Cardiac%20Transplantation

Circulation. 1995;91:1706-1713.)© 1995 American Heart Association, Inc.Occult and Frequent Transmission of Atherosclerotic Coronary Disease With Cardiac TransplantationInsights From Intravascular UltrasoundE. Murat Tuzcu, MD; Robert E. Hobbs, MD; Gustavo Rincon, MD; Corinne Bott-Silverman, MD; Anthony C. De Franco, MD; Killian Robinson, MD; Patrick M. McCarthy, MD; Robert W. Stewart, MD; Skip Guyer, RCPT; Steven E. Nissen, MDFrom the Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio.Correspondence to E. Murat Tuzcu, MD, Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F-25, Cleveland, OH 44195-5066.AbstractBackground Transplant coronary artery disease is a major cause of morbidity and mortality after cardiac transplantation. However,limited data exist regarding the potential contribution of coronary atherosclerosis in the donor heart to cardiac-allograft vasculopathy.Methods and Results We performed quantitative coronary angiography and intravascular ultrasound imaging in 50 of 62 consecutive heart-transplant recipients (40 men, 10 women, mean age, 53±9years) 4.6±2.6 weeks after transplantation. The donor population consisted of 30 men and 20 women (mean age, 32±12 years). Ultrasound imaging visualized all three coronary arteries in 22 patients, two coronary arteries in 23, and one coronary artery in 5. Ultrasound imaging detected coronary atherosclerosis (intimal thickness 0.5 mm) in28 patients (56%). However, the angiography was abnormal in only 13 patients (26%). The sensitivity and specificity of coronary angiography were 43% and 95%, respectively. With ultrasound, the average atherosclerotic plaque thickness was 1.3±0.6 mm and the cross-sectional area narrowing was 34±16%. Atherosclerotic involvement frequently was focal (85%), eccentric (mean eccentricity index,87±8), and near arterial bifurcations. Donors of the transplant recipients with coronary atherosclerosis were older than those without atherosclerosis (37±12 versus 25±10 years, P=.001). Maximal intimal thickness correlated with donor age (r=.54, P=.0001). Multivariate analysis demonstrated that donor age (P=.0001), male sex of donor (P=.0006), and recipient age (P=.03) were independent predictors of atherosclerosis.Conclusions Coronary atherosclerosis is frequently but inadvertently transmitted by means of cardiac transplantation from the donor to the recipient. Long-term outcomes of donor-transmitted coronary artery disease will require further evaluation.Key Words:transplantation • coronary disease • ultrasonicsIntroductionSurvival rates after cardiac transplantation have improved steadily during the past 2 decades. Presently, 1-year survival rates average 80% to 90% at most active centers.12 After the first year after transplantation, cardiac-allograft vasculopathy represents the principal cause of death.34Necropsy examinations have described cardiac-allograft vasculopathy as a diffuse, obliterative process characterized by concentric intimal proliferation.567 Prior reports89 have emphasized that the predominant mechanism for genesis of transplant vasculopathy is immune injury with resulting intimal hyperplasia. Transplant coronary disease eventually results in multiple myocardial infarctions, which lead to accelerated graft failure or sudden cardiac death.Both postmortem and intravascular ultrasound imaging studies have demonstrated that angiography underestimates the extent and severity of transplant vasculopathy.10111213 Although most centers perform routine surveillance angiography at annual catheterization, this screening process often fails to detect coronary disease. There is limited information regarding the prevalence of atherosclerosis in donor hearts and its effect on coronary disease after transplantation. Accordingly, we examined this phenomenon by performing quantitative coronary angiography and intravascular ultrasound imaging soon after cardiac transplantation. We sought to determine the frequency and morphological patterns of atherosclerosis transmitted from heart donors to recipients.MethodsPatient PopulationThe study group consisted of patients who underwent cardiac transplantation between December 31, 1992, and February 14, 1994.Patients who were ineligible for cardiac catheterization, who died during hospitalization, or who did not give informed consent were excluded. The study protocol was approved by the Institutional Review Board of The Cleveland Clinic Foundation. Cardiac CatheterizationRecipients were studied within 2 months after cardiac transplantation.All patients underwent right and left heart catheterization,endomyocardial biopsy, coronary angiography, and intravascular ultrasound imaging. After nitroglycerin was administered sublingually,coronary arteriography was performed with large-lumen 7F coronary-guiding catheters.14 Multiple angiographic views were obtained for optimal visualization of the coronary arteries.Coronary Intravascular Ultrasound ImagingIntravascular ultrasound imaging was performed on the recipients with a 30 MHz 3.5F ultrasound catheter (Boston Scientific) interfaced with a dedicated scanner (Hewlett Packard). The ultrasound catheter consisted of a 135-cm-long monorail device with a transducer enclosed in an acoustically transparent housing that was 20 mm from the tip. A driveshaft cable rotated the transducer at 1800 rpm to generate a 360° imaging plane angled 15° forward from perpendicular to the long axis of the catheter. The axial resolution of the imaging system, which varied with distance, averaged80 to 100 µm, whereas lateral resolution ranged from 150to 200 µm. This device generated ultrasound images at30 frames per second, and continuously recorded these images on 1/2-in Super-VHS videotape.After coronary angiography, recipients were given 3000 to 5000U IV heparin before being examined by intravascular ultrasound imaging. The operator used fluoroscopic guidance to place a0.014-in high-torque angioplasty guide wire at a distal location in the target vessel. The ultrasound catheter was placed over the guide wire at the most distal site in the coronary artery to which it could be advanced safely. The ultrasound catheter was then withdrawn gradually from this distal location during continuous imaging. At sites of atherosclerosis and adjacent normal segments, pullback was paused for identification. A cineangiogram and an audio recordingdocumented the location of the imaging probe and its proximity to branches and other anatomic landmarks at each of these sites. Proximal, mid, and distal segments of the three major epicardial coronary arteries, defined according to Coronary Artery Surgery Study (CASS) classifications, were targeted for imaging.15Ultrasound Imaging AnalysisThe intravascular ultrasound images were analyzed by blinded observers in the intravascular ultrasound imaging core laboratory. For each site examined, a short segment (10 to 20 seconds) of videotape was digitized at 30 frames per second into a 640x480-pixel matrix image with a 24-bit gray scale. The full-motion sequence was examined frame by frame to select for analysis the image with the most atherosclerosis.The selected frames were used to make the following measurements:(1) Maximal intimal thickness was measured as the greatest distance from the intimal leading edge to media-adventitia border, (2)minimal intimal thickness as the shortest distance from the intimal leading edge to media-adventitia border, (3) minimal luminal diameter as the shortest distance between opposing intimal leading edges, (4) lumen area as the area within the boundaries of the intimal leading edge, (5) vessel area as the area within the media-adventitia border, and (6) plaque cross-sectional area as the difference between vessel and lumen areas. Also,a relative measure of ultrasound percent area reduction was computed as follows: lumen area divided by vessel area multiplied by100 (Fig 1).View larger version(88K):[in this window] [in a new window]Figure 1. Measurements of lumen and vessel wall dimensions in an ultrasound image.Patients were divided into atherosclerotic and nonatherosclerotic subgroups that were stratified by the maximal intimal thickness of all examined sites. The atherosclerotic group included patients with intimal thickness 0.5 mm, whereas the nonatherosclerotic group included those with a maximal intimal thickness <0.5 mm. The distribution pattern of atherosclerosis was assessed longitudinally and circumferentially.Diffuse disease was defined as intimal thickening of the entire length of the artery, whereas focal disease consisted of intimal thickening of isolated sites. The circumferential distribution of atherosclerotic plaque was determined as follows.Angiographic AnalysisCineangiograms were reviewed in the core cineangiography laboratory by an experienced angiographer blinded to the results of the ultrasound imaging study. The angiograms were projected onto a screen at a fixed distance with a rear-projection system (Tagarno 35AX).For each coronary artery, the CASS segment classification system was used to identify the most distal site imaged by ultrasound.Stenosis severity at sites showing any luminal narrowing was measured with an Atari digital caliper system (Sandhill Scientific,Inc). For each identifiable lesion, the operator determined vessel diameter at the stenosis and at an adjacent angiographically normal reference site to quantify percent diameter stenosis.Statistical AnalysisNormally distributed data were reported as mean±SD. 2-test or Fisher's exact test was used to find significant associations between categorical variables. An unpaired t test was used to test for differences between the mean values for continuous variables in subgroups. Pearson's correlations were used to test for relations between continuous variables. Stepwise linear regression was used to determine which factors (age, sex, cytomegalovirus[CMV] virus titers for donors and recipients, ischemic time for the donor heart, rejection episodes, donor family history for coronary artery disease, smoking history, and hypertension) were significantly related to atherosclerosis after adjustment for other significant factors. A value of P.05 was considered statistically significant.ResultsPatient CharacteristicsSixty-two adult patients underwent cardiac transplantation between December30, 1992, and February 14, 1994. All but 5 underwent cardiac catheterization within 2 months after transplantation. The 5 patients not examined included 4 who died soon after the operation (1 from multiorgan failure, 1 from cerebral hemorrhage, 1 from sepsis, and 1 from aortic rupture). One additional patient had severe medical problems precluding catheterization. Of the remaining 57 patients, 50 underwent successful intravascular ultrasound imaging. The 7 patients who did not undergo imaging included 3 patients with scheduling constraints,2 with angiographically evident severe coronary artery disease,and 2 who experienced technical problems related to the equipment.The 50 cardiac transplant recipients were studied an average of4.6±2.6 weeks after the operation. This cohort included40 men and 10 women with a mean age of 53±9 years. Of the 50 recipients, 40 had positive CMV titers and 14 had experienced at least one episode of rejection requiring treatment before catheterization (Table 1).ischemic time for the donor heart, defined as the interval between removal of the donor heart and transplantation, averaged 134±40 minutes. Of the 50 donors, 31 had positive CMV titers. The medical and social histories of donors were not complete in some cases. Twenty-four of 42 donors were known smokers, 4 of 42 were hypertensive,and 3 of 24 had a family history of coronary artery disease.Because most donors were identified after major trauma, reliable basal lipid levels were not available (Table 1).All three major epicardial coronary arteries were imaged successfully in 22 patients, two arteries were imaged in 23 patients, and only one vessel was imaged in 5 patients (Table 2). Thus, 117 first-order epicardial vessels were examined in the 50 patients.The right coronary artery was not imaged in 19 patients, the left circumflex in 12, and the left anterior descending in 2. Arteries were not imaged in 14 patients because of tortuosity, in 8 because of a small-caliber vessel, in 5 because of a nondominant right coronary artery, in 4 because of coronary spasm, and in 2 for technical reasons. Of the 450 CASS segments targeted, 255 (112proximal, 96 mid, and 47 distal) were imaged (Table 2), with no complications other than reversible coronary spasm.In 22 patients, the appearance of the coronary arteries with ultrasound imaging was normal, with maximal intimal thickness <0.5 mm (Fig2). By applying a criterion for atherosclerosis requiring an intimal thickness 0.5 mm, it was determined that 28 patients(56%) had unequivocal evidence of disease (Fig 3). In this subgroup,maximal intimal thickness averaged 1.3±0.6 mm; mean luminal diameter, 3.4±1.1 mm; and average luminal cross-sectional area, 11.8±5.8 mm2. The plaque cross-sectional area averaged5.5±2.4 mm2, which represented a cross-sectional area reduction of 34±16%. Thus, a significant amount of atherosclerosis was detected in more than half the recipients studied early after transplantation.View larger version (33K): [in this window][in a new window]Figure 3.thickness in 50 cardiac transplantation patients.Atherosclerotic plaque involvement was focal rather than diffuse in24 of 28 patients. In patients with focal disease, plaque was observed most frequently near arterial bifurcation sites (Fig 4). In14 patients (50%), atherosclerotic involvement was evident near the left anterior descending–circumflex artery bifurcation.Of the 14 patients, 9 had plaque on the left anterior descending side of the bifurcation, 3 on the circumflex side, and 2 on both sides. In all cases, the plaque was on the wall opposite the arterial carina of the branching vessel. An atheroma was found near the left anterior descending–diagonal artery bifurcation in 8 patients, and plaque was seen at the circumflex-obtuse marginal bifurcation in 2 patients. One patient had a plaque in the right coronary artery at the site of bifurcation in a right ventricular branch.These patterns served to emphasize the focal nature of plaque distribution in patients studied early after transplantation.Of the 28 patients with atherosclerosis, 19 had an atherosclerotic plaque in more than one arterial segment.in these 28 patients (Fig 5mean eccentricity index was 87±8%,which demonstrated that nearly all of the plaque was located on one side of the artery. Of the 28 recipients who had atherosclerotic involvement,the eccentricity index was >50% in every patient and was >75%in 26 of 28. In all cases, the surfaces of the coronary plaques were smooth. There was no evidence of ulcerated plaque or plaque dissection in any of the imaged arteries. Calcified elements occurred in the plaques of 9 of 28 patients.View largerversion (85K):[in this window][in a newwindow]Figure 5. Top, Angiogram of the left coronary artery in the right anterioroblique projection showing mild luminal narrowing. Black arrowindicates the site of intravascular ultrasound imaging. Bottom, Two-dimensional intravascular ultrasound image revealing a large eccentricplaque in the proximal circumflex artery (black arrow).Risk Factors for AtherosclerosisDonor age and recipient age were the only variables found to be significantly different between the atherosclerotic and nonatherosclerotic groups by univariate analysis. Although all donorswere relatively young, the donors for recipients who had atherosclerotic involvement were significantly older (37±12 versus 25±10 years,P=.0003, Table 1). Linear-regression analysis revealed a moderate correlation between maximal plaque thickness and donor age (r=.54,P=.0001, Fig 6). A less-significant difference existed between the two subgroups with regard to recipient age (55±9versus 49±10 years, P=.02). Univariate analysis demonstrated no significant differences for the remaining variables, including donor hypertension, smoking history, family history of coronary disease, rejection episodes, donor and recipient CMV titers,time between transplantation and imaging, ischemic time, and number of vessels and segments imaged.View larger version (20K):Scatterplot showing correlation between donor age and intimal thickness. indicates male donors; ,and recipient age (P=.03) were independent predictors of atherosclerosis. There was no correlation between recipient and donor ages (r=.11, P=.43) to explain these findings. However, when plaque thickness was analyzed with donor age and recipient age as categorical variables (age <30 or 30) rather than as continuous factors, only donor age (P=.0001) and donor sex were significant factors for predicting atherosclerosis (P=.008,Table 3).Quantitative coronary arteriography revealed completely normal coronary arteries in 37 of 50 patients (74%). In the other 13 patients,angiographic stenosis ranged from 10% to 38% (22±7%), and ultrasound imaging confirmed the presence of a plaque in abnormal segments in 12 of these patients. Thus, coronary angiography detected atherosclerosis in only 12 of the 28 patients (43% sensitivity) who had atherosclerosis but correctly identified21 of 22 normal cases (95% specificity, Fig 7). In 3 patients,angiography detected more than one lesion; some of these lesions were in segments not imaged by ultrasound. However, in all 3of these patients, ultrasound imaging identified atherosclerosis in more than one segment.View larger version (166K): [in this window][in a new window]Figure 7. A, Arteriogram of the left coronary artery in theright anterior oblique projection. Black arrow indicatesimaging site shown in B; white arrow, imaging site shownin D. B, intravascular ultrasound image of the proximalcircumflex artery. Despite a large eccentric plaque, a largecircular lumen similar to that in D is preserved because ofremodeling. C, Left coronary angiogram in the left anterioroblique projection. Black arrow indicates imaging siteshown in B; white arrow, imaging site of proximalcircumflex artery shown in D. D, intravascular ultrasoundimage at another site in the proximal circumflex arteryshowing normal arterial morphology.DiscussionCoronary artery disease represents the major cause of late death in patients after cardiac transplantation. Cardiac-allograft vasculopathy has been reported1617 to be an immunologic process in which intimal injury leads to proliferation and, eventually, to arterial obstruction. The present study, which uses quantitative coronary arteriography and a new high-resolution intravascular ultrasound imaging device, demonstrates an alternative cause. In the first few weeks after transplantation, comprehensive imaging of multiple major epicardial coronary arterial segments revealed typical atherosclerotic plaque in 56% of recipients. Thus, unequivocal evidence of transmission of atherosclerosis from the donor to recipient was present in more than one half of the recipients.These findings are particularly striking when one considers the conservative definition that is used in the present study to classify the presence or absence of atherosclerosis. Although the normal intima in young subjects consists of only a few cell layers, limited data are available to describe the range of normal intimal thickness in adults. In a necropsy study, normal intimal thickness averaged 0.21 mm (0.10 to 0.28 mm) in 21-to 25-year-old men and 0.25 mm (0.18 to 0.35 mm) in 36- to 40-year-old men.18 In a comparative ultrasound-histology study, patients with no known coronary artery disease had intimal thicknesses averaging 0.24±0.11 mm.19 An in vivo ultrasound imaging study20 reported mean intimal thickness in a "normal" population as 0.18 mm, with 95% confidence intervals of 0.06 and 0.30 mm.However, in normal subjects, intimal thickness and echogenicity increases with age. Thus, in very young subjects, a distinct laminar structure often is not evident by intravascular ultrasound.1920 To avoid potential controversy regarding interpretation of this study, we used a high threshold (0.5 mm) for abnormal intimal thickness. This value represents intimal thicknesses at least three SDs greater than any published range of normal values.The pattern of atherosclerotic plaque in these patients was typical of atherosclerosis and distinctly different from immune-mediated transplant vasculopathy. Most atheromas were highly eccentric, with >87%of plaque on one side of the vessel. In addition, the lesions showed apredilection for sites of major bifurcations. Experimental studies suggest that low shear stress along the non–flow-dividing wall might be an important localizing force, in contrast to the high shear stress along the flow-dividing wall (carina at vessel bifurcation).21 The morphological characteristics of the plaques are typical of conventional atherosclerosis and dissimilar to vasculopathy as described in the transplant population.22Indeed, features characteristic of transplant vasculopathy, particularly diffuse, concentric intimal thickening, were absent in our study group. Thus, it is evident that the atherosclerotic changes were present in the donor hearts and transmitted to the recipients at cardiac transplantation.This study highlights the limitations of standard coronary arteriography for detecting early transplant coronary disease. Quantitative coronary angiography was relatively insensitive, revealing less than half the lesions identified by intravascular ultrasound imaging.An important explanation for the discrepancy between angiography and ultrasound imaging is provided by the anatomic pattern of early atherosclerosis. As originally described by Glagov et al,23early coronary disease is characterized by remodeling of the coronary artery, which protects against luminal encroachment of the atherosclerotic plaque. Thus, segments with major intimal thickening retain a lumen size virtually identical to adjacent, uninvolved sites. In the absence of luminal narrowing, angiography fails to detect early disease.Few demographic characteristics were useful for predicting the likelihood of donor atherosclerosis. Multiple-regression analysis showed only donor age, recipient age, and donor sex to be independent predictors.The strongest predictor was donor age, which correlated significantly with intimal thickness. Although donor sex was not (univariately)associated with maximal intimal thickness, it became a significant factor after adjusting for donor age. It is not surprising that hearts from older men tended to have a higher prevalence of atherosclerosis,since age and male sex are well-known risk factors for coronary disease. It is more difficult to explain the unfavorable effect of recipient age on atherosclerosis early after transplantation. Acute rejection,2425 CMV infection,2627 and conventional risk factors have been suggested to be possible contributors to the development of chronic transplant coronary disease, but were not significant in this study. However, information about donor hypertension, smoking, family history, and hypercholesterolemia was incomplete. Thus, a full understanding of the relation between donor risk factors and early atherosclerosis cannot be stated conclusively.In a recent report from St Goar et al,28 with a larger (4.3F)earlier-generation intravascular ultrasound catheter, 25 patients were studied within 1 month of cardiac transplantation. Imaging was limited to segments extending from the ostium of the left main coronary artery to the midportion of the left anterior descending coronary artery. In 5 of 25 patients, there was eccentric intimal thickening>0.5 mm. The difference in the prevalence of atherosclerosis between the study by St Goar et al and ours is explained by several factors. In the present study, imaging was more extensive and an improved, low-profile 3.5F ultrasound probe was used.This permitted examination of multiple segments from major epicardial coronary arteries in 86% of patients. At least two of the three major coronary arteries were imaged in 90% of recipients. In addition,our study population was larger and donors were older (32±12 versus28±8 years old).These in vivo findings provide strong evidence as to the high prevalence of coronary atherosclerosis in young and middle-aged Americans.These findings are consistent with autopsy studies performed on large populations of trauma victims during the Korean and Vietnam wars.29 30 During the Korean War, atherosclerotic plaques with a wide range of stenoses (10% to 90%)were found in 117 of 300 young soldiers.29 Autopsy studies on American soldiers killed in Vietnam revealed that 45% had some coronary atherosclerosis.30In both necropsy studies, all thedeceased were men and mean subject age was 22 years old, whereas in our study, 40% of the donors were women and the mean donor age was 32±12 years.Furthermore, necropsy studies, which often examine explanted vessels not distended by physiological pressures, represent only estimations of the severity of coronary disease.This intravascular ultrasound imaging study provides direct in vivo evidence of occult, but rather extensive, atherosclerosis in a young and presumably healthy population. Without high-resolution intravascular ultrasound imaging, detection and quantification of atherosclerosis would not have been possible in living humans. Ultrasound imaging provides unique cross-sectional information that is analogous to pathology and that cannot be obtained in coronary arteries from any other imaging technique.The older age of the donor population in this study reflects an important trend in cardiac transplantation. The limited availability of suitable donors and the long waiting lists for transplantation have increased the use of older donors.31 However, the presence of atherosclerosis in more than 80% of our donors who are 30 years old indicates a potential hazard to this approach. The presence of coronary atherosclerosis in so many transplant recipients raises an important clinical question. Does disease transmitted from the donor increase the risk of accelerated transplant vasculopathy?This important clinical question cannot be answered until angiographic, ultrasound,and clinical follow-up studies determine the long-term prognostic significance of transmitted coronary disease.Reference1. Kriett JM, Kaye MP. The registry of the International Society for Heart and Lung Transplantation: eighth official report: 1991. J Heart Lung Transplant. 1991;10:491-498. [Medline][Order article via Infotrieve]2. Bourge RC, Naftel DC, Constanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, Olivari M-T, Kasper EK, The Transplant Cardiologists Research Database Group. Pretransplantation risk factors for death after heart transplantation: a multi-institutional study. J Heart Lung Transplant. 1993;12:549-562. [Medline][Order article via Infotrieve]3. Olivari MT, Homans DC, Wilson RF, Kubo SH, Ring WS. 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