Evaluation of an implantable ventricular assist system for humans with chronic refractory heart failure. Device explant protocol.

An explant protocol was developed to investigate the effects of implantation of a left ventricular assist system (LVAS) manufactured by Novacor Division, Baxter Healthcare Corporation on the function of end organs (such as the brain, the kidney, the liver), with particular interest in examining possible complications due to LVAS support. Emphasis was placed on an analysis at the time of device removal and/or autopsy of 1) the local LVAS-host interface; 2) remote cardiovascular and end-organ effects; and 3) the impact of chronic circulatory support on the native heart. To accomplish these objectives, tissue and device samples must be obtained in an appropriate fashion to ensure photographic documentation, microscopic examination, microbiologic and biochemical assays, and compliance with regulatory and manufacturer requirements. This article describes the techniques and protocol that were proposed to ensure the quality of device explant and tissue analysis.

Increased plasma atrial natriuretic peptide levels after heart transplant: relation to ventricular expression and severity of rejection.

To determine whether elevated plasma atrial natriuretic peptide (ANP) levels observed after cardiac transplant are related to ventricular ANP expression and/or the severity of rejection, 59 ambulatory patients with cardiac transplant underwent hemodynamic evaluation, endomyocardial biopsy, and plasma ANP sampling. Forty-two of the 59 patients had right ventricular (RV) biopsy specimens immunohistochemically stained for the presence of ANP. Plasma ANP levels were elevated (p < 0.0001) in transplant patients (172 +/- 12 pg/ml) compared to normal subjects (36 +/- 4 pg/ml). Sixty-four percent of transplant patients showed stainable RV ANP on endomyocardial biopsy. There was no significant difference in plasma ANP levels between patients with or without RV ANP. The degree of RV staining did not correlate with plasma ANP levels, degree of rejection, mean atrial or systemic pressures, or specific immunosuppressive regimen. Plasma ANP levels were higher in patients with moderate or severe rejection (237 +/- 17 pg/ml) compared to patients with mild or no rejection (163 +/- 12 pg/ml; p 0.03), but there was significant overlap of values. These data suggest that ventricular ANP secretion may account for some of the increase in plasma ANP levels in cardiac transplant patients. However, increased plasma ANP levels in some transplant patients who have no RV ANP and the lack of correlation between the amount of stainable RV ANP and plasma ANP levels suggest that other mechanisms are also likely responsible for plasma ANP elevations in this setting.

Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association.

To examine the possible relationship between cardiac and skeletal muscle disease in systemic sclerosis, we reviewed computerized records of 1095 consecutive patients with systemic sclerosis. One hundred eighty three (17%) had skeletal myopathy. Thirty-nine (21%) of the 183 fulfilled criteria for myocardial disease, compared with 90 (10%) of the 912 without myopathy (p < 0.0001.) Nineteen (10%) of the 183 had clinical CHF compared with 38 (4%) of the remainder (p < 0.002.) Fifteen (8%) of the patients with myopathy died of cardiac causes compared with 27 (3%) of the 912 without myopathy (p < 0.002.) Twenty-five patients with coexistent myopathy and myocardial disease, in the absence of other identifiable contributing causes, were identified. This group was characterized by a high incidence of cardiac conduction abnormalities (60%) and by the severity of the myocardial dysfunction and arrhythmias, both atrial and ventricular that they experienced. Eighteen of these 25 patients died; 12 (67%) died suddenly. Eight of the 18 (44%) had intractable CHF, which directly contributed to their deaths. Myocardial fibrosis was the predominant histologic abnormality at autopsy. However, autopsy of a patient who died in the context of acute "myocarditis" showed severe myocytolysis with contraction band necrosis but without inflammation or fibrosis; this is consistent with possible ischemically mediated injury. We conclude that skeletal and cardiac muscle disease in systemic sclerosis are associated. Patients with myopathy are at increased risk for CHF, sustained symptomatic arrhythmias, and cardiac death, particularly sudden death.

Presence of CD4, CD8 double-negative and T-cell receptor-gamma-delta-positive T cells in lymphocyte cultures propagated from coronary arteries from heart transplant patients with graft coronary disease.

Previous studies have shown that the interleukin-2-induced propagation of lymphocytes from endomyocardial biopsy specimens, an indicator of cellular rejection, is associated with the development of graft coronary disease in heart transplant patients. To further investigate the concept of cell-mediated immune responses in graft coronary disease, we have applied the methodologies of interleukin-2-induced propagation of lymphocytes from arterial tissues. In a group of 23 patients, which included 6 heart, 6 kidney, and 11 liver transplant recipients, we observed that arterial lymphocyte growth was significantly associated with obliterative vasculopathy (p less than 0.03). T-cell phenotyping analysis of coronary artery-derived lymphocyte cultures from three heart transplant patients with graft coronary disease showed significant numbers of CD4, CD8 double-negative T cells and T-cell receptor-gamma delta cells, especially when the cultures were established with relatively high doses of 400 U/ml of interleukin-2. These data suggest that the subset of CD4-CD8-, T cell receptor-gamma delta+ T cells may play a role in the pathogenesis and progression of graft coronary disease.

Cardiac events after heart transplantation: incidence and predictive value of coronary arteriography.

Cardiac events from graft arteriopathy, including myocardial infarction, heart failure resulting from previous myocardial infarction, and sudden death, may limit long-term survival after heart transplantation. To determine the incidence of cardiac events and the use of coronary arteriography in predicting these events, the long-term results (mean follow-up, 3.5 years; standard deviation +/- 2.0) of heart transplantation in 427 patients were reviewed. Cardiac events included 19 cases of myocardial infarction, 13 cases of sudden death, and 10 cases of congestive heart failure. All these events occurred after the first year except for three cases of sudden death and one case of myocardial infarction. Cumulative incidence of cardiac events per patient year was 0.9% within the first year, increasing to 1.9% by 5 years. Cardiac events accounted for 3.8% of the deaths by the end of the first year, rising to 18% of total mortality by 7 years after heart transplantation. In patients dying after the first year of transplantation, deaths from sequelae of coronary artery disease occurred in 36% (20/55). The relative risk ("odds ratio") of any cardiac event was 3.44 (p less than 0.05) in patients with angiographic evidence of obstructive disease compared with those without evidence of disease, risk of cardiac death 4.6 (p less than 0.05) and risk of sudden death, 2.4 (not significant). Of the 13 patients who died suddenly, five seen at autopsy were found to have had a recent myocardial infarction. Of all patients who died of heart disease, recent myocardial infarction was detected in nine who were seen at autopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of panel-reactive antibody and lymphocytotoxic crossmatch on survival after heart transplantation.

Review of 463 heart transplants was undertaken to examine the relationship between level of panel-reactive antibody (PRA) and a standard donor-specific lymphocytotoxic crossmatch (LXM) on the incidence of death from hyperacute, acute, and chronic rejection. Death from chronic rejection was defined as being caused by graft atherosclerosis. Hyperacute rejection was diagnosed in 18 allografts, and only two recipients had PRA greater than 10% and another two a positive LXM. Five-year actuarial freedom from death caused by all forms of rejection correlated with PRA values as follows: PRA 0% to 10% (415 patients), 85%; PRA 11% to 25% (29 patients), 68%; PRA greater than 25% (19 patients), 57% (p less than 0.005). Additionally, there was a positive linear relationship between PRA and duration of acute rejection episodes in the first 3 months after transplantation. A positive retrospective donor-specific LXM was present in 42 of 401 patients; most of them (32 patients) were low positive (10% to 50% cell death), and none could be correlated with antibody specificity toward donor HLA antigens. Five-year actuarial freedom from death caused by rejection was 83% in those with a negative LXM, 74% in those with low-positive, and 79% in those with high-positive LXM (p = NS). Negative LXM result did not reduce the risk of death caused by rejection in any of the PRA subgroups. While PRA greater than 10% is a risk factor for rejection-related events, a negative LXM in patients with an elevated PRA does not reduce the risk of death resulting from acute or chronic rejection.

Histocompatibility and other risk factors for histological rejection of human cardiac allografts during the first three months following transplantation.

A histological analysis of 2564 endomyocardial biopsies was conducted in 349 cardiac transplant patients to determine potential risk factors for acute cellular rejection during the first three months following transplantation. This analysis dealt with the frequency, time of onset, and duration of cellular rejection. Patients on perioperative RATG experienced significantly less rejection than patients on OKT3 or without antilymphocyte antibody immunoprophylaxis. A trend was noted toward increased rejection in recipients diagnosed originally with chronic myocarditis compared with patients in other disease categories including ischemic heart disease and dilated cardiomyopathy. No significant differences were seen in histological rejection between male and female recipients. On the other hand, patients over 55 years of age were found at lower risk of histological rejection. The results of this analysis have demonstrated quite clearly, but not unexpectedly, that a greater degree of HLA mismatching correlates with increased cellular rejection. This effect was noted not only for the HLA-A,B and DR antigens, but also HLA-DQ and HLA-DRw52/53 antigens. In multivariate analysis, the highest level of statistical significance was obtained for the combined HLA-A,B,DR and DQ group. Sensitized patients with panel-reactive lymphocytotoxic antibodies of greater than 10% experienced more histological rejection than nonsensitized patients. On the other hand, a positive lymphocytotoxic crossmatch did not appear to influence cellular rejection of cardiac allografts. Also, no differences were seen in histological rejection between ABO-identical and compatible heart transplants. These findings further support the concept that donor HLA compatibility and pretransplant sensitization represent significant risk factors for cellular rejection in cardiac transplantation.

Changes in left ventricular systolic function that accompany rejection of the transplanted heart: a serial radionuclide assessment of fifty-three consecutive cases.

To examine the functional changes that accompany the development of rejection of the orthotopically transplanted heart, radionuclide ventriculograms, right heart catheterizations, and endomyocardial biopsies were performed at weekly intervals during the posttransplantation hospitalization of 53 consecutive transplant recipients. Left ventricular ejection fraction decreased in those (n = 10) who had sequential biopsies that changed from no rejection to moderate rejection (63% +/- 7% to 57% +/- 7% respectively, p = 0.007). There was an associated decrease in the peak ejection rate (4.4 +/- 1.0 to 3.9 +/- 0.8 end-diastolic volumes per second, p = 0.008) and an increase in the time to peak ejection rate (137 +/- 27 msec to 153 +/- 20 msec, p = 0.004) that accompanied the development of rejection. There was a similar decrease in left ventricular ejection fraction in those (n = 9) who had sequential biopsies that changed from no rejection to mild rejection (63% +/- 6% to 59% +/- 8%, p = 0.009). Only two of 19 patients whose biopsies changed from no rejection to either mild or moderate rejection did not have an associated decrease in ejection fraction. In patients who had a biopsy that showed definite rejection, which was then followed by histologic resolution after treatment (n = 11), left ventricular ejection fraction increased from 56% +/- 8% to 61% +/- 8%, p = 0.03. There were no significant changes in any of the parameters of diastolic function or in any of the hemodynamic parameters measured, which were associated with either the development or resolution of rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Propagation of infiltrating lymphocytes and graft coronary disease in cardiac transplant recipients.

The pattern of lymphocyte growth from endomyocardial biopsies in 55 heart transplant recipients was shown to be correlated with the subsequent development of graft coronary disease. Persistent lymphocyte growth was observed in 39 patients, and 15 of these growers (or 41%) developed graft coronary disease. In contrast, only 1 of 15 patients (or 6%) with nongrower biopsies showed subsequent graft coronary disease. Thus, biopsy growth was associated with a higher incidence of subsequent GCD (p = 0.02). A comparison between the group of 15 growers with subsequent graft coronary disease and the 24 growers without subsequent graft coronary disease did not show any differences with respect to patient age, presence of coronary artery disease in the native heart, biopsy histology, donor alloreactivity of biopsy grown lymphocytes, and immunosuppressive drug regimen. On the other hand, the number of treated rejection episodes was significantly lower in the grower group with subsequent graft coronary disease (p = 0.04). These data support the concept that graft coronary disease may involve rejection and that more immunosuppression may lower its incidence. This concept is strengthened by findings showing that alloreactive T cells can be propagated from coronary arteries of cardiac allografts with graft coronary disease.

The scalar electrocardiogram of the orthotopic heart transplant recipient.

The 12-lead scalar electrocardiograms of heart transplant recipients were examined prior to hospital discharge (N = 191), and at 1 (N = 162), 2 (N = 97), and 3 years (N = 46) after transplantation. At the pre-discharge point, 46% had right bundle branch block (RBBB) QRS morphology (QRS duration greater than or equal to 120 msec: 20 patients, less than 120 msec: 67 patients). This finding tended to be manifest on the first day following transplantation; its prevalence remained constant over 3 years of follow up. Rejection, ischemic time, preoperative pulmonary vascular resistance, and donor age were not associated with the presence of RBBB morphology. A subgroup of 46 consecutive patients (21 with RBBB morphology) underwent right-sided heart catheterization and radionuclide angiography prior to discharge. RBBB morphology was not associated with any hemodynamic abnormality at catheterization. Based on the radionuclide study, RBBB morphology was associated with a greater left anterior oblique angle required for the best visual separation of the ventricles during acquisition of the study (angle of interventricular septal plane to sagittal plane: 69 +/- 11 versus 59 +/- 9 degrees; p = 0.019), and with the presence of right ventricular dysfunction (13 of 21 versus 6 of 25 patients; p = 0.009). The high prevalence of RBBB morphology in heart transplant recipients appears to be related to posterior rotation of the long axis of the heart in the transverse plane, probably resulting from the surgical technique, and to right ventricular dysfunction.

Lymphocyte growth from cardiac allograft biopsy specimens with no or minimal cellular infiltrates: association with subsequent rejection episode.

Histologic features of endomyocardial biopsy specimens are essential in the monitoring of heart transplant patients. Significant cellular infiltrates accompanied by myocyte damage are diagnostic of transplant rejection, whereas no or minimal infiltrates (grades 0 and 1) suggest absence of rejection. Biopsy specimens were cultured on the basis of the principle that the allograft is infiltrated by activated lymphocytes, which can be expanded in the presence of interleukin-2, a lymphokine that induces proliferation of activated T cells. Although frequency of cell cultures was proportional to histologic rejection grade, 39% of biopsy specimens with grades 0 and 1 cultured during the first month posttransplantation yielded lymphocyte growth. Cell growth was observed in 28% of biopsy specimens with grades 0 and 1 obtained during the first 10 days posttransplantation. In this group (growers) 73% showed clinical rejection after 9.8 +/- 5.0 days. In contrast, 55% of nongrowers were treated for rejection after 19.1 +/- 13.8 days. For biopsy specimens obtained 11 to 20 days posttransplantation, subsequent rejection episodes were observed in 61% of growers, but in only 33% of nongrowers. For biopsy specimens obtained 21 to 30 days posttransplantation the incidence of clinical rejection was 60% versus 14%, respectively. A sequential analysis of biopsy specimens obtained during the first month posttransplantation enabled us to identify 16 persistent nongrowers; only 6 (37%) experienced clinical rejection during the first 3 months posttransplantation. Most of the persistent nongrowers were found among patients on the immunoprophylactic rabbit antithymocyte globulin protocol. These data suggest that in vitro cultures of biopsy specimens with no detectable or minimal cellular infiltration may be useful in identifying patients at risk of developing rejection.

Coronary artery fistula in the heart transplant patient. A potential complication of endomyocardial biopsy.

All follow-up annual cardiac catheterizations performed on recipients of orthotopic heart transplant were reviewed, and 14 patients with coronary artery fistula were identified. The prevalence (8.0%, 14 of 176 patients) was strikingly higher than that for patients without transplant (0.2%) who underwent routine cardiac catheterization. These 14 patients had 21 coronary artery fistulas: single in nine and multiple in five patients. Fifty-two percent arose from the right, 43% from the left anterior descending, and 5% from the circumflex coronary artery. All drained into the right ventricle. Four patients underwent oximetric evaluation, and left-to-right shunting was not detectable. No patient had symptoms attributable to the fistula. Hemodynamic measurements were similar to those of a control group of 28 age- and sex-matched recipients of heart transplant without coronary artery fistula; however, the cardiac index (p = 0.02) and pulmonary artery oxygen saturation (p = 0.03) were significantly higher, and the arteriovenous oxygen difference (p = 0.01) was significantly lower in the group with coronary artery fistula. The histologic features of rejection, large arterioles, or epicardial fat on any biopsy specimen predating coronary artery fistula diagnosis were not associated with the development of the fistula when the two groups were compared. Nine patients (11 coronary artery fistulas) had follow-up studies performed, and three fistulas were larger, three were unchanged, two were smaller, and three had resolved. No complications of coronary artery fistula developed during a mean follow-up of 28 months (range, 12-42 months).(ABSTRACT TRUNCATED AT 250 WORDS)