The first cardiac transplantation (CT) procedure was done in Capetown, South Africa, by Christiaan Barnard in 1967.3 From that time through 2012, more than 90,000 CT procedures were performed worldwide, approximately 3500 a year with about 2200 of that number being performed in the United States.30 The immediate pre-op care, the operation, and the first 6-month post-operative care cost about $1,000,000. Although most have been performed in patients with idiopathic dilated cardiomyopathy (IDC) or ischemic cardiomyopathy (IC), CT is also performed, albeit less frequently, for a variety of other cardiac conditions. In 1998 Waller and colleagues reported clinical and morphologic findings in 92 patients who had had CT for IDC, IC, or hypertrophic cardiomyopathy (HC).71 Of them, 57 had CT at Baylor University Medical Center (BUMC) Dallas from March 1993 through June 1997. (The remaining 35 patients had CT at other institutions and are not included in the present analysis.) Surprisingly, that clinico-pathologic study appears to have been the first to report morphologic findings in a systematic fashion in the recipient hearts in those 3 conditions. The present report was prompted by finding incongruity between the clinical and morphologic diagnoses in some patients having CT, and that incongruity led to a thorough analysis of that frequency in 314 patients who had had CT at BUMC in the past 20 years.
The recipient hearts in each of the 314 patients were submitted to the surgical pathology division of the department of pathology of BUMC Dallas. The patients included had undergone CT at BUMC from March 1993 through June 2012. All hearts during this period were described and classified by 1 of the authors (WCR). Figure 1 displays the number of CTs done at BUMC during each of those 20 years and the 3 major reasons for CT among the 314 patients. Each heart after formalin fixation and “cleaning” was weighed carefully by WCR, opened by him, and photographed (most by JMK). Although some were opened by parasagittal cuts, especially in those patients with HC, the cardiac ventricles in most were incised by transverse cuts parallel to the posterior atrioventricular sulcus. The resulting “bread-loaf” slices were approximately 1 cm in thickness except for the most apical portion, which was about 3 cm thick. The heart was weighed after these cuts and after all extraneous tissues were removed. The left ventricular cavity was measured both from anterior to posterior and from right to left dimensions, and the largest of these cavity numbers were used as the maximal cavity dimension. The right ventricular cavity dimension was the length from the right ventricular aspect of the ventricular septum to the endocardial lining of the right ventricular free wall along the posterior wall of this chamber. Figures 2–30
The orifices of the right and left main coronary arteries in the aorta were carefully examined for proper location and degrees of narrowing, if any. Random cuts were made in the 4 major (right, left main, left anterior descending, and left circumflex) coronary arteries, and the arteries were probed (1.5 mm diameter probe) both anterograde and retrograde. The 2 coronary orifices in the aorta were probed to determine any resistance to movement of the probe. Additionally, all incisions into the major coronary arteries were carefully explored for atherosclerotic plaques and luminal narrowing.
Each of the 4 cardiac valves was examined for abnormality.
At least 6 sections of each heart were submitted for preparation of histology slides. They included at least 2 sections of the left ventricular free wall, 1 of ventricular septum, 1 of right ventricular free wall, and 1 each of the walls of left and right atria. If coronary artery bypass grafts were present, sections of them were also prepared. Both hematoxylin-eosin and Masson stains were prepared on all myocardial sections and Movat stains were prepared on all sections of coronary bypass conduits and/or native coronary arteries. If heavy calcific deposits were palpated in the epicardial coronary arteries or in other areas of the heart, usually a radiograph was made of the recipient heart.
The clinical, echocardiographic, hemodynamic, and operative records were sought from the patients’ medical records and/or the BUMC Apollo cardiovascular database. Information regarding death of any patient was obtained from the medical records in deaths during hospitalization at the time of CT and from the Social Security Death Index for post-hospitalization deaths. Survival was assessed as March 31, 2013.
Means, standard deviations (SDs), and percentages were calculated to describe the study cohort. The Kaplan-Meier method was used to construct the survival curve for the whole population. The log-rank test statistic was computed to compare unadjusted survival curves between men and women.
The study was approved by the institutional review board at BUMC.
The main findings in the 314 patients are summarized in Tables 1 and 2. All patients at the time of CT were aged >18 years of age: 230 (73%) were men, and 84 (27%) were women. The patients included had CT only; there were no patients having heart/lung, heart/liver, or heart/bone marrow transplantation. Clinically, the patients were divided into 2 major groups: 1) ischemic cardiomyopathy (IC), 148 patients (47%); and 2) non-ischemic cardiomyopathy (N-IC), 166 patients (53%). The N-IC patients were subdivided into 11 groups, the 2 largest being IDC, 111 patients (66%), and HC, 17 patients (10%). The remaining 9 groups under N-IC consisted of 38 patients (23% of 166).
The frequency of congruity between the clinical and morphologic diagnoses is summarized in Table 1 and in Figure 2. Both the clinical and morphologic diagnoses were congruous in 272 (87%) of the 314 patients: in 142 (96%) of the 148 patients with IC and in 130 (78%) of the 166 patients with N-IC. Incongruity between the clinical and morphologic diagnoses was most glaring among the patients with HC (10 of 17 [59%]), non-compaction left ventricular cardiomyopathy (0 of 3); arrhythmogenic right ventricular cardiomyopathy (0 of 4), and cardiac sarcoidosis (0 of 8). Details of individual patients in the non-IC subgroups (excluding IDC) are tabulated in Tables 3–10.
The 148 IC patients had hearts with dilated left ventricular cavities (>3.5 cm: range, 3.5–8.5 cm [mean 5.9]); 1 or more major epicardial coronary arteries narrowed >75% in cross-sectional area by atherosclerotic plaque; 1 or more grossly visible transmural (>50% of wall thickness) scars in the left ventricular free wall with or without similar scars in the ventricular septum and right ventricular free wall; normal or nearly normal cardiac valves; and absent inflammatory, giant, neoplastic cell or non-fibrous infiltrates (such as amyloid).56 Additionally, the intramural coronary arteries were normal. Of the total 314 patients, 148 (47%) morphologically fulfilled these criteria. Of these 148 patients, 52 (35%) had had a coronary artery bypass grafting procedure previously and 22 (15%) had a left ventricular assist device. Of these 148 patients, 142 (96%) before CT were diagnosed as IC; the remaining 6 patients were diagnosed clinically as IDC because coronary angiograms, some performed several years earlier, had indicated no significant luminal narrowing, although all 6 had transmural left ventricular scars and severe (>75% cross-sectional area) narrowing of 1 or more major coronary arteries. Examples of IC are shown in Figures 3–13.
Idiopathic Dilated Cardiomyopathy
The 111 IDC patients had dilated left ventricular cavities (4.0–10.0 cm [mean 6.3]); normal or nearly normal cardiac valves; normal epicardium; no inflammatory, giant, neoplastic cells or non-fibrous interstitial infiltrates (such as amyloid) in the cardiac walls; and usually normal epicardial coronary arteries (Figures 14–17).20,51,54,71 A few patients had some atherosclerotic plaques but the plaques had narrowed the lumen ≤50% in cross-sectional area in 1 or more of the 4 major epicardial coronary arteries. Eleven patients had narrowing of 1 or more major epicardial coronary arteries >75% in cross-sectional area by plaques, but none of them had grossly visible left ventricular or ventricular septal scars. These 11 patients do not fulfill our definition of IDC because of the coronary narrowing, but none of the 11 had 1 or more grossly visible left ventricular scars. In these patients the coronary angiogram appeared to simply underestimate the degree of coronary narrowing. Their lack of myocardial scarring prevents them from being placed in the IC group. It is likely that these 11 patients actually had IDC, but because they lived in a high-cholesterol environment (United States), their coronary arteries developed significant plaque.55 Five patients with normal epicardial coronary arteries had grossly visible left ventricular free wall and/or ventricular septal scars. The 5 patients were diagnosed morphologically and clinically as IDC.23
The 17 HC patients (Table 3) had either normal sized (<4 cm) (5 patients) or dilated (>4 cm) (12 patients) left ventricular cavities and past clinical evidence of non-dilated left ventricular cavities (Figures 18–21).5,13,21,24,33,36,37,42,49,61 Transmural scarring involved the ventricular septum and left ventricular free walls in 13 patients (76%) with or without grossly visible scarring of portions of the right ventricular free wall. The ventricular septum at sometime in the past or presently was thicker than the left ventricular free wall; typical myofiber disorganization was present in the ventricular septum, and the intramural coronary arteries on histologic study were abnormal in all 13 patients with ventricular wall scarring.35 None of the 17 HC patients had clinical or hemodynamic evidence of left ventricular outflow obstruction just prior to CT. Four (24%) of the 17 patients also had severe narrowing of 1 or more epicardial coronary arteries, and all 4 had grossly visible left ventricular and ventricular septal scars. Nine other HC patients had left ventricular or ventricular septal scar without narrowing of the epicardial coronary arteries. The clinical diagnosis in 6 of the 17 patients was “non-IC," in 1 patient IC, and in 1 patient both HC and IC. Each of the latter 2 patients had coronary bypass grafting in the remote past before CT. Thus, the clinical and morphologic diagnosis were incongruous in 7 (41%) of these 17 patients.
Non-Compaction Left Ventricular Cardiomyopathy
Three patients had NCLVC (Table 4, Figures 22 and 23). Each had very dilated ventricular cavities with the non-compacted portion of left ventricular free wall in 1 or more areas being >2 times the thickness of the underlying compacted portion of the wall and unassociated with narrowing of the epicardial coronary arteries.11,45,68 Clinically, each of the 3 patients were diagnosed as “non-IC.” One of the 3 patients had a small grossly visible left ventricular scar.
Three patients had active or healed mononuclear myocarditis (Table 5, Figures 24 and 25). The key identifying mark of this condition was focal subepicardial left ventricular wall lesions.19,25,58,60,62,65 Each had mononuclear-cell infiltrates–-mainly lymphocytes–-in the left ventricular free wall or subepicardial scars with or without mononuclear-cell infiltrates and without granulomas. The hearts were of increased weight (>350 g in women; >400 g in men), and the ventricular cavities were very dilated. One of the 3 patients had significant narrowing by atherosclerotic plaque of 1 or more epicardial coronary arteries. This patient clinically was diagnosed as IC, the other 2 as “non-IC.”
Arrhythmogenic Right Ventricular Cardiomyopathy
Four patients had ARVC; pertinent findings for them are summarized in Table 6 and illustrated in Figure 26.2,4,8,12,14,28,31,32,46,64,66,70,72,73 All 4 during life were diagnosed as “non-IC.” All 4 had thinning of the right ventricular free wall with replacement of the myocardial wall focally by adipose tissue and/or scar tissue without focal thinning (except in 1 patient) of the left ventricular free wall. All 4 had very dilated ventricular chambers. Before CT all 4 had documented runs of ventricular tachycardia. Three had other family members with a similar cardiac disease.
Pertinent findings in the 8 cardiac sarcoidosis patients are summarized in Table 7 and illustrated in Figure 27.9,15,43,47,52,62,67 All 8 were diagnosed clinically as “non-IC.” Six had focal but extensive scars in the free walls of both right and left ventricles and in the ventricular septum without associated narrowing of the epicardial coronary arteries (except for 1 patient), and the scarring tended to be subepicardial. The ventricular chambers were very dilated in all 8 patients. Non-caseating giant cell granulomas were present in the ventricular walls in 7 of the 8 patients. In 1 patient the typical “hard” granulomas were present in the portion of left ventricular free wall excised to insert a left ventricular assist device but not in the recipient heart sometime later. Another patient had right and left ventricular free wall and ventricular septal scarring typical of cardiac sarcoidosis but no granulomas were found in the histologic sections of left ventricular free wall. This case we believe is an example of “burnt out” sarcoidosis.43
Pertinent findings in the 3 cardiac amyloidosis patients are summarized in Table 8, and the hearts are illustrated in Figure 28.7,10,16–18,40,53,69 The clinical and morphologic diagnoses were congruous in all 3 patients. The ventricular cavities were either not dilated or dilated to a small degree. The patients had firm—actually rubbery—myocardium, no grossly visible focal myocardial lesions but focal endocardial lesions in either the right atrium or left atrium or both and in the tricuspid valve leaflets. The presence of amyloid was confirmed by Congo-red stains of sections of the heart. Two of the 3 patients had narrowing >75% in cross-sectional area by atherosclerotic plaque, but none had grossly visible ventricular wall scars.
Pertinent findings in the 6 patients with Adriamycin cardiomyopathy are summarized in Table 9 and illustrated in Figure 29.22,26,27,41,44 The clinical and morphologic diagnoses were congruous in each. All 6 had severely dilated ventricular chambers. All had received Adriamycin for cancer treatment.
Valvular Heart Disease
Pertinent findings in the 7 patients with valvular heart disease are summarized in Table 10.39,50,57 Four had aortic valve stenosis initially and repeated valve replacements; 1 had mitral valve replacements for mitral stenosis in 1 and for pure mitral regurgitation in the other. The latter patient also had severe tricuspid valve regurgitation, which had not been approached at a previous operation. The clinical and morphologic diagnoses were congruous in all 7 patients.
Cyanotic Congenital Heart Disease
Pertinent findings in the 3 patients with cyanotic congenital heart disease are summarized in Table 11.38,63 One had complex complete transposition of the great arteries, 1 severe right ventricular hypoplasia, and 1 tetralogy of Fallot. All 3 had had more than 1 previous cardiac operation. The clinical and morphologic diagnosis were congruous in all 3.
One patient had CT for ventricular septal defect resulting from a stab wound to the heart many years earlier. Details of this patient are described elsewhere.48
The survival probabilities for all 257 patients are shown in Figure 30. Of the 257 (of 314) patients in whom survival data are available, 66 (26%) have died: 8 (12%) within 60 days of CT and 58 (88%) at later periods. The log-rank test show no significant survival differences between men and women (log-rank = 0.479, p value = 0.4926) (Figure 30).
The present study serves 2 major functions: 1) it illustrates by gross photographs of the hearts the variability that occurs morphologically in each of the etiologic categories, and 2) it determines the frequency among the 314 patients of discrepancies between the clinical and morphologic diagnoses. Just like clinical presentations and courses are quite variable among patients with various types of cardiac diseases, the morphologic features in each type of cardiac disease are also quite variable. To properly illustrate that variability a number of photographs of recipient hearts are presented.
As part of the second purpose of this report, we determined the frequency of congruity or incongruity between the clinical and morphologic diagnoses among the 314 patients. As shown in Table 1, most (96%) of the patients with IC at morphologic study had been diagnosed with that condition clinically. The discrepancy occurred when 6 patients with IC anatomically had insignificant coronary narrowing by angiography before CT, but nevertheless severe narrowing of 1 or more major epicardial coronary arteries morphologically and extensive left ventricular wall scarring. We defined IC as the presence of severe (>75% in cross-sectional area) coronary narrowing accompanied by 1 or more transmural left ventricular wall scars. The reverse occurred in the case of IDC. Of the 111 patients with IDC anatomically (no left ventricular wall lesion grossly), 11 had severe narrowing of 1 or more major epicardial coronary arteries such that these patients in actuality did not fulfill our definitions for either IC or IDC. We suspect, however, that these 11 patients actually had IDC but resided in a high-cholesterol environment (United States), where coronary atherosclerosis is so prevalent.
Most of the incongruity between clinical and morphologic diagnoses occurred in the non-IC subgroups other than IDC. Thus, among the 56 patients with non-IC, excluding the patients with IDC, only 31 (55%) had congruity between the clinical and morphologic diagnoses. Specifically, among the 17 patients with HC, the 3 with NCLVC, the 3 with mononuclear myocarditis, the 4 with ARVC, and the 8 with cardiac sarcoidosis, a total of 35 patients, only 11 (31%) had the specific diagnosis made clinically. One could argue that including the single case without cardiac granulomas in the sarcoid group is improper. The type and distribution of the myocardial scarring, however, is absolutely typical of the other cases of cardiac sarcoidosis, a type of scarring not seen by us in any other condition.43 Additionally, documented sarcoid granulomas in the lungs have been shown to disappear as the scarring increases.59 Obviously, it is not sufficient to stop clinically with the diagnosis of non-IC cardiomyopathy. Ideally, of course, the specific subgroup needs to be sought even though therapy and outcome might not be altered by that knowledge.
The present study is not the first to compare the frequencies of discrepancies between the clinical and morphologic diagnoses in patients having CT. Bortman and colleagues6 in 1994 examined the congruity-incongruity issue in 112 patients who underwent their first orthotopic CT at the authors’ institution (University of Texas Southwestern Medical Center at Dallas). Among their 64 patients diagnosed with IC clinically, all had severe coronary narrowing morphologically; of their 48 patients with IDC clinically, 12 (25%) morphologically had severe coronary disease, and 3 had acute myocarditis. Thus, of their 112 patients a discrepancy between pre- and post-transplant diagnosis occurred in 15 (13%). Neither gross photographs nor definitions of the entities were provided.
In 1999, Angelini and colleagues1 from Padua, Italy, studied the agreement or lack thereof between pre- and post-CT diagnoses in 257 patients having CT, and found a discrepancy between clinical and pathologic diagnoses in 20 patients (8%). Among their 87 patients with a clinical diagnoses of IC, 3 had IDC and 1 granulomatous myocarditis; among their 126 patients whose clinical diagnosis was non-IC, 7 morphologically had IC, 5 myocarditis, 1 ARVC, and 1 with NCLVC; among their 10 patients with a clinical diagnosis of HC, 1 had ARVC, and 1 had a cardiac fibroma.1 No gross photographs of the heart or definitions of the conditions were provided.
In 2009, Luk and colleagues29 from Toronto, Canada, studied the problem in 296 patients who had had CT from 1987 to 2006 (Table 12). The frequency of the diagnosis made clinically and after examination of the recipient heart is shown in Table 12. It is apparent that the incongruity between the clinical and morphologic diagnoses was relatively frequent. Three gross photographs of the heart were presented. Definitions of the various conditions were not provided.
It is apparent from the present and previous studies that the largest incongruity between clinical and morphologic diagnosis in patients having CT is among the non-IC subtypes, particularly the dilated (end-stage) form of HC, mononuclear myocarditis, cardiac sarcoidosis, ARVC, and NCLVC. Would the use of additional diagnostic “instruments of precision” have allowed more precise pre-CT diagnosis among the non-IC group? Possibly so, particularly more use of magnetic resonance imaging among the patients with HC and sarcoidosis.35 Would a more accurate pre-CT diagnosis among the non-IC group have led to a re-evaluation of the need for CT in the first place? Or, if clinicians had actually known the specific non-IC diagnosis, would treatment have been different and might CT have been avoided? Among the 314 patients included in this study, the morphologic and clinical diagnoses were incongruent in 42 (13%), including 7 of 17 patients with HC, 3 of 3 with NCLVC, 3 of 3 with mononuclear myocarditis, 4 of 4 with ARVC, and 8 of 8 with cardiac sarcoidosis. This incongruity certainly leaves open the possibility that, if immunosuppressive or immunomodulatory treatment had been used in certain cases, such as specific antiarrhythmic agents for ARVC or intracardiac defibrillator for non-obstructive HC with normal or near-normal left ventricular ejection fraction, this therapy might have made a difference with respect to treatment, outcome, and even potentially the need for CT.
The positive features of the present study include the fact that all hearts were examined and described and all morphologic diagnoses were provided by the same person (WCR), who has been studying cardiovascular diseases for several decades. Had many of the non-IC cases been “grossed” by a first or second year trainee, which is the modus of operation in the surgical pathology laboratory at BUMC–except for the cardiovascular cases–it is unlikely that the cases of burnt-out or end-stage HC, or ARVC, or NCLVC would have been recognized grossly, and histologic examination in these cases would unlikely have provided the proper morphologic diagnoses.
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