Acute Heart Transplant Rejection Research Articles

Detection and prediction of acute heart transplant rejection with the myocardial T2determination provided by a black-blood magnetic resonance imaging sequence

OBJECTIVESThis study aimed to determine whether the myocardial T2relaxation time, determined using a black-blood magnetic resonance imaging (MRI) sequence, could predict acute heart transplant rejection.BACKGROUNDThe use of black-blood MRI sequences allows suppression of the confusing influence of blood signal when myocardial T2is calculated to detect myocardial edema.METHODSA total of 123 investigations, including cardiac MRI and myocardial biopsy, were performed 8 ± 11 months after heart transplantation. Myocardial T2was determined using an original inversion-recovery/spin-echo sequence.RESULTSA higher than normal T2(≥56 ms) allowed an accurate detection of the moderate acute rejections evidenced at baseline biopsy (≥International Society for Heart and Lung Transplantation grade 2): sensitivity, 89% and specificity, 70% (p < 0.0001). T2was increased in grade 2 (n = 11) compared with grade 0 (n = 49, p < 0.05), grade 1A (n = 34, p < 0.05) and grade 1B (n = 21, p < 0.05); T2was further increased in grade 3 (n = 8) compared with grade 2 (p < 0.05). In addition, in patients without rejection equal to or greater than grade 2 at baseline, a T2higher than normal (≥56 ms) was correlated with the subsequent occurrence of equal or greater than grade 2 rejection within the next three months: sensitivity 63% (12/19) and specificity 78% (64/82) (p = 0.001).CONCLUSIONSMyocardial T2, determined using a black-blood MRI sequence, is sufficiently sensitive to identify most of the moderate acute rejections documented with biopsy at the same time, but is also a predictor of the subsequent occurrence of such biopsy-defined rejections.

Detection and prediction of acute heart transplant rejection with the myocardial T2 determination provided by a black-blood magnetic resonance imaging sequence

The use of black-blood MRI sequences allows to suppress the confusing influence of blood signal when myocardial T2 is calculated to detect myocardial oedema. This study was aimed at determining whether myocardial T2, determined using a black-blood sequence, could predict acute heart transplant rejection. A total number of 123 investigations, including cardiac MRI and myocardial biopsy, were performed 8±11 months after transplantation. Myocardial T2 was determined using and inversion-recovery/spin-echo sequence. A higher than normal T2 (≥ 56 ms) allowed an accurate detection of the moderate acute rejections evidenced at baseline biopsy (≥ ISHLT grade-2): sensitivity 89% and specificity, 70% (p<0.0001). T2 was increased in grade 2 (n=11; 57±5 ms) compared with grade 0 (n=49; 50±5 ms, p=0.001), grade 1A (n=34; 51±5 ms, p=0.006) and grade 1B (n=21; 51±8 ms, p=0.009); and T2 was further increased in grade 3 (n=8; 65±8 ms) compared with grade 2 (p=0.005). In addition, in patients without ≥ grade-2 rejection at baseline, a T2 higher than normal was correlated with the subsequent occurrence of ≥ grade-2 rejection within the following 3 months: sensitivity, 63% (12/19) and specificity, 78% (64/82) (p=0.001). Myocardial T2, determined using black-blood MRI sequence, is sufficiently sensitive to identify most of the moderate acute rejections documented with biopsy at the same time, but is also a predictor of the subsequent occurrence of such biopsy-defined rejections.

Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients

Irreversible acute rejection of the transplanted heart usually has a fatal outcome. Predicting which recipients are most likely to reject might allow closer monitoring and modification of treatment protocols to prevent graft loss. Recipients genetically predisposed to produce more TNF-α are those who suffer the most acute rejection episodes. Here we show that TNF-α genotype is strongly associated with death due to acute cell-mediated heart transplant rejection (Chi-square = 28.57, p < 0.0001). This subgroup of recipients should be given optimally tissue matched transplants and should be treated with the most effective immunosuppressive regimens.

Cyclosporin interaction: Interaction with concomitant orlistat leading to an acute heart transplant rejection episode: case report

Cyclosporin interaction: Interaction with concomitant orlistat leading to an acute heart transplant rejection episode: case report

Acute heart transplant rejection due to Saint John's wort

We report here acute rejection in two transplant patients due to a metabolic interaction of St John's wort and cyclosporin.

Non-invasive diagnosis of acute heart- or lung-transplant rejection using radiolabeled annexin V.

Apoptosis is a ubiquitous set of cellular processes by which superfluous or unwanted cells are eliminated in the body without harming adjacent healthy tissues. When apoptosis is inappropriate (too little or too much), a variety of human diseases can occur, including acute heart or lung transplant rejection. Our group has developed a new radiopharmaceutical, radiolabeled annexin V, which can image apoptosis. Here we briefly review the biomolecular basis of apoptosis and its role in acute rejection. We also describe the possible use of radiolabeled annexin V to screen children noninvasively for acute rejection following organ transplantation.

Noncompliance causing late acute rejection in pediatric heart transplantation: JM Ringewald, SS Gidding, DF Wax, SE Crawford, S Rodgers, SR Shah, E Pahl, CL Backer, C Mavroudis. Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL

Noncompliance causing late acute rejection in pediatric heart transplantation: JM Ringewald, SS Gidding, DF Wax, SE Crawford, S Rodgers, SR Shah, E Pahl, CL Backer, C Mavroudis. Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL

Incidence of humoral rejection in heart transplant recipients treated with tacrolimus or cyclosporine a

HUMORAL rejection is a rare but potentially fatal form of acute allograft rejection. Pathophysiologically, allosensitization against graft determinants occurs either preor posttransplantation. Preformed antibodies lead to the phenomenon of hyperacute rejection. The de novo synthesized antibodies directed against HLA antigens expressed on graft endothelium are clearly associated with humoral rejection. The diagnosis is made by histologic criteria of endothelial swelling and vasculitis and by immunohistologic demonstration of deposition of complement split products. This study was designed to explore the incidence of humoral rejection in human heart transplant recipients treated either with cyclosporine A (CyA) or tacrolimus (FK506). As a marker for humoral rejection, C4d complement fragment was used, originally described in kidney allografts, which we introduced as a marker for the diagnosis of acute humoral rejection in heart transplantation.

Detection and prediction of acute heart transplant rejection: preliminary results on the clinical use of a “black blood” magnetic resonance imaging sequence

The purpose of this study was to evaluate the sensitivity of multiparametric cardiac magnetic resonance imaging (CMR) for the detection of acute cardiac allograft rejection (ACAR).ACAR is currently diagnosed by endomyocardial biopsy, but CMR may be a noninvasive alternative because of its capacity for regional myocardial structure and function characterization.Fifty-eight transplant recipients (mean age 47.0 ± 14.7 years) and 14 control subjects (mean age 47.7 ± 16.7 years) were prospectively recruited from August 2014 to May 2017 and underwent 97 CMR studies (83 transplant recipients, 14 control subjects) for assessment of global left ventricular function and myocardial T2, T1, and extracellular volume fraction (ECV). CMR studies were divided into 4 groups on the basis of biopsy grade: control subjects (n = 14), patients with no ACAR (no history of ACAR; n = 36), patients with past ACAR (history of ACAR; n = 24), and ACAR+ patients (active grade ≥1R ACAR; n = 23).Myocardial T2 was significantly higher in patients with past ACAR compared with those with no ACAR (51.0 ± 3.8 ms vs. 49.2 ± 4.0 ms; p = 0.02) and in patients with no ACAR compared with control subjects (49.2 ± 4.0 ms vs. 45.2 ± 2.3 ms; p < 0.01). ACAR+ patients demonstrated increased T2 compared with the no ACAR group (52.4 ± 4.7 ms vs. 49.2 ± 4.0 ms, p < 0.01) but not compared with the past ACAR group. In contrast, ECV was significantly elevated in ACAR+ patients compared with transplant recipients without ACAR regardless of history of ACAR (no ACAR: 31.5 ± 3.9% vs. 26.8 ± 3.3% [p < 0.01]; past ACAR: 31.5 ± 3.9% vs. 26.8 ± 4.0% [p < 0.01]). Receiver operating characteristic curve analysis revealed that a combined model of age at CMR, global T2, and global ECV was predictive of ACAR (area under the curve = 0.84).The combination of CMR-derived myocardial T2 and ECV has potential as a noninvasive tissue biomarker for ACAR. Larger studies during acute ACAR are needed for continued development of multiparametric CMR for transplant recipient surveillance.

Vascular Effects of Cyclosporin A and Acute Rejection in Canine Heart Transplantation

Alteration of coronary vascular regulation during acute rejection may induce graft dysfunction and promote the occurrence of coronary atherosclerosis in transplant recipients. We studied the effects of treated and untreated acute rejection on coronary vascular regulation. Two groups of mongrel dogs (n = 7) underwent heterotopic heart transplantation (cervical position) and received either no treatment (group 1) or cyclosporin A (CyA), 10 mg.kg-1.day-1 (group 2). On day 7, recipient native and transplanted hearts were harvested and studied in organ chambers for coronary vascular reactivity. Transplanted hearts from group 1 displayed grade IV histologic rejection, whereas those from group 2 displayed grade IIIA to IV rejection. Intimal hyperplasia was found in the coronary arteries of both groups. Immunoperoxidase staining revealed the presence of factor VIII and of immunoglobulin M and G antibodies on the endothelium of both groups. Coronary relaxation to thrombin was impaired in transplanted hearts compared with native hearts (p < 0.05), and this was not influenced by CyA treatment. Conversely, endothelium-dependent relaxation to 5-hydroxytryptamine was enhanced in both CyA-treated (p < 0.01) and untreated groups (p < 0.05). A facilitating effect of CyA on 5-hydroxytryptamine also was seen in transplanted hearts in group 1 versus group 2 (p < 0.05), suggesting an intrinsic effect of CyA. Endothelium-independent relaxation to sodium nitroprusside and the contractile response to prostaglandin F2 alpha were not affected. In our model, acute rejection did not specifically impair cyclic guanosine monophosphate-mediated relaxation, but it did affect, in a receptor-specific manner, endothelium-dependent relaxation. Cyclosporin A appeared to enhance coronary endothelial sensitivity to 5-hydroxytryptamine.

Noninvasive markers for acute heart transplant rejection in children with the use of automatic border detection

A noninvasive method to detect heart transplant rejection would allow for increased monitoring at reduced risk. Automatic border detection is a new method to assess diastolic abnormalities. The purpose of this study was to determine whether automatic border detection of left ventricular filling detects rejection in children. Nineteen episodes of biopsy-proven rejection in 10 children were retrospectively reviewed. Echocardiograms during rejection were compared with those before rejection and during recovery. Automatic border detection indices were percentage of total left ventricular filling as a result of rapid filling, diastasis, and atrial contraction. The percentage of total ventricular filling during diastasis increased significantly during rejection (10% +/- 6% versus 15% +/- 8%, p = 0.02), and the percentage of filling during the rapid filling phase decreased during rejection (82% +/- 8% versus 77% +/- 11%, p = 0.08). These changes were even more marked for the most severe episodes of rejection. These changes resolved at recovery. Automatic border detection of left ventricular filling patterns are altered during cardiac rejection in children. Filling during diastasis increases significantly, and filling during the rapid filling phase decreases. A prospective analysis is needed to determine whether these changes in filling can obviate the need for cardiac biopsy.

Procalcitonin: A new maker for differential diagnosis of acute rejection and bacterial infection in heart transplantation

Procalcitonin (PCT) has been increasingly used as a biomarker of bacterial infection and as a tool to guide antimicrobial therapy. Despite its increased use, data in patients with solid organ transplants are limited.The study aimed to assess the frequency of rising PCT associated with infectious complications in immunosuppressed living donated liver transplantation.A single-center, retrospective observational study. Preoperative patients' demographic data, operative, anesthetic data, and postoperative clinical course were analyzed post-liver transplant (LT) till discharge from the intensive care unit.Sixty patients were classified according to the culture results' into a positive culture group & a negative one and then followed up the sepsis variables in each group. Total leukocyte count (TLC) was elevated in the positive culture group in comparison to the negative culture one and was statistically significant (P-value <0.05) till the fourth day postoperative. Procalcitonin was higher in the positive culture group than in the negative one on days 1, 3, and 5 postoperative and was statistically significant (P-value <0.05).The cutoff values in the receiver operating characteristic curve (ROC) with >90% specificity to infection post LT were PCT of ≥9 ng/ml and TLC of ≥17.3/mm3 on day one.Following up PCT level on day one with TLC is essential and will help to detect sepsis and guide early antimicrobial initiation post-liver transplantation.Combined measurements of PCT and TLC with cutoff values of <9 ng/ml and < 17.3/mm3 respectively will help to exclude infections in 83.7% of patients, thus avoiding unnecessary usage of higher generations empiric antimicrobials.

Differential localization of allograft nitric oxide synthesis: comparison of liver and heart transplantation in the rat model

Nitric oxide (NO) is a free radical with a diversity of cellular origins and potential functions. Within the realm of solid organ transplantation, NO has been the focus of much attention. Discordant reports have documented both suppression and potentiation of the alloimmune response. In addition to questions regarding its functional role, little is known of the cellular origins of NO in acute rejection of vascularized allografts. To address this question, acute rejection models of rat heterotopic heart and orthotopic liver transplantation were chosen. When compared with naive controls and isografted animals, acute rejection in both heart and liver transplantation was associated with elevated systemic levels of the NO metabolite, nitrite. This was accompanied by increased graft content of iNOS protein as determined by immunoblot analysis of protein extracts. Expression of iNOS mRNA was localized with in situ hybridization. In both heart and liver transplantation, iNOS mRNA was found in the inflammatory infiltrate accompanying acute rejection. In addition, hepatocytes also expressed iNOS mRNA in the rejecting liver allograft. In contrast, cardiac myocytes in the rejecting heart allograft did not stain for iNOS mRNA. These results indicate that organ-specific, differential cellular expression of iNOS occurs in the acutely rejecting allograft. Transcriptional regulation of iNOS may vary among various organs according to the local cellular milieu. In addition, there may be a variable allograft specific response to acute rejection which may modify the associated immunologic biology.

HLA-DR matching reduces rejection rate in heart transplantation.

We have studied the influence of serological matching for ten HLA-DR antigens on the occurrence of acute cellular rejection in heart transplantation by correlating the findings in routine endomyocardial biopsies taken during the first posttransplant year with the results of HLA typing of all recipients of a first cardiac graft and their donors during 1983-1994 at our center. We found that recipients of HLA-DR matched hearts had a lower frequency of acute cellular rejection, especially so for the moderate/severe rejection grades. Also, rejection appeared earlier in the DR-mismatched combinations. Whether the mismatch was for one or two DR antigens did not make a significant difference, neither could we demonstrate any influence of HLA-A or -B mismatches. The survival of DR-matched cardiac grafts tended to be higher at 1 year than DR-mismatched grafts, but the difference did not reach statistical significance.

Aortic aneurysm in heart transplant recipients.

The purpose of this study was to define the clinical features of aortic aneurysms occurring in heart transplant recipients. Among the 734 patients who have undergone heart transplantation at our institution over the last 14 years, we have identified 12 patients (1.6% incidence) with aortic aneurysms (9 infrarenal, 3 thoracoabdominal), making this the largest reported series of aortic aneurysms (AA) in heart transplant recipients. For nine of the 12 patients with AA (75%), the indication for transplantation was ischemic cardiomyopathy. This indication accounted for only 42% of the overall transplantation group; our data therefore show that the risk of infrarenal AA disease was higher for patients who underwent transplantation for ischemic cardiomyopathy than for other indications (p = 0.02). In two of the patients with thoracoabdominal AA, chronic dissection was identified as the specific AA cause, whereas all of the other patients in the study had nonspecific "atherosclerotic" AAs. All 12 patients were symptom free at the time of initial discovery of the AAs. Two of the patients with infrarenal AA were diagnosed with AAs before transplantation; for the seven remaining patients with infrarenal AAs, the mean time between transplantation and AA discovery was 5.0 years (range 1.2 to 11.8 years). Serial radiologic studies allowed us to determine the AA expansion rate in seven of the 12 patients. This rate varied from 0 to 2.53 cm/yr (mean 1.20 cm/yr; 1.0 cm/yr for infrarenal AA alone). Five patients with infrarenal AA underwent AA repair as the initial treatment. Three others underwent repair after their AAs significantly expanded under observation. Mean AA diameter at the time of repair was 6.9 cm. All three patients with thoracoabdominal AAs died of acute AA rupture before resection could be done, despite their initial asymptomatic state. AA diameters at time of rupture were 3.5, 6.0, and 11 cm. All of the eight patients with AA treated with surgery are alive and well (median follow-up 18 months). The only complication was acute heart transplant rejection, which occurred 11 days after AA repair in one patient. Our data suggest that AA occurrence is more likely in patients who undergo heart transplantation for ischemic heart disease than for other indications. Careful serial radiologic surveillance is warranted in any heart transplant patient with an AA, because of the apparent potential for more rapid AA expansion in this patient population than in patients who do not undergo transplantation. We conclude that early repair of infrarenal AA is indicated because excellent operative results and low morbidity rates can be achieved. An aggressive approach to thoracoabdominal AAs in this group may also be appropriate because of the apparent propensity to lethal rupture, sometimes at relatively small AA size.

Granzyme B and perforin can be used as predictive markers of acute rejection in heart transplantation

We have investigated perforin and granzyme B expression in graft-infiltrating lymphocytes of patients who underwent heart transplantation. Those proteins are commonly present in the cytoplasmic granules of cytotoxic T lymphocytes and are released upon effector-target cell interaction. From 28 patients 103 endomyocardial biopsies were obtained and examined by histology and immunocytochemical analysis using relevant monoclonal antibodies. We found that "high" biopsy histological grades were associated with perforin and granzyme B expression in graft-infiltrating lymphocytes of patients with acute severe rejection crisis. In contrast, these markers were not detected in patients without rejection or during graft stabilization. Interestingly, in patients with mild rejection and "low" histological grades, two groups could be distinguished with a differential expression of the two intracytoplasmic proteins. The presence of perforin and granzyme B-expressing cells was found to be predictive of rapid progression to severe rejection, so that this situation required additional treatment; in contrast, their absence seemed to correlate with a good graft outcome without additional treatment. Moreover, perforin and granzyme B expression seemed to be down-regulated by immunosuppressive drugs, which coincided with graft stabilization. In conclusion, our data suggest that detection of granzyme B and perforin in graft-infiltrating lymphocytes might be helpful for routinely monitoring heart transplant patients.

Rescue therapy for acute rejection using 15-deoxyspergualin (DSG) in combination with superoxide dismutase (SOD) on cardiac allografts in rats.

This study was performed to investigate the effect of combination therapy using 15-deoxyspergualin (DSG) plus recombinant human superoxide dismutase (h-SOD) on acute graft rejection in heterotopic rat heart transplantation. DSG was intraperitoneally injected for 10 days at a dose of 5 mg/kg per day, and h-SOD (15,000 or 30,000 microm/kg per day) was continuously administered via external iliac vein for approximately 8 days with a mini-osmotic pump (Alzet model 2001). Administration of the drugs was started on the 4th day after grafting. The grafts treated with h-SOD alone survived slightly longer than the control allografts. The graft survival time was significantly prolonged in the groups treated with DSG alone or DSG plus h-SOD. A higher percentage of induction of immunological unresponsiveness was achieved in the group treated with DSG plus h-SOD at 30,000 microm/kg per day. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP on the 31P nuclear magnetic resonance spectrogram are useful parameters for assessing the graft injury associated with acute rejection. The ratio of Pi/PCr and that of PCr/ATP were found to increase and decrease, respectively, in proportion to the progress in rejection. In the animals treated with DSG alone, the Pi/PCr ratio was significantly increased from the 4th day, and PCr/ATP ratio decreased from 10th day after grafting. These parameters were not improved during the observation period. However, these parameters were significantly recovered in the animals treated with DSG and h-SOD in combination. Improvement of the parameters seemed to be related to SOD dosage. These results clearly demonstrated that the oxygen free radical plays a toxic role in cardiac allografts with ongoing rejection and, therefore, the administration of h-SOD in combination with DSG can minimize the graft injury.

The histology at various stages of acute rejection in concordant xenogeneic heart transplantation. A sequential study in rodents.

In an attempt to describe early morphologic changes in heterotopic xenogeneic heart transplantation a sequential study was performed in a hamster-to-rat model. Mild morphologic changes observed after four to six h were characterized by slight interstitial edema and focal myocyte damage with fragmentation and loss of myofibrillar elements. No lymphocytic infiltration appeared. Moderate morphologic changes observed after 12-24 h were characterized by moderate interstitial edema, and the appearance of mild hemorrhage and scattered extravasated neutrophilic granulocytes. The myocardium had more widespread areas with myocyte damage, sometimes with small foci of necrotic cells and adjacent neutrophilic granulocytes and macrophages. Vascular changes with perivascular edema and swelling of the endothelium were seen and a few neutrophilic granulocytes could be found in the vessel walls. No lymphocytic infiltration appeared. Severe morphologic changes observed after 44-48 h or at the time of complete rejection were characterized by severe interstitial hemorrhage, appearance of widespread necrosis and marked vascular changes with development of leukocytoclastic-like vasculitis, possibly with thrombosis. Only a few lymphocytes appeared. The findings were essentially different from those observed in allogeneic heart transplantations, where classical first-set allograft rejection was seen. In normal donor hearts and syngeneic transplanted hearts used as controls, no significant morphologic changes were demonstrated. On the basis of this study we consider xenogeneic acute rejection to be primarily of the humoral type.

Rescue therapy for acute rejection using 15-deoxyspergualin (DSG) in combination with superoxide dismutase (SOD) on cardiac allografts in rats

This study was performed to investigate the effect of combination therapy using 15-deoxyspergualin (DSG) plus recombinant human superoxide dismutase (h-SOD) on acute graft rejection in heterotopic rat heart transplantation. DSG was intraperitoneally injected for 10 days at a dose of 5 mg/kg per day, and h-SOD (15,000 or 30,000 µm/kg per day) was continuously administered via external iliac vein for approximately 8 days with a mini-osmotic pump (Alzet model 2001). Administration of the drugs was started on the 4th day after grafting. The grafts treated with h-SOD alone survived slightly longer than the control allografts. The graft survival time was significantly prolonged in the groups treated with DSG alone or DSG plus h-SOD. A higher percentage of induction of immunological unresponsiveness was achieved in the group treated with DSG plus h-SOD at 30,000 µm/kg per day. The ratios of inorganic phosphate (Pi)/phosphocreatine (PCr) and PCr/ATP on the 31P nuclear magnetic resonance spectrogram are useful parameters for assessing the graft injury associated with acute rejection. The ratio of Pi/PCr and that of PCr/ATP were found to increase and decrease, respectively, in proportion to the progress in rejection. In the animals treated with DSG alone, the Pi/PCr ratio was significantly increased from the 4th day, and PCr/ATP ratio decreased from 10th day after grafting. These parameters were not improved during the observation period. However, these parameters were significantly recovered in the animals treated with DSG and h-SOD in combination. Improvement of the parameters seemed to be related to SOD dosage. These results clearly demonstrated that the oxygen free radical plays a toxic role in cardiac allografts with ongoing rejection and, therefore, the administration of h-SOD in combination with DSG can minimize the graft injury.

Perforin and granzyme B as markers for acute rejection in heart transplantation

Perforin and granzyme B as markers for acute rejection in heart transplantation