Porcelain aorta: A surgical dilemma in orthotopic heart transplantation

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The Role of Congestion in Cardiorenal Syndrome Type 2: New Pathophysiological Insights into an Experimental Model of Heart Failure

BACKGROUND: In cardiorenal syndrome type 2 (CRS2), the role of systemic congestion in heart failure (HF) is still obscure. We studied a model of CRS2 [monocrotaline (MCT)-treated rats] secondary to pulmonary hypertension and right ventricular (RV) failure in order to evaluate the contribution of prevalent congestion to the development of kidney injury. METHODS: Ten animals were treated with MCT for 4 weeks until they developed HF. Eleven animals were taken as controls. Signs of hypertrophy and dilatation of the right ventricle demonstrated the occurrence of HF. Brain natriuretic peptide (BNP), serum creatinine (sCreatinine), both kidney and heart neutrophil gelatinase-associated lipocalin (NGAL), matrix metallopeptidase 9 (MMP9), serum cytokines as well as kidney and heart cell death, as assessed by TUNEL, were studied. RESULTS: Rats with HF showed higher BNP levels [chronic HF (CHF) 4.8 ± 0.5 ng/ml; controls 1.5 ± 0.2 ng/ml; p < 0.0001], marked RV hypertrophy and dilatation (RV mass/RV volume: CHF 1.46 ± 0.31, controls 2.41 ± 0.81; p < 0.01) as well as pleural and peritoneal effusions. A significant increase in proinflammatory cytokines and sCreatinine was observed (CHF 3.06 ± 1.3 pg/ml vs. controls 0.54 ± 0.23 pg/ml; p = 0.04). Serum (CHF 562.7 ± 93.34 ng/ml vs. controls 245.3 ± 58.19 ng/ml; p = 0.02) as well as renal and heart tissue NGAL levels [CHF 70,680 ± 4,337 arbitrary units (AU) vs. controls 32,120 ± 4,961 AU; p = 0.001] rose significantly, and they were found to be complexed with MMP9 in CHF rats. A higher number of kidney TUNEL-positive tubular cells was also detected (CHF 114.01 ± 45.93 vs. controls 16.36 ± 11.60 cells/mm(2); p = 0.0004). CONCLUSION: In this model of CHF with prevalent congestion, kidney injury is characterized by tubular damage and systemic inflammation. The upregulated NGAL complexed with MMP9 perpetuates the vicious circle of kidney/heart damage by enhancing the enzymatic activity of MMP9 with extracellular matrix degradation, worsening heart remodeling

Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy

Background: Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT

The Peritoneum as a Natural Scaffold for Vascular Regeneration

Objective: The peritoneum has the same developmental origin as blood vessels, is highly reactive and poorly thrombogenic. We hypothesize that parietal peritoneum can sustain development and regeneration of new vessels. Methods and Results: The study comprised two experimental approaches. First, to test surgical feasibility and efficacy of the peritoneal vascular autograft, we set up an autologous transplantation procedure in pigs, where a tubularized parietal peritoneal graft was covered with a metal mesh and anastomosed end-to-end in the infrarenal aorta. Second, to dissect the contribution of graft vs host cells to the newly developed vessel wall, we performed human-to-rat peritoneal patch grafting in the abdominal aorta and examined the origin of endothelial and smooth muscle cells. In pig experiments, the graft remodeled to an apparently normal blood vessel, without thrombosis. Histology confirmed arterialization of the graft with complete endothelial coverage and neointimal hyperplasia in the absence of erosion, inflammation or thrombosis. In rats, immunostaining for human mitochondri revealed that endothelial cells and smooth muscle cells rarely were of human origin. Remodeling of the graft was mainly attributable to local cells with no clear evidence of c-kit+ endothelial progenitor cells or c-kit+ resident perivascular progenitor cells. Conclusions: The parietal peritoneum can be feasibly used as a scaffold to sustain the regeneration of blood vessels, whic

New tissue biomarkers of Antibody Mediated Rejection in Heart Transplantation

INTRODUCTION Heart transplant still represent the most important therapeutic strategy for end-stage cardiomyopathies. Humoral rejection was recognized as a distinct clinico-pathologic entity characterized by acute allograft rejection associated with the production of antidonor HLA antibodies and poor prognosis. For the first time on renal biopsy from patients with kidney function deterioration and absence of cellular rejection C4d was identified as an important diagnostic biomarker for antibody mediated rejection and was strongly correlated with the presence of circulating anti-HLA antibodies. In heart transplantation in the ISHLT working formulation of 2004 the diagnostic criteria of AMR were defined only as present or absent , recognizing grade 0 without histological and immunopathological signs of humoral rejection and grade 1 in the setting of both histological and immunopathological signs of humoral rejection. However the role of AMR remained controversial with different reported incidence between different centers. Even though we were able to obtain a better control of cellular rejection with a decreasing rate of positive Acute Cellular Rejection (ACR) requiring drug therapy modification, no concomitantly reduction in graft loss for cardiac allograft vasculopathy was observed. Recently the attention was mainly focused on humoral rejection and on our ability to detect it through immunohistopathological markers. The aims of the present thesis were summarized in three major objectives: 1) to study the pathophysiology of Antibody Mediated Rejection (AMR) in heart transplant recipients; 2) to assess the diagnostic ability of pathological features to identify AMR on monitoring post-transplant endomyocardial biopsies (EMBs); 3) to clarify the prognosis of AMR in the early and late post-transplant period. MATERIALS AND METHODS. As C4d staining has been performed on a routine basis in heart transplant recipients at the University of Padua's Heart Transplantation Center since 2005, 1.452 consecutive EMBs from 131 patients (mean age 48.9±18.3) were reviewed. Donor mean age was 41,6±15,2 years and 15% had more than 60 year old. Adult population. To study survival in patients with C4d positivity on EMBs we evaluated 985 consecutive biopsies from a total of 107 adult patients (n=85, 79% of these were males) with a median age at the time of transplantation of 55 years (range 17-73 years). Our study population was divided into 4 groups on the basis of the patients’ C4d, DSA, and graft function profile: - C4d positive, DSA negative, without graft dysfunction (asymptomatic AMR) = group 1; - C4d positive, DSA positive, without graft dysfunction (asymptomatic AMR) = group 2; - C4d positive, DSA positive, presence of graft dysfunction (symptomatic AMR) = group 3 - C4d negative, DSA negative, without graft dysfunction, control group = group 0. Pediatric population. We evaluated 226 consecutive biopsies from 24 transplant patients (mean age 8,1±6,3 years). The immunoperoxidase staining was applied routinely both in paediatric and adult patients. The staining for C4d was performed retrospectively using affinity-purified antihuman C4d rabbit polyclonal antibody. The grading system was standardized and was defined in four grades: grade 0 = negative; grade 1 = weak staining with focal distribution, grade 2 = moderate staining with multifocal distribution; grade 3 = strong staining with diffuse pattern. We considered positive grades 2 and 3.The cut off value between grade 1 and grade 2 was 50% of intramyocardial capillaries involved. Immunostaining for C3d, was performed on paraffin embedded section and using a polyclonal antibody C3d.The grading system for C3d immunostaining was the same as for C4d. Histological features of AMR on EMBs. Of the 1452 EMBs, 87 were positive for C4d staining (6% 87/1452) from 61 patients, 26 EMBs from 13 patients had repeated C4d positivity. Sixty-six patients staining negative for C4d were matched for pre-transplant diagnosis, time after transplantation age, and acute cellular rejection (ACR) grading (case-control study). Among the 61 C4d positive patients 9 were diagnosed as AMR. In this case-control study we also applied C3d staining. Two pathologists reviewed blindly all morphological features associated to humoral damage: endothelial swelling, interstitial edema, intracapillary mononuclear cells, intracapillary neutrophils, myocite damage, myocite necrosis, hemorrhage, intravascular microthrombi according to ISHLT 2005 classification. Donor specific Antibodies (DSA) Assessment. Since the study of C4d has been mainly retrospective only in a subgroup of patients circulating anti HLA antibodies could be performed. In thirty-seven patient circulating Anti HLA antibodies were assessed and resulted 26 positive and 9 negative. IgG anti-HLA reactivity in the sera, obtain before transplantation and at the time of C4d positive detection on EMBs, was analyzed using bead-based screening assays, referred to as Luminex methodology. All sera tested positive at screening, were retested with Single Antigen beads in order to determine the antibody specificity. Contrast-enhanced transthoracic Doppler echocardiography. We selected 19 patients who at the time of biopsy stained positive for C4d and in whom echocardiography was performed for Coronary Flow Reserve (CFR) evaluation using CE-TTE before and after adenosine infusion. CFR was calculated as ratio of peak diastolic velocity(hyperemia) and peak diastolic velocity (basal). Statistical analysis. . The comparison between C4d groups was conducted with the Fisher’s exact test in case of categorical variables and the Kruskal-Wallis test for quantitative variables. The Kaplan-Meier method was applied to estimate the C4d groups’ survival functions and the log–rank test was used to compare survival between groups. The Cox’s regression model was used to estimate unadjusted and sex and age adjusted hazard ratios (HR). Sensitivity and specificity, were reported with 95% confidence interval calculated with the exact method RESULTS Clinic-pathological profile of adult population The 22 patients in group 1 (61% of total C4d+ve) showed a 18 fold higher mortality risk compared to the C4d negative patients (95% CI 1.960 to 160.022). The 6 patients in group 2 had a 61 fold higher mortality risk (95% CI 3.399 to 1110.360). The 8 patients in group 3 had a 32 fold higher mortality risk (95% CI 5.884 to 179.432), overall p<0.0001 Overall the C4d positive patients showed a statistically significant reduction in survival compared to the C4d negative patients and this observation was maintained in the three different groups When the asymptomatic (groups 1 and 2) and symptomatic patients (group 3) were compared with the control group an 18 and 26 fold increase mortality risk was observed, respectively. Clinic-pathological profile of pediatric population. Seven patients (33%) showed a C4d +ve intra-graft capillary deposition. Of these 4 were positive for circulating donor specific anti HLA antibodies; none were positive in the C4d negative group. One patient presented also graft dysfunction (14% of C4d+ve) within 3 months after transplantation. One patient with C4d positivity died for heart failure after 2 years since C4d positivity detection. The other five patients with C4d positivity are still alive at 2, 3, 4 , 14 years respectively. In the C4d positive group the rejection score was higher compare to C4d negative patients. (2.2 vs 0.2, p<0,05) Morphological parameters on Endomyocardial biopsy (EMB) to detect Asymptomatic AMR (AsAMR) and Symptomatic AMR (AMR). Of the 8 histological characteristic evaluated on Hematoxilyn Eosin , only two (endothelial swelling and interstitial edema) could be considered fair predictors of C4d capillary positivity in the light of their sensitivity: endothelial swelling with a 78.7 % sensitivity (its specificity was very poor 28.8%) and interstitial edema with a 77.1% sensitivity (its specificity was 31.8%). Intracapillary macrophages had a sensitivity of 39.3% only and a specificity of 68.2%. The sensitivity and specificity of the histological parameters in EMBs of patients with C4d positivity (both asymptomatic and symptomatic) were similar to those observed in EMBs of patients affected by symptomatic AMR ROC curve combining endothelial swelling and intra-capillary aggregates of macrophages did not improve the capacity to predict presence of circulating anti HLA antibodies. Immunostaining for C3d in the diagnosis of AMR. In the asymptomatic AMR group (52 EMBs of 52 patients) 31 were also positive for C3d (59,6%, 31/52). In the symptomatic AMR group (9 EMBs of 9 patients) 5 were also positive for C3d (55% 5/9). The sensitivity of C3d to predicted DSA was 42.3% and the specificity of C3d was 56% for DSA. Combining C4d and C3d to predicting circulating DSA did not increase the sensitivity and specificity of C4d. Alloantibody profile in symptomatic AMR. Of the 9 symptomatic AMR patients, 5 had been followed up for C4d positivity on EMBs and circulating DSA. The results showed that MFI for class I and class II changed according to the treatment. High level of MFI (>10000) strongly correlated with diffuse and strong intensity of C4d staining; with MFI ranging between 1000-9000 C4d was variably detected; with MFI < 1000 C4d was always negative. Microvasculopathy and C4d. Seven out of 19 patients, in whom we performed echostress(or where ECHO stress was reduced) had C4d positive immunostaining while 12 were negative (average age 50.1±8.7 years). In the group of patients with C4d positivity 4 were late symptomatic AMR (mean time after Htx 13.9±4.9 years) and three of them died after few months since the diagnosis of AMR. Three patients had asymptomatic AMR (mean time after HTx 5.3±3.4 years). Coronary flow reserve (CFR) of patients with C4d+ was statistically significant reduced compared to C4d- group (1.28±0.48 vs 3.28±1.03 respectively, p=0.0297) suggesting a relation between humoral rejection and microvascular damage. Even in pts without CAV at angiography C4d positivity identified a low value of CFR in the C4d+ group (p=0.0502). CONCLUSIONS. Our findings indicate that C4d+ve is an important marker for diagnosis of AMR , thus identifying asymptomatic AMR . C4d predicts worse prognosis and DSA and graft dysfunction further improve risk stratification. C4d+ve and DSA can be used as early mortality predictors in patients without signs of graft dysfunction. AMR is a complex and ongoing phenomenon with different phenotypic features. Morphological parameters alone, are not adequately sensitive and carry low positive likelihood ratio as screening tools for early asymptomatic AMR detection. Screening recommendations has been recently modified to include more sensitive tests such as C4d staining in the routine protocol to improve patient risk stratification. The assessment of anti HLA antibodies, class I and II and their relation with C4d (complement activation)showed : 1) a difference in type of anti HLA-DSA in the early and late period post-transplant with class I anti HLA early appearance and class II anti HLA late onset after transplant 2) high levels of MFI correlate with C4d deposition on EMBs. Endothelial damage and complement deposition produce microvascular remodeling leading to microvasculopathy with increased graft loss.INTRODUZIONE Il trapianto cardiaco rappresenta ancora la più importante strategia terapeutica nei pezienti con scompenso cardiaco refrattario alla terapia medica. Nell’ultimo decennio la attenzione clinica è stata rivolta al rigetto umorale in seguito al dato che la percentuale di perdita del garft per rigetto cronico non è cambiata, nonostante la terapia immunosoppressiva controlli in modo ottimale il rigetto cellulo-mediato. Il rigetto umorale viene definito come una entità clinico-patologica caratterizzata dalla presenza di anticorpi anti HLA (complesso maggiore di istocompatibilità) circolanti che provocano danno endoteliale sull’organo trapiantato con conseguente impatto sulla mortalità. Per la prima volta in biopsie renali di pazienti con disfunzione del graft in assenza di rigetto cellulo-mediato, è stato evidenziato deposito di C4d sulla superficie endoteliale, sinonimo di attivazione del complemento , strettamente correlato con la presenza di anticorpi anti HLA circolanti nel siero. Le linee guida internazionali che definiscono i criteri patologici per la diagnostica del rigetto nel trapianto di cuore, solo nel 2004 per la prima volta definiscono il rigetto umorale come entità patologica distinta indicandone i criteri diagnostici istologici e immunopatologici maggiori, riconoscendo come grado 0 assenza di segni istologici e immunopatologici e grado 1 la presenza di segni istologici e immunopatologici di rigetto umorale. Nell’ultima decade la letteratura internazione ha rivolto la propria attenzione alla ricerca del significato prognostico del rigetto umorale in relazione al rigetto cronico e alla ricerca di nuovi biomarcatori per la diagnosi precoce del rigetto umorale. Gli obiettivi della presente tesi di dottorato possono essere riassunti in tre principali puntii: 1) studio della fisiopatologia del rigetto umorale o rigetto anticorpo mediato nel trapianto di cuore; 2) valutazione della capacità diagnostica dei criteri istopatologici definiti dalle linee guida internazioni del 2004, su biopsie endomiocardiche di monitoraggio post-trapainto; 3) definizione del significato prognostico del rigetto anticorpo mediato sia nella fase precoce che tardiva post-trapianto. MATERIALI E METODI. Dal 2005, nel nostro centro di riferimento per il trapianto cardiaco dell’Università di Padova, abbiamo studiato routinariamente il biomarcatore di attivazione del complemento (C4d) con tecnica immunoistotchimica su tessuto (biopsie endomiocardiche di monitoraggio). Abbiamo valutato 1452 biopsie endomiocardiche (BEM) da 131 pazienti (età media 48.9±18.3). Popolazione adulta. Per studiare la sopravvivenza di pazienti adulti che presentano una positività al C4d nel loro follow up, abbiamo studiato 985 BEM di 107 pazienti (79% maschi) con età al trapianto di 55 anni (mediana) range 17-73 anni. La nostra popolazione adulta è stata suddivisa il quattro gruppi sulla base del profilo del C4d nelle BEM, degli anticorpi circolanti anti HLA donatore specifici (DSA), e della disfunzione del graft (riduzione della frazione di eiezione, anomalie elettrocardiogarfiche): • C4d positivo, DSA negativi, assenza di disfunzione del garft (rigetto anticorpo-mediato asintomatico)= gruppo 1 • C4d positivo, DSA positivi, assenza di disfunzione del graft (rigetto anticorpo-mediato asintomatico)= gruppo 2 • C4d positivo, DSA positivi, presenza di segni clinici di disfunzione del graft (rigetto anticorpo-mediato sintomatico)= gruppo 3. • C4d negativo, DSA negativi, assenza di disfunzione clinica del graft (gruppo controllo )= gruppo 0. Popolazione pediatrica. Abbiamo valutato 226 biopsie provenienti da 24 pazienti trapiantati (età media 8,1±6,3 anni). Tecnica immunoistochimica è stata applicata routinariamente sia nella popolazione adulta sia nella popolazione pediatrica. La tecnica immunoistochimica è stata applicata sia retrospetticamente che prospetticamente usando anticorpo policlonale per C4d. Il grading per la valutazione della colorazione immunoistochimica è stata standardizzato in quattro gradi: grado 0= negativo; grado 1= debole intensità, focale coinvolgimento dei capillari; grado 2= moderata intensità e coinvolgimento multifocale dei capillari e grado 3= colorazione intensa e coinvolgimento diffuso dei capillari. Si considera positivo grado 2 e grado 3. E’ stata inoltre eseguita l’immunoistochimica per C3d su materiale paraffinato applicando lo stesso schema di valutazione del C4d. Valutazione dei criteri diagnostici morfologici di rigetto anticorpo mediato. Delle 1452 BEM valutate, 87 erano positive per il C4d (6% 87/1452) in 61 pazienti, 26 BEM di 13 pazienti hanno mostrato un C4d positivo in più di un biopsia. Sessantasei pazienti negativi per il C4d sono stati selezionati e confrontati secondo i seguenti criteri: diagnosi pre-trapianto, età dopo il trapianto, grading del rigetto cellulo-mediato (studio caso-controllo). Tra i 61 pazienti positivi per il C4d 9 avevano rigetto anticorpo-mediato sintomatico, In questo studio caso-controllo abbiamo studiato anche il C3d. Due Patologi hanno rivisto “blindly” tutti i criteri istologici associati al rigetto umorale: edema endoteliale, edema interstiziale, cellule mononucleari intracapillari, neutrofili intracapillari, danno miocitario, necrosi miocitaria, emorragia, microtrombi intravascolari in accordo con le linee guida internazionali “ISHLT working formulation “ del 2004. Determinazione degli anticorpi anti HLA donatore specifici. La valutazione degli anticorpi circolanti è stata eseguita su 37 casi, in virtù del fatto che il nostro studio è stata condotto anche retrospetticamente. E’ stata utilizzata la tecnica Luminex per testare la reattività degli anticorpi anti HLA tipo IgG con tecnica “bead-based screening assay” da sieri ottenuti pre-trapianto e post-trapianto, quest’ultimo in concomitanza con la positività del C4d nelle BEM. Inoltre in una sottopopolazione di pazienti con rigetto umorale sintomatico gli anticorpi circolanti sono stati quantificati misurando la media di intensità di fluorescenza (MFI). Valutazione della riserva coronarica tramite tecnica ecocardiografica non invasiva. Abbiamo selezionato 19 pazienti in cui al momento della biopsia endomiocardica di monitoraggio post-trapianto è stata eseguita ecocardiograficamente.La Riserva Coronarica valutata prima e dopo l’infusione di adenosina La riserva coronarica (CFR) è stata calcolata con rapporto tra picco di velocità diastolica (iperemia) e picco di velocità diastolica (basale). Analisi statistica. Il confronto tra i vari gruppi C4d è stato calcolato con test Fisher nei caso di variabili categoriali e con test di Kruskal-Wallis per variabili quantitative. E’ stato applicato il metodo di Kaplan-Meyer per studiare la sopravvivenza dei vari gruppi positivi per C4d. Test di regressione di Cox per stimare Hazard ratio. Sono state calcolate sensibilità e specificità dei vari parametri morfologici e riportate con intervallo di confidenza del 95%. RISULTATI. Profilo clinico-patologico della popolazione adulta. Ventidue pazienti del gruppo 1 (61% del totale dei C4d positivi) mostano un rischio di mortalità 18 volte maggiore rispetto al gruppo di controllo (95% CI 1,960 – 160,022).. I sei pazienti del gruppo 2 hanno un rischio di mortalità 61 volte maggiore rispetto al gruppo di controllo (95% CI 3.399-1110.360). Gli 8 pazienti del gruppo 3 hanno un rischio di mortalità 32 volte maggiore rispetto al gruppo di controllo con una p<0,0001. Se si considerano nella totalità i pazienti C4d positivi mostrano una riduzione statisticamente significativa della sopravvivenza rispetto al gruppo C4d negativo. Si osserva un aumento del rischio di mortalità sia nei gruppi 1 e 2 (asintomatici) che nel gruppo 3 sintomatico Profilo clinico-patologico della popolazione pediatrica. Sette pazienti (33%) mostrano una positività al C4d nelle BEM di monitoraggio. Di questi 4 presentavano anticorpi anti HLA circolanti; nessuno era positivo nel gruppo di controllo. Un paziente con positività al C4d ha presentato disfunzione del graft (14% dei C4d+) entro i 3 mesi dal trapianto. Un paziente C4d positivo è morto per scompenso cardiaco dopo circa 2 anni dalla comparsa della positività del C4d nelle BEM. Gli altri cinque pazienti con C4d + sono attualmente vivi a rispettivamente 2,3,4,14 anni di follow up. Nel gruppo C4d+ il “rejection score” per rigetto cellulare è maggiore rispetto al gruppo di controllo (2,2 vs 0,2, p<0,05). Parametri morfologici per la diagnosi di rigetto anticorpo-mediato sintomatico e asintomatico nelle biopsie endomiocardiche di monitoraggio. Degli 8 criteri morfologici valutati all’ematosillina ed eosina, solo due (edema endoteliale ed interstiziale) possono essere considerati predittivi di positività capillare al C4d. la sensibilità dell’edema endoteliale è del 78,8% e la sensibilità dell’edema interstiziale è del 77,1%. Accumulo intracapillare di cellule mononucleari hanno una sensibilità del 39,3% nel predire la positività al C4d. La curva ROC mostra come i due criteri valutati assieme e riconosciuti essere i più importanti associati al danno anticorpo-mediato non aumentano la capacità di predite la presenza di anticorpi circolanti anti HLA. Immunoistotchimica per C3d nella diagnostica del rigetto umorale. Nel gruppo degli asintomatici (52 BEM di 52 pazienti) 31 BEM sono positive anche per C3d (59,6%, 31/54). Nel gruppo dei sintomatici (9 BEM per 9 pazienti) 5 BEM erano positivi al C3d (55% 5/9). La sensibilità del C3d nel predire la presenza di anticorpi anti HLA circolanti è del 42,3% e la specificità del 56%. Combinando C4d e C3d la sensibilità e specificità nel predire la presenza di anticorpi circolanti non aumenta. Profilo anticorpale nei pazienti con rigetto anticorpo mediato sitomatico. Dei 9 pazienti sintomatici della nostra popolazione studiata, 5 sono stati seguiti in follow up sia per C4d sia per anticorpi circolanti. I risultati mostrano che la quantità di anticorpo circolante (MFI) cambia in relazione al trattamento. Inoltre alti livelli di MFI >10000 correlano strettamente con grado 3 del C4d (diffuso coinvolgimento capillare con colorazione intesa), con MFI tra 1000-9000 il C4d ha una intensità ed una distribuzione variabile.; con MFI <1000 C4d è sempre negativo. C4d e microvasculopatia. La riserva coronarica di pazienti con C4d

Complete Transposition of Great Arteries With Dominant Left Ventricle

We report the case of an adult patient, affected by complete transposition of great arteries with ventricular septal defect, who survived until 68 years of age without surgery, thanks to the presence of a common atrium and pulmonary stenosis. (Level of Difficulty: Advanced.