J. Stehlik

Noninvasive diagnosis of cardiac allograft rejection using echocardiography indices of systolic and diastolic function

BACKGROUND Limited and conflicting data exist on the diagnosis of cardiac allograft rejection with the use of echocardiography. The purpose of our study was to evaluate various systolic and diastolic indices, including newer tissue Doppler imaging techniques, in diagnosing cardiac allograft rejection. METHODS We prospectively performed 426 echocardiography studies at the time of endomyocardial biopsy in 54 cardiac transplant patients. We measured left ventricular (LV) systolic and diastolic dimensions, mitral inflow pattern and annular velocities, and the myocardial performance index. Biopsies were assessed for cellular rejection and antibody-mediated rejection (AMR). RESULTS Mild cellular rejection was diagnosed in 74 biopsy specimens and significant cellular rejection in 10 biopsy specimens. AMR was diagnosed in 30 biopsy specimens. In patients with mild or significant cellular rejection, no significant differences in echocardiographic parameters were observed. In patients with AMR, LV fractional shortening was significantly reduced compared with those with no AMR (mean±SD 31.8±8.9% vs 36.0±7.1%; P=.02). CONCLUSIONS Although 1 echocardiographic parameter was statistically different in the setting of rejection, lack of consistency and overlap between nonrejection and rejection groups does not permit definitive noninvasive diagnosis of cardiac allograft rejection using this imaging modality.

Retransplant and Medical Therapy for Cardiac Allograft Vasculopathy: International Society for Heart and Lung Transplantation Registry Analysis

Cardiac retransplantation for heart transplant recipients with advanced cardiac allograft vasculopathy (CAV) remains controversial. The International Society for Heart and Lung Transplantation Registry was used to examine survival in adult heart recipients with CAV who were retransplanted (ReTx) or managed medically (MM). Recipients transplanted between 1995 and 2010 who developed CAV and were either retransplanted within 2 years of CAV diagnosis (ReTx) or alive at ≥2 years after CAV diagnosis, managed medically (MM), without retransplant, constituted the study groups. Donor, recipient, transplant characteristics and long‐term survival were compared. The population included 65 patients in ReTx and 4530 in MM. During a median follow‐up of 4 years, there were 24 deaths in ReTx, and 1466 in MM. Survival was comparable at 9 years (55% in ReTx and 51% in MM; p = 0.88). Subgroup comparison suggested survival benefit for retransplant versus MM in patients who developed systolic graft dysfunction. Adjusted predictors for 2‐year mortality were diagnosis of CAV in the early era and longer time since CAV diagnosis following primary transplant. Retransplant was not an independent predictor in the model. Challenges associated with retransplantation as well as improved CAV treatment options support the current consensus recommendation limiting retransplant to highly selected patients with CAV.

Report From the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States

Cardiac transplantation remains the only definitive treatment for end‐stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less‐than‐optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state‐of‐the‐art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

Immune Function Surveillance: Association With Rejection, Infection and Cardiac Allograft Vasculopathy

BACKGROUND Rejection, cardiac allograft vasculopathy (CAV), and infection are significant causes of mortality in heart transplantation recipients. Assessing the immune status of a particular patient remains challenging. Although endomyocardial biopsy (EMB) and angiography are effective for the identification of rejection and CAV, respectively, these are expensive, invasive, and may have numerous complications. The aim of this study was to evaluate the immune function and assess its utility in predicting rejection, CAV, and infection in heart transplantation recipients. METHODS We prospectively obtained samples at the time of routine EMB and when clinically indicated for measurement of the ImmuKnow assay (IM), 12 cytokines and soluble CD30 (sCD30). EMB specimens were evaluated for acute cellular rejection, and antibody-mediated rejection (AMR). CAV was diagnosed by the development of angiographic coronary artery disease. Infectious episodes occurring during the next 30 days after testing were identified by the presence of positive bacterial or fungal cultures and/or viremia that prompted treatment with antimicrobials. RESULTS We collected 162 samples from 56 cardiac transplant recipients. There were 31 infection episodes, 7 AMR, and 4 CAV cases. The average IM value was significantly lower during infection, (P = .04). Soluble CD30 concentrations showed significantly positive correlation with infection episodes, (P = .001). Significant positive correlation was observed between interleukin-5(IL-5) and AMR episodes (P = .008). Tumor necrosis factor-α and IL-8 showed significant positive correlation with CAV (P = .001). CONCLUSIONS Immune function monitoring appears promising in predicting rejection, CAV, and infection in cardiac transplantation recipients. This approach may help in more individualized immunosuppression and it may also minimize unnecessary EMBs and cardiac angiographies.

Effect of Blood Product Transfusion-Induced Tolerance on Incidence of Cardiac Allograft Rejection

BACKGROUND Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. OBJECTIVE To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. PATIENTS AND METHODS Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. RESULTS Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. CONCLUSIONS Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.

Arterial Thrombus in a Heart Transplant Recipient

Each month, the American Journal of Transplantation will feature Images in Transplantation, a journal-based CME activity, chosen to educate participants on current developments in the science and imaging of transplantation. Participants can earn 1 AMA PRA Category 1 CreditTM per article at their own pace. This month’s feature article is titled: “Arterial Thrombus in a Heart Transplant Recipient.” Accreditation and Designation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Blackwell Futura Media Services, the American Society of Transplant Surgeons, and the American Society of Transplantation. Blackwell Futura Media Services is accredited by the ACCME to provide continuing medical education for physicians, and fulfills the requirements for the American Board of Surgery (ABS) for Maintenance of Certification (MOC). Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Statement of Need This Continuing Medical Education activity reviews and highlights the case of a heart transplant recipient who presented with an arterial thromboembolism. The differential diagnosis, etiology, and subsequent discussion on management apply broadly to the management of solid organ transplant recipients.

Recovery of Myocardial Capillary Bed (Microvascular) Density Persists in Long Term Follow Up of CAV Patients Treated With Sirolimus

(r= 0.45, p< 0.001), age (r= 0.33, p< 0.01), time after transplantation (r= 0.23, p< 0.05), copeptin (r= -0.42, p< 0.001), sTfR (r= 0.24, p< 0.05), hemoglobin (r= -0.42, p< 0.001), transferrin (r= -0.31, p< 0.01) haptoglobin (r= 0.39, p< 0.001), cystatin C (r= 0.55, p< 0.001), ejection fraction-EF (r= -0.28, p< 0.05), NYHA class (r= -0.41, p< 0.01) hsCRP (r= 0.26, p< 0.05), IL-6 (r= 0.23, p< 0.05), vWF (r= -0.40, p< 0.001) and midkine (r= 0.33, p< 0.01). In multivariate analysis, only creatinine was found to be predictor of YKL-40 (beta value 0.59, p= 0.02), explaining 56% of the variation in YKL-40 levels in heart allograft recipients. Conclusion: YKL-40 may contribute to the enhanced risk of cardiovascular complications mainly due to impaired renal function in patients after heart transplantation.

Reasons for Left Ventricular Assist Device Patient Denial: Insights into Possible Misconceptions about Mechanical Circulatory Support

Purpose Left ventricular assist devices (LVADs) are becoming a more common and effective therapy for patients with advanced heart failure. However, this technology is underutilized, and there is a general sense that many patients are referred too late, resulting in poor outcomes. The aim of this study was to determine why those patients referred for LVAD therapy who did not undergo LVAD implantation were found to be unsuitable candidates. Methods and Materials The UTAH Cardiac Transplant Program mechanical circulatory support databases were queried for all patients referred for an LVAD between 2006 and 2012. The patients were then stratified into those who received an LVAD and those who did not. For the patients who did not receive an LVAD, the reasons for referral rejection were collected and categorized. Results 604 patients were referred for an LVAD between our two centers of whom 338 (56%) did not receive an LVAD. For the rejected referral population, the average age was 59±14 years and 76% were male. The reasons for LVAD rejection are summarized below. Conclusions In our experience, more than half of patients referred for an LVAD did not receive this therapy. A substantial percent of these patients were declined on the basis of being too sick at the time of evaluation, suggesting that many patients are referred too late. More efforts to educate the referral community about the benefits of a timely referral are needed to improve outcomes and cost-efficiency of LVADs. Reason for RejectionPatients (%)Too Sick81 (24.0)- Renal or Liver Disease17 (5.0)- Acute Critical Illness16 (4.7)- Comorbidities14 (4.1)- Pulmonary Disease11 (3.3)- Multi-Organ Dysfunction7 (2.1)- GI Disorders4 (1.2)- Infection4 (1.2)- Cancer4 (1.2)- Old Age3 (0.9)- Ventricular Arrythmias1 (0.3)Medically Managed80 (23.7)Patient Declined64 (18.9)LVAD as Backup Only32 (9.5)Went to Heart Transplant32 (9.5)Lack of Funding22 (6.5)LVAD Not Needed9 (2.7)Lack of Social Support8 (2.4)Non-Compliance5(1.5)Other5 (1.5)

Fibrin on Endomyocardial Biopsy: A Significant Predictor of Cardiovascular Mortality beyond pAMR Score

Purpose Endothelial activation (EA) is the hallmark lesion of antibody-mediated rejection (AMR). Mediators of EA trigger a cascade of additional endothelial injury leading to plasma protein leakage and fibrin accumulation. We hypothesized that interstitial fibrin on endomyocardial biopsy (EMB) would correlate with AMR severity and worse outcomes. Methods and Materials The AMR scores of patients transplanted in the UTAH Cardiac Transplant Program between 1986 and 2012 were classified according to the new ISHLT nomenclature. A semiquantitative scale (0-5) was used to record the presence of fibrin in the interstitium (FInt) and vessels (FVasc) (0, no fibrin; 5, diffuse fibrin). Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable and the fibrin variables were included in separate models as additive continuous variables. Both pAMR and fibrin were measured from last biopsy and varied over the time of the study. Results 11,550 biopsies from 983 patients were analyzed. Across all pAMR values, the presence of any fibrin increased the risk of CV mortality (OR 2.8, p=0.002). On further analysis, for each one unit increase in the FInt score, an additional 20% increase in CV mortality, above that due to pAMR alone, was observed (p=0.005). In contrast, the severity of the Fvasc score did not further increase the risk of CV death beyond that due to pAMR score (p=0.359). Conclusions The presence of interstitial fibrin on EMB confers an incremental risk of CV mortality in heart transplant recipients above that due to pAMR severity alone. This may be related to a more severe and chronic form of AMR in certain patients. Whether fibrin should be required as part of the pAMR grading system warrants serious consideration. Odds ratio for CV mortality stratified by pAMR score and fibrin deposition Interstitial Fibrin 0 1 2 3 4 5 pAMR0 1.00 1.20 1.45 1.74 2.09 2.52 pAMR1 2.37 2.85 3.43 4.12 4.96 5.97 pAMR2 3.21 3.86 4.64 5.58 6.71 8.08 pAMR3 61.51 73.99 88.99 107.03 128.73 154.83

508 Microvessel Density in Cardiac Allograft Biopsies in Patients with Clinically Significant Coronary Allograft Vasculopathy Treated with Sirolimus

ROC Area 0.64 vs 0.75 0.71 vs 0.78 0.93 vs 0.96 0.75 vs 0.78 0.88 vs 0.92 0.86 vs 0.87 Sensitivity 0.56 vs 0.94 0.66 vs 0.62 0.90 vs 1.00 0.65 vs 0.79 0.71 vs 1.00 0.87 vs 0.87 Specificity 0.71 vs 0.54 0.68 vs 0.86 0.82 vs 0.86 0.75 vs 0.68 0.90 vs 0.72 0.74 vs 0.75 PPV 0.31 vs 0.32 0.78 vs 0.88 0.24 vs 0.30 0.56 vs 0.55 0.23 vs 0.13 0.43 vs 0.43 NPV 0.88 vs 0.97 0.54 vs 0.57 0.99 vs 1.00 0.81 vs 0.87 0.99 vs 1.00 0.96 vs 0.96 Prevalence 0.19 0.63 0.06 0.33 0.04 0.18 Cutoff Value 0.13 vs 0.12 0.45 vs 0.70 0.02 vs 0.05 0.35 vs 0.29 0.03 vs 0.02 0.12 vs 0.11 ROC: Receiver Operating Characteristic; PPV: Positive Predictive Value; NPV: Negative Predictive Value