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J Thorac Cardiovasc Surg 1995;109:1081-1089
© 1995 Mosby, Inc.
CARDIAC AND PULMONARY REPLACEMENT |
Birmingham, Ala.
From the Division of Cardiothoracic Surgery, Department of Surgery,a and the Division of Cardiology, Department of Medicine,bUniversity of Alabama at Birmingham, Birmingham, Ala.
Address for reprints: David C. McGiffin, MD, Associate Professorof Surgery, University of Alabama at Birmingham, Birmingham, AL 35294.
Abstract
Coronary artery disease after cardiac transplantationis a major obstacle to long-term survival. The development and progressionof coronary artery disease after cardiac transplantation was analyzed in 217consecutive patients undergoing transplantation. The actuarial freedom fromany coronary artery disease (by angiography or autopsy) was 81% at 2 yearsand 20% at 8 years after transplantation. Coronary artery disease was moreprevalent in male than female patients (30% versus 50% free of coronary arterydisease at 5 years, p = 0.01). By multivariable analysis, pretransplantationrisk factors identified for coronary artery disease included pretransplantationpositive cytomegalovirus serologic status of the recipient (p = 0.002) and older donor age (p= 0.07). Progression of coronary artery disease was variable in both timeof onset and rate. Earlier detection did not result in more rapid progression.Coronary events severe enough for retransplantation (n = 8) and/or death from coronary artery disease (n = 9) occurred in 15 patients, of whom four underwent retransplantation.The actuarial freedom from coronary events was 88% at 5 years and 79% at 8years. By multivariable analysis, only male recipient (p = 0.05) was a risk factor for coronary events. Seven of the 15patients (47%) with coronary events died suddenly of coronary artery diseasewithout prior angiographic evidence of severe coronary disease. Coronary arterydisease is progressive. Improved surveillance methods are required to detectthe disease and institute timely intervention to prevent the occurrence ofunanticipated death. (J THORAC CARDIOVASC SURG 1995;109:1081-9)
Posttransplantation coronary artery disease (CAD) is one of the majorobstacles to long-term survival after cardiac transplantation. Availableinformation suggests that the process is initiated by immune-mediated injuryto the endothelium of the coronary vessels, 
1-4 but the final expression of theinjury as CAD is undoubtedly a complex interplay between atherogenic factorsand the immunologic milieu created by donor and recipient interaction.
To better understand the incidence of, risk factors for, and progressionof CAD after cardiac transplantation in the current era, we undertook thefollowing study. The study aims included the determination of the prevalenceand pretransplantation risk factors for CAD after cardiac transplantation,analysis of the progression of CAD, and identification of risk factors forserious CAD events such as death and retransplantation.
PATIENTS AND METHODS
Patient population
Between November 1981 and January 1, 1991, 217 patients underwent cardiactransplantation at The University of Alabama at Birmingham. Seventeen patients(nine of whom died early) did not have information regarding the presenceof CAD in their initial transplanted heart and were excluded from the analysis.Consequently, the analysis includes 200 patients. Follow-up for this studywas complete through June 30, 1992.
Immunosuppression therapy
From 1981 through 1987, immunosuppression included azathioprine andprednisone. Between 1984 and 1987, cyclosporine and prednisone were used,and from 1987 to 1991, triple-drug immunosuppression consisting of cyclosporine,azathioprine, and prednisone was used. Induction therapy was used throughoutthe time frame with either rabbit antithymocyte globulin or OKT3. Acute cardiacrejection was managed initially with intravenous methylprednisolone sodiumsuccinate (Solu-Medrol) for 3 days. Refractory or recurrent episodes of rejectionwere managed with steroids and cytolytic therapy (rabbit antithymocyte globulinor OKT3), and in the latter part of the experience methotrexate and totallymphoid irradiation were also used.
Data collection
A number of pretransplantation demographic, clinical, donor, and donor/recipientmatching variables were collected (see Appendix A).
The presence and extent of CAD was assessed by posttransplantation coronaryarteriograms (n = 633), autopsy reports (n = 69), and explanted hearts (n = 12). All available angiograms on all patients were examinedby two of the investigators and each was scored according to the extent ofCAD (see CAD scoring system). Throughout thisexperience, a general protocol of yearly coronary angiography was conductedfor surveillance of CAD development. From approximately 1987 through 1991,additional surveillance angiograms were obtained at 6 weeks and 6 months aftertransplantation.
Each patient was assessed for the development of morbid or fatal eventsrelated to CAD. These "CAD events" included death resulting from CAD, retransplantationresulting from CAD, and consideration of retransplantation because of CAD(but not actually performed because of extenuating medical circumstances).
CAD scoring system
A scoring system was developed to grade the angiographic severity ofCAD in the epicardial arteries and also take into account the impact of specificdisease on overall myocardial perfusion. The severity of angiographic diseasewas graded (0 to 5) in 17 segments of the major coronary arteries and theirepicardial branches. A weighting factor (maximum of 4) was assigned to eachcoronary artery segment on the basis of the relative importance of the lesionwith respect to myocardium supplied. The segment score and the weighting factorwere multiplied and then all were summed to generate a total angiographicscore (see Appendix B). In general, a score exceeding 15 indicated severethree-vessel CAD. The angiograms were also categorized according to the presenceor absence important disease in each of the three major coronary artery systems.A score of 4 or more in the left anterior descending or circumflex territoryand a score of 3 in the right coronary system were considered indicative ofimportant disease in that territory (see Appendix B).
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5 to identifypotential pretransplantation risk factors associated with the angiographicappearance of any disease and CAD events. The rate of progression of diseasewas analyzed by linear and nonlinear regression. RESULTS
Incidence of cardiac transplant CAD
Sixty-eight patients had angiographic or autopsy evidence of cardiactransplant CAD (angiographic score greater than 0) over the 10-year studyperiod. At 1 year and 8 years after transplantation, 91% and 20%, respectively,of patients were free of angiographic CAD (Fig. 1). The hazard function indicates a progressivelyrising risk of developing CAD (Fig. 2).
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Table I). A non-risk-adjusted comparison of freedom from CADstratified by pretransplantation CMV serologic status suggests that the effectof pretransplantation CMV serology is apparent after about 4 years (Fig. 4). The effect of donor age on the subsequentdevelopment of CAD was most pronounced for donors older than 35 years (Fig. 5). Among donors older than 35 years, 16were 35 to 40 years and 4 were 40 to 45 years. No relationship was identifiedbetween recipient age and development of CAD.
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Table II). Among the studies revealing CAD, 37% of these hadimportant single-vessel disease, 5% two-vessel disease, and 13% three-vesseldisease. In 45%, the CAD was considered trivial (TableIII). Of the 69 autopsied hearts, 51 (74%) had no evidenceof CAD (score 0), 4 had mild CAD (score 1 to 10), 3 had a score of 10 to 15,and 11 (16%) had severe CAD (score 
15). Analyzed according to number ofvessels involved, 4% of the autopsied hearts had single-vessel disease, 3%two-vessel disease, and 17% three-vessel disease. For the overall group, themean CAD score increased over time, but even at 8 years the mean CAD scoreremained less than 10. Throughout the study period, the mean CAD score formale patients was consistently greater than that for female patients (Fig. 6). To examine the rate of progression ofCAD relative to the first appearance of disease, we examined the rate of increasein angiographic CAD score for each patient with CAD as a function of the yearafter transplantation in which CAD first appeared (Fig.7). Although there is considerable variability,it is noteworthy that earlier appearance of CAD (for example, within the first2 years) was not associated with more rapid disease progression. Particularlyafter the second year, the rate of progression among groups was similar.
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CAD events after cardiac transplantation
Among the 200 patients, 15 CAD events occurred (see again Patients and methods). Four patients underwent retransplantationfor CAD, four additional patients were considered for retransplantation becauseof extensive CAD but were denied the operation because of coexisting medicalproblems (two of these subsequently died of CAD), and seven patients diedunexpectedly of CAD (identified at autopsy) who did not have extensive CADidentified by previous angiography. Thus 47% of serious CAD events were unanticipatedon the basis of routine surveillance angiography.
Of the total of 95 deaths from all causes in the 217 transplant recipients,only nine could be attributed to CAD Of the 19 deaths occurring between thethird and eighth years after transplantation, only four (21%) were due toCAD. The remaining causes of death more than 3 years after transplantationwere malignancy (n = 3), rejection (n = 4), pulmonary embolism (n= 1), suicide (n = 1), cirrhosis (n = 1), renal failure (n= 1), cerebral hemorrhage (n = 1), multisystemfailure (n = 1), multifocal leukoencephalopathy(n = 1), and unknown (n = 1).
The actuarial and parametric freedom from a serious CAD event was 71%at 8 years (Fig 8). The linear slope of the hazard functionindicates a gradually increasing risk of such an event over time (Fig.9). By multivariable analysis, the onlypretransplantation risk factor identified for a subsequent CAD event was recipientmale gender (p = 0.05). At 6 years, nearly30% of male recipients had a CAD event compared with about 2% among femalerecipients (Fig. 10).
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Limitations of the study
In this study, coronary arteriography formed the basis of detectionof posttransplantation CAD. Although recognized as the standard diagnostictechnique for coronary arteriopathy, angiography is known to be a less sensitivemethod of coronary disease detection than autopsy studies 6-8 and the morerecenttechnique of intracoronary ultrasonic imaging. 9,10 The relative insensitivity ofcoronary arteriography may relate in part to the pathologic basis of posttransplantationvasculopathy, in that the primary lesion is a proliferative response of thevascular wall smooth muscle cells, which is distributed throughout the lengthof the coronary arteries. 11,12 Angiographically, this proliferation may appearas concentric luminal narrowing in small intramyocardial coronary arterieswith abrupt ending of distal branches. 13,14 The diffuse nature of the processwith resultant narrowing of luminal caliber throughout the length of coronaryvessels contributes to the difficulty of angiographic detection of abnormalities.In addition to this proliferative response, there is a superimposed atheroscleroticcomponent that results in the eccentric lesions more typical of native CAD. 6 Thus the findings in this studyrelative to the incidence of CAD are likely a minimum estimate.
Regarding the risk factor analysis, this study examined only pretransplantation variables as predictors of posttransplantationCAD. The aim of this analysis was to identify patient subsets before transplantationwho may be more vulnerable to posttransplantation CAD and events. Furtherstudies of this type will be necessary to incorporate detailed multivariableanalyses of posttransplantation phenomena, including such variables as rejectionhistory, CMV disease, complex lipid alterations, tobacco habits, and developmentof obesity. Previous studies have alluded to some of these factors in thedevelopment of posttransplantation vasculopathy. 11,15-19
This study is also limited by a relatively small number of patientsat a single institution. There would be obvious advantages to a multiinstitutionalstudy of posttransplantation vasculopathy, which might more accurately reflectthe variability of this disease. On the other hand, however, this study hasthe advantage of complete review of all angiograms in the experience. Otherreports in the literature have often relied totally on angiographic reportsfrom the patient records rather than a separate individual review of all angiograms.
Incidence and pretransplantation risk factors for cardiac transplantCAD
The incidence of angiographically apparent CAD in this study of 80%at 8 years is consistent with the findings of other reports. 17,20,21 However, the true incidence of at least theproliferative component is much greater. In a study of autopsy and explantedheart material, essentially all patients had important coronary artery lesionsby 12 months after transplantation. 22
The finding of older donor age as a risk factor for CAD developmentwas previously noted by Gao and colleagues 23 in a univariate analysis, but the effect was weak In the presentstudy, the effect of older donor age was most prominent for donors older than35 years, although the number of older donors in this experience was limited.Presumably, this donor age effect relates to an increased propensity for atheroscleroticchanges in the older donor.
The association between recipient pretransplantation CMV-positive serologyand the development of CAD is provocative. It is particularly interestingthat the apparent effect of CMV serology was manifest only after about 4 years(see again Fig. 4). Perhaps this delay relates in someway to the long dormant interval typically observed before the activationof CMV disease. Although this study did not address the possible impact ofposttransplantation CMV disease or seroconversion, Loebe and colleagues 15 noted a higher incidence of positiveCMV serology among patients with coronary vasculopathy. A number of clinicalstudies have reported an association between CMV infection and the subsequentdevelopment of CAD. 15,24-26 It hasbeen postulated that CMV may promote graft intimal disruption by modulatingmajor histocompatibility antigens, endothelial monocyte antigens, endothelialcell antigenicity, or adhesion molecules, thus producing an enhanced immunologictarget. 11,27 CMV nucleic acids have been detected in the endothelial cellsand smooth muscle cells of the coronary arteries in a significant proportionof hearts with transplant vasculopathy. 28
CAD progression
Little published data is available regarding the details of CAD progressionafter cardiac transplantation. In this study, both the time of angiographicappearance and the rate of progression after disease-free intervals were variable.It is of interest, however, that earlier detected CAD was not associated witha more accelerated rate of CAD progression (see again Fig.7). These findings are consistent with a hypothesis that incorporates immunologicevents (manifesting at a variable period after transplantation) initiatingintimal damage with superimposed development of accelerated atherosclerosisas an independent phenomenon. Support or rejection of this hypothesis willrequire further complex analyses.
Morbid and fatal CAD events
The important mortality associated with the development of posttransplantationCAD has been reported by Uretsky, 29 Keogh, 30 and others.Keogh and colleagues 30 reportedan actuarial survival of 44% at 2 years after angiographic appearance of greaterthan 40% stenosis in one or more major epicardial vessels. Survival was particularlypoor in patients with extensive three-vessel disease. The CAD event-free survivalin the present study was 71% at 8 years. This rate is surprisingly high giventhe mere 20% freedom from angiographically detectable CAD by 8 years and maypartially reflect an aggressive use of PTCA for posttransplantation CAD. Ina multiinstitutional study, Halle and colleagues 31 reported favorable intermediate-term results ofPTCA therapy in this setting. Despite the serious implications of CAD development,coronary vasculopathy accounted for a small proportion of late mortality (20%of deaths occurring 3 to 8 years after transplantation). This mortality issomewhat lower than might be expected given the disease incidence and itsprogressive nature, and it underscores the importance of also focusing diagnosticand therapeutic efforts at other causes of late mortality, such as rejection,infection, and malignancy.
The inadequacy of yearly surveillance coronary arteriography as a methodfor preventing CAD mortality is supported by the important incidence of CAD-relateddeaths that were unanticipated by previous angiographic studies. Thus thereclearly is a need for more sensitive invasive and noninvasive techniques fordetection of the posttransplantation CAD process.
From this study we draw the following inferences:
Appendix: DISCUSSION
Dr. Severi P. Mattila (Helsinki, Finland).
Vasculopathy is one of the most important factors influencing the late
outcome of patients after cardiac transplantation. Our experience is limited
to 150 patients, with 78% survival at 8 years. In one patient with CMV who
died we found extreme vasculopathy with enormous intimal thickening of the
coronary arteries. Therefore, we decided to review all of the cases of symptomatic
CMV infection, as well as doing endomyocardial biopsy and coronary angiography,
and we compared these two groups of patients.
Table I summarizes the occurrence of the occlusive
changes in coronary arteries of the patients with CMV infection and in the
other group of patients. At 2 years there was a statistically significant
difference between the two groups. Thus in our experience CMV infection seems
to accelerate the vasculopathy in the coronary arteries.
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Table II shows the histologic part of our study,
and it confirms the coronary arteriographic study. The intimal thickening developed earlier in those
patients with CMV infection, but at 4 years there was no statistically significant
difference in our series.
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Dr. McGiffin.
The association between CAD after cardiac transplantation and CMV infection
has been demonstrated before, and you have provided more confirmatory information.
Obviously some complex interplays are involved, with immunologic risk factors
and also probably the more traditional atherosclerotic risk factors. It is
interesting to speculate on why CMV should be associated with CAD. Perhaps
it is in part the result of endothelial damage of the coronary arteries producing
an inflammatory response with the production of cytokines, resulting in the
proliferative process that we see in the coronary arteries.
Dr. Norman E. Shumway (Stanford, Calif.).
In any instance did you detect angina in the patients? We have wondered
about that for many years.
Dr. McGiffin.
Yes, some of these patients did have classic angina, and others had
angina-equivalent symptoms. I guess this response may suggest some reinnervation
of the heart. That I the only evidence of reinnervation that we have observed.
Dr. Shumway.
We thought that these symptoms might be due more to left atrial distention
in patients who are having moderate cardiac failure with their CAD rather
than an indication of true reinnervation.
Dr. Robert M. Mentzer, Jr.(Madison, Wis.).
One of the problems with this disease is that it can be difficult to
differentiate typical atherosclerosis from cardiac allograft vasculopathy.
This problem is going to become more complex as we use organs from older donors.
Currently, we use angiography to differentiate the two diseases. This technique,
however, may not be the best way of assessing progression of disease despite
the fact that transplant vasculopathy differs pathologically from typical
atherosclerosis. One diagnostic alternative that may give us more insight
into differentiation and progression is intravascular ultrasography. We and
others are beginning to realize that this may be a much better technique for
diagnosing transplant vasculopathy as well as monitoring progression.
What has been your experience in the use of intravascular ultrasonography? Can you shed any light on new techniques for differentiating and following the course of the two diseases?
Dr. McGiffin.
You are absolutely correct. Intracoronary ultrasonography is almost
certainly more sensitive than angiography, which is very insensitive. We have
not yet used intracoronary ultrasonography, but we will be starting that very
soon. It will be interesting to see in a few years' time with the increased
sensitivity of this test whether the same risk factors that we have demonstrated
will also be operative when we are using a more sensitive method.
Dr. Davis C. Drinkwater (Los Angeles, Calif.).
We have noted another risk factor for transplant CAD. We recently reported
at the International Society for Heart and Lung Transplantation Meeting that
the preservation solution may be related as a cofactor with this process.
We have better results with our University of Wisconsin solution in terms
of length of preservation and functional outcomes, but we also saw a significant
increase in the prevalence of coronary arterial vasculopathy at a 36-month
mean follow-up in our first 100 patients in whom this solution was used.
Do you have any information on the preservation solution, and did you vary it in your own patient population?
Dr. McGiffin.
I am familiar with the information that you presented in Italy, and
it is very interesting. We did not include preservation solution as a risk
factor in this multivariable analysis.
Appendix: APPENDIX A
Variables for analysis
Demographic:
Age, gender, number of pregnancies, race, weight, height, body surface
area.
Clinical:
Diagnosis, blood type, CMV serology, panel reactive antibody, immunosuppression
protocol, cholesterol, triglyceride, tobacco use.
Donor:
Age, gender, race, weight, height, body surface area, blood type, pressors.
Donor/recipient matching:
Age, gender, race, body surface area, weight, blood type, crossmatch,
human leukocyte antigen mismatches.
Multivariate equation for CAD
Constant phase: intercept - 000859
Late phase: donor age (years) 00897 ± 0.0412, recipient pretransplantation
positive CMV serology 2.22 ± 0.65, 
= 1, 
= 1, 
=
1, 
= 4.48, intercept = 1.013 x 10-10
Multivariate equation for CAD event
Late phase: male recipient 206 ± 1.04, = 1, = 1,
= 1, = 2.01, intercept = 6.98 x 10-6 .
Appendix: APPENDIX B. CAD SCORE
Each of the 17 portions of the coronary arteries is graded as follows:
50% and <70% 70% Diffuse narrowing is given a score of 2 unless there is a discrete stenosis that warrants a higher score. Numbers in parentheses in the table are for left dominant systems.
Footnotes
Read at the Seventy-fourth Annual Meeting of The
American Association for Thoracic Surgery, New York, N.Y., April 24-27, 1994. 
References
This article has been cited by other articles:
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  C. Schmidt-Lucke, A. Aicher, P. Romagnani, B. Gareis, S. Romagnani, A. M. Zeiher, and S. Dimmeler Specific recruitment of CD4+CD25++ regulatory T cells into the allograft in heart transplant recipients Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2425 - H2431. [Abstract] [Full Text] [PDF]
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 T. Hussain, M. Burch, M. J. Fenton, P. M. Whitmore, P. Rees, M. Elliott, and P. Aurora Positive Pretransplantation Cytomegalovirus Serology Is a Risk Factor for Cardiac Allograft Vasculopathy in Children Circulation, April 3, 2007; 115(13): 1798 - 1805. [Abstract] [Full Text] [PDF]
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 D. J. Kutsogiannis, G. Pagliarello, C. Doig, H. Ross, and S. D. Shemie Medical management to optimize donor organ potential: review of the literature: [Traitement medical pour optimaliser le potentiel de don d'organe : une revue documentaire]. Can J Anesth, August 1, 2006; 53(8): 820 - 830. [Abstract] [Full Text] [PDF]
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 S. D. Shemie, H. Ross, J. Pagliarello, A. J. Baker, P. D. Greig, T. Brand, S. Cockfield, S. Keshavjee, P. Nickerson, V. Rao, et al. Organ donor management in Canada: recommendations of the forum on Medical Management to Optimize Donor Organ Potential. Can. Med. Assoc. J., March 14, 2006; 174(6): S13 - S32. [Full Text] [PDF]
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S. D. Shemie, H. Ross, J. Pagliarello, A. J. Baker, P. D. Greig, T. Brand, S. Cockfield, S. Keshavjee, P. Nickerson, V. Rao, et al. La prise en charge des donneurs d'organes au Canada : recommandations du forum Optimiser le maintien du donneur afin d'accroitre le nombre d'organes admissibles pour la transplantation Can. Med. Assoc. J., March 14, 2006; 174(6): SF14 - SF32. [Full Text] [PDF]
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K. Wenke, B. Meiser, J. Thiery, D. Nagel, W. von Scheidt, K. Krobot, G. Steinbeck, D. Seidel, and B. Reichart Simvastatin Initiated Early After Heart Transplantation: 8-Year Prospective Experience Circulation, January 7, 2003; 107(1): 93 - 97. [Abstract] [Full Text] [PDF]
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 S. R. Kapadia, S. E. Nissen, K. M. Ziada, G. Rincon, T. D. Crowe, N. Boparai, J. B. Young, and E. M. Tuzcu Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study J. Am. Coll. Cardiol., July 1, 2001; 38(1): 206 - 213. [Abstract] [Full Text] [PDF]
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