Induction of major histocompatibility complex antigens within the myocardium of patients with active myocarditis: a nonhistologic marker of myocarditis.

The histologic diagnosis of active myocarditis is frequently difficult to establish. A nonhistologic marker of immune activation would be clinically useful in identifying cases of immune-mediated myocarditis. A viral etiology with subsequent autoimmunity to cardiac antigens has been implicated in human myocarditis. Because autoimmunity and viral disease are commonly associated with increased expression of major histocompatibility complex (MHC) antigens on targeted tissue, we examined endomyocardial biopsy samples from patients with active myocarditis for abnormal levels of MHC antigen expression. Thirteen patients with active myocarditis and eight control patients with other well-defined cardiac diagnoses (coronary disease, amyloidosis or neoplasm) were studied. A sensitive radioimmunoassay was developed that utilized monoclonal antibodies to human MHC class I and class II antigens in order to quantitate the expression of both of these antigens within each biopsy. Abnormal MHC class I and class II antigen expression was present in 11 of 13 myocarditis specimens and 1 of 8 control samples (specificity 88%, sensitivity 84.6%). Active myocarditis samples had approximately a 10-fold increase in MHC class I and class II expression. Immunoperoxidase staining localized abnormal MHC expression primarily within microvascular endothelium and along myocyte surfaces (11 of 13). This study is the first to demonstrate a marked increase in major histocompatibility complex antigen expression within the myocardium of patients with active myocarditis. The identification of abnormal histocompatibility antigen expression within an endomyocardial biopsy may prove a useful adjunct to the histologic diagnosis of myocarditis.

Aortic valve selection in the elderly patient.

To determine the influence of valve selection on valve-related morbidity and mortality and patient survival, comparative long-term performance characteristics of mechanical (N = 68) and bioprosthetic (N = 73) heart valves were analyzed for 141 patients more than 70 years old who underwent isolated aortic valve replacement between 1970 and 1985. Cumulative patient follow-up was 491 patient-years (average, 4.3 years per patient). Hospital mortality was 18% and 19% for patients with mechanical valves and bioprosthetic valves, respectively. Survival at 5 years was 61 +/- 7% (+/- the standard error) and 67 +/- 10% for recipients of mechanical valves and bioprosthetic valves, respectively. Male sex (p = 0.014) and urgency of operation (p = 0.006) were independent risk factors for hospital mortality. Atrial fibrillation increased valve-related mortality (p = 0.01). No patient required reoperation or experienced structural valve failure. While anticoagulant-related hemorrhage was increased in recipients of mechanical valves (9.2 +/- 2.1%/patient-year) compared with recipients of bioprosthetic valves (2.3 +/- 1.1%/patient-year), it did not result in a death or lead to permanent disability. There was no difference in freedom from any valve-related complication at 5 years. However, when all morbid events are considered, recipients of bioprosthetic valves experienced fewer valve-related complications than patients receiving mechanical valves (10.7 +/- 2.3%/patient-year versus 17.6 +/- 2.5%/patient-year, respectively; p less than 0.05). The reduced incidence of anticoagulant-related hemorrhage and the infrequent need for warfarin sodium anticoagulation favor selection of a bioprosthetic heart valve in patients older than 70 years.

Creatine kinase activity and temperature in children after cardiac surgery.

The preoperative and postoperative serum creatine kinase (CK) activity and postoperative temperatures were studied in children undergoing surgery for congenital heart disease. Using multiple linear and logistic regression and analysis of variance, associations were found between postoperative CK activity (>2000 IU/L) and the use of succinylcholine, aortic cross-clamp time (>30 minutes), cardiopulmonary bypass time (>60 minutes), the development of fever (>38.5 degrees C), and complications. Complications were defined as hemodynamic instability, poor peripheral perfusion, metabolic acidosis, and eventual multiple organ failure. Associations were also found between postoperative fever and the development of complications. The results suggest that children who develop serum CK elevations greater than 2000 IU/L and fever greater than 39.5 degrees C during the early postoperative period after cardiac surgery more often develop serious complications.

Comparative analysis of mechanical and bioprosthetic valves after aortic valve replacement.

Comparative long-term performance characteristics of Björk-Shiley mechanical and bioprosthetic valves were analyzed for patients undergoing aortic valve replacement between 1976 and 1981. A total of 419 patients received either a standard Björk-Shiley (n = 266) or bioprosthetic (porcine, n = 126, or pericardial, n = 27) aortic valve. Cumulative patient follow-up was 1,705 patient-years; the average patient follow-up was 4.1 +/- 2.7 years. Survival data were obtained for all but 11 patients (97% complete follow-up) up to 9 years after operation. Survival at 5 years was 81% +/- 4% (+/- standard error) for Björk-Shiley and for bioprosthetic valve recipients. Valve failure in the Björk-Shiley group was predominantly due to valve-related mortality and did not result from structural failure. Patients with bioprosthetic valves experienced valve failure as a result of prosthetic valve endocarditis and intrinsic valve degeneration. Although patients with bioprostheses experienced a lower incidence of valve-related morbidity than Björk-Shiley valve recipients (p less than 0.03), no difference could be demonstrated in the incidence of valve-related mortality or valve failure at 5 years between bioprosthetic and Björk-Shiley valves. Mortality rate from valve failure was higher for Björk-Shiley (86%, 12/14) than bioprosthetic valves (36%, 5/14) (p less than 0.01).

Arteriolar vasculitis on endomyocardial biopsy: a histologic predictor of poor outcome in cyclosporine-treated heart transplant recipients.

The histologic pattern of severe, potentially lethal cardiac rejection in transplant recipients who are treated with cyclosporine may be difficult to distinguish from mild or moderate rejection. The purpose of this study was to determine whether specific histologic abnormalities seen on endomyocardial biopsy could identify which histologic patterns of rejection are associated with progression to graft dysfunction or graft failure. We performed a blinded, retrospective analysis of endomyocardial biopsies from our initial 19 transplant recipients. Group 1 was composed of five patients who developed graft failure or dysfunction after transplantation. Group 2 was composed of the remaining 14 patients with normal hemodynamics and function at heart catheterization 1 year after transplantation. Seventeen histologic parameters were semiquantitatively graded, and comparisons between the two groups were made with the Student's t test. Of the 17 parameters, only arteriolar vasculitis was significantly increased in group 1 versus group 2 biopsies (p = 0.002). Arteriolar vasculitis was identified in four of five patients in group 1 and was unique to group 1. Of 53 group 1 biopsies, eight patients had foci of arteriolar vasculitis and were seen up to 88 days before graft failure. Therefore the finding of arteriolar vasculitis on endomyocardial biopsy may identify high risk rejection episodes in transplant recipients who are treated with cyclosporine.

Histologic predictors of acute cardiac rejection in human endomyocardial biopsies: a multivariate analysis.

To identify specific histologic abnormalities that could predict early cardiac rejection before the development of myocyte necrosis, 167 consecutive endomyocardial biopsy samples from 18 cardiac transplant recipients were retrospectively analyzed and 17 histologic variables were semiquantitatively graded from 0 to 3. Forty-five biopsy samples contained foci of myocyte necrosis and were labeled Rejectors. The two samples immediately preceding Rejector biopsies were labeled Predictors (n = 44). All remaining samples were labeled Others (n = 78). Endocardial and interstitial infiltrates, interstitial mononuclear cells, pyroninophilic mononuclear cells, polymorphonuclear leukocytes and other cells (eosinophils and plasma cells) were significantly increased in graded severity in Rejector biopsy samples as compared with Predictors or Others (p less than 0.001, ANOVA testing). These variables cannot distinguish Predictor biopsy specimens from Others. On the other hand, interstitial edema, perivascular karyorrhexis and perivascular infiltrate with intermyocyte extension are histologic abnormalities that can distinguish Predictor biopsy samples from Others (p less than 0.001, ANOVA testing). Multiple logistic regression analysis indicates that the relative risk of developing myocyte necrosis when a biopsy sample contains interstitial edema is 8.1. With perivascular infiltrate with intermyocyte extension in addition, the relative risk is 41.4. In summary, three histologic abnormalities have been identified that help predict the future development of myocyte necrosis within the next two endomyocardial biopsies. Biopsy specimens with these abnormalities probably represent early cardiac rejection before the development of myocyte necrosis.

Histologic pattern of early heart allograft rejection under cyclosporine treatment.

The histologic abnormalities associated with early heart rejection in cyclosporine-treated patients are not fully characterized. To study these abnormalities, Lewis rats received ACI heart-lung allografts and two weeks of cyclosporine treatment. Then the therapy was discontinued. Controls were sacrificed at that time; other animals were sacrificed three, six, and nine days later. The rejection score was determined solely by the percentage of necrotic myocardium, while 13 other histologic parameters were semi-quantitatively graded to identify parameters of early rejection of the heart. There was no evidence of myocardial necrosis or significant inflammation three days after discontinuation of therapy. At six and nine days, despite the absence of myocyte necrosis, there were significant increases in the grades for interstitial and endocardial inflammation, venous cuffing, perivascular inflammation with intermyocyte extension and arterial vasculitis. Our quantitative and semi-quantitative histologic analysis identified abnormalities of the early stage of heart rejection that may provide clues in defining rejection prior to the development of myocyte necrosis.