The Diagnosis and Management of Cardiac Allograft Vasculopathy

Denton A. Cooley's 50th Anniversary New Developments in in Medicine the Diagnosis and Management of Cardiac Allograft Vasculopathy

Mandeep R. Mehra, MD The major cause of late death in cardiac transplant recipients is cardiac allograft vascu- Hector 0. Ventura, MD lopathy, also referred to as cardiac transplant atherosclerosis, which occurs in as many Frank W. Smart, MD as 45% of transplant who survive than 1 It differs from Dwight D. Stapleton, MD recipients longer year. typical Tyrone J. Collins, MD atherosclerosis in that intimal hyperplasia is concentric and diffuse, the internal elastic Stephen R. Ramee, MD lamina remains intact, calcification is rare, and the disease tends to develop rapidly. Joseph P. Murgo, MD Intravascular ultrasound and coronary angioscopy are more sensitive diagnostic mea- Christopher J. White, MD sures of cardiac allograft vasculopathy than is coronary angiography. Although retransplantation at present seems to be the only definitive therapy for cardiac allograft vasculopathy, it has shown only fair results. Recent studies have suggested that calcium entry blockers and angiotensin-converting enzyme inhibitors may play a beneficial role in delaying the progression of cardiac allograft vasculopathy. (Tex Heart Inst J 1995; 22:138-44)

A dvances in immunosuppression and improved recipient selection have resulted in an increased survival of cardiac allograft recipients, with 1-year survival rates approaching 85%.1-3 Despite this improvement in patient survival, the most common cause of late death is cardiac allograft vasculopathy, a unique and unusually accelerated form of coronary artery disease. Early experiments with canine cardiac transplantation in the late 1960s by Kosek and colleagueS4s 1st reported this phenomenon, and its occurrence in human cardiac This series in recognition allografts was subsequently verified by Thomson6 and by Bieber's group. Car- of Dr Cooley's 50th diac allograft vasculopathy is angiographically evident in as many as 45% of heart anniversary in mediclne is continued from the transplant recipients who survive 3 or more years;8 and these patients have a 5- December 1994 and fold greater relative risk of developing other cardiac events, such as myocardial March 1995 issues. infarction, terminal heart failure, and sudden death.8 This report reviews the current concepts in the diagnosis and management of Key words: Angioscopy; cardiac allograft vasculopathy, with specific consideration of the pathologic char- coronary vessels/ultra- acteristics, diagnosis, and treatment of the disease. sonography; graft occlusion, vascular; transplantation, homologous Pathologic Characteristics

From: The Ochsner Medical Several histopathologic studies by Billinghamr"" have established the diffuse na- Institutions, Section of ture of cardiac allograft vasculopathy, which affects the major epicardial vessels Internal Medicine, Depart- along their entire length from the base of the heart to the apex and the epicardial ment of Cardiology, New Orleans, Louisiana 70121 and intramyocardial branches. In fact, this disease is not limited to the coronary vasculature, for it has been demonstrated to involve the venous structures" and the great vessels within the cardiac The classic lesion consists Section editors: allograft.'2 allograft Grady L. Hallman, MD of progressive concentric myointimal proliferation that appears as intimal thick- Robert D. Leachman, MD ening and ultimately results in luminal occlusion.'0 John L. Ochsner, MD There are several differences between this condition and the more commonly seen native atherosclerosis (Table I). The latter demonstrates eccentric, focal, and Address for reprints: proximal lesions of major epicardial coronary arteries.9 These lesions contain Hector D. Ventura, MD, calcium, disrupt the internal elastic and over many Con- Ochsner Medical Institutions, lamina, develop years. 1514 Jefferson Highway, versely, cardiac allograft vasculopathy is associated with concentric, diffuse, and New Orleans, LA 70121 distal lesions of the coronary vessels and branches. The internal elastic lamina is

1,38 Cardiac Allograft Vasculopathy Volume 22, Nitinber 2, 1995 TABLE 1. Histopathologic Findings in Cardiac Allograft duration of 2.5 years. Patients underwent an annu- Vasculopathy and Coronary Artery Disease al follow-up examination, including 2-dimensional echocardiography, supine rest and bicycle exercise- Cardiac Allograft gated wall-motion study, 48-hour Holter recording, Factors under Vasculopathy: Coronary Artery Comparison Findings Disease: Findings oral dipyridamole thallium-201 SPECT (single pho- ton emission computed tomographic) imaging, and Localization Diffuse, distal Focal, proximal coronary angiography. In regard to the presence of arrhythmia, ambulatory electrocardiographic moni- Intimal proliferation Concentric Eccentric toring detected significant differences between the Internal elastic lamina Intact Disrupted groups with and without cardiac allograft vasculopathy. The sensitivity and specificity of dipyri- Vasculitis Infrequent Never damole thallium-201 SPECT imaging were 21% and Calcium deposit Absent Present 80%, respectively, comparable with a sensitivity and specificity for supine bicycle exercise radionuclide Rate of development Months Years angiography of 21% and 77%, respectively. The inability of noninvasive studies to detect differences in myocardial uptake or redistribution may ensue intact, calcification is rare, a low grade of vasculitis from the diffuse nature of the disease. is occasionally present, and the disease tends to develop rapidly.9"10 Invasive Diagnosis Histopathologic studies, however, have demon- Coronary Angiography. Both the patient's inabil- strated that more typical focal and complicated ath- ity to experience angina pectoris and the poor pre- erosclerotic plaques may also be present in older dictive value of noninvasive tests have led to the cardiac allografts, indicating that cardiac allograft establishment of annual surveillance angiography as vasculopathy has a spectrum of pathologic features. the primary method used to detect and follow the Thus, it has been demonstrated that early intimal development of cardiac allograft vasculopathy. proliferation progresses after transplantation, as sub- A grading system has been developed by Gao and sequent increases in lipid deposits and calcification associates"' for the standard definition of coronary occur in the coronary vessels.'3 Over time, these lesions on the basis of angiographic appearance. more typical atherosclerotic processes are likely su- Lesions can be classified as Type A, B, or C. Type A perimposed upon the cardiac allograft. lesions are discrete and tubular stenoses of the proximal epicardial vessels; Type B lesions are character- Diagnosis ized by diffuse concentric narrowing of the middle or distal coronary vessels and can be subclassified Clinical Symptoms into Type Bi lesions (indicating an abrupt narrow- To rely on the presentation of clinical symptoms for ing) or B2 lesions (indicating smooth concentric ta- the diagnosis of cardiac allograft vasculopathy can pering); Type C lesions are characterized by distal be perilous, since the lack of afferent autonomic in- narrowing and irregularities and by loss of small nervation results in the inability of most allograft branches.'5 In patients with cardiac allograft vascu- recipients to experience angina pectoris. Although lopathy, angiographic Type Bi, B2, and C lesions are partial restoration of the allograft's nerve supply more commonly found, whereas Type A lesions are occurs in up to one third of heart transplant recipi- seen only rarely. Conversely, in patients with typical ents who survive at least 1 year, cardiac allograft coronary atherosclerosis, Type A lesions predomi- vasculopathy rarely presents with angina. Therefore, nate and Type Bi, B2, and C lesions are almost never silent myocardial infarction, heart failure with the seen.'5 Although coronary angiography may have a loss of allograft function, and sudden death are its high specificity in diagnosing cardiac allograft vas- most common forms of presentation.8 culopathy, it has been shown to underestimate the presence of disease and, therefore, has not proved Noninvasive Diagnosis to be a sensitive method. The insensitivity of coro- Noninvasive studies routinely used to diagnose con- nary angiography in diagnosing cardiac allograft ventional coronary artery disease have not been vasculopathy has been demonstrated both by histo- found to be useful in diagnosing cardiac allograft pathologic studiesl6l8 and by comparison with intra- vasculopathy. vascular ultrasound diagnosis.'9 In 1 histopathologic A study by Smart and coworkers'4 assessed the study of 10 failed human allografts, Johnson and use of several noninvasive tests for detecting allo- associates'7 showed the presence of significant inti- graft vasculopathy in 73 cardiac transplant recipients mal hyperplasia in 75% of angiographically normal who were followed prospectively for an average coronary segments. Quantitative coronary angiog-

Texas Heart Institutejournal Cardiac Allograft Vasculopathy 139 raphy, performed either manually or by automated video densitometry, may improve the estimation of coronary narrowing. It may, therefore, be a more sensitive method of diagnosing cardiac allograft vasculopathy.20 Other Coronary Artery Imaging Techniques. Cor- onary angioscopy and intravascular ultrasonog- raphy, 2 novel intracoronary imaging methods, have been used recently in heart transplant recipients to evaluate the morphology of cardiac allograft vasculopathy. These methods have proved to be more sensitive than coronary angiography and have al- lowed more precise evaluation of the morphologic characteristics of the atherosclerotic plaque and the Fig. 1 Yellow plaque. Left panel: Angiographic views of the structure of the vessel wall.21-24 In a recent histologic right coronary artery at 3 years (A) and 4 years (B). Right panel: Corresponding angioscopic appearance demonstrating study, Siegel's group25 validated the images obtained yellow plaque. by these techniques, demonstrating a high concor- dance with histologic classification. CoronaryAngioscopy. Studies from our institution indicate that coronary angioscopy is more sensitive than coronary angiography for detecting cardiac allograft vasculopathy.2' The 1st study consisted of 37 cardiac transplant recipients who underwent coronary angioscopy with a steerable microangioscope at the time the I of annual coronary angiography. When the 2 methods were compared, only 13% of the coronary sites were abnormal by quantitative B coronary angiography, whereas 84% of the sites were abnormal by coronary angioscopy (p=0.005). The abnormalities seen by coronary angioscopy were pigmented (yellow) or nonpigmented (white) plaque, with or without coronary stenosis. In a 2nd study, 20 cardiac transplant recipients Fig. 2 White plaque. Left panel: Angiographic views of the left anterior descending artery at 1 year (A) and 2 years (B). underwent coronary angioscopy at baseline and an- Right panel: Corresponding angioscopic appearance demon- nually thereafter.22 Angioscopic findings were classi- strating white plaque. fied as: Normal; Grade 1, pigmented yellow or white plaque without stenosis; Grade 2, <50% stenosis; or Grade 3, .50% stenosis. Normal or Grade 1 angioscopic findings were prevalent 1 to 2 years after that provides accurate quantitative information cardiac transplantation, whereas Grade 2 or 3 angio- about vessel wall thickness and morphology, and scopic findings were prevalent 3 to 5 years after about luminal dimensions in vivo (Fig. 3). Further- transplantation. more, intravascular ultrasound enables a more Angioscopic findings in native coronary athero- sensitive assessment of calcification than either sclerosis appear as a yellow plaque, owing to lipid angiography or angioscopy.22 deposits, and lesions of restenosis after balloon di- Intimal thickening resulting from myointimal lation are seen as a white plaque that results from hyperplasia is the hallmark of cardiac allograft vascu- smooth muscle cell proliferation and fibrosis.26 lopathy and can be detected early by intravascular Therefore, in heart transplant recipients, those le- ultrasound. Fitzgerald and colleagues27 demon- sions that appear pigmented (Fig. 1) likely contain strated that intravascular ultrasound can detect in- lipid deposits, whereas nonpigmented lesions (Fig. timal thickening of as little as 178 jum. While the 2) are due to myointimal proliferation and fibrosis. intracoronary ultrasound appearance of normal Further long-term studies are needed to delineate coronary artery walls is homogenous and without the clinical use of coronary angioscopy in diagnos- evidence of layering, a 3-layered appearance is ab- ing cardiac allograft vasculopathy. normal and associated with intimal hyperplasia. Sev- Intravascular Ultrasound. Intravascular ultra- eral studies from our institution22'28 and others'9 have sound has now emerged as a safe clinical tool for shown that intravascular ultrasound is more sensi- the early diagnosis of cardiac allograft vasculopathy tive than coronary angiography for diagnosing car-

140 Cardiac Allograft Vasculopathy Volume 22, Number 2, 1995 data on vessel wall morphology is useful for detecting the presence of cardiac allograft vasculopathy. The functional significance of intimal thickening was evaluated in a study by Anderson and cowork- ers32 that showed that intimal thickening begins as a heterogenous process and increases in extent over time. This study also demonstrated that endothelial dysfunction occurs before the appearance of intimal thickening. Furthermore, we and others3-35 have shown that intimal hyperplasia progresses as time passes after transplantation. The excellent reproduc- ibility of measurements of luminal and intimal areas by intravascular ultrasound suggests that this tech- Fig. 3 Measurement of plaque area by intravascular ultrasound. nique can also be used serially, to characterize the rate of progression of disease and to evaluate the IA = intimal area; 11 = intimal index; LA = lumen area; effects of putative risk factors and therapeutic inter- TA = total area ventions (Fig. 4). In addition, intimal hyperplasia can predict clinical outcome in cardiac transplant recipients. In a diac allograft vasculopathy. We have found that 80% study that used intravascular ultrasound to evaluate of coronary segments in cardiac transplant recipients 74 consecutive heart transplant patients,-j6 the find- manifested intimal thickening by intravascular ultra- ing of severe concentric intimal thickening (>0.5 sound, although only 10% of these were evident on mm) identified a group of patients at high risk for routine angiography.28 St. Goar and co-authors19 have cardiovascular events, including sudden death, myo- established a useful grading classification of ultra- cardial infarction, and need for revascularization sound findings in heart transplant recipients: Class (Fig. 5). 0, no measurable intimal layer; Class I (minimal), an intimal layer <0.3 mm of the vascular circumference; Treatment Class II (mild), an intimal layer <0.3 mm but measurable in >1800 of the vascular circumference; Class Prevention III (moderate), an intimal layer 0.3 to 0.5 mm thick, Although cardiac allograft vasculopathy is thought to or an intimal layer >0.5 mm thick involving <180° of be an immunologic disease, advances in immuno- the vascular circumference; and Class IV (severe), suppression have not decreased its incidence.37 >0.5 mm intimal thickening involving >1800 of the However, prevention remains the primary goal of vascular circumference or an intimal layer >1.0 mm most centers in their approach to cardiac allograft in any 1 area of the vascular circumference.'9 vasculopathy. The introduction of instruments into vessels raises the concern that catheter-induced vascular wall dam- Risk Factor Modification age may accelerate the proliferative process, espe- Most heart transplant centers encourage risk factor cially in arteries that have no apparent disease. In a modification in the hope that the expression of car- study that analyzed 170 cardiac transplant patients diac allograft vasculopathy can at least be delayed. who underwent 240 intracoronary studies, no clini- Although hyperlipidemia and obesity are positively cal morbidity was seen. In addition, there was a low correlated with the occurrence of cardiac allograft incidence of vascular spasm, and no evidence of ac- vasculopathy, no studies have demonstrated conclu- celerated progression of disease was noted. There- sively the beneficial impact of lipid lowering or fore, intravascular ultrasound can be used safely in weight loss on this disease. Moreover, treatment of vessels not undergoing therapeutic intervention.29 post-transplant hypertension has not been demon- In addition to delineating morphologic character- strated to reduce the development of cardiac allo- istics, intravascular ultrasound affords an opportu- graft vasculopathy. nity to assess the transplanted vessel's responses to pharmacologic stimuli. It has been shown that the Pharmacologic Interventions vessel's vasodilatory response to nitroglycerin is at- Since platelets are an integral constituent of endo- tenuated during episodes of acute rejection, and is thelial injury in immune and nonimmune vascular independent of the degree of intimal thickening.30 damage, there is an intuitive logic in using platelet- Furthermore, Heroux and colleagues31 have dem- modifying agents. However, studies with initially onstrated that combining data on the vascular re- encouraging reports of the efficacy of aspirin, di- sponses of endothelium-dependent vasodilators with pyridamole, and warfarin in small groups of patients

Texas Heart histituteJournal Cardiac Allograft Vasculopathy 141 A E 0.6- 0.5-

enS 0.3 - T

B 0.2 ::0.1 *EO0 c Control ACE CEB ACE I &CEB Fig. 6 Intimal hyperplasia as detected by intravascular ultrasound at the end of the 1st postoperative year, in heart trans- Fig. 4 Progression of intimal hyperplasia despite a normal plant recipients treated with angiotensin-converting enzyme angiogram. Left panel: Angiographic views of the left anterior inhibitors (ACE 1), calcium entry blockers (CEB), or both. descending artery at 1 year (A) and 3 years (B) after transplantation. Right panel: Corresponding ultrasound images demonstrating a significant increase in intimal thickening. Post Tx = post-transplantation have suggested that these agents may retard the disease. However, this has not been conclusively demonstrated in human cardiac transplant recipients. Group 11(20%) 20 - Percutaneous Interventions A recent multicenter study has shown that percu- 0 16- taneous transluminal coronary angioplasty can be 4- 12 - performed in cardiac allograft vasculopathy with a a) morbidity and short-term success similar to those in 0L) 0 8± native atherosclerosis.44 Coronary angioplasty45 and .a_ atherectomy46 have been performed successfully for 4- Group 1 (2%) U discrete proximal stenoses. Therefore, the goals of percutaneous interventions in cardiac transplant re- Mild-Moderate Severe Intimal Hyperplasia Intimal Hyperplasia cipients are to reduce the occurrence of clinically silent morbid events and to prolong allograft func- Fig. 5 The degree of intimal hyperplasia as indicated by tion in patients awaiting repeat transplantation. intravascular ultrasound predicts cardiac events. Repeat Transplantation Currently, retransplantation is the only definitive have yielded rather disappointing results at follow- therapy for severe cardiac allograft vasculopathy. up." Although the use of dipyridamole has beer However, the survival rates for retransplantation are largely abandoned, some transplant centers still rou- significantly lower than those for primary heart tinely use platelet-active agents, such as aspirin, ir transplantation (1-year survival, 50% versus 80%, re- heart transplant recipients. spectively).4748 Using quantitative angiography, Schroeder anc associates39 have suggested that calcium entry block Conclusion ers, specifically diltiazem, may delay the progressiorA of cardiac allograft vasculopathy and may also resul t There is an urgent need to investigate the effective- in regression of these lesions. Using intravascula]r ness of pharmacologic therapy in heart transplant ultrasound, we have recently shown that heart trans patients by using more sensitive and precise imag- plant recipients, treated with either calcium entr~ ing techniques, such as intravascular ultrasound and blockers or angiotensin-converting enzyme inhibiI intracoronary angioscopy. Unless therapeutic ad- tors, have a significantly lesser degree of intima vances are made, the long-term success of cardiac hyperplasia at 1 year after cardiac transplantatior transplantation will remain in jeopardy. than do matched, untreated control patients.4" Long er follow-up studies with larger numbers of patientv References are needed to confirm these findings (Fig. 6). Ani mal studies evaluating the role of dehydroepian 1. Hosenpud JD. Novick Rj, Breen Tj. Daily OP. The registrv drosterone,41 omega-3 fatty acids,42 or angiopeptin4~3 of the International Society for Heart and Lung Transplanta-

142 Cardiac Allograft Vasculopathy Vb/nine 22. iViiinbei- 2, 1995 tion: eleventh official report-1994. J Heart Lung Transplant 21. Ventura HO, Jain A, Mesa JE, White CJ, Ramee SR, Collins 1994; 13:561-70. TJ, et al. Angioscopy and ultrasound in cardiac transplanta- 2. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, tion: assessment and comparison of intracoronary morphol- Young JB, Kubo SH, et al. Pretransplantation risk factors for ogy [abstract]. J Am Coll Cardiol 1992;19:173A. death after heart transplantation: a multiinstitutional study. 22. Ventura HO, White CJ, Jain SP, Smart FW, Jain A, Stapleton The Transplant Cardiologists Research Database Group. J DD, et al. Assessment of intracoronary morphology in car- Heart Lung Transplant 1993;12:549-62. diac transplant recipients by angioscopy and intravascular 3. Kriett JM, Kaye MP. The registry of the International Society ultrasound. Am J Cardiol 1993;72:805-9. for Heart Transplantation: seventh official report-1990. J 23. Ramee SR, White CJ, Collins TJ, Mesa JE, Murgo JP. Percuta- Heart Transplant 1990;9:323-30. neous angioscopy during coronary angioplasty using a steer- 4. Kosek JC, Hurley EJ, Lower RR. Histopathology of orthotopic able microangioscope. J Am Coll Cardiol 1991;17:100-5. canine cardiac homografts. Lab Invest 1968;19:97-112. 24. Potkin BN, Bartorelli AL, GessertJM, Neville RF, Almagor Y, 5. Kosek JC, Hurley EJ, Sewell DH, Lower RR. Histopathology Roberts WC, et al. Coronary artery imaging with intravascu- of orthotopic canine cardiac homografts and its clinical cor- lar high-frequency ultrasound. Circulation 1990;81:1575-85. relation. Transplant Proc 1969;1:311-5. 25. Siegel RJ, Ariani M, Fishbein MC, Chae JS, Park JC, Maurer 6. Thomson JG. Production of severe atheroma in a trans- G, et al. Histopathologic validation of angioscopy and intra- planted human heart. Lancet 1969;2:1088-92. vascular ultrasound. Circulation 1991 ;84: 109-17. 7. Bieher CP. 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144 Cardiac Allograft Vasculopathy Volume22, Number2,1995