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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 Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality after heart transplantation (HT) and is a significant predictor of adverse outcomes. We aimed to investigate the influence of pharmacologic therapies administered to the recipient before HT on PGD. Methods Between 1997-2017 we assessed 279 HT patients. Pharmacological therapies at the time of HT were reviewed, including a statin, spironolactone, amiodarone, beta-blockers (BBs) and ACE-inhibitors (ACEIs). Endpoints included PGD (defined according to the ISHLT consensus statement), in-hospital mortality, 1- and 5-yr survival. Results In the group of patients diagnosed with PGD (102; 36.5%) vs the non-PGD group, fewer had received pre-HT statins (35 vs 75%, p<0.001) or spironolactone (32 vs 81%, p<0.001), and more, amiodarone therapy (70 vs 29%, p<0.001). Donor characteristics were similar. Multivariate analysis consistently demonstrated that pre-HT treatment with a statin or spironolactone was independently associated with a significant 74% and 87% reduced risk for PGD, while pre-HT amiodarone therapy was independently associated with a significant >4-fold increased risk for PGD (Figure). Statin therapy was independently associated with a significant reduction in PGD severity (OR 0.26, 95% CI 0.03-0.74). In-hospital mortality was significantly lower for patients treated with a statin (9 vs 21%, p=0.006) or spironolactone (7 vs 27%, p<0.001) vs nontreated patients, with a corresponding significantly higher 1-yr (89 vs 73%, p=0.001; 91 vs 67% p<0.001) and 5-yr survival (86 vs 67%, p=0.002; 88 vs 60%, p<0.001, respectively). Conversely, 5-yr survival was significantly lower for patients treated with amiodarone (67 vs 82%, p=0.008). Pre-HT therapy with a BB or an ACEI was not associated with PGD. Conclusion Pre-HT statin or spironolactone therapies are independently associated with a reduced risk for PGD and mortality, whereas amiodarone therapy is associated with an increased risk. [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]

Carbohydrate antigen 125 (CA125), a marker for ovarian cancer, is thought to be associated with the clinical severity of heart failure (HF) and fluid congestion. Mesothelial cells in the pericardium, pleura, peritoneum and M¨ullerian epithelium produce CA125 presumably in response to mechanical (congestion) stress. With the growing use of left ventricular assist device (LVAD) for advanced HF, assessment of right ventricular (RV) function and hemodynamics is of major interest. We aimed to assess CA125 as a predictor of right heart function and hemodynamics. All 164 patients hospitalized for advanced HF in 2015-2019 were prospectively assessed for CA125 and B-type natriuretic peptide (BNP) levels combined with echocardiography and right heart study. Patients were stratified into 4 groups: high BNP-high CA125 (HB-HC), high BNP-low CA125 (HB-LC), low BNP-high CA125 (LB-HC), and low BNP-low CA125 (LB-LC). High CA125 (>35 IU/ml) significantly predicted high BNP (>400 pg/ml) (95% CI 1.01-1.02, p<0.001). High CA125 accurately predicted an elevated right atrial (RA) pressure irrespective of BNP level (even when the later was low; LB, Figure). Conversely, low CA125 predicted a low RA pressure, even when BNP was high (HB). RV function, assessed by echocardiography, was significantly severely reduced for the HB-HC group (29%) vs the LB-HC (17%), HB-LC (9%), and LB-LC (4%) groups (p<0.001). In an unadjusted analysis, each unit elevation of CA125 was associated with a significant 9% higher odds-ratio (OR) for RA pressure>10mmHg (95% CI 1.06-1.13, p<0.001). After adjustment for gender, hemoglobin and comorbidities, BNP was not significantly associated with RA>10mmHg, whereas CA125 continued to be independently associated with a 9% higher OR for RA>10mmHg, per unit of change (95% CI 1.05-1.15, p<0.001). CA125 independently predicts RA pressure and RV function in advanced HF patients. CA125 is a promising marker for risk stratification of patients being evaluated for LVAD implantation. [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]