Giuseppe Feltrin

Immune and Nonimmune Predictors of Cardiac Allograft Vasculopathy Onset and Severity: Multivariate Risk Factor Analysis and Role of Immunosuppression

We studied 361 patients, to evaluate risk factors for cardiac allograft vasculopathy (CAV) onset and severity/diffusion in heart transplantation (HT). Rejection scores (RS) on endomyocardial biopsy were calculated (first year and whole follow‐up). CAV onset was defined as any lesion seen at yearly angiography. A CAV severity/diffusion index was calculated for each patient summing up the scores of all lesions. Cox multivariate analysis included: donor age, sex, and weight; recipient sex, age, pre‐HT diagnosis, hypertension, diabetes and hyperlipidemia post‐HT; number of treated rejections and RS; and immunosuppressive dosage at 3, 6, and 12 months. CAV frequency was 2% at 1 year, 22% at 5 and 39% at 10 years. Risk factors for CAV onset were older donor age [p < 0.0001, relative risk (RR) = 9.9], male donor (p < 0.001, RR = 3.2), high RS for severe (≥ 3A) grades (p < 0.02, RR = 2.01), high cyclosporine at 3 months (p < 0.02, RR = 1.9). Risk factors for CAV severity/diffusion were higher donor weight (p < 0.01, RR = 7.5), high prednisone dosage at 1 year (p < 0.0001, RR = 21.1), and coronary disease pre‐HT (p < 0.002, RR = 9.7). High RS was an independent predictor for CAV onset, not severity/diffusion. This suggests an immune basis for CAV onset and nonimmune modulation for progression. High RS for severe grades may provide a predictor for patients at risk.

Skin cancer in heart transplant recipients: frequency and risk factor analysis

BACKGROUND The frequency of skin cancer is increased among organ transplant recipients, but the predisposing risk factors are controversial. It is also unclear whether heart transplant patients face an increased risk compared to recipients of other organs, e.g. kidney transplants. METHODS We performed univariate and multivariate analysis of risk factors for skin cancer in 252 heart transplants and in a control series of 228 kidney transplants followed up at a single center. An extensive dermatologic examination was carried out; baseline features, type of immunosuppression, number of 3A rejection episodes, extent of sunlight exposure and skin type were recorded. Multivariate analysis (Cox regression) included: age at transplantation, sex, skin type (Fitzpatricks criteria), presence of solar keratosis, presence of warts, type of organ, sunlight exposure. RESULTS During follow up skin cancer was more common among heart transplants (40, 16 %) than in kidney transplants (16, 7%, p = 0.004). The cumulative incidence of skin cancer by life table analysis increased from 16% after 5 years to 33% after 10 years in heart transplant patients and from 6% to 17% in kidney transplants (p 10000 hours (relative risk = 2.8), but not organ type were significant risk factors. CONCLUSION Age at transplant, skin type and sunlight exposure, but not type of organ and type of immunosuppressive regimen, are associated with increased risk of skin cancer in heart transplantation.

Coronary flow velocity pattern and coronary flow reserve by contrast-enhanced transthoracic echocardiography predict long-term outcome in heart transplantation.

Background— We assessed coronary flow velocity pattern and coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) as markers of major adverse cardiac events (MACE) related to cardiac allograft vasculopathy (CAV) after heart transplantation (HT). Methods and Results— Deceleration time of diastolic flow velocity (DDT) and CFR were measured in the left anterior descending coronary artery (LAD) by CE-TTE in 66 consecutive HT patients (follow-up 19±5 months). CFR was calculated as the ratio of hyperemic to basal diastolic flow velocity. Angiographies were analyzed by a qualitative grading system; CAV was defined as changes grade II or higher. MACE were cardiac death, stent implantation, and heart failure. Patients with MACE had higher CAV incidence (P=0.004) and grade (P=0.008), shorter DDT (P=0.006), and lower CFR (P=0.008). A receiver-operating characteristic–derived DDT cutpoint ≤840 ms (area under the curve 0.793; P=0.01) was 75% specific and 86% sensitive for predicting MACE, with positive predictive value (PPV) and negative predictive value (NPV) of 33% and 97%, respectively (P=0.002). A CFR cutpoint of ≤2.6 (area under the curve 0.746; P=0.01) was 62% specific and 91% sensitive for predicting MACE (PPV =32%, NPV =97%) (P=0.001). Patients with CFR ≤2.6 and patients with DDT ≤840 ms had a lower survival free from MACE (P=0.006 and P=0.009, respectively). By Cox regression, only a lower CFR predicted the risk of MACE (relative risk 3.1; 95% CI, 1.26 to 7.9; P=0.01). Conclusions— In HT patients, shorter DDT and lower CFR by CE-TTE are reliable markers for CAV-related MACE. CFR is the main independent predictor of MACE.

Posttraumatic stress disorder and depression in heart transplantation recipients: the relationship with outcome and adherence to medical treatment

OBJECTIVE There is growing evidence of the importance of psychiatric risk factors for predicting the outcome of heart transplantation (HT) recipients. The aim of our study was to investigate the role of major depression and posttraumatic stress disorder (PTSD) in the prediction of the outcome of HT in a consecutive sample of 107 recipients. METHOD All subjects of the study underwent a structured diagnostic interview for assessing the presence of pretransplant and posttransplant major depression and transplantation-related PTSD 1 to 5 years after HT. The adherence to medical treatment was assessed some months after the structured interview. The medical outcome (acute rejections, cancer, mortality) was followed up for 8 years on average after the interview, using a prospective design. RESULTS Estimated frequency of psychiatric diagnoses after HT was 12% for transplantation-related PTSD and 41% for major depression. The presence of an episode of major depression prior to HT is a significant independent risk factor for posttransplant malignancies. Age, posttransplant malignancies and poor adherence are significant predictors of mortality in the survival analyses. CONCLUSIONS The present study highlights the importance of the assessment of psychosocial variables and psychiatric diagnoses before and after transplantation in HT recipients. Our findings have important clinical implications and require replication with larger samples.

Influence of Inflow Cannula Length in Axial-flow Pumps on Neurologic Adverse Event Rate: Results From a Multi-center Analysis

BACKGROUND The application of axial-flow pumps in patients with end-stage heart failure reveals a significantly reduced infectious complication rate as compared with rates observed with pulsatile devices. The remaining adverse event rate relates mainly to thromboembolic complications with neurologic consequences. We investigated the dependence of the neurologic adverse event rate on the length of the inflow cannula. METHODS A total of 216 consecutive patients with an axial-flow pump (INCOR; Berlin Heart GmbH, Berlin, Germany) were included in a retrospective multi-center analysis. In 138 patients, a short inflow cannula (24-mm tip length into the left ventricle), and in 78 patients a long inflow cannula (tip length 34 mm) was applied. RESULTS Patients with a long inflow cannula (LC) demonstrated a better survival rate than those with a short inflow cannula (SC) at the end of the observation period (LC, 63.4%; SC, 52.9%; p = 0.05). The thromboembolic adverse event rate was also significantly lower. Only 3 of the 78 patients (3.8%) with an LC had a thromboembolic adverse event (thromboembolic events per patient-year = 0.11) as compared with 32 (23.2%) of SC patients (thromboembolic events per patient-year = 0.50, p < 0.001). CONCLUSIONS Patients with a long inflow cannula had a better survival rate and a lower incidence of cerebrovascular adverse events than patients with a short inflow cannula.

MRI in the assessment of muscular pathology: a comparison between limb-girdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies.

PurposeThe continuous discovery of new subtypes of neuromuscular disorders demands more accurate imaging analyses. We set out to establish the specific patterns of muscular involution using magnetic resonance imaging (MRI).Materials and methodsA systematic clinical evaluation based on the Medical Research Council scale and MRI was completed in ten patients with calpainopathy [limb-girdle muscular dystrophy (LGMD)-2A], 16 with dysferlinopathy (LGMD-2B), ten with hyaline body myopathy (HBM), six with myotonic dystrophy (MD) types 1 and 5 with MD type 2. Severity of fibroadipose degeneration was specifically staged using T1-weighted sequences. Turbo inversion recovery magnitude (TIRM) sequences were used to assess oedema-like changes.ResultsT1 scans showed recurrent patterns of fibroadipose replacement, whereas TIRM images revealed differences in oedema-like changes between the various diseases. In LGMD, the posterior compartments are more vulnerable to degeneration. In HBM, fatty muscle degeneration and oedema are allocated to muscles of the posterior compartments of the leg. In MD, fatty muscle degeneration and oedematous changes are allocated to muscles of the anterior thigh and posterior lower leg.ConclusionsImaging examination suggests a characteristic pattern of muscle involvement. MRI represents an important diagnostic technique useful in differential diagnosis, thanks to the distinctive patterns observed in the distribution of muscular changes between the different muscular diseases.RiassuntoObiettivoLa continua scoperta di nuovi sottotipi di patologie neuromuscolari rende necessaria un’analisi di imaging adeguata. Ci si prefigge di descrivere specifici modelli di involuzione muscolare con la risonanza magnetica (RM).Materiali e metodiLa valutazione clinica, basata sulla scala del Medical Research Council, e la RM sono state eseguite su 10 pazienti con calpainopatia (LGMD2A), 16 con disferlinopatia (LGMD2B), 10 con miopatia a corpi ialini (HBM), 6 con distrofia miotonica di tipo 1 (MD1) e 5 con il tipo 2 (MD2). La severità della degenerazione fibroadiposa è stata valutata con sequenze pesate in T1. Le sequenze turbo inversion recovery (TIRM) sono state usate per valutare l’edema.RisultatiLe immagini T1-pesate hanno mostrato modelli ricorrenti di sostituzione fibro-adiposa, mentre le immagini TIRM hanno rivelato differenze nell’interessamento edematoso dei muscoli. Nella LGMD i compartimenti muscolari posteriori sono più vulnerabili alla degenerazione. Nella HBM, l’involuzione adiposa e l’edema sono appannaggio dei muscoli dei compartimenti posteriori dell’arto inferiore. Nella MD, l’involuzione adiposa del muscolo ed i segni di edema interessano soprattutto i muscoli della coscia anteriore e della gamba posteriore.ConclusioniL’esame di diagnostica per immagini suggerisce un modello caratteristico di coinvolgimento muscolare. La RM rappresenta un’importante tecnica diagnostica utile nella diagnosi differenziali grazie ai diversi pattern di interessamento muscolare.Purpose. The continuous discovery of new subtypes of neuromuscular disorders demands more accurate imaging analyses. We set out to establish the specific patterns of muscular involution using magnetic resonance imaging (MRI). Materials and methods. A systematic clinical evaluation based on the Medical Research Council scale and MRI was completed in ten patients with calpainopathy [limb-girdle muscular dystrophy (LGMD)-2A], 16 with dysferlinopathy (LGMD-2B), ten with hyaline body myopathy (HBM), six with myotonic dystrophy (MD) types 1 and 5 with MD type 2. Severity of fibroadipose degeneration was

Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection.

ABSTRACT Human cytomegalovirus (CMV) infection represents a major threat for heart transplant recipients (HTXs). CMV-specific T cells effectively control virus infection, and thus, assessment of antiviral immune recovery may have clinical utility in identifying HTXs at risk of infection. In this study, 10 CMV-seropositive (R+) pretransplant patients and 48 preemptively treated R+ HTXs were examined before and after 100 days posttransplant. Preemptive treatment is supposed to favor the immune recovery. CMV DNAemia and gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay were employed to assess the viremia and immune reconstitution. HTXs could be categorized into three groups characterized by high (>100), medium (50 to 100), and low (<50) spot levels. Early-identified high responders efficiently controlled the infection and also maintained high immunity levels after 100 days after transplant. No episodes of grade ≥2R rejection occurred in the high responders. Midresponders were identified as a group with heterogeneous trends of immune reconstitution. Low responders were 41% and 21% of HTXs before and after 100 days posttransplant, respectively. Low responders were associated with a higher incidence of infection. The effect of viremia on immune recovery was investigated: a statistically significant inverse correlation between magnitude of viremia and immune recovery emerged; in particular, each 10-fold increase in viremia (>4 log10 DNAemia/ml) was associated with a 36% decrease of the ELISPOT assay spot levels. All episodes of high viremia (>4 log10 DNAemia/ml) occurred from 1 to 60 days after transplant. Thus, the concomitant evaluation of viremia and CMV immune reconstitution has clinical utility in identifying HTXs at risk of infection and may represent a helpful guide in making therapeutic choices.

Can C4d immunostaining on endomyocardial biopsies be considered a prognostic biomarker in heart transplant recipients

Background. The aim of this study was to assess the significance of positive C4d capillary immunostaining of endomyocardial biopsies and its correlation to clinical outcome in adult heart transplant recipients. Methods. Nine hundred eighty-five endomyocardial biopsies from 107 heart transplant recipients were evaluated. Immunostaining for detection of intragraft C4d capillary deposition was performed on paraffin-embedded tissue using anti-human C4d polyclonal antibody. Results. Positive staining of C4d was present in 36 patients (34%) and antibody-mediated rejection in eight patients (7%). The patients were subdivided into four groups on the basis of their C4d, circulating antidonor antibodies (donor-specific antibodies [DSAs]), and graft function: group 1=C4d positive, DSA negative, and no graft dysfunction; group 2=C4d positive, DSA positive, and no graft dysfunction; group 3=C4d positive, DSA positive, and signs of graft dysfunction, and group 0 (control)=all negative. An higher mortality risk was found in C4d-positive patients, when compared with negative ones (unadjusted hazard ratios: group 1: 18, group 2: 61, and group 3: 32-fold risk; P<0.0001). Conclusions. Antibody-mediated rejection is a complex and ongoing phenomenon with different phenotypic features. C4d positive predicts worse prognosis. C4d negative and DSA can be used as early mortality predictors in patients without signs of graft dysfunction.

Role of morphologic parameters on endomyocardial biopsy to detect sub-clinical antibody-mediated rejection in heart transplantation.

BACKGROUND The present study evaluated if morphologic parameters detect signs of early sub-clinical or latent stages of antibody-mediated rejection (AMR) and their correlation with C4d staining in cardiac transplants recipients. METHODS The study reviewed 1,270 endomyocardial biopsies (EMB) from 131 patients. Of these, 61 stained positive for C4d in the absence of acute cellular rejection >2R. Sixty-six EMB specimens negative for C4d were matched for pre-transplant diagnosis, time after transplantation, age, and acute cellular rejection (ACR) grading. Histopathologic evaluation and C4d staining were performed on formalin-fixed, paraffin-embedded sections using the C4d polyclonal antibody. RESULTS Of the 8 histologic characteristics evaluated, only endothelial swelling (78.7% sensitivity, 28.8% specificity; positive likelihood ratio, 1.10) and interstitial edema (77% sensitivity, 31.8% specificity; positive likelihood ratio, 1.13) could be considered fair predictors of C4d capillary positivity. The presence of mononuclear cells in capillaries in relation to C4d positivity showed 39.3% sensitivity and 68.2% specificity. Combining the parameters endothelial swelling and mononuclear cells in capillaries, sensitivity was 31.1% (95% confidence interval [CI] 19.9-44.3) and specificity was 71.2% (95 CI, 58.8-81.7), with a positive likelihood ratio of 1.08 (95% CI, 0.68-1.84). CONCLUSIONS Our results showed that histologic parameters did not always detect signs of early sub-clinical or latent stages of AMR. Combining the parameters of endothelial swelling and intracapillary mononuclear cells did not significantly improve the sensitivity or specificity. Screening recommendations should, therefore, be modified to include more sensitive tests such as C4d staining in the routine protocol to improve patient risk stratification.

C2 is superior to C0 as predictor of renal toxicity and rejection risk profile in stable heart transplant recipients

To assess whether cyclosporine A (CsA) 2‐h peak (C2) is superior to trough levels (C0) for Neoral dose monitoring in heart transplantation (HT), we studied 928 C0–C2 paired determinations from 313 stable HT patients (257 male, aged 50 ± 14 years at HT, follow‐up 6.9 ± 4 years), on a C0‐based regimen. Our target C0 levels (ng/ml) were 150–400 (first 3 months), 150–300 (4–12 months), 100–250 (>12 months). Mean C0 and C2 levels were 268 ± 80 and 1031 ± 386, respectively (first 3 months); 230 ± 49 and 955 ± 239 (4–12 months); 157 ± 53 and 745 ± 236 (>12 months). For patients within the target C0, the corresponding C2 were 600–1500 (first 3 months), 600–1300 (4–12 months), 400–1100 (>12 months). C2 correlated with C0 (r = 0.64, P = 0.0001). C2 correlated better with CsA dose than C0 (r = 0.41, P = 0.0001 vs. r = 0.33, P = 0.0001). Between patients, CsA dose varied by a factor of 9.3; the C/dose ratio varied by a factor of 8.5 for C2 and of 15.6 for C0. Patients with higher C2 (>740) had higher severe rejection score at 2 years (P = 0.02) than patients with lower C2. This did not apply to C0. Both C2 and C0 correlated with blood urea (r = −0.18, P = 0.0001; r = −0.12, P = 0.0002) and creatinine (r = −0.19, P = 0.0004; r = −0.19, P = 0.0001 respectively). By logistic regression higher C2 (>740) was associated with higher total severe rejection score at 2 years (P = 0.006). C2 showed better correlation with CsA dose, renal function, rejection profile and less variability between patients than C0. C2 may improve CsA‐based immunosuppression in HT.