richard Popp for advice and review of the manuscript and Ann Schwartzkopf for assistance in collection of the ultrasound data.
- Received October 23, 1995.
- Revision received April 6, 1996.
- Accepted April 16, 1996.
- Copyright © 1996 by American Heart Association
Bieber C, Hunt S, Schwinn D. Complications in long-term survival of cardiac transplantation. Transplant Proc.. 1981;8:207-211.
Uretsky B, Murali S, Reddy P, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, Bahnson HT. Development of coronary artery disease in cardiac tranplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation.. 1987;76:827-834.
Joshi A, Oyer P, Billingham M. Pathology of the heart in heart-lung transplantation. J Heart Lung Transplant.. 1994;13:S34.
Richardson M, Pomerance A, Mitchell A, Banner N, Yacoub M. Coronary artery disease in heart-lung transplant recipients: angiographic and histological findings. J Heart Lung Transplant.. 1994;13:S40.
Sarris G, Smith J, Shumway N, Stinson E, Oyer P, Theodore J. Long-term results of combined heart-lung transplantation: the Stanford experience. J Heart Lung Transplant.. 1994;13:S40.
Liang DH, Schwarzkopf A, Botas J, Alderman EL, Popp RL, Yeung AC. Reproducibility of serial intravascular ultrasound in transplant recipients. Circulation. 1994;90(suppl I):I-639.
St Goar FG, Pinto FJ, Alderman EL, Valantine HA, Schroeder JS, Gao SZ, Stinson EB, Popp RL. Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of ‘angiographically silent’ intimal thickening. Circulation.. 1992;85:979-987.
Dennis C, Caine N, Sharples L, Smyth R, Higenbottam T, Stewart S, Wreghitt T, Large S, Wells FC, Wallwork J. Heart-lung transplantation for end-stage respiratory disease in patients with cystic fibrosis at Papworth Hospital. J Heart Lung Transplant. 1993;12(pt 1):893-902.
Heroux AL, Silverman P, Costanzo MR, O'Sullivan EJ, Johnson MR, Liao Y, McKierman TL, Balhan JE, Leya FS, Mullen GM. Intracoronary ultrasound assessment of morphological and functional abnormalities associated with cardiac allograft vasculopathy. Circulation.. 1994;89:272-277.
St Goar FG, Pinto FJ, Alderman EL, Fitzgerald PJ, Stinson EB, Billingham ME, Popp RL. Detection of coronary atherosclerosis in young adult hearts using intravascular ultrasound. Circulation.. 1992;86:756-763.
Lowry RW, Kleiman NS, Raizner AE, Young JB. Is intravascular ultrasound better than quantitative coronary arteriography to assess cardiac allograft arteriopathy? Cathet Cardiovasc Diagn.. 1994;31:110-115.
Kobashigawa J and the Multicenter Intravascular Ultrasound Group. Does rejection correlate with development of ACAD? results of a multicenter study using ICUS. J Heart Lung Transplant.. 1995;14:S16.