Year Of Heart Transplantation Research Articles

Rejection Requiring Treatment within the First Year following Heart Transplantation: The UNOS Insight.

(1) Background: Heart failure is an extremely impactful health issue from both a social and quality-of-life point of view and the rate of patients with this condition is destined to rise in the next few years. Transplantation remains the mainstay of treatment for end-stage heart failure, but a shortage of organs represents a significant problem that prolongs time spent on the waiting list. In view of this, the selection of donor and recipient must be extremely meticulous, considering all factors that could predispose to organ failure. One of the main considerations regarding heart transplants is the risk of graft rejection and the need for immunosuppression therapy to mitigate that risk. In this study, we aimed to assess the characteristics of patients who need immunosuppression treatment for rejection within one year of heart transplantation and its impact on mid-term and long-term mortality. (2) Methods: The United Network for Organ Sharing (UNOS) Registry was queried to identify patients who solely underwent a heart transplant in the US between 2000 and 2021. Patients were divided into two groups according to the need for anti-rejection treatment within one year of heart transplantation. Patients' characteristics in the two groups were assessed, and 1 year and 10 year mortality rates were compared. (3) Results: A total of 43,763 patients underwent isolated heart transplantation in the study period, and 9946 (22.7%) needed anti-rejection treatment in the first year. Patients who required treatment for rejection within one year after transplant were more frequently younger (49 ± 14 vs. 52 ± 14 years, p < 0.001), women (31% vs. 23%, p < 0.001), and had a higher CPRA value (14 ± 26 vs. 11 ± 23, p < 0.001). Also, the rate of prior cardiac surgery was more than double in this group (27% vs. 12%, p < 0.001), while prior LVAD (12% vs. 11%, p < 0.001) and IABP (10% vs. 9%, p < 0.01) were more frequent in patients who did not receive anti-rejection treatment in the first year. Finally, pre-transplantation creatinine was significantly higher in patients who did not need treatment for rejection in the first year (1.4 vs. 1.3, p < 0.01). Most patients who did not require anti-rejection treatment underwent heart transplantation during the new allocation era, while less than half of the patients who required treatment underwent transplantation after the new allocation policy implementation (65% vs. 49%, p < 0.001). Patients who needed rejection treatment in the first year had a higher risk of unadjusted 1 year (HR: 2.25; 95% CI: 1.88-2.70; p < 0.001), 5 year (HR: 1.69; 95% CI: 1.60-1.79; p < 0.001), and 10 year (HR: 1.47; 95% CI: 1.41-1.54, p < 0.001) mortality, and this was confirmed at the adjusted analysis at all three time-points. (4) Conclusions: Medical treatment of acute rejection was associated with significantly increased 1 year mortality compared to patients who did not require anti-rejection therapy. The higher risk of mortality was confirmed at a 10 year follow-up. Further studies and newer follow-up data are required to investigate the role of anti-rejection therapy in the heart transplant population.

Early Post Heart Transplant Coronary Anatomic-Physiologic Characterization: ECAV Study

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) is a leading cause of mortality and graft failure after heart transplantation. Early detection of CAV and accurate prognostication are essential for development of novel therapies and tailored patient management. The goal of this prospective study is to characterize anatomic-physiologic alterations in the coronary vasculature in the first year of heart transplantation to determine coronary phenotypes and predictors of early CAV. <h3>Methods</h3> Consecutive adult heart transplant (HT) recipients were enrolled from 2 Canadian institutions between January 2018-March 2021 (NCT03217786). Participants underwent comprehensive coronary evaluation at 3- and 12- months post HT with invasive coronary angiography (ICA), intravascular ultrasound (IVUS), optical coherence tomography and measurements of fractional flow reserve, coronary flow reserve and the index of microcirculatory resistance. Additional assessments included serum biomarker testing, microvasculopathy evaluation on endomyocardial biopsy and myocardial blood flow quantification by cardiac positron emission tomography. CAV was defined on ICA according to the ISHLT CAV_0-3 grading scale. Rapidly progressive CAV was defined on IVUS as ≥0.5 mm increase in maximal intimal thickness between baseline and 12-month follow-up studies. <h3>Endpoints</h3> We will present data from 86 HT patients (baseline demographics in Table), phenotyping early post transplant longitudinal changes in the coronary intima (intimal volume, percentage intimal volume, plaque characteristics), vessel remodeling and hemodynamics. Regression analysis will be performed to identify coronary anatomic-physiologic predictors of rapidly progressive CAV. This data will determine the role of early post transplant invasive coronary assessments for early CAV detection and identify high-risk patients who may benefit from early therapeutic intervention and intensive surveillance.

Immunologic Abnormalities Associated With Health Status of Heart Recipients Long Term After Transplantation

With improvements in survival rates, health-related quality of life is an important outcome parameter to evaluate the effectiveness of transplantation. We aimed to identify potential immunologic abnormalities as factors associated with poorer health-related quality of life at distinct scales of the 36-Item Short Form Health Survey in heart transplant recipients long term after transplantation. One hundred heart transplant recipients were evaluated in a single center. Short-form 36 questionnaires were sent by mail to participants. All patients were clinically and immunologically evaluated after the first year of heart transplantation. A high prevalence of several immunologic abnormalities persisted even after the first year of transplantation, including IgG hypogammaglobulinemia, low IgG-specific antipneumococcal antibodies, C4 hypocomplementemia, CD8 T-cell lymphocytopenia, and CD19 B-cell lymphocytopenia. Older recipients (>55 years), posttransplant diabetes, digestive complications, and posttransplant infections were associated with lower physical functioning scores (scale < 60). Older recipients (>55 years), pretransplant diabetes, pretransplant arterial hypertension, posttransplant digestive complications, and lower CD8 counts were associated with lower physical role scores (scale <25). In a single center study, lower CD8 cell counts were found to be associated with poorer health status in heart recipients after the first year of transplantation.

Don't Go Breakin’ My Heart: Lack of Association between Granulocyte Colony Stimulating Factor and Development of Acute Cellular Rejection

Purpose Neutropenia commonly occurs after heart transplantation (HT) and granulocyte colony-stimulating factor (GCSF) may be used for treatment of neutropenia in this setting. Published data is lacking on the incidence and etiology of neutropenia, and the safety of GCSF with respect to subsequent risk of acute rejection. Methods This was a retrospective study in adult HT recipients from 2012-2018 at a single institution. All patients who received at least one dose of GCSF were identified and compared with patients without a history of therapy in the first year of HT. Patients were evaluated for acute cellular rejection (ACR) ≥2R within 3 and 12 months after GCSF. This was compared with the incidence of ACR in the non-GCSF group starting 4.5 months after HT (as the mean time to first neutropenic episode was 142 days in the GCSF group). Categorical variables were compared using the chi-square test. Results Of the 211 recipients included in the overall cohort, 71.1% were male, 58.3% were Caucasian, and 24.2% had ischemic cardiomyopathy. Mean age was 52.5 ± 12.1 years. In this cohort, 71 (33.6%) developed 136 episodes of neutropenia (mean 1.9 episodes/patient) requiring at least one dose of GCSF. Moderate (ANC 501-999/mcL) and severe (ANC ≤500/mcL) neutropenia was seen in 41.9% and 25% of cases, respectively. 78.9% of neutropenic cases were thought to be medication related based on chart review. Nearly all patients were induced with ATG (94.3%) and 24.6% were primary mismatch for cytomegalovirus. Each cycle of GCSF required on average 3.4 doses, with a mean total dose of 18.8 mcg/kg. The mean ANC nadir and peak was 850 ± 580/mcL and 7,520 ± 5,210/mcL, respectively. The mean time from HT to first neutropenic episode was 142 ± 100 days. Incidence of ACR ≥2R within the first 3 and 12 months was not significantly different between the GCSF (3 mo.: 9.9% and 12 mo.: 14.1%) and non-GCSF groups (3 mo.: 4.3% and 12 mo.: 18.6%) (p>0.05). Conclusion In this study, GCSF treated neutropenia occurred in one-third of patients within the first year after HT. GCSF does not appear to increase subsequent risk of ACR within the first year after GCSF administration.

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.

Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression

BackgroundHeart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure.MethodsWe generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression.ResultsBased on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10− 4].ConclusionsOur results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation.

Characteristics, risks, and outcomes of post-transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%-15% of patients within 3years. Data >3years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P=0.003) and Epstein-Barr virus (EBV) naivety (HR 1.65, P=0.02). Survival after late PTLD was 86% and 68% at 1 and 5years, with nonwhite race (HR 2.27, P=0.03) and earlier year of HT (HR 1.03, P=0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.

Risk of early, intermediate, and late rejection following heart transplantation: Trends over the past 25 years and relation to changes in medical management. Tertiary center experience: The Sheba Heart Transplantation Registry

To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25years, and their relation to changes in medical management. The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3months (early), 3-12months (intermediate), and 12+ months (late). HT era was dichotomized as follows: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, and everolimus) vs older therapies (AZA, CSA). Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR=0.44 [95% CI 0.22-0.88]), intermediate (OR=0.02 [95% CI 0.003-0.11]), and late rejections (OR=0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%, 21%, 18%, respectively). In contrast, the risk reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period. Major rejection rates following HT have significantly declined over the past 2 decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients.

IgG Hypogammaglobulinemia One Year After Heart Transplantation: A Persistent Risk Factor for Severe Infection.

Objective. We have previously described that IgG hypogammaglobulinemia (HGG: IgG<600 mg/dL) during the first month after transplantation is a risk factor for severe infection during the first year after heart transplantation. Our group remains concerned, however, about the persistence of this problem in a subgroup of patients long-term after transplantation and regarding its potential impact on infection risk. Hypothesis: HGG is a risk factor of severe infection long-term after transplantation. Objective: To characterize the prevalence of HGG and its impact on the prevalence of severe infections in heart recipients after the first year of transplantation. Methods. Design. Retrospective study. 122 heart recipients. IgG monitoring was performed at month 12 after transplantation by nephelometry. Clinical follow-up from one-year after transplantation to development of infection or latest visit: 24-111 months. Clinical outcomes: Severe infection defined as all infections that required antimicrobial therapy in hospital after the first year of transplantation. Statistics: Logistic regression. Results. The prevalence of HGG after transplantation was as follows: day 7 (35.4%), day 30 (50%), day 90 (33%), day 180 (23.7%), 1 year (18%). During the follow-up period after the first year of transplantation, 26 patients (21.3%) developed at least one episode of severe infection. Distribution of infection: Bacterial meningitis (n=1), bacterial pneumonia (n=10), other bacterial infections (n=6), CMV disease (n=5), other viral infection (n=1), systemic aspergillosis (n=1), intestinal strongyloidiasis (n=1), severe influenza A (n=1). HGG at month 12 was a risk factor of severe infection (Odds-ratio [OR] 24, p<0.001) and of deadly infections (OR 9.5, p=0.0037). Clinical variables that were associated with infection risk were: receptor negative for CMV serology and patients who had CMV or bacterial infections during the first year. In multivariate logistic regression analysis long-term HGG was an independent predictor of infection (OR 21, p<0.001) after adjustment by clinical variables. Conclusion: HGG at one year of heart transplantation is a risk factor of infection. IgG monitoring must be performed up to the first year after transplantation.

Association of Prior Implantation of HeartMate II Left Ventricular Assistive Device with Post-Heart Transplant Mortality

Purpose The impact of continuous-flow left ventricular assistive devices (LVAD) on post-heart transplant survival has not being well explored. This study investigates post-heart transplant mortality associated with prior implantation with the HeartMate II (HMII) LVAD in cohort of heart transplant recipients in the United Network for Organ Sharing (UNOS) database. Methods and Materials The study population includes patients (n=43,968) listed after April 2004 in the UNOS database– the era of continuous-flow LVADs. Of the 6,150 patients on LVADs, we further limited our sample to include only patients implanted with HMII LVAD prior to heart-transplantation (n=1,389) and those without any LVAD (n=19,693). Preliminary descriptive statistics suggested extensive heterogeneity in patient characteristics between HMII assisted patients and non-LVAD assisted patients. Subsequently, propensity scores were used to match HMII assisted patients and non-LVAD patients using these covariates – recipient characteristics (age, gender, race, UNO list status, duration on wait list, diabetes, BMI, education, kidney function, chronic comorbidities, ICD implantation, infection, acute graft rejection, inotropes use, and ischemic time), and donor characteristics (age, gender, race, and BMI). This resulted in a final control sample of 5,902, with a median age of 54 years (range, 18 – 77 years). Time from heart transplant to death was evaluated using both stratified and time-dependent CPH (spell out CPH) models. Results HMII was associated with higher risk of 30-day (HR=1.58, 95%CI: 0.83 – 2.72, p=0.18) and one-year mortality (HR=1.80, 95%CI: 1.10 – 2.94, p=0.02) with statistical significance observed for only one-year mortality. The use of HMII however was observed to be associated with lower risk of mortality after a year of post-heart transplant surgery, HR=0.62, 95%CI: 0.53 – 0.72, p Conclusions HeartMate II may improve post-heart transplantation survival among patients that survive past their first year of heart transplantation.

Patterns of Acute Cellular Rejection the First Year after Heart Transplantation: A Single Center Retrospective Study at Skåne University Hospital in Lund 1988-2010

Purpose Our purpose was to investigate patterns of acute cellular rejection (ACR) the first year after heart transplantation (HT). Methods and Materials Records from all 215 HT patients followed in Lund 1988-2010, including 219 HTs (five re-HTs) and 2990 endomyocardial biopsies (EMBs), were studied. Routine EMBs taken 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and extra EMBs taken upon suspicion of ACR, were graded according to the 1990-ISHLT-working-formulation. End of follow up was June 30, 2012. Results The frequency, and severity, of ACRs, were low, with 7% of routine and 14% of extra EMBs showing 1 st -year ACR≥grade 2. There were more (p st -year ACRs≥grade 2 among EMBs; in HTs performed 1988-1999 (9.56%, “Early Era”) than 2000-2010 (5.54%, “Late Era”) , performed 16-52 (8.82%) than 1-12 (6.33%) weeks after HT, in sex-mismatched (10.37%) than sex-matched HTs (6.32%) , and in HTs with pediatric (11.31%) than adult (7.11%) donors. Long-term survival was better (p st -year ACRs≥grade 2 compared to one or more 1 st -year ACRs≥grade 2; with 94% vs. 83% and 87% vs. 70% alive 5- and 10 years after HT, respectively. The same applied for patients with no 1 st -year ACRs≥grade 3A/3B compared to one or more 1 st -year ACRs≥grade 3A/3B; with 92% vs. 82% and 82% vs. 69% alive 5- and 10 years after HT, respectively. Conclusions The low frequency of 1 st -year ACRs≥grade 2 reflects an effective immunosuppression, resulting in high patient survival. The poorer long-term survival in patients with 1 st -year ACRs≥grade 2 and ≥grade 3A/3B stresses the importance of careful follow-up, with continuous adjustments of immunosuppression. The patterns of 1 st -year ACRs≥grade 2 in relation to year of HT, week after HT, sex-matching between recipient and donor, and age of donor, may provide guidance in treatment of ACR the first year after HT, and in selection of recipients and donors for HT.

Emergency Unprotected Left Main Percutaneous Coronary Intervention in a Heart Transplant Patient

Cardiac allograft vasculopathy is the leading cause of graft failure and death after the first year of heart transplantation. The optimal therapy for unprotected left main coronary artery disease in transplanted hearts has not been established. We report a case of emergency unprotected left main percutaneous coronary intervention in a transplanted heart after an aborted sudden death in a patient who was waiting for coronary artery bypass graft surgery.

475 Correlation of Immunological Markers with Graft Vasculopathy Development in Heart Transplantation

Heart transplantation (HT) remains the tretament of choice in patients with end-satge heart failure. Cardiac allograft vasculopathy (CAV) is the major cause of death after the first year of HT. Althought CAV is thought to be multifactorial in origin it is primarily an immune mediated disease. When CAV is diagnosed by coronary angiography usually the disease is fare advanced. There is a need to develop and test, non-invasive surrogate markers capable of its early detection.The main objective of this study is the assessment of immunological markers as mediators of CAV development.

Treatment of Left Main Coronary Artery Stenosis with Drug-Eluting Stent Following Heart Transplantation

Cardiac allograft vasculopathy is the leading cause of death after the first year of heart transplantation. The optimal treatment for unprotected left main coronary artery disease in orthotopic heart transplantation (OHT) patients is unknown. Two OHT patients with left main disease following heart transplantation underwent percutaneous coronary intervention (PCI). Technical success was achieved in the patients with drug-eluting stents inserted to cover the lesions in the left main coronary artery. After 16 months follow-up, one patient died of multiorgan failure, the other was alive and free from myocardial infarction or target vessel revascularization. We conclude that the unprotected PCI for the left main coronary artery stenosis in transplanted heart is feasible.

Assessment of Immunological Markers as Mediators of Graft Vasculopathy Development in Heart Transplantation

Heart transplantation (HT) remains the treatment of choice for patients with end-stage heart failure. Cardiac allograft vasculopathy (CAV), a diffuse form of coronary atherosclerosis, is the major cause of death after the first year of HT. CAV is thought to be multifactorial in origin. Although nonimmune factors may play a role in CAV development, it is primarily an immune-mediated disease. CAV is diagnosed by routine annual coronary angiography, and usually when diagnosed, the disease is advanced. There is a need to develop noninvasive surrogate markers for early detection. For this purpose, careful immune monitoring and graft histologic assessment are mandatory. The main objective of this study was the assessment of immunologic markers as mediators of CAV development in HT. Flow cytometry was performed to assess peripheral blood mononuclear cell populations forming CD3, CD4, CD8, CD19, CD56, Th1 (CD3+IFNγ+) or Treg (CD4+CD25highFoxP3+) markers among 20 de novo HT recipients. The control group included 13 patients who were more than 2 years post-HT (four with and nine without CAV) as well as 20 healthy subjects. CAV-related events over 2 years' follow-up correlated with the Th1/Treg ratio. An increased Th1 lymphocyte percentage was detected over the follow-up. Patients with medium and high Th1/Treg ratios showed higher acute rejection scores as well as greater incidences of CAV. These results indicated that the Th1/Treg ratio may represent a valuable marker to monitor allospecific T-cell responses in peripheral blood. Changes in the Th1/Treg ratio may help in the early detection of patients at risk for CAV. More studies with longer follow-up are needed to confirm these preliminary results.

Do clinical diagnoses correlate with pathological diagnoses in cardiac transplant patients? The importance of endomyocardial biopsy

Heart transplantation remains the last treatment option for patients with end-stage cardiac disease. Such diseases include ischemic cardiomyopathy, nonischemic cardiomyopathy and other conditions such as arrhythmogenic right ventricular dysplasia, cardiac sarcoidosis and cardiac amyloidosis. To review the changes that have occurred over time in the etiology of heart disease in patients requiring heart transplantation, and to compare the clinical and histological diagnoses of explanted hearts from patients with progressive cardiac disease. The pathological findings of 296 surgically excised hearts over a 20-year period (January 1987 to July 2006) at one institution were examined. Patients were separated into groups based on year of heart transplantation. The tissue was examined to determine the underlying cardiac pathology leading to congestive heart failure. Patient records were reviewed for preoperative clinical diagnoses and other relevant data, including pretransplant endomyocardial biopsy (EMB) results, information regarding left ventricular assist devices and, finally, evidence of disease recurrence in the grafted heart. A shift in the underlying etiology was found in patients who underwent heart transplantation from 1992 to 1996, and 1997 to 2001. Between 1987 and 1997, the majority of transplant cases consisted of ischemic cardiomyopathies. From 1997 to 2001, the majority of patients had nonischemic cardiomyopathies, and this trend continued to 2006. A majority of patients with ischemic and hypertrophic cardiomyopathy were diagnosed correctly (96.5% and 82%, respectively) before transplantation. Most patients diagnosed post-transplant with lymphocytic (viral, 15%), hypersensitive/ eosinophilic (25%) and giant cell (100%) myocarditis, arrhythmogenic right ventricle dysplasia (100%), cardiac sarcoidosis (83%) and iron overload toxicity- associated cardiomyopathy (100%) had been misdiagnosed in pretransplantation investigations. Investigations before transplantation did not include an EMB. Of all 296 patients, 51 patients (17%) were misdiagnosed. Excluding the patients with ischemic cardiomyopathy, 46 of 152 patients (30%) were misdiagnosed before transplantation. Although cardiac transplantation is a viable treatment option for patients with a variety of cardiac diseases, accurate diagnosis of patients before transplantation remains a priority. Accurate diagnosis of particular diseases (sarcoidosis, myocarditis, iron toxicity-associated cardiomyopathy and others) allows for proper treatment before transplantation, which may slow down disease progression and improve patient outcomes. Furthermore, it is important to accurately diagnose patients with diseases such as sarcoidosis, amyloidosis and particular types of myocarditis because these can readily recur in the grafted heart. The risk for recurrence must be known to practitioners and, most importantly, to the patient. We strongly recommend the use of EMB if a nonischemic cardiomyopathy is suspected, because the results may alter the diagnosis and modify the treatment strategy.

Abstract 2093: Myocardial Upregulation of mRNA Angiotensin II Receptor Subtype 1 (AGTR1) at One Year of Heart Transplantation is Associated with Worse Long-term Clinical Outcome Including Skin Cancer.

Background: We have previously shown that myocardial upregulation of mRNA gene expression of angiotensin II receptor subtype 1 (AGTR1) is associated with transplant vasculopathy evidenced by coronary intravascular ultrasound at one year following heart transplantation. Objectives: This study was undertaken to evaluate the long-term clinical outcome of heart transplant patients in relation to upregulation of mRNA AGTR1. Methods: A total of 45 heart transplant patients, mean age 55±12 years (78% male) had heart biopsy analysis for mRNA AGTR1 (Taqman PCR) at one year of transplantation. Dual Immunofluorescence staining for AGTR1 and vWF was also performed. Patients were divided into 2 groups according to the mRNA AGTR1 expression: Group I (n= 24), AGTR1 ≤2.0 and Group II (n=21), AGTR1 &gt; 2.0. Patients underwent annual coronary angiography and were followed up for a mean period of 7.6±2.1 years. Transplant coronary vasculopathy was defined as angiographic evidence of coronary obstruction greater than 30% in the absence of donor coronary artery disease. Results: The 2 groups had similar baseline characteristics. During follow up, Group II patients tended to have increased risk of diabetes mellitus (57.1% versus 29.2%, P= 0.058) and renal insufficiency (61.9% versus 33.3%, P= 0.055) defined by serum creatinine greater than 1.5 mg/dl. Group II patients had a worse survival (10 year K-M survival: 61% versus 86%, log-rank P= 0.061) and increased vasculopathy (10 year K-M freedom from vasculopathy: 19% versus 66%, log-rank P= 0.036). Since the renin-angiotensin system has been implicated in the development of various cancers, we also evaluated the clinical outcome of malignancy in relation to mRNA AGTR1. Interestingly, the 10 year K-M freedom from any malignancy tended to be worse in Group II patients (46% versus 77%, log-rank P= 0.063) and statistically significantly different in skin cancer (57% versus 86%, log-rank P= 0.034). Conclusions: Myocardial upregulation of mRNA AGTR1 at one year of heart transplantation is associated with worse clinical outcome including skin cancer. These findings may call for the need of prospective randomized trials to evaluate if the natural course of these patients could be altered with the use of angiotensin receptor blockers.

Lowering Asymmetric Dimethylarginine (ADMA) concentrations suppresses graft coronary artery disease in a murine heterotopic heart transplantation model

Aims: Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. A reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in the development of endothelial dysfunction and the structural changes, characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We investigated whether lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient suppresses GCAD and long-term immune response in murine cardiac allografts.

Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease

Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. The reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in endothelial vasodilator dysfunction and the structural changes that are characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We hypothesized that lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient might suppress GCAD and long-term immune responses in murine cardiac allografts. In one series, donor hearts of C-H-2(bm12)KhEg (H-2(bm12)) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2b) transgenic mice overexpressing human DDAH-I or WT littermates and procured after 4 hours of reperfusion (WT and DDAH-I recipients, n=6 each). In a second series, donor hearts were transplanted into DDAH-I-transgenic or WT mice and procured 30 days after transplantation (n=7 each). In DDAH-I recipients, plasma ADMA concentrations were lower, in association with reduced myocardial generation of superoxide anion (WT versus DDAH-I, 465.7+/-79.8 versus 173.4+/-32.3 micromol.L(-1).mg(-1).h(-1); P=0.02), inflammatory cytokines, adhesion molecules, and chemokines. GCAD was markedly reduced in cardiac allografts of DDAH-I-transgenic recipients as assessed by luminal narrowing (WT versus DDAH, 79+/-2% versus 33+/-7%; P<0.01), intima-media ratio (WT versus DDAH, 1.1+/-0.1 versus 0.5+/-0.1; P<0.01), and the percentage of diseased vessels (WT versus DDAH, 100+/-0% versus 62+/-10%; P<0.01). Overexpression of DDAH-I attenuated oxidative stress, inflammatory cytokines, and GCAD in murine cardiac allografts. The effect of DDAH overexpression may be mediated by its reduction of plasma and tissue ADMA concentrations.

End-stage renal failure and cardiac mortality after heart transplantation.

Coronary artery disease (CAD) is the leading cause of mortality after the first year of heart transplantation. End-stage renal failure (ESRF) is more frequent because of long-term survival. Impact of ESRF on cardiac mortality in heart transplant patients is unappreciated. The hypothesis of accelerated CAD in uremic patients has been suggested. In Pitié La Salpêtrière hospital, 1211 heart transplants have been performed between 1982 and 2001. Thirty-three patients have reached ESRF. A case-control study was performed to identify risk factors responsible for ESRF and to appreciate the impact of ESRF on cardiac mortality. In cases at 6 months, serum creatinine tended to be higher (159 +/- 31 micromol/L vs. 141 +/- 44 micromol/L, p = 0.06) and cyclosporine (CSA) dosage (mg/kg) was significantly lower (5.4 +/- 1.8 mg/kg vs. 7.7 +/- 2.7 mg/ kg, p = 0.002). Mean triglyceride level after transplantation until dialysis was significantly lower in cases (2.18 +/- 0.82 mmol/L vs. 1.48 +/- 0.62 mmol/L, p = 0.002). In cases and controls, cardiac mortality was responsible for 67% (10 of 15) and 38% (three of eight) of all deaths, respectively. High triglyceride level (> or = 2 mmol/L) was associated with cardiac mortality [p < 0.03, hazard ratio (HR) = 3.89]. Kaplan Meier cardiac free survival rates were significantly lower in cases than in controls (p < 0.03). These data suggest that CSA nephrotoxicity could result from individually determined susceptibility and that hypertriglyceridemia may have a negative impact on renal function and cardiac mortality. The risk of cardiac mortality is increased in heart transplant patients with ESRF. The hypothesis of accelerated atherosclerosis in ESRF patients after heart transplantation leading to higher cardiac mortality incidence needs further study.