Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective and prospective study in 162 patients.

BACKGROUND: Cardiac papillary fibroelastoma (CPF) is a primary cardiac neoplasm that is increasingly detected by echocardiography. The clinical manifestations of this entity are not well described. METHODS AND RESULTS: In a 16-year period, we identified patients with CPF from our pathology and echocardiography databases. A total of 162 patients had pathologically confirmed CPF. Echocardiography was performed in 141 patients with 158 CPFs, and 48 patients had CPFs that were not visible by echocardiography (<0.2 cm), leaving an echocardiographic subgroup of 93 patients with 110 CPFs. An additional 45 patients with a presumed diagnosis of CPF were identified. The mean age of the patients was 60+/-16 years of age, and 46.1% were male. Echocardiographically, the mean size of the CPFs was 9+/-4.6 mm; 82.7% occurred on valves (aortic more than mitral), 43.6% were mobile, and 91.4% were single. During a follow-up period of 11+/-22 months, 23 of 26 patients with a prospective diagnosis of CPF that was confirmed by pathological examination had symptoms that could be attributable to embolization. In the group of 45 patients with a presumed diagnosis of CPF, 3 patients had symptoms that were likely due to embolization (incidence, 6.6%) during a follow-up period of 552+/-706 days. CONCLUSIONS: CPFs are generally small and single, occur most often on valvular surfaces, and may be mobile, resulting in embolization. Because of the potential for embolic events, symptomatic patients, patients undergoing cardiac surgery for other lesions, and those with highly mobile and large CPFs should be considered for surgical excision.

Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty.

The pathologic changes in the coronary arteries of three patients who died 5, 17 and 62 days, respectively, after percutaneous transluminal coronary angioplasty were studied. Changes in the vessel wall seen early after angioplasty included focal denudation of the endothelium, splits in the intima extending to and along the inner aspect of the media, focal intimal necrosis and adventitial hemorrhage. Extensive medial dissections were seen in the coronary arteries of the two patients who died 5 and 17 days after coronary angioplasty. Fibrin was deposited on the surface of the intima, within intimal cracks and in areas of intimal and medial necrosis. Focal proliferation of smooth muscle cells was prominent on neointimal surfaces of the coronary artery from the patient who died 17 days after angioplasty. The previously dilated coronary segment from the patient who died 62 days after angioplasty was stenosed by an extensive recent proliferation of smooth muscle cells that were distributed over the entire circumference of the intimal surface as well as within gaps in the old atherosclerotic plaques. This type of intimal proliferation would appear to be responsible for the recurrent coronary artery stenosis that develops in some patients after coronary angioplasty.

Cystic medial necrosis of the aorta in patients without Marfan's syndrome: surgical outcome and long-term follow-up.

A retrospective analysis was performed to determine the surgical outcome and long-term follow-up of patients with documented cystic medial necrosis of the aorta. Ninety-three patients were diagnosed as having cystic medial necrosis at the Cleveland Clinic between July 1963 and December 1987 (72% men aged 26 to 77 years, mean 55). Patients who met the standard diagnostic criteria for Marfan's syndrome were deliberately excluded. Sixty-eight percent of the patients had a diastolic murmur and chest roentgenogram revealed a dilated aortic arch in 58% and cardiomegaly in 63%. Cardiac catheterization in 76 patients demonstrated aortic root dilation in 78%, aortic regurgitation in 72%, aortic dissection in 32% and coronary artery disease in 32%. Ninety patients underwent surgery including composite graft repair with reimplantation of the coronary arteries in 34%. Follow-up, obtained on 90 (97%) of the 93 patients, ranged in duration from 0 to 137 months (mean 29). Thirty-four of the 90 patients died (age range 30 to 75 years, mean 60). Ninety-four percent of the known causes of death were related to the cardiovascular system; 65% were the result of aortic dissection or rupture or sudden death. Ninety-six percent of survivors were in New York Heart Association functional class I or II. Overall estimated survival at 1, 3 and 5 years was 72.2%, 63.5% and 57.4%, respectively. Actuarial survival in patients who underwent composite graft reconstruction was 84% at 5 years. The presence of a diastolic murmur at initial presentation was associated with a poor prognosis (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Sclerosing vasculopathy of the central nervous system in nonelderly demented patients.

Three nonelderly patients without hypertension whose clinical and radiologic features otherwise resembled Binswanger's subcortical arteriosclerotic encephalopathy underwent biopsy of the hyperintense periventricular lesions seen on magnetic resonance imaging. The pathologic findings of the periventricular lesions consisted of gliosis with mild rarefaction and edema of the white matter. All patients had a sclerosing vasculopathy of unknown cause, which involved numerous small vessels within the periventricular lesions. The vessels stained negatively for amyloid, amyloid precursors, desmin, vimentin, keratin, immunoglobulin, and complement. On electron microscopy, small arteries, arterioles, venules, and capillaries were characterized by swollen astrocytic foot processes surrounding the vessels; dense, perivascular collagen packing; crystalline arrays of filaments within basement membrane; giant lipid-laden lysosomes within perivascular cells; and narrowing of the vascular lumina. Similar changes were not seen in a control group of 19 patients. The pathologic features of the vessels in these cases are distinct from the vasculopathy associated with Binswanger's subcortical arteriosclerotic encephalopathy. We suggest that a spectrum of vasculopathies may be associated with dementia and periventricular hyperintense lesions on magnetic resonance imaging.

Intra-arterial thrombolysis of embolic proximal middle cerebral artery occlusion from presumed atrial myxoma.

The role of thrombolysis in brain ischemia in patients with atrial myxoma is unknown. A patient with acute brain ischemia and previously undiagnosed atrial myxoma recanalized an occluded middle cerebral artery with intra-arterial thrombolysis. Arterial occlusion from presumed myxoma may be amenable to fibrinolysis. Angiography before treatment in patients with atrial myxoma excludes a myxomatous pseudoaneurysm and permits site-specific thrombolytic instillment.

Chloroquine neuromyotoxicity. Clinical and pathologic perspective.

Six cases of toxic myopathy and/or neuropathy with chloroquine and/or hydroxychloroquine therapy are described. Two patients had unique clinical and pathologic evidence of cardiomyopathy secondary to chloroquine or hydroxychloroquine therapy. One patient had polyneuropathy secondary to chloroquine toxicity. This may be the first documentation of several features of chloroquine/hydroxychloroquine toxicity: morphologic changes in human peripheral nerve in chloroquine toxicity; chloroquine/hydroxychloroquine cardiomyopathy diagnosed by endomyocardial biopsy; and hydroxychloroquine myotoxicity. Chloroquine is a neuromyotoxin that affects nerves and cardiac and skeletal muscles. Discontinuation of chloroquine and hydroxychloroquine resulted in marked improvement in most cases. The reversibility of the symptoms emphasizes the importance of recognizing potential signs of nerve, muscle, and cardiac toxicity in patients being treated with chloroquine or hydroxychloroquine.

Parenchymal cell proliferation in coronary arteries after percutaneous transluminal coronary angioplasty: a human tissue bank study.

PURPOSE: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a limitation of this technique. Arterial wall cell proliferation is a component of restenosis preventable with intravascular brachytherapy. This study attempts to locate the sites of cellular proliferation after PTCA so as to aid the optimization of this therapy. METHODS AND MATERIALS: Autopsy records from January 1, 1985 through December 31, 1995 were reviewed, and 27 patients who received PTCA prior to death were identified who also had evidence of PTCA on histologic examination of the arterial sections. The sections were subjected to immunohistochemical staining for proliferating cell nuclear antigen (PCNA) to detect the proliferating cells in the arterial sections, followed by image analysis to determine the proliferative index (PI) of all regions and layers of the section. RESULTS: The PI did not differ significantly according to vessel region (plaque, plaque shoulder, or portion of vessel wall with lowest plaque burden), vessel layer (intima, media, adventitia), or evidence of prior PTCA. There was a trend toward a higher PI in young lesions. CONCLUSION: Cell proliferation in the vascular wall after PTCA was found throughout the treated arterial section's axial plane, not only in the periluminal region.

Comparison of whole-blood cyclosporine levels and the frequency of endomyocardial lymphocytic infiltrates (the Quilty lesion) in cardiac transplantation.

Endomyocardial lymphocytic infiltrates (ELI), or "Quilty" lesions are morphologically and immunohistochemically distinct and are thought to be due in part to Cyclosporine therapy. In order to evaluate the relationship of ELI to CsA therapy, we compared the whole-blood CsA levels (WBCsA) with the frequency of ELI in our cardiac transplant patients. From January 1, 1987 to January 1, 1988, 364 concurrent endomyocardial biopsies and WBCsA were performed on 43 cardiac transplant patients. All biopsies were evaluated for acute rejection. ELI were recognized as well-circumscribed, flat or pedunculated lesions within the endomyocardium composed of mature T lymphocytes with pockets of B lymphocytes and occasional macrophages and plasma cells. All WBCsA were trough levels and were determined by high-pressure liquid chromatography. Results were evaluated using a logistic regression model for clustered data. ELI were observed in 17.9% (65/364) biopsies, and 60.5% (26/43) of patients had at least one ELI during the study period. The mean WBCsA was 155.2 ng/ml (SD = 62.9) in the ELI-positive group, and 190.2 ng/ml (SD = 97.0) in the ELI-negative group. Applying the regression model revealed a statistically significant negative correlation between WBCsA and the presence of ELI (P = 0.033)--that is, a lower WBCsA was associated with an increased probability of ELI. The frequency of clinically significant rejection was lower in the ELI-positive biopsies, and this correlation approached statistical significant (P = 0.053). These data suggest that ELI are unrelated to increased WBCsA and may represent an idiosyncratic reaction to CsA, or be related to factors other than CsA therapy.

Evidence for rejection of homograft cardiac valves in infants.

OBJECTIVE: Concern about the durability of small homograft cardiac valves has been expressed by surgeons, and evidence has been found that homograft valves evoke a recipient immune response. We reviewed our experience with homograft valves for evidence of rejection. METHODS: A search of our files revealed 11 homograft cardiac valves removed at reoperation and one at autopsy. Six valves were from adults, five were from infants, and one was from a 13-year-old child. Immunohistochemical studies with antibodies against smooth muscle actin, CD20, CD43, CD34, and CD68 were performed on the homografts containing inflammatory infiltrates. These valves happened to be the valves from the five infants. These five valves were also stained with Gram and Gomori's methenamine silver stains. RESULTS: The failed homografts from the adults and 13-year-old child showed leaflet calcification, fibrosis, and degeneration, but no inflammation. The valves from the infants all failed in less than 8 months. The valve leaflets were thickened, and the valve leaflets and aortic sleeves contained a hyperplastic intimal layer with numerous spindle cells positive for smooth muscle actin embedded in a glycosaminoglycan matrix. The homografts contained multiple foci of inflammation consisting of T lymphocytes (in all five infant valves) and B lymphocytes (in three of the five infant valves). Special stains for organisms were negative. CONCLUSIONS: Rapid failure plus lymphocytic infiltration in valve leaflets and aortic sleeves is consistent with rejection. The hyperplastic intima is similar to coronary arteries in transplant-associated vascular disease. Our observations are consistent with other reports of rapid failure of homograft valves in this age group.

The predictive value of serum enzymes for perioperative myocardial infarction after cardiac operations. An autopsy study.

We evaluated the utility of serum enzyme and isoenzyme activities for detecting autopsy-proved perioperative myocardial infarction in patients who died after cardiac operations. We studied 79 patients who had autopsies performed after coronary artery bypass grafting or valve replacement, or both. Thirty-seven had histologic evidence of a perioperative myocardial infarction. We found statistically significant differences between the group of patients with infarction and the group without infarction when we compared the mean activities of creatine kinase, creatine kinase MB, aspartate aminotransferase, and the lactate dehydrogenase-1/lactate dehydrogenase-2 ratio. The postoperative changes in serum enzymes were analyzed by logistic regression for their relation to perioperative myocardial infarction. Creatine kinase MB exhibited the best diagnostic association with the presence of perioperative myocardial infarction. The lactate dehydrogenase-1/lactate dehydrogenase-2 ratio correlated to a lesser extent with infarction. Adjustment of the diagnostic cutoff to 133 U/L for creatine kinase-MB measured 15 hours after operation yielded a sensitivity of 0.60 and a specificity of 1.0. This study demonstrates that no combination of enzyme activity changes after operation can completely discriminate all patients with perioperative myocardial infarction from those without. Nonetheless, measurement of creatine kinase MB activity provide 96% accuracy for diagnosing infarction at a prevalence of 10%.

Coronary artery bypass grafting with the right gastroepiploic artery.

The excellent results of coronary artery bypass with the internal mammary artery and the increasing numbers of patients who need coronary reoperations, but for whom conventional bypass conduits are not available, have prompted us to evaluate alternative arterial bypass conduits. The right gastroepiploic artery has been used as a coronary bypass graft in 36 patients (32 men), whose ages ranged from 29 to 71 years. Twenty-two patients had had previous coronary bypass grafting and six of these were undergoing their third bypass operation. The right gastroepiploic artery was used as an in situ graft to the right coronary artery or circumflex branches for 17 patients and as an aorta-coronary ("free") graft in 19 patients, six to the left anterior descending or diagonal, six to the circumflex, and seven to the right coronary artery. In conjunction with right gastroepiploic artery grafting, 16 patients received bilateral internal mammary artery grafts and 17 received one internal mammary artery graft. Histologically, right gastroepiploic artery segments from 18 patients could not be distinguished from internal mammary artery segments, and no evidence of atherosclerosis was found. Two patients died in the hospital, one intraoperatively and one 3 months after the operation, of a perioperative stroke. Perioperative morbidity included wound complication in three and reexploration for bleeding in two. At late follow-up 1 to 38 months after operation, two late deaths had occurred and 21 patients were free of symptoms. Postoperative angiography (postoperative interval 1 week to 13 months) was performed in nine grafts, three in situ grafts to the right coronary artery and six free grafts that included two to the left anterior descending, three to the circumflex, and one to the right coronary artery. All right gastroepiploic artery grafts were patient. The right gastroepiploic artery is an arterial conduit that can be used as an in situ graft to posterior coronary vessels and as a free graft to any coronary arterial system. Early graft patency has been excellent, and the histologic similarity between the right gastroepiploic artery and the internal mammary artery suggest that the long-term results will be favorable.

Long-term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts.

Serial arteriograms were obtained in 501 patients after coronary bypass grafting. Study I within 5 years of operation (mean interval 15 months) and Study II more than 5 years after (mean interval 88 months, range 60 to 147 months). One hundred patients received both internal mammary artery and saphenous vein grafts: 37, mammary artery grafts only, and 364, vein grafts only. In Study I, 645 (82%) of 786 vein grafts were patent, 42 (5%) stenotic or irregular, and 99 (13%) occluded. Of 140 mammary artery grafts, 136 (97%) were patent, two (2%) stenotic, and two (2%) occluded. Of the 645 vein grafts patent in Study I, 357 (55%) remained patent in Study II, 119 (18%) were stenotic or irregular, and 169 (26%) were occluded. Of 136 mammary artery grafts patent in Study I, 130 (96%) were unchanged, one was stenotic, and five (4%) were occluded in Study II. Early vein graft patency was influenced by the coronary artery grafted and by angina. Progression of vein grafts patent at Study I to stenosis or occlusion at Study II was associated with increasing postoperative interval (p less than 0.00001), interval myocardial infarction (p less than 0.001), angina (p less than 0.001), diabetes (p less than 0.004), hypercholesterolemia (p less than 0.006), and hypertriglyceridemia (p less than 0.02); it was not influenced by the coronary artery grafted. Within 5 years of operation, mammary artery graft patency exceeded vein graft patency. Between 5 and 12 years after operation, the attrition rate of vein grafts greatly exceeded that of mammary artery grafts (p less than 0.0001).

Mechanical properties of myxomatous mitral valves.

OBJECTIVE: We sought to characterize the mechanical properties of normal and myxomatous mitral valve tissues. METHODS: We tested 113 mitral valve sections from patients undergoing mitral valve repair or replacement for myxomatous mitral valve prolapse and sections from 33 normal valves obtained at autopsy. RESULTS: Myxomatous mitral valve leaflets were more extensible than normal leaflets when tested parallel to the free edge (41.2% +/- 18.5% vs 17.3% +/- 6.7% circumferential strain [mean +/- SD]; P <.001), as well as perpendicular to the free edge (43.2% +/- 19.4% vs 17.3% +/- 6.7% radial strain; P <.001). Myxoid leaflets were less stiff circumferentially (4.0 +/- 1.6 vs 6.1 +/- 1.4 kN/m; P <.001) and radially (4.5 +/- 1.1 vs 6.1 +/- 1.4 kN/m; P <.001) than normal leaflets. Leaflet strength, however, was similar in both groups. CONCLUSIONS: Myxomatous mitral valve leaflets are physically and mechanically different from normal mitral valve leaflets. They are more extensible and less stiff. Compared with chordae examined previously, however, they are affected much less. Myxomatous mitral valve disease may therefore affect the collagen in the chordae more severely than that in the leaflets.

Vein graft disease: the clinical impact of stenoses in saphenous vein bypass grafts to coronary arteries.

The influence of coronary artery stenoses on patient survival and event-free survival is known, but no studies have reported the long-term outcome of patients with stenoses in saphenous vein bypass grafts. We retrospectively studied 723 patients who underwent a postoperative angiographic study that documented a stenosis of 20% to 99% in at least one saphenous vein graft and who did not undergo reoperation or percutaneous transluminal coronary angioplasty within 1 year after that catheterization. The mean follow-up interval was 83 months (range 1 to 237 months). For comparison, a group of 573 patients who underwent a postoperative catheterization that did not show any vein graft stenosis were also followed up. Cox regression analyses were used to identify predictors of late survival, reoperation-free survival, and event-free survival. For the entire group of patients with stenotic vein grafts, moderate or severe impairment of left ventricular function (p less than 0.001), interval between operation and catheterization (p less than 0.001), older age (p = 0.001), triple-vessel or left main coronary artery disease (p = 0.004), and stenosis of the vein graft to the left anterior descending coronary artery (p = 0.09) were associated with decreased late survival. Patients with an operation-to-catheterization interval greater than or equal to 5 years were at particularly high risk, and multivariate analyses of that subgroup confirmed that a stenotic graft to the left anterior descending artery was a strong predictor of decreased survival (p less than 0.001), decreased reoperation-free survival (p less than 0.001), and decreased event-free survival (p less than 0.001). Patients greater than or equal to 5 years postoperatively with greater than or equal to 50% stenosis of vein grafts to the left anterior descending artery had survival of 70% and 50% at 2 and 5 years after catheterization, compared with 97% and 80% for those with greater than or equal to 50% stenosis of the native left anterior descending artery (p = 0.002). Late vein graft stenoses are more dangerous than native coronary stenoses. Late stenoses in saphenous vein grafts to the left anterior descending coronary artery predict a high rate of death and cardiac events and are an indication for reoperation.

Atheroembolism from the ascending aorta. An emerging problem in cardiac surgery.

As the ages of patients undergoing cardiac operations have increased, noncardiac causes of death have increased. To identify these causes of death, we analyzed the autopsy findings in 221 patients undergoing myocardial revascularization or valve operations between 1982 and 1989. Mean age was 65.6 +/- 9.5 years and the range was from 32 to 94 years; 130 patients (58.8%) were male. Autopsies were complete in 129 patients (58.4%) and limited to the chest and abdomen in the remainder. Embolic disease was identified in 69 patients (31.2%). Atheroemboli or abnormalities consistent with atheroemboli were identified in 48 patients (21.7%). Fourteen patients had thromboembolism and 7 had disseminated intravascular coagulation. The prevalence of atheroembolic disease increased dramatically from 4.5% in 1982 to 48.3% in 1989 (p = 0.001). Atheroembolic disease was found in the brain in 16.3% of patients, spleen in 10.9%, kidney in 10.4%, and pancreas in 6.8%. Thirty (62.5%) of the 48 patients had multiple atheroembolic sites. Atheroemboli were more common in patients undergoing coronary artery procedures (43/165; 26.1%) than in those undergoing valve procedures (5/56; 8.9%) (p = 0.008). There was a high correlation of atheroemboli with severe atherosclerosis of the ascending aorta. Atheroembolic events occurred in 46 of 123 patients (37.4%) with severe disease of the ascending aorta but in only 2 of 98 patients (2%) without significant ascending aortic disease (p less than 0.0001). Forty-six of 48 patients (95.8%) who had evidence of atheroemboli had severe atherosclerosis of the ascending aorta. There was a direct correlation between age, severe atherosclerosis of the ascending aorta, and atheroemboli. Incremental risk factors for atheroembolic are peripheral vascular disease and severe atherosclerosis of the ascending aorta.

Clinical temporary ventricular assist. Pathologic findings and their implications in a multi-institutional study of 41 patients.

Forty-one patients, distributed among four centers, had left (33 patients), right (five), or bilateral (three) temporary ventricular assistance with textured (24) or smooth (17) surfaced diaphragm pumps, during an evaluation supported by the National Institutes of Health. Cardiac failure had occurred in 39 postoperative patients (after aorta-coronary bypass [23], valve replacement [four], both [nine], or other [three]), with total cardiopulmonary bypass time mean 306 minutes (range 69 to 600). Two patients had cardiomyopathy. Death of 35 nonsurvivors was due to myocardial necrosis (14), hemorrhage (nine), cerebrovascular accidents (three), infection (three), and other (six). Mean duration of support in all patients was 62 hours. In 16 patients (40%) whose condition improved, cardiac assist duration was mean 127 hours (range 48 to 264), compared with mean 19 hours (range 1 to 120) in 25 who did not. Of 17 patients in whom duration of support exceeded 72 hours, 15 (88%) improved, 11 were weaned, and six survived long term. Tissue examination (in 33 patients) by biopsy at pump implantation or autopsy revealed coagulation or contraction band myocyte necrosis, with or without hemorrhage, in 26 patients; of these, 10 improved and six were long-term survivors. Pump-related complications (two) included pulmonary embolism, most likely related to a cannulation site thrombus, and an aortic cannulation site infection in one patient each. This study suggests that mechanical cardiac assist may be accomplished with a low complication rate; should not necessarily be denied to patients with existing necrosis, because myocardial necrosis does not preclude improvement or survival; and frequently leads to functional myocardial recovery if patients survive early noncardiac complications, often the result of long duration of cardiopulmonary bypass.

Does successful bridging with the implantable left ventricular assist device affect cardiac transplantation outcome?

OBJECTIVES: We sought to determine whether cardiac transplant recipients who required a bridge to transplantation with an implantable left ventricular assist device had a different outcome than patients who underwent transplantation without such a bridge. METHODS: A retrospective study of 256 cardiac transplants from 1992 to 1996 included 53 patients who received the HeartMate left ventricular assist device and 203 patients who had no left ventricular assist device support. RESULTS: Left ventricular assist device transplants increased from 8% of all transplants in 1992 (n = 63) to 32% in 1995 (n = 65) and 43% in 1996 (n = 14 year to date). Patients with and without left ventricular assist device had similar age and sex distributions. Left ventricular assist device recipients were larger (body surface area 1.96 vs 1.86 m2, p = 0.004). They were more likely to have ischemic cardiomyopathy (70% vs 45%, p = 0.001) and type O blood group (51% vs 34%, p = 0.06). All patients with left ventricular assist device and 42% of those without had undergone previous cardiac operations by the time of transplantation (mean number per patient 1.5 vs 0.3, p < 0.001). More patients in the left ventricular assist device group had anti-HLA antibodies before transplantation (T-cell panel reactive antibody level > 10% in 66% of left ventricular assist device group vs 15% of control group, p < 0.0001). Waiting time was longer for the left ventricular assist device than for patients in status I without a left ventricular assist device (median 88 vs 37 days, p = 0.002). There was no difference in length of posttransplantation hospital stay (median 15 days for each) or operative mortality (3.8% vs 4.4%). Mean follow-up averaged 22 months. No significant difference was found in Kaplan-Meier survival estimates. One-year survival was 94% in the left ventricular assist device group and 88% in the control group (difference not significant). Comparison of posttransplantation events showed no significant difference in actuarial rates of cytomegalovirus infection (20% vs 17%) or vascular rejection (15% vs 12%) at 1 year of follow-up. Similar percentages of patients were free from cellular rejection at 1 year of follow-up (12% vs 22%, p = 0.36). CONCLUSIONS: Left ventricular assist device support intensified the donor shortage by including recipients who otherwise would not have survived to transplantation. Bridging affected transplant demographics, favoring patients who are larger, have ischemic cardiomyopathy, have had multiple blood transfusions and complex cardiac operations, and are HLA sensitized. Successfully bridged patients wait longer for a transplant than do UNOS status I patients without such a bridge, but they have similar posttransplantation hospital stay, operative mortality, and survival to those of patients not requiring left ventricular assist device support.

Activation of intravascular macrophages within myocardial small vessels is a feature of acute vascular rejection in human heart transplants.

BACKGROUND: We investigated the pathogenesis of acute vascular rejection by performing immunofluorescent screening on frozen sections for C1q, C3c, and immunoglobulin M in endomyocardial biopsy specimens from all new heart transplants. METHODS: Immunofluorescence for C4c, C5, immunoglobulin G, and immunoglobulin A was performed on all positive endomyocardial biopsy specimens. Twenty-eight positive endomyocardial biopsy specimens from six patients were identified, and 22 of those were studied with transmission electron microscopy. RESULTS: Endothelial hyperplasia and myocyte necrosis were prominent in the five female patients with positive immunofluorescence. In addition, macrophages with ultrastructural cytologic features of activation were seen filling capillaries and venules in intimate contact with endothelium and exiting those vessels. Activated macrophages were large cells with abundant cytoplasm and ruffled borders and contained numerous lysosomes, rough endoplasmic reticulum, and mitochondria. Intravascular activated macrophages were identified in five of six patients with positive immunofluorescence but were not seen in any of the endomyocardial biopsy specimens with negative immunofluorescence, including multiple examples of moderate (grades 2 to 3B) and severe (grade 4) acute cellular rejection. In the five female patients with activated macrophages, acute vascular rejection recurred multiple times with one fatality. Review of the files showed three additional, similar cases. The one male patient with positive immunofluorescence but without activated macrophages had only a single episode of acute vascular rejection. CONCLUSIONS: Complement and antibodies can activate macrophages, so this finding is not surprising. To the best of our knowledge, this is the first report of the intravascular activation of macrophages, and the first association of this process with acute vascular rejection. Activated macrophages may contribute to myocyte necrosis in acute vascular rejection by compromising blood flow in small vessels.

Comparison of myocardial cell injury in acute cellular rejection versus acute vascular rejection in cyclosporine-treated heart transplants.

BACKGROUND: Myocyte necrosis has been cited as a key feature in the diagnosis and classification of both moderate and severe acute cellular rejection (International Society for Heart and Lung Transplantation grades 3A to 4). However, our previous work suggests that myocyte necrosis is not a typical feature of cellular rejection. METHODS: To clarify this point and to elucidate differences between cellular rejection and acute vascular rejection, we compared the light and electron microscopic features of 35 consecutive endomyocardial biopsy specimens from six patients with acute vascular rejection diagnosed with positive immunofluorescence, 12 consecutive endomyocardial biopsy specimens from three patients with mixed acute vascular rejection and cellular rejection, and 435 endomyocardial biopsy specimens of International Society for Heart and Lung Transplantation grades 2 to 4 cellular rejection. RESULTS: Endomyocardial biopsy specimens from eight of nine patients with acute vascular rejection and mixed acute vascular rejection/cellular rejection exhibited classic myocyte necrosis as the typical form of myocardial cell injury. Myocyte necrosis was characterized by lysis of the sarcolemma, marked swelling of mitochondria, and intramitochondrial flocculent densities. In contrast, the typical form of myocardial cell injury in cellular rejection was reversible. Reversible cellular rejection was characterized by extensive loss of myosin filaments and Z-lines with subsarcolemmal and intracytoplasmic accumulation of Z-band material. Cell swelling, mitochondrial swelling, intramitochondrial densities, and lysis of sarcolemma were not observed. CONCLUSIONS: We conclude that myocyte necrosis is a characteristic feature of acute vascular rejection, whereas reversible myocardial cell injury is characteristic of cellular rejection, including grade 4. Myocyte necrosis is not a feature of cellular rejection. The presence of true myocyte necrosis in endomyocardial biopsy specimens from cyclosporine-treated heart transplants implicates some process other than cellular rejection. Processes producing myocyte necrosis include acute vascular rejection, peritransplantation ischemia, and accelerated atherosclerosis.

Recurrence of giant cell myocarditis in cardiac allograft.

BACKGROUND: Giant cell myocarditis causes essentially irreversible fulminant left ventricular dysfunction with associated conduction abnormalities and congestive failure. Response to immunosuppressive therapy is poor and cardiac transplantation is the only viable treatment option. The histologic hallmarks of giant cell myocarditis include a polymorphous inflammatory response with numerous multinucleated giant cells and extensive myocyte necrosis in a geographic pattern. There were 38 patients who received a cardiac transplant for giant cell myocarditis in the Giant Cell Myocarditis Registry. Among these patients, there were 9 recurrences of disease in the allograft. Concern has been expressed that recurrence of giant cell myocarditis in the allograft might be a contraindication for cardiac transplantation in the future. METHODS: In our single-center analysis we describe the clinical and histologic findings of 5 patients transplanted for giant cell myocarditis at the Cleveland Clinic. RESULTS: All but 1 of the patients were New York Heart Association (NYHA) class 4 with an average cardiac index (CI) of 1.52 liters/min x m(2). Of the 5 patients transplanted, 1 developed recurrent giant cell myocarditis. Routine right ventricular endomyocardial biopsy at 1 week exhibited severe multifocal myocardial fibrosis in addition to mild acute vascular rejection and mild grade 1A cellular rejection. Follow-up biopsy in this patient indicated grade IIIA moderate acute rejection in addition to multinucleated giant cells. Two distinct inflammatory processes were noted consisting of foci of T-cell inflammation identified by immunohistochemistry to be consistent with rejection, and a second inflammatory process with few mononuclear cells staining for macrophage or T-cell markers with eosinophils and myocyte necrosis consistent with giant cell myocarditis. Follow-up right ventricular endomyocardial biopsies (RVBXs) in this patient have subsequently demonstrated improvement in the degree of inflammatory infiltrate without vascular or significant cellular rejection. Vascular rejection was noted in 1 of the remaining 4 patients and was treated successfully with muramab-CD3 and plasmapheresis. CONCLUSIONS: Giant cell myocarditis should be expected to recur in the allograft and often does so concurrently with rejection. However, the disease in the allograft responds to therapy in a favorable manner, which differs dramatically from that in the native heart. This might be the result of detection of the disease at an earlier stage than in the native heart, or the immunosuppression milieu in the allograft. The favorable response to therapy suggests that the likelihood of recurrence of giant cell myocarditis should not be considered a barrier to transplantation.