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BACKGROUND Red blood cell distribution width (RDW) has been emerging as a strong predictor of mortality among patients with cardiovascular disease. The aim of this study was to verify if RDW is able to predict survival after heart transplantation (HTx). METHODS Two hundred and eighteen recipients who underwent HTx between 2000 and 2013 were classified into three groups according to the pre-HTx RDW tertile values (14.6 and 16.4%), and their outcomes were compared. Mean follow-up was 6.6 ± 4.2 years. RESULTS RDW correlated with other markers of chronic pathological conditions, such as the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score (P = 0.002) and Charlson Comorbidity Index (P

Purpose Cardiac allograft vasculopathy (CAV) represents a relevant issue after Heart Transplantation (HTx), affecting mid and long-term outcomes. Coronary artery disease (CAD) of the donor graft has been implicated in the pathogenesis and progression of CAV. Although definitive data are still lacking, CAD of the donor graft represents an exclusion criteria in many transplant Units. We analyzed the outcomes of patients who underwent HTx from donor hearts affected by no-severe CAD. Methods Patients who received a graft, evaluated with coronary angiogram before the retrieval, were divided into two groups according to the presence or not of no-severe CAD (with lesions ≤50%) of the donor graft (groups CAD and NCAD, respectively). The outcomes analyzed were survival and freedom from grade ≥2 CAV. The study period was between 1990 and 2018. Median follow up was 86 months (range 0.3-317). Results There were differences between CAD and NCAD groups according to the baseline characteristics, as reported in Table 1. Survival and Freedom from grade ≥2 CAV were similar between the two groups at mid term (p=0.47 and p=0.66, Figure 1). At adjusted multivariate analysis for both survival and freedom from grade ≥2 CAV, donor CAD was not considered a significant risk factor. Conclusion Coronary angiogram plays a reliable role in identifying suitable organs, even those affected by CAD. In fact, no-severe donor CAD does not seem to affect survival and development of high grade CAV, more likely due to immunological factors. If confirmed by larger studies, these finding could encourage the employment of donor hearts affected by CAD.

Increasing recipient (RA) and donor age (DA) are independently associated with mortality after Heart Transplantation (HT). The aim of this study was to analyse the impact of age-matching on HT survival. 485 recipients who underwent HT between 1990 and 2018 in our Institution were divided into four groups: RA50 (Group 2), RA>60-DA60-DA>50 (Group 4), and their outcomes were compared. Emergency HT, bridge with MCS and re-HT were excluded. Mean follow-up was 109±84 months. The survival of Group 1 patients was significantly higher than that of patients in other groups (p=0.001). The outcome of young recipients who received older donor grafts did not significantly differ from that of older recipients. At multivariate analysis, donor age, recipient age, Diabetes Mellitus and hypercholesterolemia correlated with long-term mortality. Demographic variables 1 (d/r) 2 (r/D) 3 (R/d) 4 (D/R) P Value Recipients data No. of patients 241 61 107 76 – Female, n (%) 50 (21) 16 (26) 17 (16) 11 (14) 0.25 Age (years), mean ± sd 49±10 54±7 64±3 65±3 In this study, the use of hearts from older donors did not affect survival of older recipients; conversely, in young recipients it increased the risk of mortality.

Purpose The ex-vivo normothermic perfusion in Heart Transplantation (HTx) allows to expand the donor pool by reducing the ischemic time and providing graft evaluation. Aim of the study was to compare the traditional cold storage (CS) and ex-vivo normothermic perfusion (EVP) in HTx employing marginal donors. Methods Since 2011, 87 HTx employing marginal donors (age>55 years; expected ischemic time>4h; LVEF 14mm; drug abuse; cardiac arrest; CAD) in standard recipients has been performed, CS was utilized in 70 cases (80%) and EVP in 17 (20%). Pre-operative data, survival and complications at short and long term were analysed. Endomyocardial biopsies were collected at time of organ retrieval (T0), before implantation (T1) and after aortic declamping (T2) for light and electron mycroscopy. Blood samples were collected at T0 and T2 from coronary sinus and peripheral vein for metabolomic evaluation . Results Preoperative data were similar in the two groups. Three organs (15%) were considered not suitable for HTx after EVP. Ischemic time and surgical time were shorter in EVP group, which showed a better short and long term survival: a 5-year survival of 100% vs. 94%, 82% and 73% at 30-day, 1 and 5 years respectively in CS group (p=0.06) and less overall complications (65% vs. 89%, p=0.02). In CS group, endomyocardial biopsies showed a tendency for more prominent myocardial damage after heart reperfusion, especially underlined by mitochondrial and organelles dysfunction (figure1). Conclusion EVP permits to exclude not suitable grafts, to reduce complications and to obtain optimal HTx survival. Pathological findings show a tendency for better myocardial protection.

Purpose Candidate selection and donor allocation should promote equitable access to heart transplantation (HTX) according to patients’ needs, avoiding HTX in patients (pts) who are too well or too sick to get benefit. The national HTX database was analyzed to identify which variables were related to the competing events of getting HTX or dying on the waiting list (WL), and to post-transplant survival. Methods Pts aged 14 years or more, who were listed for primary HTX from May 2012 and December 2016, were followed until January 2018, death or delisting for worsening. The incidence of death on the WL or of HTX were analyzed according to Aalen-Johansen method. Post-HTX survival was evaluated with Kaplan-Meyer method. Univariate and multivariate cause-specific Cox proportional hazard model was used to identify candidates’ variables related to access to HTX or death on the WL, and preoperative recipients’ variables related to post-HTX mortality. Results Of 1611 listed pts (males 78%, median age 54 y), 10% died and 45% received HTX within 1 year. At the end of follow-up 932 pts (males 73%, median age 53y) had undergone HTX: 13% were bridged with LVAD, 17% were on short-term mechanical circulatory support (MCS), 28% received HTX with emergency heart allocation, and 42% were medically treated outpatients. One-, 3- and 5-years post-HTX survival was 78%, 72% and 69% respectively. Variables which were significantly related to study outcomes at univariate and multivariate analysis are shown in the Table. Conclusion The higher risk of WL mortality associated with variables that reflect disease severity and medical urgency is limited by allocation rules. Blood type 0 pts are disadvantaged in the current system. 1-y probability of both getting HTX and dying on the WL was lower in LVAD pts. Short term MCS and emergency HTX were associated with higher rate of death after HTX only at univariate analysis: predictors of post-HTX death should be analyzed separately in these high-risk subgroups.

Purpose Heart transplantation (HTx) is the best therapeutic option for patients suffering from end-stage heart failure, but the shortage of donor hearts still represents a crucial problem. Methods Since 1985 to December 2017, a total of 611 HTx in 600 patients have been transplanted at our Centre. The aim of the study is to analyze the short- and long-term results of HTx in patients with older donor age, comparing the Results The mean age at HTx was 55±11.1 years. Of these, 561 (91%) received a donor heart Recipients transplanted with donors Conclusion In the older donor groups, the incidence mortality is highest in the first month from HTx; conversely, it appears similar at 1-year between donor

Purpose Increasing recipient (RA) and donor age (DA) are independently associated with mortality after Heart Transplantation (HT). The aim of this study was to analyse the impact of age-matching on HT survival. Methods 485 recipients who underwent HT between 1990 and 2018 in our Institution were divided into 4 groups: RA 50 (Group 2), RA>60-DA 60-DA>50 (Group 4), and their outcomes were compared. Emergency HT, bridge with MCS and re-HT were excluded. Mean follow-up was 109 ± 84 months. Results Preoperative data reported in Table 1. 30-day mortality across the groups was 4.9%, 9.8%, 8.1%, 9.2% from Group 1 to 4 (p=0,4). The survival of Group 1 was significantly higher than that of other groups (p=0,001), figure 1. The outcome of young recipients receiving older donor grafts did not significantly differ from that of older recipients. At multivariate analysis , donor age (HR 1,02; 95%CI:1,007-1,04) and recipient age (HR 1,05;95%CI:1,02-1,09) correlated with long-term mortality. Conclusion In this study, the use of hearts from older donors did not affect survival of older recipients; conversely, in young recipients it increased the risk of mortality. Older donor organs employment is advisable to expand the donor pool, but donor-recipient age matching should be taken into account to improve long-term outcomes.

OBJECTIVES Since patient compliance following organ transplantation is considered a limiting factor for long-term outcome, psychosocial assessment is commonly employed to evaluate suitability for organ transplantation. We analysed the impact of psychosocial characteristics on long-term outcome after heart transplantation in our institution. METHODS The outcomes of 345 patients (82% male, mean age: 56 ± 11 years) who had undergone a heart transplant since 1999 were evaluated taking into consideration major clinical and psychosocial findings. The impact on survival of the psychological habitus, substance abuse, economic status, education level, presence of caregivers and distance from the hospital (Area 1

OBJECTIVES Improvement of clinical results in heart transplantation (HTx) has favoured the expansion of indication criteria towards aged population. The impact of increasing recipient age is controversial and, owing to donor shortage, the debate still remains whether HTx is justified for older patients. We analysed age as a prognostic factor at long-term after HTx and if it should be a determinant in organ allocation. METHODS Data of 364 consecutive patients who underwent cardiac transplantation between 1999 and 2014 at the University Hospital of Udine were analysed. Patients were divided into three groups according to age (Group 1: 18-40, Group 2: 41-59, Group 3: ≥ 60 years) and survival and major complications were evaluated at long-term (mean follow-up 6.7 ± 4.5 years, range 1-15.7 years). RESULTS Preoperatively, renal failure (2.9, 16.1, 39.5%, P < 0.01) and cardiovascular factors such as diabetes (1.2, 17.1, 36.4%, P < 0.01), systemic hypertension (5.9, 31.5, 40.8%, P < 0.01) and dyslipidaemia (5.9, 40.3, 42.9%, P < 0.01) were more common in older patients (Group 3), as well as ischaemic cardiopathy (0, 42.6, 49.7%, P < 0.01). Donor age was lower in younger recipients (Group 1) (33 ± 15, 39 ± 14, 45 ± 14 years, P < 0.01). Older patients showed a worse long-term survival (hazard ratio 1.7; 1.1-2.5), also after adjusting for major cardiovascular risk factors, renal failure and donor age. In fact, 15-year survival was 100% in Group 1, while at 1, 5, 10 and 15 years survival was 88, 78, 69 and 56% in Group 2, and 87, 68, 49 and 43% in Group 3, respectively. Even major long-term complications were less frequent in younger patients in terms of neoplasms (P < 0.01), rehospitalizations (P < 0.01) and a tendency to higher freedom from other complications such as cytomegalovirus infections, renal failure and dialysis. CONCLUSIONS Our results showed a significantly different outcome according to recipient age, even when adjusted for major risk factors. Notably, patients younger than 40 years showed 100% long-term survival, and apparent lower rate of complications due to immunosuppression. Since 15-year survival in patients ≤40 years is twice that of patients ≥60 years, recipient age should be taken into account in organ allocation.

Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM of mycophenolate mofetil requires area under the curve AUC determinations but appears laborious, costly, and clinically impractical. To overcome these problems, limited sampling strategies (LSS) have been proposed in adult and pediatric renal transplant patients. The purpose of this study was to develop an LSS in heart transplant patients. Forty-four mycophenolic acid (MPA) full AUC(0-12h) profiles were generated by high-performance liquid chromatography in nine heart transplant patients during the first 12 weeks posttransplant. Each patient received concomitant cyclosporine and prednisone therapy. Multiple stepwise regression analysis was used to define the time points of MPA levels to explain the MPA AUC(0-12h). Agreement between abbreviated AUC and the full AUC(0-12h) was tested by means of a Bland and Altman analysis. The highest coefficient of determination r(2) among MPA AUC and single concentrations (r(2) = .610) was observed with C(2), while C(12) provided the lowest one (r(2) = .003). Stepwise linear regression showed that the minimal model with the best estimation of MPA AUC(0-12h) was obtained at timed values of 1.25, 2, and 6 hours. The corresponding estimated model was AUC = 5.568 + 0.902 * C(1.25) + 2.022 * C(2) + 4.594 * C(6) (r(2) = .926). Bland and Altman analysis revealed good agreement between predicted AUC and full AUC. A further interesting model equation obtained by four samples was AUC = 3.800 + 1.015 * C(1.25) + 1.819 * C(2) + 1.566 * C(4) + 3.479 * C(6) (r(2) = .948).

At the moment, there is no score to evaluate clinical risk in heart transplantation. There is a need for such an instrument due to the extended criteria for donations and for recipient evaluation for transplantation. We divided the 203 consecutive patients who underwent heart transplantation (HTx). Between January 1999 and December 2007 into two groups: high and low risk based on several common well-defined variables. Donors were also divided into high- and low-risk groups. We matched the four groups to obtain risk cohorts: GA (high risk), GB and GC (intermediate risk) versus GD (low risk). We analyzed the 30 day-mortality showing a significant difference between GD and the other groups (P = .05) in contrast to no significant difference in 1- and 3-year survival rates among GA, GB, GC, and GD. Although the development of a specific score for heart transplantation is desirable and would be useful, a careful, case-by-case evaluation is indispensable.

Background Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration–time curve (MPA-AUC0–12h) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC0–12h, however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. Objective To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. Patients and Methods In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 × C1.25 + 2.022 × C2 + 4.594 × C6 and (2) 3.8 + 1.025 · C1.25 + 1.819 × C2 + 1.566 × C4 + 3.479 × C6. Agreement between abbreviated AUC and the full AUC0–12h was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. Results The 2 LSS algorithms used predicted the corresponding MPA-AUC0–12h with a mean bias of −4.85% and −3.6% and mean precision of 15.9% and 14%, respectively. Conclusions The MPA-AUC0–12h obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC0–12h using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.

Background Mild, long-term non-compliance with immunosuppressive treatment after organ transplantation is common, and can result in early mortality. One possible source of non-compliance is the belief that the treatment is ineffective or unnecessary. This study investigates patients perception of the efficacy of their immunosuppressive treatment in a sample of heart transplant patients. Methods A questionnaire was given to 67 heart transplant recipients. The first part of the questionnaire addressed health-related behavior and attitude toward the immunosuppressive medication, using self-report questions. In the second part of the questionnaire, participants evaluated the perceived risk of rejection associated with non-compliant behaviors described in 8 scenarios. Results The data from the self-report questions showed a mild level of behavioral non-compliance, increasing over time, and a mild level of medication non-compliance. One third of the medication non-compliant patients chose the inefficacy or non-necessity of the treatment as a main cause of non-compliance. The second part of the questionnaire showed that subjective perceived efficacy of the immunosuppressive treatment decreased over time. Conclusions Medication non-compliance is fostered by many factors. One of these is the belief that the treatment is ineffective or unnecessary. This belief increases over time, and could be the result of a non-clinical selective-attention bias. J Heart Lung Transplant 2003; 22:000–000.

The results of heart transplantation in a consecutive series of 19 end-stage valvular disease patients (15 male, aged 48 ± 8 years) were analysed retrospectively. The indication for heart transplantation was heart failure due to left and/or right ventricular dysfunction ; 16 patients had undergone previous valve surgery, but prosthetic dysfunction was present in only one patient. All patients were in NYHA class IV, 15 were on oral anticoagulants and 5 on i.v. cathecolamine support. There were four in-hospital deaths (21%) and one late death (5%), resulting in a 1-year mortality rate slightly, but not significantly, higher than that of patients transplanted for other indications (16%). Mean follow-up of the survivors was 48 ± 33 months (range 9-95) ; 5-year actuarial survival was similar to that observed among the other heart transplantation patients (74 ± 10% vs 77 ± 3%, P = NS). The incidence of acute rejection and infection was also similar in valvular disease and non-valvular disease patients. Kidney and liver function at 1 year post-heart transplantation was preserved in all cases ; cardiac catheterization revealed normal graft function in all patients and the absence of coronary lesions in all but two. In conclusion, in our limited experience morbidity and mortality in patients transplanted for end-stage valvular diesease seem to be similar to those of patients undergoing heart transplantation for other etiologies. [Eur J Cardio-thorac Surg (1995) 9 : 521-525]

THE presence or history of neoplastic disease was a traditional contraindication to heart transplantation (HTx), because of the fear of increased risk of tumor recurrence and lymphoproliferative disorders with chronic immunosuppression. More recently, recipient selection criteria have been extended both in kidney and in HTx, including patients (pts) cured for neoplastic disease and without recurrence for at least 2 years. Here we report our 12-year experience of HTx in pts with heart disease and a history of cancer involving other organs, and in those in whom chemotherapy for cancer resulted in heart failure due to toxic cardiomyopathy.

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen and ultraviolet light. The treatment seems to induce an inhibition of both humoral and cellular rejection after transplantation. Objective Since recurrent rejection (RR) continues to be a severe complication after heart transplantation (HTx) and the immunosuppressive regimes used for the treatment are often associated with increased morbidity and mortality, we investigated whether ECP could have a beneficial effect on the number and severity of rejection episodes. Methods Eleven HTX recipients (5 M and 6 F, mean age 48.5 yrs) with RR were enrolled in the study. ECP was performed at weekly intervals during the 1st month, at 2 week intervals during the 2nd and 3rd month, and then monthly for another 3 months. Results The fraction of biopsies (EMB) with a grade 0/1A rejection increased during ECP from 46% to 72% while the EMB showing a 3A/3B rejection decreased from 42% to 18%. It is also noteworthy that out of the 78 EMB performed during ECP only one showed a 3B rejection in comparison with 13 out of 110 EMB in the pre-ECP period. Six rejection relapses were observed in a total follow-up of 60 months, two of them occurring during the tapering of oral steroid. Four relapses were reversed by ECP, one by IV steroids and the last by methotrexate after the failure of both IV steroids and ECP. The mean doses of immunosuppressive drugs resulted lower after 6 months of ECP: steroids were reduced from 13 to 8.25 mg/day, cyclosporine from 375 to 285 mg/day, azathioprine from 55 to 35 mg/day. Conclusions ECP is a well tolerated treatment. Its administration allows better RR control and significant reduction in immunosuppressive therapy. (Int J Artif Organs 2000; 23: 49–54)

Patients with cardiovascular disease have cognitive function disturbances that are still evident after heart transplantation (HT). The aim of this study was to evaluate cerebral function in transplant patients and to assess whether cyclosporine therapy was responsible for cerebral abnormalities 1 year after transplantation. Six HT patients, eight liver transplant (LT) patients, and ten age-matched healthy controls underwent regional cerebral blood flow (rCBF) assessment by the (99m)Tc-hexamethyl-propylene-amineoxime ((99m)Tc-HM-PAO) single-photon emission computed tomography (SPECT) technique. The rCBF was correlated with cyclosporine blood levels. rCBF in HT and LT patients was similar to that of controls in all regions assayed, except for the frontal inferior region of HT patients, where it was significantly lower than in controls. No correlations between rCBF and cyclosporine blood levels were found in either HT or LT patients. In conclusion, the cerebral abnormalities seen in patients after HT but not after LT may be due to long-standing cerebral hypoperfusion resulting from severe heart disease, whereas cyclosporine does not account for such functional alterations.