Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function.

BACKGROUND: Assessment of myocardial viability by 99mTc-sestamibi remains controversial. Accordingly, we investigated the use of sestamibi as a marker of myocardial viability, defined by histopathology, and for predicting improvement of myocardial function after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: 99mTc-sestamibi perfusion tomography and radionuclide angiography were performed within 2 days before CABG in 21 patients with > or = 75% stenosis of the left anterior descending coronary artery and resting anterior wall dyssynergy. During CABG, transmural myocardial biopsies were obtained from the dyssynergic anterior wall and from normal myocardial segments to determine the extent of viable myocardium by histopathology. Improvement of regional left ventricular function was evaluated by radionuclide angiography at 6 to 8 weeks after CABG. There was a good correlation (r=.85, P<.001) between the quantified sestamibi activity and the extent of viable myocardium determined morphometrically. Among 21 biopsied dyssynergic myocardial segments, 11 improved their function after CABG and 10 failed to improve. Biopsied segments with improved postoperative function had significantly higher sestamibi activity (81+/-5% versus 49+/-16%, P<.0001) and significantly lower extent of interstitial fibrosis (7+/-4% versus 31+/-21%, P=.0002) than segments that failed to improve. A 55% threshold of 99mTc-sestamibi activity had positive and negative predictive values of 79% and 100%, respectively, for recovery of function after CABG in the biopsied segments. CONCLUSIONS: Myocardial 99mTc-sestamibi activity correlates well with the extent of viable myocardium and predicts improvement in regional function after CABG. This lends support to the use of sestamibi as a myocardial viability agent.

Pathologic correlates of aortic plaques, thrombi and mobile "aortic debris" imaged in vivo with transesophageal echocardiography.

OBJECTIVES: This study sought to evaluate the pathologic correlates of aortic atheromas, thrombi and mobile "aortic debris" imaged in vivo by transesophageal echocardiography (TEE). BACKGROUND: Atherosclerotic plaques with various complexity, thrombi and debris are frequently identified by TEE during imaging of the aorta. However, pathologic data to characterize these lesions imaged in vivo are lacking. METHODS: Intraoperative TEE was performed prospectively in 31 patients undergoing repair of aortic aneurysm or dissection. TEE was used to guide the surgeon to mark aortic areas of interest that were sent for pathologic examination. A four-point scoring system was used for both TEE and pathologic evaluation to grade the degree of involvement of the aortic wall with atheroma. Ultrasound video intensity of the aortic wall lesions was measured and compared with quantitative measures of wall composition at pathologic examination. The presence of thrombi and mobile aortic debris by TEE was noted and compared with pathologic findings. RESULTS: Histologic-TEE correlations were possible in 62 aortic segments. There was 73% exact agreement between TEE and pathologic grading. Discrepancies were mostly in the inability of TEE to detect superficial ulcerations. However, separation of normal aorta and minimal intimal thickening (grades I and II) from more complex atheromas (grades III and IV) was observed in 93%. For identification of thrombus, TEE had a sensitivity of 91% (29 of 32 segments) and a specificity of 90% (27 of 30 segments). Mobile aortic debris were identified in six aortic segments and were confirmed at pathologic examination to be thrombi. Ultrasound video intensity increased with worsening complexity of atheroma and related significantly to aortic plaque composition at pathologic evaluation (r = 0.80, p < 0.0001). Ultrasound intensity of thrombi and mobile debris was similar and was lower than that of complex atheromas. CONCLUSIONS: Thus, in the evaluation of aortic pathologic segments, TEE can assess aortic plaque complexity and identify thrombus formation, findings that may have important therapeutic implications.

Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study.

BACKGROUND: 99mTc sestamibi and 201 Tl are tracers that allow equivalent detection of myocardial infarction. However, because sestamibi does not undergo as much time-dependent redistribution as does 201Tl, it has been considered suboptimal for the detection of myocardial viability. METHODS AND RESULTS: Fifteen consecutive patients with ischemic cardiomyopathy who underwent orthotopic cardiac transplantation received an intravenous injection of 99mTc sestamibi at 1 to 6 hours before transplantation. Rotational tomography of the excised, intact, native hearts was performed to quantify the extent of myocardial hypoperfusion. The hearts were then sliced and reimaged on a gamma camera, followed by pathological quantification of the extent and severity of scarred and normal myocardium. Samples of normally and abnormally perfused myocardium underwent gamma well counting to determine tissue radioactivity and were examined under light microscopy for delineation of myocardial structure after trichrome staining. The mean extent of scintigraphic scar quantified through the use of rotational tomography was 45 +/- 14% of the left ventricle and correlated closely with pathological scar size (r = .89), despite a slight overestimation. Scintigraphic scar size determined with planar imaging of the individual myocardial slices also correlated closely with pathological scar size (r = .88). A good correlation existed between tissue 99mTc sestamibi activity determined through well counting and histological evidence of myocardial viability (r = .89). Most hypokinetic and 40% of akinetic/dyskinetic myocardial segments contained scintigraphically and histologically normal myocardium. CONCLUSIONS: 99mTc sestamibi scintigraphy can be used to accurately quantify the extent of myocardial scarring. Furthermore, the relative sestamibi activity in perfusion defects, measured several hours after administration, is a good indicator of myocardial viability determined with microscopy.

Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy.

The mechanism of death as a result of allograft ischemic heart disease is not well characterized. Ventricular tachycardia and fibrillation may not be the terminal events they often are in the general population. We report observations in a 41-year-old man with cardiac allograft arteriopathy who died suddenly while wearing an ambulatory monitor. The lethal rhythm was a progressive bradycardia terminating in asystole. Autopsy revealed epicardial and small vessel intramyocardial, coronary arteriopathy, and only mild allograft rejection. It is our belief that ischemia caused the bradycardic sudden death. We would like to hypothesize that prophylactic permanent pacemaker implantation may prevent bradycardic sudden death and improve survival in heart transplant patients with coronary disease.

Elevated soluble interleukin-2 receptor levels early after heart transplantation and long-term survival and development of coronary arteriopathy.

Rejection dynamics after heart transplantation might be characterized by soluble interleukin-2 receptor levels. To determine whether elevated levels early (measured by enzyme-linked immunosorbent assay once weekly the first 3 weeks at time of heart biopsy) after transplantation predict mortality and development of coronary disease, the means of these three determinations and the endomyocardial biopsy scores (McAllister scale 0-10) were compared for survivors and nonsurvivors and patients who had coronary arteriopathy develop and those who did not. Fifty-five patients alive 30 days after heart transplantation were prospectively followed up. Overall, 47 patients were male (85%), and the median age was 51 years. Mean +/- SD follow-up was 26 +/- 15 months (range, 1 to 54 months). There were 38 survivors (69%), and coronary arteriopathy developed in 15 patients (27%). Whereas mean +/- SD heart biopsy scores for the early weeks were similar between survivors and nonsurvivors (3.6 +/- 1.4 vs 4.4 +/- 1.6; p greater than 0.05), the difference in soluble interleukin-2 receptor levels was significant (703 +/- 362 U/ml vs 1793 +/- 1070 U/ml; p less than 0.001). A mean level less than 1000 U/ml in any given patient predicted long-term survival with a 76% sensitivity, 79% specificity, and 88% negative predictive value. Mean receptor levels for those patients in whom coronary arteriopathy did not develop were 880 +/- 846 U/ml and for those with this difficulty, 1410 +/- 590 U/ml (p = 0.001). Late morbidity and mortality after heart transplantation seem predicted by early elevation of plasma soluble interleukin-2 receptor levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation.

Successful cardiac transplantation requires suppression of rejection, and endomyocardial biopsy is generally used to quantify this and guide immunotherapy. Biopsy, however, is an invasive, costly, cardiac catheterization with repetition limited. Since rejection requires lymphocyte activation, an alternative method of assessing rejection dynamics might be ELISA determination of soluble interleukin-2 receptor (sIL-2R) levels since induction of the interleukin-2 ligand and its receptor is required. Reports suggest that sIL-2R levels rise during kidney, liver, and heart-lung allograft rejection and heart recipients have an adverse prognosis if sIL-2R is elevated postoperatively. It is unclear, however, if serial measurements or single determinations are sufficient or if change from a baseline assessment is important. The purpose of this study was to determine if an isolated sIL-2R level after heart transplant predicted endomyocardial biopsy score at that moment. To do this, we prospectively followed 60 consecutive patients after orthotopic heart transplant and correlated 479 endomyocardial biopsy scores (McAllister scale 0-10) with matched sIL-2R levels. Regression analysis demonstrated minimal relationship between sIL-2R level and biopsy score (r =.11, r2 =.01, P=.009). When the maximum sIL-2R level for each individual patient was compared with the matched biopsy score, regression analysis revealed r=.04, r2=.001, P=.8. Likewise, when all biopsy scores and sIL-2R levels for each patient were meaned, analysis showed r=.14, r2=.02, P=.26. Thus in heart transplant patients, there is poor correlation between an isolated biopsy score and matched sIL-2R level. However, when mean +/- SEM sIL-2R was determined for severe rejection (score 7-10) and compared with sIL-2R for all other grades, it was significantly higher (1600 +/- 257 vs. 423 +/- 57 U/ml; P=.012). Still, the sensitivity, specificity, and predictive value of an sIL-2R level above 1000 U/ml predicting severe rejection was only 52%, 63%, and 8%. It would be difficult, therefore, to use a single sIL-2R determination after heart transplant to foretell the endomyocadial biopsy score. Serial measurements or quantification of a change in sIL-2R level from baseline might be more predictive of rejection severity.

Serial changes in nuclear magnetic resonance relaxation times after myocardial infarction in the rabbit: relationship to water content, severity of ischemia, and histopathology over a six-month period.

To determine the serial changes in T1 and T2 relaxation times of myocardial infarction, and their relationship to observed changes in water content, regional myocardial blood flow, and histopathology, rabbits were studied at 14 time intervals ranging from 30 min to 6 months after coronary artery ligation. All values were compared to a control group. Hearts were subdivided into infarct and normal segments for measurement of blood flow, water content, and relaxation times (20-MHz spectrometer); other hearts were excised intact for histopathologic studies. T1 relaxation time of infarcted myocardium did not change significantly compared to control over the 6-month study period. T2 relaxation time increased (P less than 0.0001) at 3 days and returned to baseline by 2 months. Consonant with the increase in T2 of infarct, nuclear magnetic resonance (NMR) images at 3 days demonstrated an increase in signal intensity of infarct compared to surrounding normal myocardium. At 6 months, marked myocardial thinning was observed without changes in signal intensity. Changes in T2 of infarcted myocardium were not related to changes in water content or severity of ischemia, but correlated best with infarct healing and scar formation as detected on histopathology. In conclusion, the findings of this study indicate that T2 relaxation time of the infarcted myocardium increases markedly at 3 days and remains elevated for 2 months. These changes correlate best with the onset and progression of infarct healing. These data demonstrate the potential of T2-weighted NMR imaging for assessing healing patterns following ischemic myocardial injury.

Xanthomatous bronchiolitis obliterans with cholesterol pneumonia.

Reported is an instance of bronchiolitis obliterans due to the accumulation of lipid-laden cells within bronchiolar walls and lumina. The bronchiolar lining had extensive squamous and goblet cell metaplasia with focal ulceration. Scattered foci of cholesterol pneumonia, composed of acicular crystals with an associated foamy lipid material and type II alveolar epithelial cell hyperplasia, were present. The patient had no history related to this unusual pulmonary disease, although preoperatively her serum cholesterol level was mildly elevated. She was treated with pulmonary and cardiac allotransplantation.

Seeding of arteriovenous prostheses with homologous endothelium. A preliminary report.

Endothelial cell seeding of expanded polytetrafluoroethylene (e-PTFE) arteriovenous prostheses was performed to compare seeding with homologous vs. autologous cells and to study the effect of homologous seeding with a larger vs. a smaller number of cells. Sixteen dogs were randomly assigned to four equal groups: I, control; II, light homologous seeded; III, heavy homologous seeded; and IV, autologous seeded. Bilateral femoral arteriovenous loop grafts were inserted in all. Efficiency of seeding was assessed by cell counts of instilled vs. retained cells. All grafts remained patent and were harvested approximately 8 weeks after implantation. Samples were evaluated grossly by scanning electron microscopy and light microscopy. There was a direct correlation between number of cells instilled and number retained for each graft; group III received and retained the largest number (p less than 0.001 and p less than 0.05, respectively). The amount of thrombus deposition on the lumen of all grafts was grossly the same. Endothelium was demonstrated in samples obtained from the midgraft of groups III and IV; in contrast no endothelium was seen in groups I and II. The percentage of endothelialized surface was not determined. No immunologic cellular reaction was detected in any of the samples. We conclude that in the animal laboratory it is possible to seed e-PTFE arteriovenous prostheses successfully with homologous cells and to improve the efficiency of seeding by implanting a larger number of cells obtained from an endothelial cell bank. The potential applications of this technique to the clinical field are discussed herein.

Hemodynamic and morphologic features of arteriovenous angioaccess loop grafts.

Bilateral femoral A-VLG (5 acute, 5 chronic) were implanted in 10 dogs (e-PTFE, 6 mm ID, 25 cm length). Acute studies included measurements of cardiac output (CO) and systemic vascular resistance (SVR). Blood pressure and pressure waveforms in the graft were obtained by retrograde catheterization and pull-back readings. Chronic dogs were sacrificed 8 wks postimplant; samples were obtained following a standardized protocol and studied by light microscopy (LM) and scanning electron microscopy (SEM). Hemodynamic data show a rise in CO, a decline in SVR and a high flow through each graft. Pull-back readings show a gradual drop in pressure and loss of pulsatility from the arterial to the venous side of the graft. LM studies show IH primarily in the proximal vein. SEM showed limited pannus ingrowth endothelium close to the anastomoses and otherwise a thrombus layer throughout the lumen. A-VLG are associated with high flow, pressure drop and loss of pulsatility. Proximal vein IH is a reproducible lesion. We conclude there is severe hemodynamic stress from disturbed flow and high flow velocity and it plays a critical role in the development of venous intimal hyperplasia in AV loop grafts.

Aortic arch aneurysm. A sentinel of extensive aortic disease requiring subtotal and total aortic replacement.

Aneurysm of the thoracic aorta is a serious form of disease because it may be extensive or associated with a more distant aneurysm. This manifestation occurs in about one-third of the cases. The actuarial 5-year survival of nontreated patients is only 13% with many patients dying from aortic rupture. The 5-year survival of our patients with aneurysm of the descending thoracic aorta treated by graft replacement is 58% with the two most common causes of late death being myocardial infarction and rupture of another aortic aneurysm. Effective treatment consists of initial total aortic examination, continued follow-up examination, and total replacement of disease. Aneurysmal disease that involves the entire aortic arch is especially prone to extensive involvement because it is due to diffuse aortic dissection or medial degenerative disease in most cases. The latter is most common, being present in 63 of our 81 patients requiring total arch replacement. The disease was extensive in all cases with degenerative medial disease and required extensive graft replacement. In fact, the entire thoracic aorta was involved in ten, the entire thoracic aorta and substantial segments of abdominal aorta in ten, and the entire aorta in 12 patients. Most of these patients were women (84%) over 65 years of age (63%) or older, ten (37%) were over 70 years. Associated pulmonary disease was frequent, aortic valvular insufficiency was present in 12 (38%), and symptoms were present in most. Treatment consisted of removing the disease when possible in stages, the arch in one and the remaining disease in another with the sequence and interval depending upon indications and condition of the patient. A total of 53 operations were performed in these 32 patients, the arch replaced in 29, the descending thoracic aorta in eight, and the thoracoabdominal aortic segment in 16 patients. All of the disease was replaced in 21, including the entire aorta in eight and incompletely replaced in 11 patients. Sixteen (76%) of the former are still alive 4 months to 6 1/3 years. Six (55%) of those in whom operation was limited to replacement of the symptomatic aortic segment because of limited risk are still alive. Of the ten deaths occurring during the study period, four (40%) and perhaps five (50%) were due to natural rupture of unresected disease which indicates its progressive nature and suggests the need for aggressive surgical treatment.

Platelet-mediated thrombosis in stenosed canine coronary arteries: inhibition by nicergoline, a platelet-active alpha-adrenergic antagonist.

The effects of nicergoline, a new agent that blocks alpha-adrenergic receptors and inhibits platelet phospholipase, were evaluated in a canine model of platelet-mediated coronary thrombosis. In 48 open chest dogs, the circumflex coronary artery was stenosed by plicating the artery wall with a suture. Thirty-four of the 48 dogs exhibited cyclic reductions in flow in the stenotic vessel, followed by a sudden return to control levels. The reductions in flow were unabated in all but two dogs after heparin administration (1,000 U/kg per h), unaffected by large doses of nitroglycerin and nifedipine and associated with platelet aggregates in the stenotic segment (demonstrated by histologic and electron microscopic examination). These observations support the conclusion that the flow reductions were caused by platelet aggregation rather than by fibrin deposition or vasospasm. Twenty dogs were monitored for 1 hour after heparin administration and then assigned to a control (n = 7) or nicergoline-treated (n = 13; 1 mg/kg intravenously) group. In control dogs, cyclic reductions in flow continued unchanged for another hour, whereas in the treated group they were markedly decreased in 1 dog and completely abolished in the other 12 dogs. Aspirin (30 mg/kg intravenously) suppressed flow reductions in all control dogs, confirming the primary role of platelet aggregation in the phenomenon. This study provides a modified model of platelet-mediated thrombosis in stenosed coronary arteries. Furthermore, the results indicate that nicergoline can effectively interfere with platelet function in vivo. The potent antithrombotic activity exhibited by nicergoline might enhance the therapeutic usefulness of this vasodilator.

Tophaceous mitral value: Report of a case.

A tophus was identified in a surgically resected, prolapsed mitral value in a patient with tophaceous gout. It had the characteristic histologic pattern and contained birefringent, dichroic crystals consistent with uric acid. This represented an incidental finding.

Myocardial abscesses.

A review of postmortem materials from two teaching hospitals, accumulated in a 14-year period (1962--1975), disclosed 63 patients with myocardial abscesses among 12,359 autopsies, an incidence of 0.5%. All 63 patients had multi-focal myocardial abscesses; the lesions were grossly discernible in six patients. Coexisting infective endocarditis was present in approximately 20% (12) of the 63 patients with myocardial abscesses. Candida and Staphylococcus aureus were most common organisms responsible for the abscesses. Candida was identified in 23 patients (37%) by histologic examination of the heart sections, and 11 of these also had antemortem blood cultures positive for Candida. Staphylococcus aureus was cultured from the antemortem blood of 22 patients, two of whom also showed candidal organisms in the heart at necropsy. Eighty-one per cent (51) of 63 patients had abscesses in one or more extracardiac organs. It appeared that most of the myocardial abscesses had resulted from disseminated sepsis. Surgical conditions, malignancy and alcoholic hepatic disease were the most frequent primary conditions in patients with myocardial abscesses.

Ultrastructure of human bronchiolo-alveolar cell carcinoma.

Ultrastructural features were correlated with a series of special staining reactions in eight cases of bronchiolo-alveolar carcinoma. Ultrastructural, all tumors were similarly composed of large cells with abundant cytoplasm and small nuclei in close contact with each other. Straight membranes or complex interdigitations occurred within adjacent tumor cells, attached to each other by scattered desmosomes. Microvilli or cilia abutted from free surfaces of the cells, and were noted in different stages of evolution. Numerous organelles were seen in the cytoplasm, including prominent mitochondria and single or coalescent secretory vacuoles with granular matrix resembling mucin. Other cytosomes less commonly found were irregular, partially lamellated inclusions and dark, homogeneous structures without limiting membranes. The stroma of the tumors was rich in elastin and collagen. Both the number of secretory vacuoles in the cytoplasm of tumor cells and the amount of connective tissue fibrils in the stroma of the tumors correlated well with the findings in the series of special staining reactions. No definite ultrastructural feature was present to identify the tumors as orginating from Type II alveolar epithelial cells, but the possibility exists that they arose in the bronchiole, from undifferentiated basal cells or mucinous cells per se. Our impression in these eight cases studied is consistent with the view that bronchiolo-alveolar carcinomas are indistinguishable at the ultrastructural level from other bronchogenic adenocarcinomas.