Search

Hypomagnesemia is commonly observed in heart transplant (HT) recipients receiving calcineurin inhibitors. Since low serum magnesium (s-Mg) has been implicated in the progression of atherosclerosis, potentially leading to worsening coronary heart disease, arrhythmias and sudden death, we investigated the association between s-Mg and HT outcomes. Between 2002 and 2017, 150 HT patients assessed for s-Mg were divided into high (≥1.7 mg/dL) and low s-Mg groups according to the median value of all s-Mg levels recorded during the first 3 months post-HT. Endpoints included survival, cardiac allograft vasculopathy (CAV), any-treated rejection (ATR) and NF-MACE. Kaplan-Meier analysis showed that at 15 years after HT, both survival (76 vs 33%, log-rank p = 0.007) and freedom from CAV (75 vs 48%, log-rank p = 0.01) were higher in the high versus low s-Mg group. There were no significant differences in freedom from NF-MACE or ATR. Multivariate analyses consistently demonstrated that low s-Mg was independently associated with a significant 2.6-fold increased risk of mortality and 4-fold increased risk of CAV (95%CI 1.06 to 6.4, p = 0.04; 95%CI 1.12 to 14.42, p = 0.01, respectively). In conclusion, low s-Mg is independently associated with increased mortality and CAV in HT patients. Larger multi-center prospective studies are needed to confirm these findings and to examine the effect of Mg supplementation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT)., Methods: Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association., Results: Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15-32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02-6.77, p = 0.05)., Conclusions: Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.

Purpose: We investigated the implications of early recurrent 1R rejections for long-term outcomes after heart transplantation (HT) and evaluated the prognostic significance of 1990 ISHLT grading 1B/2 versus 1A., Methods: Data on all patients who underwent HT between 1992 and 2017 were reviewed. Patients with ≥2 endomyocardial biopsies graded 1R in the first 3 months were classified as "recurrent 1R." Those patients were further categorized according to 1A vs. 1B/2. Outcomes (>3 months) were long-term rejections and the combined endpoint of cardiac allograft vasculopathy (CAV) and cardiovascular (CV) mortality., Results: Sixty-nine out of 228 patients were classified as recurrent grade 1R. In the recurrent 1R group, 2R rejection rate was significantly higher (2.6 ± 0.6 vs 1.2 ± 0.4, p = 0.03), while survival free of rejections was lower (5-year: 57.1% vs. 72.3%, p = 0.022). Multivariate analysis showed that early recurrent 1R rejection was associated with a 30% increased risk for subsequent major rejection. Among 28 patients classified as 1B/2 of the recurrent group, rejection scores were higher, while survival free of rejections was lower, compared to 37 patients of the recurrent group classified as 1A (5-year: 57.1% vs. 72.7%, p = 0.013). Kaplan-Meier analysis showed that CAV/CV mortality at 10 years of follow-up was significantly higher among the recurrent 1R group (38% vs. 18% p < 0.05). Multivariate analysis showed that early recurrent 1R rejections were associated with a 2.5-fold increased risk for CAV/CV mortality., Conclusion: Early recurrent grade 1R rejections negatively affect long-term outcomes. The adverse outcomes are experienced mainly by 1R patients subcategorized as1B/2 and not 1A., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The donor's mode of brain death (BD), being associated with impairment of myocardial function and hemodynamic performance, impacts the prognosis of the heart transplantation (HTx) recipient., Methods: All patients who underwent HTx between 1996 and 2017 were categorized according to donor's BD mechanism: traumatic BD (TBD) versus non-traumatic BD (NTBD)., Results: The TBD group included 105 recipients, and the NTBD group, 85 recipients. Kaplan-Meier survival analysis showed that overall survival was significantly higher for recipients of TBD hearts (10-year survival 58.1 vs. 37.6%, p = 0.044). Consistently, multivariate analysis showed that TBD was independently associated with a significant 43% reduction in mortality [95% confidence interval (CI) 0.42-0.75, p = 0.033]. Rejection rate was lower in the TBD group (total rejection score 0.44 ± 0.32 vs. 0.51 ± 0.38, p = 0.04; any rejection score 0.38 ± 0.26 vs. 0.45 ± 0.31, p = 0.030), and freedom from cardiac allograft vasculopathy (CAV) was significantly higher in recipients of traumatic vs. non-traumatic donors (10 years: 82.9 vs. 62.4%, log-rank p-value = 0.024). Multivariate analysis showed a significant 42% reduction in CAV [hazard ratio (HR) = 0.58, 95% CI 0.51-0.85, p = 0.022)., Conclusion: Mode of brain death significantly impacts HTx outcomes, with TBD being associated with reduced mortality, rejections and CAV.

Objective: Potential interactions between donor-recipient age difference and outcomes after heart transplantation are not well known. We thus aimed to study the impact of donor-recipient age difference on heart transplantation outcomes., Methods: Between 1995 and 2017, we assessed 234 heart transplantation patients. Based on donor-recipient age difference histogram, we stratified these patients into three groups: older donors (donor-recipient difference > 0; n = 48), younger donors (donor-recipient difference 0 to -20 years; n = 82), and much younger donors (donor-recipient difference <-20 years; n = 104)., Results: The baseline metabolic risk profile of the recipients was significantly higher for the much younger donor group compared with the younger and older groups, including hypertension (52% vs 33% vs 25%, P = 0.002), dyslipidemia (51% vs 51% vs 29%, P = 0.027), diabetes (30% vs 16% vs 17%, P = 0.044), and smoking history (53% vs 46% vs 29%, P = 0.024), respectively. There were no significant differences between the groups in long-term survival, cardiac allograft vasculopathy, or rejection-free survival in unadjusted and adjusted analyses. In the much younger donor group, gender matching was associated with a lower incidence of primary graft dysfunction (37% vs 58% P = 0.05)., Conclusions: Donor-recipient age difference does not significantly impact long-term heart transplantation outcomes., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Ethnicity may affect graft longevity and recipient mortality after heart transplantation (HTx). We hypothesized that differences in ethnic origin between Arabs and Jews undergoing HTx in Israel may contribute to differences in long-term outcomes., Methods: The study population comprised all 254 patients who underwent HTx between 1991 and 2017 in a tertiary medical center located in the center of Israel. Patients were categorized as either Jews (226 patients, 89%) or Arabs (28 patients, 11%). The primary end point was cardiac allograft vasculopathy (CAV), secondary end points were cardiovascular (CV) mortality and the combined end point of CAV/CV mortality., Results: In comparison with Jews, Arab patients were significantly younger (ave. age 42 vs. 50) and had shorter in-hospital stay (45 vs. 80 days). However, Kaplan-Meier survival analysis showed that at 10 years of follow-up CAV rates were significantly higher among Arabs (58%) compared with Jews (23%; log-rank P = 0.01) for the overall difference during follow-up. Similar results were shown for the separate end point of CV mortality and the combined end point of CAV/CV mortality. Multivariate analysis, which controlled for age, gender, statin treatment, and other potential confounders, showed that Arab recipient ethnic origin was associated with a significant > 2.5-fold (p = 0.01) increase in the risk for CAV; a > 4-fold increase in the risk for CV mortality (p = 0.001); and approximately 4-fold increase in the risk for the combined end point (p = 0.001). These findings were validated by propensity score analysis., Conclusions: Our data suggest that Arab ethnic origin is associated with a significantly increased risk for CAV and mortality following HTx. Suggested explanations contributing to ethnic disparities in Israel include socioeconomic, environmental and genetic factors. Further studies are required to evaluate whether more aggressive risk factor management in the Israeli Arab population following HTx would reduce CAV and CV mortality in this high-risk population. Increased awareness and early intervention of the Israeli healthcare system and cooperation with the Arab community is of paramount importance.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The impact of donor-recipient ethnic matching on heart transplantation (HT) has been poorly studied with inconclusive results. We aimed to investigate the impact of ethnic matching on HT outcomes in Israeli multiethnic patients., Methods: The study comprised 168 patients who underwent HT from 1990-2017. Patients and their donors were ethnically categorized to Jews and Arabs. Primary end points were all-cause in-hospital and late mortality; secondary end points included primary graft dysfunction (PGD), rejections, and vasculopathy., Results: Donor-recipient ethnic matching was found in 111 patients, while 57 were ethnically mismatched. Baseline characteristics were similar in both groups. Ethnic mismatching was associated with >7-fold (P = 0.018) increased risk for in-hospital mortality and >8-fold (P < 0.001) increased risk for PGD. Kaplan-Meier survival analysis showed that overall survival at 10 years was significantly higher among matched patients (73% vs 43%, log-rank P < 0.001). Multivariate analysis showed that ethnic mismatching was associated with an approximately fourfold higher risk for death (P < 0.01). These findings were validated by propensity score analysis. The ethnic mismatched group experienced significantly higher rejection rates compared with the matched group with lower survival free of rejections (log-rank P = 0.029). No differences in vasculopathy were found., Conclusions: Donor-recipient ethnic mismatch is an important independent predictor of early- and long-term outcomes following HT, and is associated with increased risk for PGD, rejections, and mortality. These findings will help to design tailored treatment protocols leading to improved outcomes after HT., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Heart transplantation (HT) is the treatment of choice for patients with end-stage heart failure. The HT unit at the Sheba Medical Center is the largest of its kind in Israel., Objectives: To evaluate the experience of HT at a single center, assess trends over 3 decades, and correlate with worldwide data., Methods: Between 1990 and 2017, we reviewed all 285  adult HT patients. Patients were grouped by year of HT: 1990-1999 (decade 1), 2000-2009 (decade 2), and 2010-2017 (decade 3)., Results: The percentage of women undergoing HT has increased and etiology has shifted from ischemic to non-ischemic cardiomyopathy (10% vs. 25%, P = 0.033; 70% vs. 40% ischemic, for decades 1 vs. 3, respectively). Implantation of left ventricular assist device as a bridge to HT has increased. Metabolic profile has improved over the years with lower low-density lipoprotein, diabetes, and hypertension after HT (101 mg/dl, 27%, and 41% at decade 3, respectively). There has been a prominent change in immunosuppressive treatments, currently more than 90% are treated with tacrolimus, compared with 2.7% and 30.9% in decades 1 and 2, respectively (P < 0.001). Cardiac allograft vasculopathy (CAV) rates have declined significantly (47% vs. 17.5% for decades 1 and 2, P < 0.001) as have the combined endpoint of CAV/death. Similarly, the current incidence of acute rejections is significantly lower., Conclusions: Our analysis of over 25 years of a single-center experience with HT shows encouraging improved results, which are in line with worldwide standards and experience.

Aim: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality after heart transplantation (HT). Enhanced platelet reactivity is a contributing factor. We aimed to investigate the association between early initiation of aspirin therapy post-HT and the 15-year risk of the development of CAV., Methods: We studied 206 patients who underwent HT between 1991 and 2016. Multivariate Cox proportional hazards regression modeling was employed to evaluate the association between early aspirin initiation and the long-term risk of CAV., Results: Ninety-seven patients (47%) received aspirin therapy. At 15 years of follow-up, the rate of CAV was lowered by sixfold in patients treated with aspirin compared with the non-treated patients: 7% vs 37% (log-rank P-value<.001). The corresponding rates of the combined end-point of CAV or death were also lower in patients treated with aspirin, compared with the non-treated patients: 42% vs 78% (log-rank P < .001). Consistently, multivariate analysis showed that early aspirin therapy was associated with a significant 84% (P < .001) reduction in CAV risk, and with a corresponding 68% (P < .0001) reduction in the risk of the combined end-point of CAV or death. We further validated these results using a propensity score-adjusted Cox model., Conclusions: Early aspirin initiation is independently associated with a significant reduction in the risk of CAV., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx., Methods: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses., Results: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients., Conclusions: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aim: To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management., Methods: The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3 months (early), 3-12 months (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)., Results: 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., Conclusions: 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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nonadherence (NA) to immunosuppressive (IS) medications after organ transplant is a major risk factor for transplant failure, morbidity, and treatment costs. This study examined the association between feelings of indebtedness and guilt toward the donor, and IS medication adherence among HTx patients., Methods: In this cross-sectional, descriptive, correlational study, a convenience sample of 102 HTx patients, from the outpatient facility of a tertiary medical center in Israel, completed the BAASIS, a validated instrument for assessing adherence, and reported their feelings of indebtedness and guilt toward the donor., Results: Missing a dose or skipping two or more doses, taking medication >2 hours before or after the recommended dosing time, altering the prescribed amount, or completely stopping the IS treatment in the last 4 weeks, characterized 64 patients (64%). The highest score received the item "timing nonadherence," characterizing 58 patients (56.9%). Age, waiting time, and time since transplant, guilt feelings, and indebtedness to donor explained 17% (R 2 =.17) of the variance in adherence (χ 2 (5) =13.22, P=.021), with age, time since transplant, and guilt feelings significantly explaining adherence., Conclusion: Physicians and nurses should inquire about the presence of guilt feelings, as they might be associated with NA to medications after HTx., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The shortage of available donor hearts limits the number of cardiac transplantations worldwide and in Israel as well. This organ shortage results in 15%-20% annual mortality of heart transplant candidates. For the sub-group of hospitalized decompensated heart failure patients depending on continuous inotropic support (Status I), the annual mortality is over 50%. Suboptimal utilization of donor hearts has been one of the reasons for the organ shortage. In 2004, only 42% of the potential donor hearts in Israel were eventually transplanted. The objective of this report is to define guidelines regarding the suitability of potential cardiac donors allowing more liberal criteria for accepting borderline donor hearts. Implementing the new guidelines will permit the utilization of organs that otherwise would have been discarded.

Background: Patients in cardiogenic shock (CS) or with terminal heart failure (THF) are at imminent risk of death while waiting for heart transplantation (HTx). Implantation of left or bi-ventricular assist device (LVAD/BiVAD) as a bridge to HTx may save many of these doomed patients' lives., Patients and Methods: Between March 1994 and December 2006, 29 terminally ill patients (age 2.5-65 years, mean 48 years) underwent VADs implantation as bridge to HTx. The HeartMate VE LVAD was used in 18 patients, Thoratec pneumatic BiVAD in 7, Berlin Heart Excor BiVAD in one, and HeartMate II axial flow, Thoratec pneumatic and Biomedicus centrifugal LVADs in one each. Indications for VADs implantation were CS in 16 patients (55%) and intractable THF in 13 pts (45%). Etiologies were ischemic in 20 patients, idiopathic dilated, myocarditis and congenital in 2 patients each, and valvular, post partum and HTx graft vasculopathy in one patient each., Results: Seventeen patients (59%) survived VADs implantation and underwent HTx or are ongoing. Mean survival on VADs was 72 days (range 1-353 days, total 5.2 patient years). Seven patients (24%) were discharged home while on LVAD support for a mean of 146 days. Nine of the transplanted patients (64%) were discharged home. In 4 LVAD patients the cause of death was RV failure necessitating later implantation of RVAD., Conclusions: VADs implantation as bridge to HTx in CS or THF saves many of these doomed patients, sometimes providing quality out-of-hospital life while waiting for HTx. Early recognition of RV failure and liberal use of BiVAD is important.

Purpose: We hypothesized that total orthotopic heart transplantation (TOHT) improves humoral rejection hemodynamics compared with biatrial transplantation or standard orthotopic heart transplantation (SOHT)., Methods: We reviewed 1942 biopsies from 134 patients (pts) and right heart catheterization data obtained at endomyocardial biopsy. Biopsies that displayed humoral rejection by histological findings and positive immunofluorescence for immunoglobulins and complement were analyzed. Patients with pacemakers, atrial fibrillation or beta-blocker therapy at the time of biopsy were excluded. Thirty-two pts after TOHT and 22 after SOHT matching these criteria were identified., Results: Demographic data, underlying disease, pretransplant hemodynamics, and donor demographics were similar. Cardiac output and index were higher in the total orthotopic group (5.9+/-1.1 vs 5.1+/-1.4 L/min, p=0.027; 3.3+/-0.5 vs 2.8+/-0.6 L/min/m2, p=0.016). Right atrial and pulmonary capillary wedge pressure were lower after TOHT (7+/-3 vs 11+/-5 mmHg, p<0.001; 13+/-4 vs 16+/-5 mmHg, p=0.035). Pulmonary pressures, pulmonary vascular resistance and heart rate were similar., Conclusion: TOHT offers improved hemodynamics during humoral rejection as evidenced by higher cardiac output and index with lower right atrial and pulmonary capillary wedge pressures. Future studies must examine the potential benefits of TOHT during combined cellular and humoral rejection events.

Background: We hypothesized that total orthotopic heart transplantation (TOHT) improves hemodynamics during cellular rejection compared with biatrial transplantation (SOHT)., Methods: We reviewed 1942 biopsies from 134 patients (pts) and right heart catheterization data obtained at endomyocardial biopsy. Biopsies that displayed cellular rejection grade 1B as classified according to International Society for Heart and Lung Transplantation (ISHLT) criteria were analyzed. Pts with pacemakers, atrial fibrillation, or beta-blocker therapy at the time of biopsy were excluded. Twenty-three pts after TOHT and 38 after SOHT were identified to match these criteria., Results: Demographic data and pretransplant hemodynamics were similar. TOHT pts had a higher mean cardiac index than SOHT recipients (3.3 +/- 0.8 vs 2.7 +/- 0.5 L/min/m(2); P =.002). Right atrial mean pressure was lower after TOHT (8 +/- 4 vs 11 +/- 4 mm Hg; P =.006). Pulmonary pressures, pulmonary vascular resistance, and heart rate were similar., Conclusions: TOHT offers improved hemodynamics during cellular rejection grade 1B as evidenced by higher cardiac output and index with lower right atrial pressures. Future studies must examine the potential benefits of TOHT during more severe rejection events.

Background: Vascular endothelial cells are primary targets for injury during both cellular and humoral allograft rejection (AR). In cardiac transplantation, the role of humoral immunity in mediating AR has not been extensively characterized., Methods: Antibodies against human vascular endothelial cells (AECA) were measured using a cellular ELISA developed from human umbilical vein endothelial cells in 80 consecutive patients after cardiac transplantation. The aim was to determine the incidence of AECA formation after transplantation and their association with different types of AR, graft survival, and development of cardiac allograft vasculopathy (CAV). At least eight serum samples obtained from each patient were examined for AECA and an endomyocardial biopsy was performed at regular intervals during the first year after transplantation., Results: Of the 80 patients examined, 31 were AECA (+) and 49 patients were AECA (-). There were no significant differences between the AECA (+) and (-) groups when examined for age, sex, and pretransplantation ischemia time. A significant correlation was found between the presence of AECA and humoral AR (P<0.015). AECA positivity did not correlate with the presence of cellular AR or the number of rejection episodes. In addition, allograft survival at 2 years after transplantation was significantly better in the AECA (-) group compared with that in the AECA (+) group (89.8% vs. 71.0%, P<0.0004). The persistence of AECA positivity during the first year after transplantation was also associated with a significantly greater incidence of CAV when compared with the patients who were AECA (-) (25.8% vs. 14.3%, P<0.004)., Conclusions: AECA may be important in the mediation of humoral AR, may decrease allograft survival, and may identify a high-risk group for CAV.

Background: Alcohol has potential deleterious effects on donor heart function. This study was conducted in rats to determine whether long-term alcohol ingestion produces impaired hemodynamic performance while maintaining a normal left ventricular ejection fraction in donor hearts before transplantation and whether donor cardiac function is affected after heart transplantation., Methods: Rats fed 30% alcohol in their drinking water for 12 weeks were compared with rats fed a normal diet. Left ventricular ejection fraction was measured by echocardiography with Simpson and single plane Dodge formulas in living sedated rats after 10 and 12 weeks of alcohol feeding. Explanted heart function was assessed before and 3 days after heterotopic heart transplantation (no immunosuppression) with a Langendorff preparation., Results: Blood ethanol levels at 4 and 8 weeks were 0.08 +/- 0.04 and 0.08 +/- 0.09 gm/dl. Left ventricular ejection fraction was similar in the group fed an alcohol diet for 12 weeks when compared with the control group (65.4% +/- 1.6% vs. 66.5% +/- 2.9%, p = 0.33). Explanted alcohol-fed hearts before transplantation had significantly lower maximum and developed pressures and had a blunted response to 0.1 ml 10(-9) mol/L isoproterenol. After transplantation alcohol-fed hearts had significantly lower maximum and developed pressures and decreased maximum rates of pressure rise and pressure decline. Allografts (ACI to Lewis) exhibited decreased function in comparison with isografts (ACI to ACI)., Conclusions: Alcohol feeding for 12 weeks in rats does not affect pretransplantation left ventricular ejection fraction, but it impairs explanted heart function, both before and after transplantation, resulting in a subclinical cardiomyopathy that is worsened by the presence of allograft rejection. Long-term alcohol exposure and rejection have independent, additive detrimental effects on left ventricular performance of the transplanted heart. Alcohol-exposed hearts may not be suitable donors.

Discussions of the ethics involved in allocating scarce resources often proceed without a grounding in factual experience. This study explored whether there was statistical evidence to support the use of set age limits in patient selection criteria for heart transplantation. Many transplant teams have selection criteria that include age limits, excluding patients more than 60 or 65 years of age from being considered as transplant candidates. The hypothesis was made that patients in the age bracket of 60-69 should have a comparable success rate with transplantation to that of younger recipients when selected by using the same medical and psychiatric criteria. Based on their clinical observations, the authors postulated that the elderly would report better quality of life postoperatively than younger control subjects.

The effective treatment of refractory allograft rejection with murine antihuman monoclonal antibody muromonab-CD3 (OKT3) and of patients with renal dysfunction has led to its use as induction therapy. The optimal protocol for OKT3 prophylaxis remains to be established. We compared 59 patients consecutively transplanted with the total orthotopic technique between 1/92 and 5/94. The first 21 patients were treated with OKT3 for 14 days, the next 19 for 10 days, and the last 19 for 7 days. Patients operated with different surgical techniques or other induction treatment were excluded. We compared length of stay (total and ICU), time to first rejection, rejection incidence and infection incidence (cytomegalovirus separately), and survival. Preoperative characteristics were similar except for significantly younger age in the 10-day group (p = 0.04). Preoperative hemodynamic parameters were similar except for a significantly higher left-ventricular ejection fraction (21%) in the 7-day group. Length of stays in the ICU and hospital were similar for the three groups (p = NS). Freedom from cellular rejection was lower with the 7 days course (p = 0.02), but freedom from humoral rejection was slightly higher (p = 0.11). However, patients in the 7-day group required treatment for rejection less frequently than patients in the other two groups (95% untreated at 2 months vs. 43% in the 14-day and 53% in the 10-day group; p = 0.002). There were no differences in incidence of infections, including cytomegalovirus. Survival was similar between the groups. There was one death in the 14-day and 1 in the 10-day group, both due to rejection. In conclusion, OKT3 therapy can be reduced safely to 7 days with a higher overall incidence of rejection but no increased necessity to treat for rejection, and no difference in infection incidence.

Objective: Pretransplant pulmonary vascular resistance > or = 4 Wood-units predisposes to right ventricular failure after heart transplantation. Total orthotopic heart transplantation with bicaval and pulmonary venous anastomoses offers synchronous contractions of the atria and a normal ventricular filling pattern, but requires longer ischemic time than standard orthotopic heart transplantation. To test if total orthotopic heart transplantation improves resting hemodynamics in pts with high preoperative pulmonary vascular resistance, we analyzed 65 pts with standard and 65 with total orthotopic heart transplantation transplanted between 12/88 and 7/94. Of these, 18 with total and 15 with standard orthotopic heart transplantation had a preoperative pulmonary vascular resistance > or = 4 Wood-units., Methods: Right heart catheterization data were obtained at each endomyocardial biopsy. All data from biopsies at both 2 weeks and 1 year posttransplant that were free from humoral or greater than 1A cellular rejection (9 versus 13 pts) were included in a two way ANOVA. Pts with postop pacemakers, atrial fib or beta-blocker therapy at the time of biopsy were excluded., Results: Ischemic time was different (172 +/- 44 versus 142 +/- 28 min, P = 0.03). Demographics, NYHA class, pre-TX hemodynamics, donor age and inotropes were similar. Cardiac output and index were higher in the total orthotopic group at 2 weeks (6.5 +/- 1.7 versus 5.1 +/- 1.0 l/min; 3.4 +/- 0.9 versus 2.8 +/- 0.6 l/min per m2) and 1 year (7.1 +/- 2.0 versus 4.9 +/- 1.1 l/min, P = 0.002; 3.6 +/- 1.1 versus 2.6 +/- 0.5 l/min per m2, P = 0.009). Right atrial and pulmonary arterial mean pressure (mmHg) were lower with total orthotopic heart transplantation at 2 weeks (6 +/- 4 versus 9 +/- 5, P = 0.04; 22 +/- 3 versus 25 +/- 7, P = 0.1) and 1 year (5 +/- 2 versus 7 +/- 3, P = 0.02; 19 +/- 4 versus 25 +/- 7, P = 0.03). Pulmonary capillary wedge pressure (mmHg) was borderline nonsignificant (11 +/- 4 versus 13 +/- 7 at 2 weeks, 8 +/- 3 versus 14 +/- 5 at 1 year, P = 0.055), as well as pulmonary vascular resistance (1.9 +/- 1 versus 2.5 +/- 1 at 2 weeks, 1.5 +/- 0.6 versus 2.7 +/- 1.7 WU at 1 year, P = 0.051)., Conclusions: Total orthotopic heart transplantation improves cardiac output and index in pts with high preoperative pulmonary vacular resistance. There is a lower mean RA and PA pressure perhaps due to less tricuspid and mitral regurgitation. In view of the frequently observed restrictive filling pattern after cardiac transplantation, total orthotopic heart transplantation can be beneficial until this pattern has subsided by preserving atrioventricular synchrony and offering better atrial transport.

Diabetes mellitus with preexisting end-organ damage (EOD) is considered a contraindication for heart transplantation. The outcome of such patients has not been well characterized. Among 138 patients transplanted between 12/88 and 7/94, 29 were diabetic (11 insulin-dependent); of these, 12 had preexisting EOD, defined as a creatinine clearance < or = 50 ml/min, a 24-hour urine protein concentration > or = 500 mg/L or typical symptoms of peripheral or autonomic polyneuropathy, and 17 had no EOD. We compared diabetics with and without EOD and non-diabetics (n = 109) for operative mortality, length of stay, serum creatinine, fasting glucose levels, and postoperative prednisone doses at 1,6, and 12 months. Actuarial survival and freedom from rejection and infection were analyzed. Both diabetic groups were significantly older than nondiabetics, Ischemic time, operative mortality, surgical technique, ICU- and total length of stay were similar. Actuarial survival and freedom from rejection were similar among the three groups. Infection rates including CMV did not differ. Serum creatinine levels increased in all groups compared to pretransplant levels (p = 0.001), but without significant differences among the groups. Post-transplant glucose levels at 6 and 12 months were higher for diabetic patients with EOD than for those without or for nondiabetics (183, 153, and 94 mg/dl at 6 months, p = 0.01; 202, 161, and 102 mg/dl at 12 months, p = 0.0001). Prednisone dosage was lower in diabetics with EOD at 6 months, but did not differ among the three groups at 12 months. The incidence of angiographically proven transplant vasculopathy did not differ at 1 and 2 years. Diabetics with preexisting EOD undergoing heart transplantation experience similar short- and intermediate-term results when compared to diabetics without EOD and nondiabetics. Metabolic control is more difficult to achieve, as indicated by higher fasting glucose levels. Larger and longer-term prospective studies have to confirm our findings, since the shortage of donor organs would increase if such patients were transplanted routinely.

Total orthotopic heart transplantation (TOHT) requires longer surgery than standard orthotopic heart transplantation (SOHT), but offers normal anatomy and synchronous atrial contraction. We endeavored to test whether TOHT improves resting hemodynamics. We analyzed 60 patients with SOHT and 66 with TOHT transplanted between 12/89 and 7/94. Age, preoperative NYHA class, ejection fraction, and donor characteristics were similar. After applying exclusion criteria at 2 weeks postoperatively, 53 SOHT and 58 TOHT patients were accepted for further study. Right-heart hemodynamics were examined at 2 weeks and 6 months posttransplant. Despite a longer ischemic time (161 +/- 36 vs. 142 +/- 37 min, p = 0.004), cardiac output and index were higher in the TOHT group at 2 weeks (6.1 +/- 1.4 vs. 5.4 +/- 1.0 L/min, TOHT vs. SOHT, p = 0.01; and 3.3 +/- 0.7 vs. 2.9 +/- 0.6 L/min/m2, p = 0.005) but similar at 6 months (5.9 +/- 1.2 vs. 5.6 +/- 1.4 L/min; and 3.0 +/- 0.6 vs. 2.9 +/- 0.7 L/min/m2). Right-atrial pressure was lower with TOHT at both time points (7 +/- 4 vs. 9 +/- 4 mmHg, p = 0.02: and 5 +/- 2 vs. 7 +/- 3, p = 0.0006). Wedge pressure was similar at 2 weeks (12 +/- 5 vs. 13 +/- 5, p = 0.045). Heart rate (bpm) was higher at both time points with TOHT (84 +/- 10 vs. 75 +/- 12, p = 0.0003: and 90 +/- 12 vs. 82 +/- 9, p = 0.0006). Pulmonary vascular resistance was similar at both time points. Despite a longer ischemic time, total orthotopic heart transplantation does not impair postoperative cardiac function. There is an early improvement in cardiac output, a sustained higher heart rate reflecting preservation of donor sinus node function, and a lower right-atrial pressure.

Background: Careful donor and recipient selection are important factors for the success of heart transplantation. Currently, donors with a history of alcohol use are routinely accepted despite the potential deleterious effects of alcohol on the heart., Methods: We examined the frequency of chronic alcohol use (> 2 ounces of pure alcohol daily for > or = 3 months) among organ donors and the outcome of the receipients after heart transplantation. Of 99 consecutive patients who underwent transplantation between December 1988 and August 1993 with an adequate donor history, 17 (17%) had a history of chronic alcohol use (alcohol group), and 82 (83%) did not (nonalcohol group). All recipients received triple-drug immunosuppression, and 10 to 14 days of OKT3., Results: Survival rates at 1 and 2 years were significantly lower in the alcohol group (61% +/- 13% and 61$ +/- 13%) than in the nonalcohol group (95% +/- 3% and 91% +/-4%, p = 0.0001). Most deaths in the alcohol group occurred within 3 months after transplantation. The incidence of rejection episodes did not differ significantly. Fatal rejection occurred more frequently in the alcohol group and was associated with severe ventricular dysfunction before death. Cox multiple regression analysis identified donor alcohol use as an independent risk factor for death after heart transplantation., Conclusions: A substantial proportion (17%) of heart donors have a history of chronic alcohol use. The unfavorable early outcome of patients receiving hearts from alcoholic donors suggests the presence of a subclinical alcoholic cardiomyopathy before transplantation and poor tolerance of rejection episodes after transplantation. Larger prospective studies are needed to determine the mechanism of fatal rejection and whether such hearts can be used safely for transplantation.

A 68 year-old man underwent surgical repair of a ventricular septal defect following an acute myocardial infarction. Recurrent interventricular septal rupture with significant left-to-right shunting led to progressive deterioration in cardiac function and intractable heart failure. The patient underwent orthotopic heart transplantation three months after his initial operation, and he is clinically well sixteen months after transplantation.

Background: Endocardial lymphocytic infiltrates, known as Quilty effect, are a common finding of uncertain pathogenesis in cardiac allografts. Quilty effect was not observed before the use of cyclosporine A for immunosuppression and is not generally regarded as a manifestation of rejection. We hypothesized that the endocardial localization of Quilty effect may be related to a relative absence of cyclosporine A in this region., Methods: We used an indirect immunofluorescence staining method with rabbit polyclonal anti-cyclosporine A antibodies to detect cyclosporine A in fresh frozen sections of 27 cardiac allograft endomyocardial biopsies. Staining was graded 0 to +3. Negative controls were from untreated transplant candidates and from biopsies with the primary antibody omitted., Results: On comparison of endocardial and myocardial fluorescence in biopsy specimens from patients treated with cyclosporine A, there was less endocardial (0.7 +/- 1.1, p < 0.0001) than myocardial (2.2 +/- 0.5) staining. However, in biopsy specimens with Quilty effect (n = 12), this difference was significantly greater (endocardial = 0.2 +/- 0.6 versus myocardial = 2.3 +/- 0.5; p = 0.005) than in specimens without Quilty effect (n = 10) (endocardial = 1.4 +/- 1.2 versus myocardial = 2.1 +/- 0.6; p = 0.7). Endocardial thickness as measured by ocular micrometry was significantly greater in regions with (32 +/- 19 microns) than without (7 +/- 4 microns) Quilty effect, with involved regions showing increased connective tissue (p < 0.0001). In patients with and without Quilty effect, no differences in donor or recipient demographics, prevalence of diabetes, or plasma cyclosporine A levels were found., Conclusions: Although it has been postulated that Quilty effect is due to the presence of cyclosporine A in cardiac tissue (toxic effect or immunologic reaction), these data suggest that Quilty effect is related to reduced endocardial presence of cyclosporine A, leading to localized, contained, and usually not clinically significant endocardial rejection.

Orthotopic heart transplantation (OHT) with bicaval and pulmonary venous anastomoses avoids the large atrial anastomoses of the standard biatrial technique. To determine whether the bicaval technique improves atrial performance, we used Doppler echocardiography to study 13 patients with bicaval OHT, 15 with biatrial OHT, and 8 normal subjects. All were in sinus rhythm and free of rejection. Left atrial size, transmitral (M) and late diastolic (A) mitral flow velocity integrals were measured. Atrial transport (A/M, %) and atrial ejection force (kilodynes, calculated from peak A-wave velocity and mitral orifice area) were assessed. Left atrial dimensions in the bicaval (4.3 +/- 0.5 cm) and biatrial groups (4.9 +/- 0.9 cm) were larger than in controls (3.3 +/- 0.8 cm, p < 0.05). Left atrial transport (37% +/- 12% and 35% +/- 12%) and ejection force (14.1 +/- 6.9 kdyne and 10.2 +/- 7.8 kdyne) were similar in the bicaval group and controls (p not significant) but were significantly lower in the biatrial group (20% +/- 19% and 3.6 +/- 4.0 kdynes, p < 0.05). The bicaval and pulmonary venous technique of OHT produces more physiologic atrial function compared with the biatrial technique as evidenced by greater atrial ejection force and more normal atrial transport.

Background: Cytomegalovirus is a frequent cause of infection and morbidity after heart transplantation, especially in patients treated with antilymphocytic drugs where the incidence may be as high as 50%., Methods: To determine the efficacy of combined antiviral and intravenous immune globulin therapy for prevention of cytomegalovirus disease in transplant recipients receiving OKT3 and to compare two different antiviral drug regimens, we reviewed 115 transplant recipients from December 1988 to December 1993 who survived for more than 30 days. Of these, 29 received oral acyclovir for 3 months (group A) and 86 received intravenous ganciclovir for 2 weeks followed by oral acyclovir up to 3 months (group G); all received six infusions of 5% intravenous immune globulin over 2 months. All patients had OKT3 for 10 to 14 days and triple-drug immunosuppression., Results: Cytomegalovirus disease (pneumonitis, gastroenteritis, or leukopenia with fever) occurred in 10% of patients (12 of 115 patients) and was confirmed by positive culture, typical microscopic inclusions, or polymerase chain reaction. In 91 seropositive recipients, there was a trend to less cytomegalovirus disease in group G (3.0%, 2 of 67 patients) than in group A (12.5%, 3 of 24 patients) (p = 0.11), which was more apparent in recipients with seropositive donors where the incidence was reduced from 16.7% (group A) to 2.4% (group G; p = 0.08). In 24 seronegative recipients, cytomegalovirus disease incidence was higher overall and not significantly less in group G (26%, 5 of 19 patients) than in group A (40%, two of five patients) (p = Not significant)., Conclusions: Prophylaxis with combined antiviral and immune globulin therapy produces a low (10%) incidence of cytomegalovirus disease in OKT3-treated heart transplant recipients. In seropositive recipients treated with combined therapy, ganciclovir may be more effective than acyclovir. Larger trials and more aggressive prophylactic strategies are needed in seronegative patients who receive hearts from seropositive donors.

Objectives: We hypothesized that orthotopic heart transplantation with bicaval and pulmonary venous anastomoses preserves atrial contractility., Background: The standard biatrial anastomotic technique of orthotopic heart transplantation causes impaired function and enlargement of the atria. Cine magnetic resonance imaging (MRI) allows assessment of atrial size and function., Methods: We studied 16 patients who had undergone bicaval (n = 8) or biatrial (n = 8) orthotopic heart transplantation without evidence of rejection and a control group of 6 healthy volunteers. For all three groups, cine MRI was performed by combining coronal and axial gated spin echo and gradient echo cine sequences. Intracardiac volumes were calculated with the Simpson rule. Atrial emptying fraction was defined as the difference between atrial diastolic and systolic volumes, divided by atrial diastolic volume, expressed in percent. All patients had right heart catheterization., Results: Right atrial emptying fraction was significantly higher in the bicaval (mean [+/- SD] 37 +/- 9%) than in the biatrial group (22 +/- 11%, p < 0.05) and similar to that in the control group (48 +/- 4%). Left atrial emptying fraction was significantly higher in the bicaval (30 +/- 5%) than in the biatrial group (15 +/- 4%, p < 0.05) and significantly lower in both transplant groups than in the control group (47 +/- 5%, p < 0.05). The left atrium was larger in the biatrial than in the control group (p < 0.05). Cardiac index, stroke index, heart rate and blood pressure were similar in the transplant groups., Conclusions: Left and right atrial emptying fractions are significantly depressed with the biatrial technique and markedly improved with the bicaval technique of orthotopic heart transplantation. The beneficial effects of the latter technique on atrial function could improve allograft exercise performance.

A 30-year-old man underwent aortic and mitral valve replacement for the treatment of Q fever endocarditis. Postoperatively, paravalvular leak of the mitral prosthesis, progressive deterioration in cardiac function, and intractable heart failure developed. As a result, the patient underwent orthotopic heart transplantation 15 months after his initial valve operation. The patient is clinically well 14 months after transplantation.

The frequency of cocaine use among donors is currently unknown. Cocaine has cardiotoxic effects and could affect the outcome of heart transplantation. To examine the frequency of nonintravenous cocaine use in organ donors and the outcome of heart transplantation with such donors, we retrospectively analyzed the clinical, biopsy, and donor information on 112 consecutive patients who underwent transplantation between December 1988 and August 1993. Ten patients were excluded because of incomplete information regarding the donor's cocaine status. Of the remaining 102 patients, 16 (16%) had a positive donor history for nonintravenous cocaine use (cocaine group) and 86 patients (84%) had a negative history (noncocaine group). Survival, frequency of cellular rejection (grade > or = 1B), and humoral rejection were compared between the two groups. Survival rates at 30 days (100% versus 97% +/- 2%) and at 1 year (93 +/- 7% versus 89 +/- 3%) were similar (p = not significant, cocaine versus noncocaine group). Freedom from rejection was similar at 30 days (81% +/- 10% versus 79% +/- 4% cellular rejection-free, 33% +/- 14% versus 60% +/- 6% humoral-free) and 6 months (34% +/- 12% versus 55% +/- 5% cellular-free, 16% +/- 11% versus 36% +/- 6% humoral-free) (p = not significant). No significant difference was found in donor inotropic support before procurement, ischemic time, length of stay in intensive care unit, or total stay in the hospital. In conclusion, a high incidence of nonintravenous cocaine use exists among donors. The outcome of patients who receive transplanted hearts obtained from nonintravenous cocaine users is favorable, suggesting that the use of such hearts is safe.

We present our experience with an alternative technique for orthotopic heart transplantation. It consists of total excision of the recipient's atria, with the donor's heart implantation performed using bicaval end-to-end anastomoses as well as pulmonary venous anastomoses. Forty consecutive patients receiving transplants in this fashion were compared with 64 patients who underwent orthotopic transplantation with the standard technique. The incidence of postoperative tricuspid regurgitation was reduced in patients receiving transplants with the new surgical approach (p = 0.003). In addition, the need for pacemaker implantation for severe bradyarrhythmia in the early (0 to 6 weeks) posttransplantation period (p = 0.003) was eliminated. Although not statistically significant, there was a trend in the reduction of postoperative mitral regurgitation in patients who received transplants by the modified technique. Based on this experience, we believe this modified technique for orthotopic heart transplantation has an anatomic and physiologic advantage that may improve long-term hemodynamic results.

Purpose Obesity and overweight have become a global epidemic and are associated with an increased risk for cardiovascular disease. Immunosuppressive medications carry the risk of weight gain and further challenge heart transplantation (HT) patients. Since both fat mass (FM) and fat-free mass (FFM), each with its discrete features, contribute to total body weight (TBW), we aimed to characterize the post-HT change in TBW and its implications for HT outcomes. Methods Between 1997 and 2017 we assessed 221 HT patients. Changes in TBW, FM and FFM were reviewed at 1,5, and 10 years after HT. Endpoints included survival, freedom from cardiac allograft vasculopathy (CAV), freedom from any-treated rejection (ATR), and non-fatal major adverse cardiac events (NF-MACE). Results Median TBW increased by 7.5% at 1 year after HT, with a significant rise in the obese category (27 vs 12%, p <0.001) and with FM rather than FFM making the main contribution (23 vs 3%, p<0.001). Peak weight gain was reached at 5 years post HT. Multivariate analysis showed that the percent change in weight was independently associated with a significantly increased risk for CAV (HR 1.03; 95% CI 1.01-1.06). When patients were divided according to median TBW percent change (high vs low groups), Kaplan-Meier survival analysis showed that 10-year freedom from CAV and ATR was significantly higher for the low TBW change group (Figure). In addition, 10-year freedom from NF-MACE was significantly higher for the low TBW change group (p=0.044). There was no difference in survival. Consistently, multivariate analyses showed that the high TBW change group was independently associated with a significant 2.8-fold increased risk for CAV (95% CI 1.3-5.9, p=0.01), and >3-fold increased risk for ATR (95% CI 1.4-8.6, p=0.01). Conclusion Weight gain at 1 year after HT, contributed mostly by FM, is independently associated with an increased risk for CAV and ATR. In monitoring HT patients, emphasis should be placed on weight gain and on measures to prevent it. [ABSTRACT FROM AUTHOR]

Purpose Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Lower cardiovascular (CV) mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of diabetes mellitus (DM) in HT patients, we investigated the association between metformin therapy and CV outcomes after HT. Methods The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV and the combined end-point of CAV or CV mortality. Treatment with metformin and the development of CAV or the combined end-point of CAV or CV mortality were assessed as time-dependent factors in the analyses. Results Fifty-five HT patients (53%) were treated with metformin whereas 48 (47%) patients were not. Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30% vs. 65%; log-rank p=0.044; Figure); similarly, the combined risk of CAV or CV mortality was lower in the metformin-treated patients (32% vs. 68%; log rank p=0.01; Figure). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p=0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p=0.003) in the risk for CAV or CV mortality. Conclusion In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or CV mortality after HT. [ABSTRACT FROM AUTHOR]

Purpose Heart transplantation (HT) is uniquely associated with potential hormonal thyroid therapy implications, viz.: (1) Cardiac surgery is associated with a reduction in T3 levels (2) Administration of T3/T4 to the brain-dead organ donor is associated with increased recovery of transplantable hearts (3) Thyroid hormones directly influence myocardial function, having positive inotropic and chronotropic effects, which are modified in the transplanted heart. We aimed to study the effect of hormonal thyroid therapy to the donor on primary graft dysfunction (PGD). Methods The 209 HT patients assessed from 1992 to 2018 were divided into 2 groups, depending on whether their donors had received T4 (n = 33) or not (n = 176). The primary endpoint was PGD defined according to the ISHLT consensus statement. Results Group of recipients from T4 treated donors was characterized by lower pulmonary pressure (30±11 vs 36±14 mmHg, p = 0.03) lower ACEI therapy (48 vs 72%, p=0.018) and higher female gender (36 vs 14%, p=0.005). There were no other significant differences in donors clinical or echocardiographic parameters between the two groups. Incidence of PGD was significantly higher in recipients from donors who received T4 compared with recipients from donors who did not receive T4 (58 vs 35%, p=0.022). Severity of PGD was significantly higher in patients whose donors received T4 (43 vs 25% moderate/severe, p=0.007). Multivariate analysis showed that donor T4 therapy was independently associated with a significant >5-fold increased risk for PGD (OR=5.38, 95%CI 1.79-17.78; Fig). These results remained consistent after propensity score analysis. Conclusion Donor hormonal thyroid therapy is independently associated with increased risk of PGD. Hypothesizing a "withdrawal effect" as the cause, administration of thyroid hormonal therapy to the recipient at time of reperfusion may oppose this negative effect. Further prospective studies are needed to validate this hypothesis-generating study. [ABSTRACT FROM AUTHOR]

Purpose Hypomagnesemia is commonly observed in heart transplant (HT) recipients treated with calcineurin inhibitors. Low serum magnesium (s-Mg) is associated with inflammation and disturbances in the regulation of vascular tone and endothelial function and has been implicated in the progression of atherosclerosis, potentially leading to worsening coronary heart disease, atrial and ventricular arrhythmias and sudden cardiac death. We therefore investigated the association between s-Mg and HT outcomes. Methods Between 2002 and 2017 we assessed 150 HT patients for s-Mg levels. In accordance with the median value of all s-Mg levels recorded during the first 3 months post-HT, patients were divided into high (n=68) and low (n=82) s-Mg groups. Endpoints included survival, freedom from cardiac allograft vasculopathy (CAV), freedom from any-treated rejection (ATR) and non-fatal major adverse cardiac events (NF-MACE). Results Mean s-Mg was 2.0±0.3mg/dL vs 1.6±0.1 mg/dL for the high and low s-Mg groups, respectively (p<0.001). Baseline patient and donor clinical and demographic characteristics were similar for the two groups. Kaplan-Meier survival analysis showed that at 15 years after HT survival was higher in the high s-Mg group than in the low s-Mg group (82 vs 38%, log-rank p=0.013, Figure). Similarly, 15-year freedom from CAV was significantly higher in the high vs low s-Mg group (82 vs 42%, log-rank p<0.001, Figure). There were no significant differences in freedom from NF-MACE or ATR between the two groups. Multivariate analyses consistently demonstrated that low s-Mg was independently associated with a significant >3-fold increased risk of mortality and >4-fold increased risk of CAV (95% CI 1.3-11.8, p=0.02; 95% CI 1.6-15.1, p=0.01 respectively). Conclusion Low post-HT s-Mg is independently associated with increased mortality and CAV in HT patients. Larger prospective studies are needed to confirm these findings and to examine the effect of Mg supplementation. [ABSTRACT FROM AUTHOR]

Viral triggers have been implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), the Achilles heel of heart transplantation (HT). Cytomegalovirus is associated with impaired coronary endothelial function, and in pediatric HT patients a variety of viruses, particularly adenovirus, are associated with graft dysfunction or loss. Hepatitis B virus (HBV) is associated with vasculitis and vascular processes in non-HT patients. We thus investigated the association between HBV seropositivity and CAV after HT. The 173 HT patients assessed for HBV serology from 1997 to 2017 were divided into hepatitis B core antibody (HBcAb) positive (n=29) and HBcAb negative (n=144) groups. Primary outcomes were CAV and the combined end-point of CAV or cardiovascular mortality. Baseline patient and donor clinical and demographic data for the 2 groups were similar. Kaplan-Meier analysis showed that 20-year freedom from CAV was significantly higher in the HBcAb-negative vs HBcAb-positive group (80 vs 50%, log-rank p=0.003, Figure 1A). Similarly, 20-year freedom from CAV or cardiovascular mortality was higher for the HBcAb-negative group (75 vs 45%, log-rank p=0.018). Consistently, multivariable analysis showed HBcAb positivity to be independently associated with a significant ∼3-fold increased risk of CAV (95% CI 1.38-5.01, p=0.003, Figure 1B), and a 2-fold increased risk of CAV or cardiovascular mortality (95% CI 1.11-3.90, p=0.021). Hepatitis B seropositivity is independently associated with an increased risk of CAV in HT recipients. Future studies are needed to examine the effect of anti-viral therapies. [ABSTRACT FROM AUTHOR]

Purpose Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium (Mg) deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT). Methods Between 2002 and 2017 we assessed 101 non-DM HT patients. S-Mg levels were reviewed during the first year post-HT. In accordance with the mean value of all s-Mg levels recorded during the first year, patients were divided into high s-Mg (≥1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association: hemoglobin A1c ≥6.5%; fasting plasma glucose ≥126 mg/dL; or random plasma glucose ≥200 mg/ dL. Results Baseline clinical and demographic characteristics for the high s-Mg (n=42) and low s-Mg (n=59) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high s-Mg vs low s-Mg (84% vs 22% log-rank test, p=0.003, Figure). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies and mean creatinine values of the first year post-HT, showed that low s-Mg was independently associated with a significant >5-fold increased risk for NODAT (95% CI 1.35-21.04, p=0.02). Patients with low s-Mg levels had a significantly higher rate of cerebrovascular events than patients with high s-Mg (15.5% vs 0, p=0.02). Conclusion Low post-HT s-Mg level is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, on the risk for NODAT and on clinical outcomes should be evaluated. [ABSTRACT FROM AUTHOR]

Purpose With the growing shortage of organ donors, marginal donor organs are increasingly accepted, which may partially explain the continued increase in donor age. The potential interactions between donor-recipient (D/R) age difference and outcomes after heart transplantation (HT) are not well known, and organ allocation systems do not routinely consider D/R age matching. We thus aimed to study the impact of D/R age difference on HT outcomes. Methods Between 1995-2017 we assessed 234 HT patients. Based on D/R age difference histogram, we stratified these patients into 3 groups: older donors (D/R difference >0; n=48), younger donors (D/R difference 0 to -20 years; n=82), and much younger donors (D/R difference <-20 years; n=104). Endpoints included long-term survival, freedom from cardiac allograft vasculopathy (CAV), freedom from any treated rejection (ATR) and primary graft dysfunction (PGD). Analyses were adjusted for recipient age, donor age, and clinical variables, including gender matching and predicted heart mass (pHM) difference. Results The baseline metabolic risk profile of the patients was significantly higher for the younger donor groups, including hypertension (52%/33%/25%, p=0.002), dyslipidemia (51%/51%/29%, p=0.027), diabetes (30%/16%/17%, p=0.044) and smoking history (53%/46%/29%, p=0.024), respectively. There were no significant differences between the groups in long-term survival, freedom from CAV or ATR in unadjusted and adjusted analyses (Table). In the much younger donor group (D/R difference <-20 years) gender matching was associated with a lower incidence of PGD (37% vs. 58% p=0.05). Controlling for differences in pHM reversed this association. Conclusion D/R age difference does not significantly impact long-term HT outcomes. However, among younger donors with a D/R age difference <-20, gender matching was associated with a lower incidence of PGD. Given the constant shortage of donor hearts, organs from older donors with a high D/R age difference can be successfully utilized. [ABSTRACT FROM AUTHOR]