Serial changes during acute cardiac allograft rejection: quantitative ultrasound tissue analysis versus myocardial histologic findings.

OBJECTIVES: The aim of this study was to assess 1) whether quantitative ultrasound tissue analysis by serial measurements of myocardial echo amplitudes can detect and monitor the onset and degree of acute cardiac rejection, as well as its resolution of acute rejection during treatment, and 2) whether changes in myocardial echo amplitudes are modified by repeat additional rejection episodes. BACKGROUND: Previous experimental studies, all involving heterotopic heart transplantation, have consistently shown reproducible alterations in myocardial echo amplitude during acute rejection episodes untreated by immunosuppressive agents. METHODS: Two-dimensional echocardiographic long-axis views were obtained daily under strict standardization in 12 dogs after heterotopic cervical heart transplantation (mean survival time 16.1 days) and digitized into a 256 x 256 x 8 matrix. Myocardial echo amplitudes were analyzed by gray level histogram statistics in regions of interest (45 x 12 pixels) within the proximal septum and posterior wall and correlated with the results of daily transmural myocardial biopsies. Maintenance immunosuppressive therapy consisted of cyclosporine, azathioprine and steroids. Additive steroids were given during acute cardiac rejection. RESULTS: All dogs experienced at least one moderate or severe episode of acute cardiac rejection. Successful resolution and repeat acute rejection were observed in three dogs. On 65 days, the left ventricular biopsy specimens showed no evidence of acute rejection. Mild acute rejection was present on 36, moderate on 29 and severe rejection on 40 days. End-diastolic mean (+/- SD) gray level increased progressively from 100.7 +/- 20.4 for no acute cardiac rejection to 113.8 +/- 23.1 for mild rejection (p = NS vs. no rejection) to 126.0 +/- 16.1 for moderate rejection (p < 0.01) and to 136.3 +/- 12.6 for severe rejection (p < 0.01). In each individual dog, a correlation between daily measurements of mean gray levels and histologic cardiac rejection grades was found (rmean = 0.80 +/- 0.14 [range 0.57 to 0.97], n = 12). In three dogs with transient complete histologic resolution of acute cardiac rejection, mean gray level did not return to values before rejection (108.0 +/- 15.4 vs. 87.2 +/- 8.4). The subsequent second episode of rejection was characterized by higher gray level values than those associated with the first rejection episode (141.3 +/- 14.4 vs. 124.3 +/- 20.9). CONCLUSIONS: Acute cardiac rejection is associated with a progressive increase in mean gray level. Changes in myocardial echo amplitudes in individuals may thus prove a useful tool for the noninvasive detection and monitoring of acute rejection. Increased mean gray level values after resolution of rejection may indicate persistent structural tissue abnormalities after rejection and demonstrate the need to define new baseline values after histologic resolution of an acute rejection episode.

Inotropic response to DPI 201-106 in the failing human heart.

1. The present study was designed to characterize the positive inotropic response to DPI 201-106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery. 2. The positive inotropic responses to isoprenaline and milrinone and cardiac beta-adrenoceptor density were also determined. 3. DPI 201-106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure, in a concentration-dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of beta-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2+ was similar in tissues from both groups of patients. 4. The positive inotropic effect of DPI 201-106 was not antagonized by adenosine or carbachol, whereas both compounds reduced the positive inotropic effect of isoprenaline. 5. DPI 201-106 did not increase the Ca2+ -sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2+ -sensitivity was obtained with trifluoperazine. 6. It is concluded that DPI 201-106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II-III and indicates that its mechanism of action is cyclic AMP-independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201-106 in the failing human heart.

Heart transplantation: hemodynamics over a five-year period.

Long-term hemodynamic evaluation after heart transplantation has rarely been reported. Fifty-seven heart transplant recipients (mean age, 42.1 years: range, 22 to 56 years) were investigated with annual cardiac catheterization. Mean follow-up was 2.2 years (range, 1 to 7 years). Years 1 through 5 were evaluated statistically. Hemodynamic variables did not change significantly during the 5-year period. Mean aortic pressure (105 +/- 16 to 115 +/- 17 mm Hg, minimum and maximum annual average value +/- SD of the 5-year period) and LVEDP (13 +/- 6 to 15 +/- 7 mm Hg) were slightly elevated. Borderline values were found for mean pulmonary artery pressure (18 +/- 4 to 21 +/- 5 mm Hg), systemic vascular resistance (1407 +/- 227 to 1487 +/- 409 dynes.sec.cm-5), pulmonary vascular resistance (86 +/- 42 to 118 +/- 66 dynes.sec.cm-5), and heart rate (85 +/- 17 to 95 +/- 14 beats/min). Mean right atrial pressure (5 +/- 2 to 8 +/- 4 mm Hg), cardiac index (2.8 +/- 0.6 to 3.5 +/- 1.1 L/min/m2), end-diastolic volume (111 +/- 37 to 137 +/- 35 ml) and ejection fraction (69% +/- 10% to 75% +/- 9%) were in the normal range. Pressure-volume loops for each year excluded the development of either restrictive or dilated cardiomyopathy with time. Contractility, as measured by imposing afterload stress, was normal in 12 of 14 representative patients. Prevalence of coronary abnormalities (circumscript coronary stenoses, diffuse vessel obliteration or dilated angiopathy) increased from 14.9% in the first to 66.7% in the fifth year. Of the patients, 93% received antihypertensive drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive methods of rejection diagnosis after heart transplantation.

For clinical follow-up and prognosis in heart transplant patients, it is important to understand accurately the presence and extent of cardiac allograft rejection. Since the introduction of endomyocardial biopsy, almost 40 different noninvasive diagnostic procedures for the recognition of myocardial rejection have been proposed. However, endomyocardial biopsy is invasive and not suitable for frequent monitoring. If the pattern of rejection shows a focal distribution, false-negative results can be expected. Discrepancies between biopsy findings and allograft function are obviously possible. State-of-the-art information will be given on the most reliable noninvasive methods for rejection diagnosis, which can be differentiated from electrophysiology (fast-Fourier-transformed electrocardiography and intramyocardial electrocardiography), echocardiography, immunologic methods (cytoimmunologic monitoring, transferrin receptors, and interleukin-2 receptors), various biochemical markers (neopterines, prolactin, urinary polyamines, and beta 2-microglobulins), radioisotopic techniques (antimyosin-monoclonal antibodies, thallium, technetium, and gallium scintigraphy and indium-labeled cells), as well as magnetic resonance imaging. Thus modified and patient-adapted antirejection therapy can be provided if the decision for or against antirejection therapy is not based on biopsy findings alone but rather is confirmed along with histologic, electrophysiologic, biochemical, immunologic, and functional parameters.

HIV infection after heart transplantation: a case report.

A 38-year-old man received a heart transplant because of dilated cardiomyopathy in 1984, at a time when no HIV screening test was available. Two and a half years after heart transplantation he was found to be HIV seropositive, but as of March 1990 he was still without symptoms of clinical AIDS. Neither the patient nor the organ donor belonged to any of the known risk groups, and a retrospective analysis revealed that presumably cryoprecipitates of clotting factors were the vectors of transmission.

Carcinoma of the breast and heart transplantation: a case report.

A 35-year-old woman underwent heart transplantation in 1986 because of dilated cardiomyopathy that developed after mitral valve replacements in 1971, 1975, and 1982. Additionally, a carcinoma of the left breast was diagnosed in 1984, leading to mastectomy, and in 1985 a local recurrent tumor had to be resected. In 1988 her gallbladder was removed after repeated episodes of biliary colic. Despite her eventful history, the patient is in good physical condition with normal heart performance and no signs of progression of the breast cancer under triple-drug immunosuppression.

Bridging to transplant: allogeneic heart transplantation after xenografting.

Xenografting seems to be a solution to use to bridge time intervals when desperately needed allograft cannot be obtained. A following allograft was never ventured. Nine dogs (weight, 20 to 25 kg; age, 2 years) underwent right cervical heart transplantation. Donors were silver foxes (3 to 4 kg). The animals were treated by triple-drug therapy consisting of cyclosporine, methylprednisolone, and azathioprine in clinical dosages. For control, six recipients received only allogeneic hearts and the identical immunosuppression. After rejection of the xenograft, a second allogeneic heart was anastomosed subsequently to the same right cervical vessels. Routine histologic and immunohistologic examinations were performed. Thromboxane B2 and 6-keto-prostaglandin F1 alpha were determined daily in peripheral blood. After final rejection the sensitization of the recipient was controlled by hemagglutination test. Survival time of the xenografts was 9.6 +/- 1.2 days; the subsequent allogeneic hearts under the same therapy beat for 4.5 +/- 5.0 days. The average survival time of control hearts was 18 +/- 1.9 days. The five hyperacute second allografts showed signs of humoral rejection by absence of inflammation. The release of thromboxane B2 was different in hyperacute, accelerated, or cellular rejection. In contrast to the long-functioning grafts, thromboxane B2 persisted during hyperacute rejection at a high level. However, 6-keto-prostaglandin F1 alpha showed no significant differences between longtime survivors and hyperacute rejecting hearts. After xenogeneic transplantation, all recipients showed hemagglutinating titers between 1:4 and 1:16. Allogeneic grafts have a different kinetics of rejection after xenogeneic heart transplantation compared with control hearts. Thromboxane B2 seems to be an important mediator in hyperacute rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics and dynamics of acute rejection after heterotopic heart transplantation.

Right cervical, heterotopic heart transplantation was performed in 18 mongrel dogs. Study design was based on three different groups (n = 3 x 6). Standard immunosuppression consisted of triple drug therapy in all dogs. Groups II and III received high dose steroids during acute rejection. In group III the native hearts of previous recipients (groups I and II) were used as donors for heterotopic transplantation ("domino" principle). The hearts were examined by daily transmural biventricular biopsies and graded according to Billingham classification. Cytoimmunologic monitoring (n = 345; activation index from peripheral and coronary sinus blood) and fast Fourier transformation ECG (n = 80; area under the curve; surface recordings) served as daily noninvasive methods. Optionally antimyosin scintigraphy (n = 25; single photon emission computed tomography; heart-to-lung ratio) was performed and immunohistologically confirmed by peroxidase staining of the antibody (n = 61). Kinetics of rejection was not uniform in group I (onset after 5.7 days) and biphasic in group II (clear rejection-free interval: 6.8 days). Group III developed a continuously persisting rejection, despite repeated high-dose steroids, with an early onset (3.2 days). The invasive data, consisting of 587 punch biopsies, showed no significant difference between right and left ventricular rejection. Clearly focal rejection appeared in 51.5% of the cases, with subendocardial involvement in 54%. Cytoimmunologic monitoring significantly (p less than 0.001) correlated with daily biopsies in groups I and II. The activation index from coronary sinus blood was two times higher than in peripheral blood. Fast Fourier transform ECG identified the onset of rejection with great accuracy (p less than 0.01). The heart-to-lung ratio of antimyosin scintigraphy corresponded exactly to the various stages of rejection (p less than 0.001). High-dose steroids led to a clear reduction of the ratio in 26% cases. Peroxidase staining showed typical locations of the antibody, depending on the grade of rejection (p less than 0.001). Considering the results of pathology in this transplantation model, relying on endomyocardial biopsy alone in a clinical setting may not seem advisable. Although the results of this study must be confirmed clinically, the simultaneous use of cytoimmunologic monitoring and fast Fourier transformation ECG may prove to be valuable to day-to-day monitoring for acute rejection in the early postoperative course. If both methods indicate the onset of an acute rejection, antimyosin scintigraphy and endomyocardial biopsy, respectively, should be performed to confirm and grade the suspected diagnosis.

Treatment of acute left heart failure using dobutamine and intraaortic counterpulsation. Animal experiments and first clinical experiences.

Ten anesthetized mongrel dogs had a left anterolateral thoracotomy; the left anterior descending coronary artery was then ligated. After 60 min five animals each were treated either with dobutamine (4 microgram/min/kg; for 10 min), or with dobutamine and intraaortic counterpulsation. Combined treatment of cardiogenic shock proved superior. Those five dogs had significantly lower heart rates and dp/dt/p-values. Due to IABP the non-ischemic parts of the left ventricle were better perfused; there was no difference in treatment with regard to ischemic parts. The combined treatment was successfully inaugurated in two patients with cardiogenic shock.

Antimyosin antibodies in cardiac rejection.

The antimyosin antibody is often applied to find out scintigraphically whether myocarditis, myocardial infarction, or (recently) cardiac rejection is present. In the past, a lot of experimental work and clinical studies were done to determine its position, especially for the noninvasive detection of cardiac transplant rejection. Efforts are focused on comparing its diagnostic benefit with that of endomyocardial biopsy. The feasibility of rejection grading and diagnostic reliability are essential parts of this discussion. On the basis of large prospective clinical studies and the information from several experimental animal trials, some important findings can be assumed. Antimyosin scintigraphy after the application of indium 111-labeled antimyosin antibodies is a reliable tool to detect or exclude noninvasively cardiac rejection in adults and children. A distinction among three rejection intensities is possible, as confirmed by immunohistologic examinations. Antimyosin scintigraphy is an important noninvasive method for detecting cardiac rejection, with considerable advantages compared with endomyocardial biopsy.

The mosaic bioprosthesis in the aortic position: hemodynamic performance after 2 years.

BACKGROUND: The Mosaic bioprosthesis is a porcine valve combining several new features to improve hemodynamics and durability: a low profile stent for reduced flow obstruction, zero pressure fixation to maintain the natural collagen crimp, and the amino oleic acid antimineralization treatment to enhance durability. METHODS: Fifty-five Mosaic valves were implanted in the aortic position since February 1994. Data from these patients (group 1) were compared with data from 52 patients who had received a Hancock Modified Orifice II aortic valve (group 2). The mean patient age was 72.0 (+/-5.9) years for group 1 and 76.8 (+/-4.7) years for group 2. Clinical examinations including transthoracic echocardiography were performed 6 and 24 months postoperatively. RESULTS: Mild aortic insufficiencies were found in 2 patients in group 1 and in 3 patients in group 2. There were no embolic or bleeding complications. One Mosaic patient required reoperation due to mitral insufficiency. During the reoperation, a small (approximately 3 mm) thrombus was noted on the outflow side of a Mosaic cusp. The valve was removed and replaced prophylactically. In the 2-year follow-up, hemodynamic measurements showed mean pressure gradients of 12.4 mm Hg for the 21 mm, 11.3 mm Hg for the 23 mm, and 15.4 mm Hg for the 25 mm prostheses in the Hancock group. In the Mosaic group, mean pressure gradients were 14.8 mm Hg for the 21 mm, 10.9 mm Hg for the 23 mm, and 11.5 mm Hg for the 25 mm valves. Differences between pressure gradients and effective orifice areas of the Hancock and the Mosaic valves were not statistically significant. Early mortality in group 1 was 3.6% and in group 2 3.8%. Overall mortality was 12.7% and 13.5%, respectively. CONCLUSIONS: The Mosaic valve has low pressure gradients for all sewing ring diameters. Compared with the Hancock Modified Orifice valve, there was no statistically significant gradient difference but a tendency toward better hemodynamics was noted in the Mosaic group after 2 years.

The Mosaic bioprosthesis in the aortic position at five years.

BACKGROUND AND AIM OF THE STUDY: The study aim was to collect intermediate-term data on the Mosaic bioprosthesis implanted in the aortic position. The device has been in clinical use since February 1994. METHODS: The Mosaic bioprosthesis is a stented porcine aortic valve, which combines a zero pressure differential fixation technique and anti-mineralization treatment with amino oleic acid for improved tissue durability. Between February 1994 and May 1999, 100 patients (49 females, 51 males; mean age at implant 73.4 +/- 7.3 years (range: 31-87 years) underwent aortic valve replacement with the Mosaic prosthesis in our department. Concomitant procedures were performed in 40% of cases. Patients were followed up prospectively at annual intervals; the mean follow up was 2.7 years (total 273.7 patient-years (pt-yr)) and was 100% complete. RESULTS: Total early mortality (within 30 days) was 3.0%; the late mortality rate was 4.4%/pt-yr and included a valve-related mortality rate of 0.7%/pt-yr. The freedom from event rates at five years were 97.3 +/- 1.9% for permanent neurological, 99.0 +/- 1.0% for transient neurological, 95.9 +/- 3.2 for thrombosed prosthesis, 95.6 +/- 2.2% for anti-thromboembolic-related hemorrhage, 100% for primary valvular leak, 96.9 +/- 3.0% for non-structural dysfunction, 100% for endocarditis, and 92.0 +/- 4.9% for explant. The mean systolic gradients were 15.2, 13.1 and 10.1 mmHg for the 21, 23 and 25 mm valve sizes, respectively. CONCLUSION: The clinical and hemodynamic performance of the Mosaic prosthesis was highly satisfactory during the first five years after clinical introduction. Further data will be necessary to confirm long-term durability.

Intraoperative local fibrinolysis as emergency therapy after early coronary artery bypass thrombosis.

OBJECTIVE: Acute graft occlusion early postoperatively after coronary artery bypass grafting (CABG) is a rare but dramatic complication, frequently making resuscitation necessary. Emergency reoperation with reanastomosing of the concerning grafts is the normal procedure to restrict the otherwise unavoidable myocardial damage. Mortality in these cases is up to 50%. Due to this unsatisfying situation, we perform since 1995 in such cases an adjuvant intraoperative intracoronary installed fibrinolysis with recombinant tissue type plasminogen activator (rt-PA; alteplase). METHODS: Between 1/1994 and 8/1998, 4231 patients underwent CABG. In 18 of these patients, emergency reoperation within the first 12 h after CABG due to clinical signs of acute myocardial infarction was necessary. In nine of the patients (group II) additionally intraoperative rt-PA lysis of the involved vessel/s has been performed. When the peripheral anastomosis was reopened and the thrombotic material was removed, we inserted for this a left atrial-catheter (LA-catheter) of 1.2 mm in diameter, into the coronary artery. Then we administered within 3-5 min, up to 100 mg rt-PA (t1/2: 5-9 min.) locally into the vessel. All patients were treated postoperatively with acetylsalicyl acid (ASA) and heparine. RESULTS: In group I (n = 9; seven males, two females) without thrombolytic therapy, 78% of the patients (n = 7) could not have been prevented from large myocardial infarction despite emergency reoperation. Three of these patients died during or early after reintervention. In group II with fibrinolytic therapy (n = 9) three of the patients developed Q-wave myocardial infarction following reoperation. None of the patients died. Creatinkinase maximum were in group I significantly higher than in group II (group I: CK = 1254 units/I, CK-MB = 197 units/l; group II: CK = 502 units/l, CK-MB = 61 units/l; P < 0.01). Postoperative bleeding was considerable elevated in both groups. In group I, 832 ml/24 h (375-1420 ml), in group II 1164 ml/24 h (520-1560 ml). Lysis-associated complications were not observed. CONCLUSIONS: Reoperation of patients with acute thrombotic bypass occlusion after CABG is characterized by a high mortality and morbidity. If additionally fibrinolysis is performed, a sufficient myocardial perfusion seems to be restored. A short half-life in combination with the presented non-systemic application technique of rt-PA seem to prevent unpredictable bleeding. Rt-PA lysis apparently contributes very effectively to the restoration of the macro- and microcirculation within the infarct-related area. Thrombolytic therapy during cardiac surgery with rt-PA is feasible, its application easy and harmful complications are not seen.

Cytoimmunological monitoring after homograft valve replacement.

Examination results concerning immunological reactions in cryopreserved allograft valves during the early postoperative course are so far not available. Cytoimmunological monitoring (CIM) is a well established method to prove rejection reaction after allograft transplantation and was used in this study. Allograft valves were harvested from patients who underwent heart transplantation, and did not require sterilizing in antibiotic solutions. The valves were dissected, conserved and subsequently frozen to -40 degrees C and stored in a freezing system at -196 degrees C. During the first 3 weeks following allograft implantation, CIM was performed daily. An activation index (AI) was determined from the cytological evaluation of the mononuclear concentrate in the peripheral blood. An increase of the AI > 1 was defined as an immunological reaction. As control we performed 98 CIM examinations in eight patients who underwent bioprosthetic valve replacement in the aortic position. Echocardiography (TTE and TEE) was used postoperatively as function control. Out of 16 patients who underwent cryopreserved aortic valve implantation in the aortic position, 336 CIM-results were obtained. An immunological reaction could be detected in all patients, starting on the 5th day on average. Comparing ABO-compatible (group I, n = 9) with ABO-incompatible (group II, n = 7) allografts, the AI-maximum in group I was 1.4 with a mean duration of 1.5 days. Group II was characterized by more intensive immunoreactions (mean = 2.3) which proved to be even more prolonged (mean = 3.3 days, P < 0.05). Nevertheless it became apparent that all observed immunological events were completely reversible without the need for immunosuppressive drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of rejection episodes on the development of coronary artery disease after heart transplantation.

Since 1981, 77 of 116 patients undergoing heart transplantation (HTx) have survived from 6 months to 8 years. Graft control involved a total of 871 endomyocardial biopsies (EMB) and 141 angiographies. Sixteen patients developed coronary artery disease (CAD) manifesting itself 7-60 months after HTx (20.7%). These patients (15 male, 1 female) experienced multiple rejection episodes (RE) and more than half suffered from hypercholesterolaemia and hypertension (n = 10). A mean rejection score (Billingham grading) of greater than 1 (mean = 1.6 +/- 1.1) was calculated in all patients with CAD at the time of angiography or autopsy. By contrast, the mean rejection score ranked less than 1 in patients with undetectable or resolved CAD (means = 0.4 +/- 0.38). This rate is not remarkably different from the rejection score in patients (n = 61) without CAD (mean = 0.2 +/- 0.4). The 8 patients alive (56 +/- 18 months) showed a low number of RE/year (mean = 1.1 +/- 0.4) compared with means = 1 +/- 0.9 in patients without CAD. Eight patients expired within a short period (mean = 31 +/- 26.9) and had a significantly higher number of RE/year (mean = 4.3 +/- 2.9; P less than 0.01 vs. no CAD, CAD alive). Autopsy (n = 6) and angiographic studies (n = 46) demonstrated diffuse, concentric, obliterative arterial disease in all vessels (type A) in 6 patients (RE/yr: mean = +/- 5.5 +/- 2.3), single stenoses in major coronary vessels (type B) in 7 patients and ordinary atherosclerosis (3-vessel disease) comparable to ischaemic heart disease (type C) in 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

CT and MR evaluation of pericardial constriction: a new diagnostic and therapeutic concept.

Eighty patients with pericardial constriction confirmed by catheter data were studied by CT (n = 79), MR imaging (n = 24), or both. To determine the validity of these imaging methods for subsequent treatment, 30 patients' studies were evaluated retrospectively (1980-1984) and 50 (1985-1991) prospectively. Twenty patients from the first group and 30 patients from the second group underwent pericardiectomy. By systematic analysis of CT scans and MR images it was possible to characterize the morphology of pericardial constriction (n = 80); to identify global (n = 27), right-sided (n = 46), left-sided (n = 2), annular (n = 2), effusive (n = 2), and epicardial (n = 1) forms of pericardial constriction; and to define parameters of myocardial atrophy and fibrosis (n = 17). Seventeen patients had myocardial atrophy, fibrosis, or both. Seven of them underwent pericardiectomy; all died of acute myocardial failure (100%). Four (9.3%) of 43 patients without myocardial atrophy or fibrosis died as a consequence of other complications. The method of thoracotomy and periepicardiectomy was continuously adjusted to the preoperative CT and MR findings. Thus, the clinical use of CT and MR imaging in patients with known or suspected pericardial constriction is based on (a) exclusion of patients with restrictive hemodynamics from diagnostic thoracotomy, (b) preoperative determination of the method of thoracotomy and extent of pericardiectomy, and (c) exclusion of patients with myocardial atrophy or fibrosis from pericardiectomy.

Scintigraphy and immunohistology of antimyosin-Fab during graft rejection.

Up to now, the cellular localization pattern of monoclonal antimyosin antibodies (AMA) during acute rejection has not been described. Focused on this the authors made immunohistochemical and scintigraphic studies (AMS) with AMA in an animal transplantation model. Heterotopic cervical heart transplantation was performed in 12 mongrel dogs. Immunosuppression consisted of triple drug therapy. As standard the grafts were examined by daily transmural biopsies and routine histology. Dependent on the daily biopsy results, 0.5 mg of indium 111 ((111)In)-labeled AMA-Fab was injected. Subsequently every 2 hours transmural biopsy cylinders were taken out of the right ventricle and examined in indirect peroxidase staining technique. Forty-eight hours after AMA injection, scintigraphy in single photon emission computed tomography (SPECT) technique (AMS) was carried out and the heart-to-lung ratio (H/L-ratio) was calculated. The immunohistochemical maximum of AMA accumulation could be found 20 to 72 hours after AMA injection. This means that a scintigraphic examination should be done earlier than 20 hours and later than 3 days after injection. Dependent on the grades of bioptic rejection diagnosis a specific morphologic AMA localization was seen (grade I+II intercellular and slightly intracellular detection of AMA, grade III strongly intracellular and in particular perinuclear accumulation of the antibody, p<0.01). Moreover, the authors found a good correlation between scintigraphic H/L-ratio results and the corresponding histologic findings (grade I: H/L = 2.1 +/- 0.2; grade II: H/L = 3.1 +/- 0.2; grade III: H/L = 3.5 +/- 0.3; n = 19; p<0.02). The recently described positive AMS scans even in cases of mild rejection seem to be subject to an intercellular AMA localization. This typical AMA morphology during mild rejection favors the theory of the pore-forming protein allowing the efflux of myosin fragments as effector mechanism of cytotoxic lymphocytes in the early phase of acute rejection. The immunohistochemical AMA examination could explain the present discrepancy between positive AMS results of an intracellular protein in cases of mild or moderate acute rejection when visible cellular damage in the corresponding routine histology is absent.

Acute mesenteric ischemia after open heart surgery.

Acute mesenteric ischemia is a rare but severe complication after open heart surgery. Its incidence (0.2-0.4%) is quite low, but mortality rates are ranging between 70% and 100%. From October 1992 to December 1996, 4,640 patients underwent open heart surgery with cardiopulmonary bypass: 74.6% coronary artery bypass graft (CABG) operations, 23.2% valve replacement including aortic repairs, and 2.2% corrections of congenital heart diseases or tumors of the heart. The overall mortality rate (30 days) was 3.4%, and after CABG, 2.9%. Twelve patients (0.26%), following CABG (one combined with aortic valve replacement, one with mitral reconstruction, and one with carotid disobliteration) developed signs of acute mesenteric ischemia in the early postoperative period (day 1 to 5). In all patients various abdominal symptoms, leukocytosis, acidosis, hyperlactatemia, hyperosmolality, renal failure, and, finally, hemodynamic instability were observed. Eleven patients underwent emergency laparotomy. Mesenteric angiography was done if possible in still stable patients (n=7); it showed severe stenosis or occlusion prior to the operation in each case. Other diagnostic methods were not reliable. In six patients (55%) during the first look, extensive bowel necrosis was found and in five patients an ischemic intestine but no necrosis was detected. Of these, three patients were affected by extensive bowel gangrene at the second look. In the fourth patient a disseminated peripheral ischemia of the entire small intestine was found intraoperatively. After mechanical release and stimulation normal bowel function could be reestablished. One patient underwent percutaneous transluminal angioplasty prior to the laparotomy. Bowel perfusion was still deteriorated but no necrosis was found intraoperatively. These patients were the only survivors in the investigated group; 10 of 12 patients (83.3%) died in the early postoperative period (day 1 to day 6). Predisposing factors for mesenteric ischemia are: arteriosclerotic patients after CABG (100%), age >70 years (91.7%), hyperosmotic dehydration (100%), and cardiac ischemia in 25%. Mesenteric ischemia is a fatal complication with high mortality rates after open heart surgery, especially in older, dehydrated patients with generalized atherosclerotic vessel disease. As the acute mesenteric ischemia usually starts during anesthesia or in the early postoperative period, setting of immediate diagnosis is very difficult. With the occurrence of typical symptoms diagnostic and therapeutic procedures (angiography and laparotomy) must be done very urgently owing to the life-threatening mesenteric process. When mesenteric gangrene already has taken place, the prognosis is very poor, despite extensive resection. Prevention can be exercised by avoiding perioperative hyperosmotic dehydration of patients at high risk.

Valve replacement for chronic mitral insufficiency; long-term follow up using technetium pertechnetate scintigraphy.

Technetium Pertechnetate Scintigraphy was performed in 12 patients (9 men and 3 women, average age 48 +/- 13 years) on an average 19.8 +/- 11 months after valve replacement for chronic mitral insufficiency. Preoperative conventional ventriculography had revealed increased enddiastolic and endsystolic volumes (230.9 +/- 66 resp. 73.5 +/- 26 ml). 59.4 +/- 9% of the stroke volume (157.5 +/- 47 ml) regurgitated into the left atrium. Ejection-fraction (67.7 +/- 6%) was normal in all cases. Postoperative first pass technique was employed using a fast multicrystal camera (Baird Atomic, system 77). Volumes were assessed measuring normalized total count rate (count integral of the left ventricle divided by the maximum count density). 19.8 +/- 11 months after valve replacement enddiastolic and endsystolic volumes revealed normal at rest (121.8 +/- 38 resp. 52.8 +/- 35 ml) and after maximum exercise (122.0 +/- 29 resp. 37.6 +/- 22 ml). Ejection fraction responded physiologically to exercise by rising from 57.7 +/- 12 to 69.7 +/- 10%.

Comparison of acute rejection in sensitized ("domino") and unsensitized donor hearts following heterotopic transplantation.

Right cervical heart transplantation was performed in 18 mongrel dogs. Three experimental groups (6 dogs in each) were set up. Group I and II dogs received unsensitized donor hearts, while Group III dogs received the potentially sensitized native hearts of Group I and II dogs, following final rejection episodes in those animals. We call the transplantation of a native heart out of a previous recipient "domino" transplantation. Immunosuppression consisted of standard triple-drug therapy in all dogs. Groups II and III received, additionally, high-dose steroids during acute rejection episodes. The donor hearts were assessed daily via transmural biventricular biopsy (graded according to Billingham's criteria), and these results were compared with results of daily cytoimmunologic monitoring (n=259 for activation-index), used as a noninvasive method. Supplementally, antimyosin scintigraphy (n=25, heart-to-lung ratio) was employed for rejection diagnosis. The rejection type was determined by calculating T-cell/B-cell ratios with the aid of fluorescein-conjugated monoclonal antibodies. The invasive data consisted of 587 transmyocardial biopsy results, which were used to establish the rejection kinetics. In the domino grafts of Group III, acute rejection had an earlier onset (an average of 3.2 days) and was permanent, despite repeated cortisonepulse therapy. In contrast, acute rejection followed a biphasic course in Group II (average rejection-free interval, 6.8 days) and was non-uniform in Group I (onset after an average of 5.7 days). Cytoimmunologic monitoring corresponded significantly (p < 0.001) with daily histologic findings in Groups I and II, but not with those in Group III (domino grafts). The T-cell/B-cell ratio increased in Groups I and II (to an average of 3.9), as would be expected during acute cellular rejection. In contrast, the T-cell/B-cell ratio decreased in Group III (to an average of 1.1). The heart-to-lung ratio, as determined by antimyosin scintigraphy, accurately revealed the various stages of acute rejection in all groups (p < 0.001). We conclude that the native heart appears to become sensitized during acute rejection episodes of a heterotopically transplanted heart. Cytoimmunologic monitoring and calculation of T-cell/B-cell ratios support this conclusion. In addition, we conclude that cyto-immunologic monitoring and antimyosin scintigraphy are highly specific and sensitive tools for diagnosis of cellular rejection.