Cardiac Transplant Patients Research Articles

Implantable cardioverter-defibrillators in cardiac transplant recipients: A systematic review from the Electrophysiology Collaborative Consortium for Meta-analysis-ELECTRAM investigators.

Implantable cardioverter-defibrillator (ICD) in patients with heart failure with reduced ejection fraction reduces mortality secondary to malignant arrhythmias. Whether cardiac transplant patients considered high risk for sudden death (SD) derive similar benefits remains controversial. Systematic search, without language restriction, using PubMed, EMBASE, SCOPUS, Google Scholar, and ClinicalTrials.gov was performed from inception to June 4, 2020, for studies that had reported outcomes in patients who had ICD implanted after cardiac transplant. The outcomes studied were as follows: (a) SD and (b) appropriate and inappropriate ICD therapies. Seven studies (from 1983 through 2018) with a total of 338 cardiac transplant patients who received ICD met study inclusion criteria. The mean age was 48.37±14.85 years, and 70.4% were men. The pooled incidence of SD was 16.3% (95% CI 6.2-29.0%; I2 =66%). Appropriate and inappropriate ICD therapies were observed in 12.1% (95% CI 5.3-20.4; I2 =0%) and 3.5% (95% CI 0.11-9.58%; I2 =0%), respectively during the follow-up period (27.48±24.27 months). The most common cause for SD was heart failure (15.6%), followed by electromechanical disassociation, malignant ventricular arrhythmias (4.7% each, respectively), and cardiac allograft vasculopathy (CAV) (3.1%). Furthermore, approximately 60% (10/17) of patients with appropriate ICD shocks had CAV. Despite, low incidence of arrhythmic mortality, there remains an increased burden of ventricular arrhythmias, as evident by a 12% appropriate ICD shock rates, suggesting ICD might be a practical decision in selected cardiac transplant patients deemed high risk of SD (i.e., patients with advanced CAV and left ventricular systolic dysfunction).

A nationwide 16 year analysis of trends and impact of arrythmias in transplant recipients

Abstract Background Orthotopic heart transplantation is the most effective long-term therapy for end-stage heart disease. Denervation of transplanted heart with the loss of autonomic modulation, vasculopathy, utilization of immunosuppressant drugs, and risk of allograft rejection may result in change in the prevalence of arrhythmias in transplanted hearts. Purpose To describe the trends, distribution and the clinical impact of arrhythmias in transplanted hearts in a large nationwide population. Methods We queried the National Inpatient Sample with administrative codes. Cardiac transplant patients were identified using procedure ICD-9-CM codes 37.5 and 33.6. Common arrhythmias were extracted using appropriate validated ICD-9-CM codes. Statistical Analysis System (SAS) version 9.4 was used for analysis of data. Results There was a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States and 16342 (54.4%) of these had arrhythmias. The prevalence of total arrhythmias increased from 53.6% (n=1,158) in 1999 to 67.3% (n=1,575) in 2014. The most common arrhythmia was atrial fibrillation (26.83%) followed by ventricular tachycardia (22.86%) and the prevalence of individual arrhythmias is as shown in Figure 1. Cardiogenic shock was higher in transplanted hearts with arrhythmias when compared with patients without arrhythmias (25.96% vs 18.18%; p<0.001). Transplant recipients with arrhythmias were also associated with an increased use of mechanical circulatory device (18.22% vs 12.67%, p<0.001). The use of implantable cardiac defibrillators and permanent pacemaker was also higher in the arrhythmia group (2.19% vs 0.63% and 40.43% vs 30.24% respectively, p<0.0001). However, there was no significant difference in inpatient mortality between transplant recipients with arrhythmias and without arrhythmias (7.72% vs 6.90%, p=0.225). Further, there was no significant difference in frequency of strokes between the groups (4.98% vs 5.08%; p=0.857). The total hospital cost when adjusted for inflation was significantly higher in the arrhythmic patients, with an average cost of about $570,415±9,590 vs $439,707±8362 in patients without arrhythmias (p<0.0001). The mean length of hospitalization was 44.2±0.8 days in patients with arrhythmias compared to 33.9±0.8 days in patients without arrhythmias (p<0.0001). Conclusion A significant proportion of patients with heart transplant have cardiac arrhythmias and are associated with worse in-hospital outcomes of cardiogenic shock, increased length of stay, and cost of hospitalization. However, they are not associated with worse inpatient mortality. Funding Acknowledgement Type of funding source: None

Total Lymphoid Irradiation in The Treatment and Prevention of Pediatric Cardiac Allograft Rejection — A 23-Year Experience

Despite the development of increasingly efficacious immunosuppressive agents, allograft rejection is still a leading cause of morbidity and mortality in pediatric heart transplant patients. Total lymphoid irradiation (TLI) has emerged as a secondary treatment for recurrent cardiac allograft rejection refractory to medication in adults. However, there is limited evidence for long-term TLI efficacy and safety in the pediatric cohort. Our objectives were to evaluate 1) the long-term effects of TLI in treating recurrent pediatric cardiac allograft rejections at a single institution, and 2) the outcome of a unique prophylactic TLI protocol for re-transplant cardiac allograft in pediatric patients. This study included pediatric cardiac transplant patients who received TLI between 1996 and 2014, and who underwent regular right ventricular endomyocardial biopsies. TLI of 800 cGy in 10 fractions was delivered twice a week to the mantle and periaortic/splenic fields. Indication of TLI for treatment of allograft rejection included recurrent episodes (≥ 3) of rejection (defined as ISHLT Grade ≥ 1B/1R) or rejection episodes that failed to respond to medical therapy. Prophylactic TLI was indicated for patients who received a re-transplant cardiac allograft. Follow-up on these patients ended on January 23, 2020, comprising of 23 years of single institutional data. Comparisons in endpoints were performed using paired-sample, non-parametric tests. Eighteen patients underwent TLI for treatment of recurrent cardiac allograft rejection (n = 11, treatment cohort) and/or for rejection prevention in a re-transplant graft (n = 10, prophylactic cohort). Three patients completed 2 courses of TLI for both treatment and prevention of graft rejection. Median follow up was 10.1 years (range 0.5-23 years). In the treatment cohort, TLI demonstrated a trend to prolong the time to graft rejection, from a median of 62 days before TLI to 320 days after TLI (p = 0.054). In the prophylactic cohort, TLI increased ten-year graft survival from 11.1% to 44.4% (n = 9 due to a patient lost to follow-up; p = 0.38). Nine out of 10 patients underwent re-transplant due to graft coronary artery disease in the initial allograft – 1 patient developed coronary vessel narrowing in the re-transplant graft requiring a drug-eluting stent 17.1 years after prophylactic TLI, while the other 8 patients had no evidence of any narrowing, stenosis, or coronary allograft vasculopathy (CAV) in the re-transplant graft (mean CAV-free graft survival 9.4 years). During long-term follow-up, there was no incidence of hematological malignancies or blood dyscrasias. Our study showed that TLI was well tolerated and safe in long-term follow-up. It not only demonstrated a trend to prolong the time to graft rejection, but also showed promising results in preventing CAV and lengthening graft survival if given prophylactically. Further investigation into the role of treatment and prophylactic TLI is warranted.

TCT CONNECT-247 Outcomes of Percutaneous Coronary Intervention in Cardiac Transplant Patients: A Bi-national Analysis Derived From the United Kingdom and United States

TCT CONNECT-247 Outcomes of Percutaneous Coronary Intervention in Cardiac Transplant Patients: A Bi-national Analysis Derived From the United Kingdom and United States

Beta-blocker therapy in heart transplant recipients: A review.

Beta-blockers are essential drugs for the treatment of many cardiovascular diseases, such as heart failure, acute and chronic ischemic heart disease, tachyarrhythmias, and hypertension. However, these drugs have not been used in cardiac transplant patients for many years owing to the fear that they could reduce cardiac output and functional capacity. In recent years, however, some evidence has shown that even in cardiac transplanted patients, β-blockers are useful and effective in the treatment of sinus tachycardia, supraventricular and ventricular tachyarrhythmias, left ventricular systolic dysfunction, and arterial hypertension. Furthermore, some data have shown that the use of β-blockers is associated with reduced mortality in heart transplant recipients. In this review, we summarize this evidence with particular emphasis on the practical aspects of the use of β-blockers in post-transplantation patients to promote the use of this important class of drugs in clinical practice.

Loss of troponin-T labelling in endomyocardial biopsies of cardiac transplant patients is associated with increased rejection grading.

Acute cellular rejection after cardiac transplantation surgery is routinely monitored by pathological assessment of haematoxylin and eosin (H&E) histology of endomyocardial biopsies (EMB). Unfortunately, there is considerable variation in the diagnosis of rejection that has been attributed to the subjectivity involved in assessing the degree of (a) inflammatory infiltrate and (b) myocyte damage. In this work, we sought to investigate the potential of high contrast confocal microscopy for numerically assessing inflammatory infiltrate and myocyte damage in EMB histology. Confocal microscopy was used to capture images from EMB fluorescently labelled for nuclei (DAPI), f-actin (phalloidin), troponin-T (anti-body), and extracellular matrix and cell border (wheat germ agglutinin). Images from 28 biopsy procedures were captured. Standard pathological grading of H&E histology identified the following rejection gradings: 6 0R, 16 1R, 6 2R and no 3R. Confocal imaging was able to identify equivalent features of rejection provided by H&E histology but at higher contrast facilitating quantification. Lymphocytic infiltrate was calculated as the ratio of non-myocyte nuclei to total nuclei. This metric was found to be significantly higher in the biopsies from 2R patients compared to both 1R and 0R patients (P<.05). Myocyte damage was quantified as the loss of troponin-T labelling normalised to f-actin labelling. This metric of myocyte damage found significantly lower amounts of troponin-T in the biopsies from 2R patients compared to those with a 0R rejection grading (P<.05). Confocal imaging and simple image processing routines show potential for numerically assessing both inflammatory infiltrate and myocyte damage in endomyocardial biopsy.

Over-diagnosed prostate cancer in solid organ recipients: lessons from the last 3 decades.

Prostate cancer (PC) is the most common neoplasia in men. With aging of solid organ transplant recipients (SOTR), its incidence is likely to increase. The aim of this study was to analyze PC screening results retrospectively in renal transplant recipients (RTR), hepatic transplant recipients (HTR) and cardiac transplant recipients (CTR). A retrospective monocentric study of PC diagnosed in renal, hepatic or cardiac transplanted patients since 1989 was performed. All the patients were followed annually by digital rectal examination and prostate serum antigen (PSA) dosage. 57 PC were diagnosed in 1565 SOTR male patients (3.6%): 35 RTR, 15 HTR, and 7 CTR. Standard incidence ratio (SIR) was 41.9. Mean age at the time of diagnosis was 64.5 (60.5-69.2). Mean time between transplantation and PC diagnosis was 95.7 (39.0-139.5) months. Median PSA rate was 7.0 (6.2-13) ng/mL. Clinical stages were T1, T2, and T3, respectively, for 29, 22 and 6 patients. Diagnosis was done by screening in 52 patients, after prostatitis in 1 and bone pain in another. Three PC were discovered on prostate chips after transurethral resection. Two patients were treated by active surveillance. 39 (68%) patients (25 RTR, 11 HTR and 3 CTR) were treated by radical prostatectomy. Histological results were 30 pT2 and 9 pT3 tumors, with 7 positive surgical margins. Gleason score was 5, 6, 7, 8 and 9 in, respectively, in 2, 24, 11, 1 and 1 patients. One patient with positive pelvic nodes was treated with hormonal therapy (HT). One had a biochemical relapse at 10months and underwent salvage radiotherapy. Median follow-up was 85.2months (46.1-115.0). 23 (40.4%) patients died. Two (3.6%) RTR and 1 (1.8%) CTR died from their PC. Standard incidence ratio were, respectively, 42.4, 48.2 and 39 in RTR, HTR and CTR. Systematic screening in male SOTR after 50years old could not be recommended. In the last 3 decades, we diagnosed too many low-risk prostate cancers strongly increasing the SIR but failing to decrease prostate cancer related mortality. SOTR should undergo individual screening with prior MRI when PSA rates are high. Management should not be different from that of the general population.

CLINICAL CHARACTERISTICS AND OUTCOME OF HERPES ZOSTER IN SOLID ORGAN TRANSPLANT PATIENTS: A SINGLE CENTER CASE SERIES

Background: Solid organ transplant recipients (OTR) are at increased risk for herpes zoster (HZ), primarily due to immunosuppressive medication. HZ may cause to serious complications including cutaneous dissemination, postherpetic neuralgia (PHN), involvement of visceral organs, encephalitis and death. Methods: We retrospectively analyzed solid OTR who have developed HZ in between December 2018 and December 2019. Medical records were reviewed to assess the clinical characteristics and outcome of HZ in those patients. Additionally, patients with severe pain who had required opioid analgesics and/or gabapentin were called back for follow up examination. Results: There were 16 patients (Eight males and eight females) with a mean age of 43 (range, 11-58 years). Thirteen (81%) patients were renal transplant recipients, whereas three (19%) were cardiac transplant recipients. Median time from organ transplantation to onset of HZ was 39.5 months (range, 5.4-254.6 months). Visceral disease or mortality did not occur in any of the patients. Most common (69%) complaint was pain. Four patients (25%) were asymptomatic, and presented only with skin lesions. Thoracic region (9 patients) was the most common localization followed by genital-gluteal (4 patients), lower extremity (one patient), and ophthalmic region (one patient). Vesicles (75%) were the most common clinical presentation. Distribution of lesions was in single dermatome in 13 (81%) patients. One patient additionally had scattered vesicles adjacent to the primary dermatome, and two had scattered vesicles (<20) distant to the primary dermatome. Nine (56%) patients had received rejection treatment before the diagnosis of HZ. Majority (87.5%) of patients were on triple immunosuppressive regimen at the onset of HZ. For the treatment of HZ, four (%25) patients received outpatient treatment with oral valacyclovir therapy. Ten (62.5%) patients were hospitalized for the first few days (due to renal dysfunction, severe skin lesions, presence of lesions outside the primary dermatome, severe pain, or living out-of-town), and continued with oral antiviral therapy when discharged. One renal transplant patient with ophthalmic HZ and one cardiac transplant patient with hypoxic brain injury completed the antiviral treatment (intravenous acyclovir) in hospital. Renal dose adjustment was done in 8 (50%) patients. The doses of immunosuppressive drugs were reduced only in two cardiac transplant patients. Although 8 (%50) patients required potent analgesic treatment including opioid analgesics and/or gabapentin in the acute phase, only one that had ophthalmic HZ developed PHN. Among patients with severe pain, the longest duration of pain was 1.5 months. The patient with ophthalmic HZ later presented with transient third and sixth cranial nerve palsy without venous thrombosis and brain involvement. Conclusion: With prompt initiation of patient-adjusted therapy, post-transplant HZ seems most likely to have a favorable course. Prospective studies including large number of OTR and immunocompetent individuals with HZ are needed.

P55 Immunosuppression in the first six weeks following paediatric cardiac transplant

AimThe aim of this audit was to establish whether immunosuppression was being prescribed correctly and whether target levels were being reached during the first six weeks post-transplant.1 2MethodThe standards were discussed and agreed, due to an absence of standardised local or national written protocols, with the lead paediatric cardiothoracic transplant consultant and a specialist transplant liaison nurse. The paediatric transplant database provided a list of patients between October 2016 and July 2018, from which paediatric cardiac transplant patients were included in this audit. All data were collected retrospectively, for the first six weeks post-transplant, from patient’s electronic records.ResultsTwenty-three patients were included in the audit; fifteen males and eight females and the mean age was 6 years old. The standards for the timing and dosing of the first ciclosporin dose were met for 87% and 78% of patients respectively. Six patients (26%) had a ciclosporin level within the target range by day 4 post-transplant, for the remaining seventeen patients the average was day 9 post-transplant. The mean levels remained within this range or slightly above after day 9. Azathioprine or mycophenolate was started within 7 days of transplant in 6 patients (23%). Four patients (17%) had documented episodes of rejection; in one patient all other standards were met and in the other three only one additional standard was not met. Nineteen patients (83%) did not have a documented episode of rejection.ConclusionsPost-transplant management is individualised based on multiple factors such as clinical conditions e.g. renal/liver impairment and whether other agents such as ATG or steroids are being used.1 The lack of documentation around the treatment decisions made it difficult to explain deviations from standards in this audit. Ciclosporin standards were not met completely but were most likely unfeasible due to a narrow target range and the time between first dose and level monitoring. There did not appear to be a clear association between standards not being met and episodes of rejection. It would be beneficial to repeat this as a larger, prospective audit using revised standards.ReferencesCostanzo MR, Costanzo MR, Dipchand A, et al. The international society of heart and lung transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914–56.Sandimmun Concentrate for Solution for Infusion 50 mg/ml - Summary of Product Characteristics (SmPC) - (eMC) [Internet]. [cited 2018 Sep 2]. Available from: https://www.medicines.org.uk/emc/product/1036

Clinical characteristics and in hospital outcomes of heart transplant recipients undergoing percutaneous coronary intervention: Insights from the National Inpatient Sample.

Cardiac transplant patients are at increased risk of Coronary Allograft Vasculopathy which requires percutaneous coronary intervention (PCI). We aim to determine national epidemiology describing trends, mortality, and morbidity risks in patients with heart transplant undergoing PCI. We used Nationwide Inpatient Sample (NIS) data from 2002 to 2014 to identify adult hospitalizations with PCI using ICD 9 codes. Acute myocardial infarction (AMI), cardiac transplant status and complications were identified using validated ICD-9-CM diagnosis codes. Endpoints were in-hospital mortality and peri-procedural complications. Propensity match analysis was performed to compare the end-points between DES and BMS. Total 8,613,900 patients underwent PCI, of which 1,531(0.002%) patients had prior heart transplant status. Among these 1,531 PCIs, 311(20%) were due to AMI including 125(8%) due to STEMI. 74% of PCIs were done in males and 78% of the PCIs were performed in the 60-79 age group. Out of 1,380 stents placed, 1,090 were DES (79%) and 290 (21%) were BMS. Mortality was higher in the BMS versus DES (8.34% vs. 3.45%, p = .012), CONCLUSION: We concluded that majority of the population who underwent PCI were older males. DES was used more than BMS. The use of BMS is associated with increased mortality, cardiac complications and Acute Kidney Injury requiring dialysis compared with DES which likely is representative of preferential use of DES in these patient population.

Incidence of vasoplegic syndrome after cardiac transplantation in patients treated with sacubitril/valsartan.

Vasoplegic syndrome (VS) is associated with poor outcomes after heart transplantation (HT). Our aim was to determine whether SAC/VALS is associated with VS after HT. We retrospectively analyzed all consecutive HT performed in three centers between January 2017 and August 2018. VS was defined as vasopressor need (norepinephrine or epinephrine >.5mcg/kg/min or vasopressin) for more than 24hours to maintain a mean arterial pressure >70mmHg. Ninety-six recipients underwent HT in the study period: 60 elective HT with no LVAD, 5 elective HT on long term LVAD, and 31 emergent HT: 3 on long-term LVAD and 28 on temporary mechanical circulatory support. Fourteen patients were on SAC/VALS treatment at the time of transplant, and 82 were not. The global incidence of VS was 15.6%, with no significant differences between the groups (7.14% in with SAC/VALS vs 17.07% in no-SAC/VALS). In conclusion, in our small cohort SAC/VALS was not associated with VS development.

Quantitative cardiac magnetic resonance T2 imaging offers ability to non-invasively predict acute allograft rejection in children.

Monitoring for acute allograft rejection improves outcomes after cardiac transplantation. Endomyocardial biopsy is the gold standard test defining rejection, but carries risk and has limitations. Cardiac magnetic resonance T2 mapping may be able to predict rejection in adults, but has not been studied in children. Our aim was to evaluate T2 mapping in identifying paediatric cardiac transplant patients with acute rejection. Eleven paediatric transplant patients presenting 18 times were prospectively enrolled for non-contrast cardiac magnetic resonance at 1.5 T followed by endomyocardial biopsy. Imaging included volumetry, flow, and T2 mapping. Regions of interest were manually selected on the T2 maps using the middle-third technique in the left ventricular septal and lateral wall in a short-axis and four-chamber slice. Mean and maximum T2 values were compared with Student's t-tests analysis. Five cases of acute rejection were identified in three patients, including two cases of grade 2R on biopsy and three cases of negative biopsy treated for clinical symptoms attributed to rejection (new arrhythmia, decreased exercise capacity). A monotonic trend between increasing T2 values and higher biopsy grades was observed: grade 0R T2 53.4 ± 3 ms, grade 1R T2 54.5 ms ± 3 ms, grade 2R T2 61.3 ± 1 ms. The five rejection cases had significantly higher mean T2 values compared to cases without rejection (58.3 ± 4 ms versus 53 ± 2 ms, p = 0.001). Cardiac magnetic resonance with quantitative T2 mapping may offer a non-invasive method for screening paediatric cardiac transplant patients for acute allograft rejection. More data are needed to understand the relationship between T2 and rejection in children.

Hypertension in cardiac transplant recipients: tackling a new face of an old foe.

Systemic hypertension (HTN) is a common complication arising in the heart transplant recipient. This article aims to review the most current literature and update readers on the epidemiology, pathophysiology and management of HTN in heart transplant patients. In contrast to the general nontransplant hypertensive patient population, traditional risk factors, including family history of HTN, obesity and diabetes, play a minor role in the genesis of posttransplant HTN. Dysregulation in sodium and water balance, vascular stiffness, endothelial dysfunction, abnormal cardiorenal neural reflexes resulting from immunosuppression and cardiac denervation seem to be the predominant factors leading to postheart transplant HTN. Calcineurin inhibitors induced nephrotoxicity and steroid use further contributes to posttransplant HTN. Owing to the paucity of data, particularly randomized controlled trials to guide the evaluation and management of HTN in the cardiac transplant patients, much of the available data come from the renal transplant population. The choice of antihypertensive should be based on timing related to transplantation and patient's comorbidities. Although calcium channel blockers and loop diuretics are the preferred agents in the early postheart transplant period, angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers may be beneficial in the late postheart transplant period especially in the setting of diabetes and in the presence of proteinuria.

Impact of Induction Therapy in Cardiac Transplant Patients in the Current Era

Approximately half of all heart transplant programs utilize induction therapy during the early postoperative period. However, differences in survival using modern induction therapies have not been investigated in the current era. We selected all adult patients from the United Network for Organ Sharing (UNOS) database who underwent first time heart transplantation between 2008-2017 and received either induction therapy with anti-thymocyte globulin (ATG; n= 3747) or basiliximab (n=5157) or had no induction treatment (n=10,485). Kaplan Meier curves and multivariable Cox models compared the differences in survival among all three groups. Mean age of patients was 53.5 years and 25.7% were females. In general, patients who received ATG had longer wait times on the waitlist, had slightly higher ischemic times and there were fewer male recipients with female donors in this group. Upon follow up, 4,236 patients died. Kaplan Meier curves as displayed (Figure) suggested improved survival for those who received ATG compared to Basiliximab. In multivariable models, compared to patients who received ATG, those who received Basiliximab had higher risk of death (hazard ratio 1.11; p 0.02). There were no statistical differences in survival when patients who received ATG were compared to those who did not receive any induction therapy. In conclusion, induction therapy with ATG is associated with marginal survival benefit compared to induction therapy with basiliximab however there were no differences in long-term survival of patients who receive ATG when compared to those who did not receive any induction therapy.

The Use of Artificial Intelligence (AI) Machine Learning to Determine Myocyte Damage in Cardiac Transplant Acute Cellular Rejection

Cardiac transplant patients must be on lifelong surveillance for the occurrence of acute cellular rejection (ACR). Despite potent immunosuppressants, ACR occurs when recipient T cells recognize donor antigens to cause cardiac myocyte destruction. Identifying myocyte damage is critical for determining the grade of rejection, and thus greatly impacts treatment decisions. The aim of this study is to determine if a machine learning algorithm can reach acceptable performance of identifying myocyte damage representative of ACR from benign conditions. AI technology has recently been under robust investigation in cancer pathology but is in its infancy in transplant pathology. This is the first AI algorithm to our knowledge, to identify myocyte damage in cardiac transplant patients. All regions of myocyte damage were annotated by a board-certified cardiac pathologist at a high-volume cardiac transplant center. Cases diagnosed as antibody-mediated rejection (AMR) were excluded. Annotations were extracted using the Openslide software and fed into a convolutional neural network which used the locked VGG16 base for transfer learning. Keras was used for AI modeling and training. Four annotation classes were included in the algorithm (normal, healing injury, Grade 1R1A and Grade 1R2). A total of 19,617 annotations (10,855 regions of ACR, 5002 healing injury, 3760 normal) were completed from 200 hematoxylin and eosin slides scanned using a Leica Aperio AT2 digital whole slide scanner at 40X magnification. The AI algorithm successfully distinguished myocyte damage (Grade 1R2) from non-myocyte damage (Grade 1R1A) with 94% validation accuracy. ACR was distinguished from healing injury with 98-99% validation accuracy, and from normal cardiac myocytes with 99% validation accuracy. This study provides evidence for the first time, that a machine learning algorithm can be taught and validated to distinguish myocyte damage ACR from non-myocyte damage ACR. To our knowledge, this is one of the first AI tools developed in cardiac transplant pathology that may be used as an adjunct tool to decrease inter-observer diagnostic variability and reduce diagnostic error amongst pathologists.

Post-Cardiac Transplant Lymphocytic Thyroiditis Secondary to Amiodarone Use in the Pre-Transplant Period

Amiodarone is a commonly used anti-arrhythmic medication for atrial and ventricular arrhythmias in end-stage heart failure. Due to heavy iodine content, amiodarone is implicated in a variety of thyroid disorders, which could lead to adverse outcomes in cardiac transplant (CT) patients. Data on the development of post-CT lymphocytic thyroiditis (LT) in patients with pre-CT amiodarone use is limited. We aimed to study the development of amiodarone-induced LT in CT patients in a tertiary care transplant center in the United States. We retrospectively reviewed medical records of patients who underwent CT from 03/2010 to 10/2018 (N=137) at our center. 11 patients were excluded (10 = lack of pre-CT records, 1 = pre-transplant LT). The final cohort (N=126) was divided into two groups- those who developed post-CT LT vs. those who didn't. Baseline characteristics were compared between the groups, and predictors of post-CT LT were identified using regression modeling on Stata 15.0. Mean age of the cohort was 55.9 years, 80 % were men and 89 % were Caucasians. Incidence of post-CT LT was 10.3 % and mean time from transplant to the diagnosis of LT was 26.9 months. Patients who developed LT were similar in demographics as well as clinical characteristics but had significantly higher use of amiodarone (53.8 % vs 25.7 %, p=0.03), higher dose of amiodarone (343 mg vs 252 mg, p=0.049) and lower left ventricular ejection fraction (LVEF) (10.9 % vs 16.6 %, p=0.03) before transplant (Table 1). On univariate regression analysis, use of amiodarone [OR (p) = 3.4 (0.04)], African-American race [OR (p) = 4.4 (0.05)] and lower LVEF [OR (p) = 0.89 (0.046)] predicted post-CT LT. To our knowledge, this is the first study examining the incidence of post-CT LT secondary to amiodarone use in the pre-transplant period. The incidence of LT in our study was 10.3 % and was associated with pre-transplant amiodarone use, underpinning the importance of recognizing this side effect of amiodarone in the post-CT period.

A Novel Immunosuppressive Regiment for Cardiac Transplant Patients

Heart transplantation remains curative for end-stage heart failure. The choice between immunosuppressive regimens is guided by several principles: mitigating the risk of rejection early after transplantation, limiting drug toxicity of immunosuppressants, and minimizing over-suppression. We sought to investigate the efficacy of a novel immunosuppressive regimen targeting a lower therapeutic range (LTR) for Tacrolimus without antecedent induction therapy compared with a standard therapeutic range (STR). The protocol was implemented after 2016 and included the administration of Tacrolimus to a goal trough of 6-8 ng/mL immediately post transplant, Mycophenolate mofetil 1000-15000 mg BID, and Prednisone 1 mg/kg/day post-op divided into two doses and tapered by 5 mg Daily. A retrospective chart review was performed comparing transplant outcomes utilizing the novel LTR immunosuppression regimen compared to STR from 2008-2019. Primary outcomes included infection, bone marrow suppression and rejection within the first 3 years of transplantation. Of the 83 patients analyzed, 25 (30%) received the lower Tacrolimus dosing regimen (LDR), and 58 received the standard dosing regimen (SDR). Patients in the LDR group were younger (56.2 +/- 12.2 years vs 61.8 +/- 10.4 years) and less likely to be male (68% vs 87.9%). Rates of high risk CMV donor/recipient status was similar between the two groups. There was no statistically significant difference between the LDR group and SDR group with respect to rates of infection (44% vs 34.5%, p=0.41), bone marrow suppression (20% vs 13.8%, p=0.47), or > 2R CMR (24% vs 32.8%, p=0.42). In this single-center study we compared a conventional post-transplant immunosuppression regimen with one that utilized a lower Tacrolimus trough goal (6-8ng/mL). There was no statistical difference between the two groups in rates of rejection, bone marrow suppression, or infectious complications. We present a successful novel immunosuppression regiment that could serve to benefit patients with intolerance to higher doses of calcineurin inhibitors with no adverse outcomes. Future studies are needed to determine the impact of LTR on renal function.

Survival in the First Year of Heart Transplantation in a Center of a Developing Country, Infection versus Rejection as Causes of Mortality

Despite advances in recent years in the surgical technique, immunosuppression and management of complications, infection continues to be a major cause of morbidity and mortality in heart transplantation. Taking into account the allocation of resources by health systems, habits and socio-economic status of patients in Latin America, it is assumed that there is a higher risk of infection in these countries, but the actual effect of the infection on post-transplant survival, and if adapted prophylaxis schemes for opportunistic microorganisms correspond to the reality of the patients. The objective of this study was to determine the survival in the first year of the patients sometimes heart transplant, evaluate the clinical and microbiological characteristics of the infections according to 3 periods of post-transplant follow-up, and compare the mortality associated with the infection versus rejection in a heart transplant center in Colombia. Observational, analytical, retrospective study in a center of IV level in Medellín, Colombia. They included 133 cardiac transplanted patients between 2012 and 2016, the average age was 47.7 years (SD +/- 12 years), 86% were men and 64.7% the cause of the transplant was idiopathic heart disease. The average ischemia time was 218 min (SD 58.22 min). During the first year, 60 infections were considered (45.11%, 60/133), during the first month 21.05%, 29.9% of the month 2-6 and 14.73% in the month 7-12. The majority of infections were 45% viral, 33% bacterial and 6.3% fungal. During the first year after transplant, 18 patients died (13%), due to 9% infection and rejection (4.51%). In a transplant center in Colombia that does not perform universal prophylaxis for CMV, viruses are the first cause of post-transplant infection. The rate of invasive fungal infection is very low. Infections are the leading cause of post-transplant death, doubling the risk associated with rejection, they must establish effective measures for their control.

Thanatogenomic Investigation of the Hydroxymethylome and Mitochondrial Genome of Cadaveric Cardiomyocytes: Proposal for a Proof-of-Concept Study.

BackgroundCardiovascular disease (CVD) remains the leading cause of death in the United Arab Emirates (UAE). One of the common CVDs is hypertrophic cardiomyopathy (HCM). Recent studies conducted in heart cells of mice have shown that this condition involves a chemical modification called hydroxymethylation of the DNA of heart cells.ObjectiveObjectives of the proposed research are to profile the distribution of 5-hydroxymethylation in the cardiomyocyte (CMC) genome of cadaveric cardiac tissue and cardiac biopsy specimens; to compare the hydroxymethylome of cadaveric CMCs with that of cardiac biopsy specimens from HCM patients and/or cardiac transplant patients (control) undergoing cardiac catheterization; to histologically appraise sarcomere distribution and mitochondrial morphology of CMCs in the presence of HCM; to correlate the mitochondrial genome with the HCM phenotype; and to integrate anatomy with biochemistry and genetics into the instructional design of HCM in the core medical curriculum at Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU).MethodsNormal and hypertrophic heart specimens will be obtained from 8 whole-body cadavers (2/8, 25% control and 6/8, 75% HCM). Myocardial biopsy specimens will be obtained from cardiothoracic and transplant units at the Cleveland Clinic in Abu Dhabi, UAE. As this is a proof-of-concept study, we plan to recruit 5 patients with HCM, where HCM has been diagnosed according to the guidelines of the 2014 European Society of Cardiology Guidelines. Patients with valvular heart disease, history of myocarditis, regular alcohol consumption, or cardiotoxic chemotherapy will be excluded. The control biopsy specimens will be obtained from patients who had received heart transplants. Three investigational approaches will then be employed: (1) gross anatomical evaluation, (2) histological analysis, and (3) profiling and analysis of the hydroxymethylome. These investigations will be pursued with minor modifications, if required, to the standard protocols and in accordance with institutional policy. The objective associated with the education of health professionals will be addressed through a strategy based on Graham’s knowledge translation model.ResultsThis study is at the protocol-development stage. The validated questionnaires have been identified in relation to the objectives. The MBRU and the Cleveland Clinic Abu Dhabi Institutional Review Board (IRB) are reviewing this study. Further clarification and information can be obtained from the MBRU IRB. There is funding in place for this study (MBRU-CM-RG2019-08). Currently, we are in the process of standardizing the protocols with respect to the various molecular techniques to be employed during the course of the study. The total duration of the proposed research is 24 months, with a provision for 6 months of a no-cost extension.ConclusionsThe spectrum of CVDs has recently received significant focus from the public health sector in the UAE. HCM is a common familial heart disease, contributing to the sudden increase in the mortality rate of young Emiratis in the UAE. Incorporating artificial intelligence into the identification of epigenetic risk factors associated with HCM will promote accurate diagnosis and lead to the development of improved management plans, hence, positive patient outcomes. Furthermore, integration of these findings into the instructional design of undergraduate, postgraduate, and continuous professional development medical curricula will further contribute to the body of knowledge regarding HCM.International Registered Report Identifier (IRRID)PRR1-10.2196/17241

Right Ventricular Assist Devices After Heart Transplantation

BackgroundSevere right ventricular failure (RVF) has a significant incidence among cardiac transplant patients. It is a serious complication and an independent risk factor for postoperative mortality. In this setting, ventricular assist devices (VADs) must be considered if conservative medical management fails. This study sought to examine our series of patients with early RVF after heart transplantation requiring VAD support. MethodWe analyzed consecutive, adult heart transplant recipients at a third level intensive care unit who underwent transplantation from January 2011 to March 2019 requiring post-transplant mechanical circulatory support for RVF. Demographic characteristics, clinical data, complications, and survival rates were collected. ResultsTen patients were included. Median age was 50 years (range, 31.7-57). Eight patients (80%) were male. The most frequent indication for heart transplantation was ischemic heart disease (4 patients) followed by dilated cardiomyopathy and congenital heart disease (2 patients). Preoperative pulmonary hypertension was present in 6 patients. Three patients required a VAD before transplant. Whole survival rate was 60%. After heart transplantation, 7 patients required renal replacement therapy, 2 patients suffered a hemorrhagic stroke, and 5 patients needed a tracheostomy for long-term ventilation. ConclusionPatients who develop RVF after transplantation have an increased incidence of complications and high mortality after surgery. VADs could be implanted immediately after heart transplantation in high-risk patients.