ࡱ> q`bjbjqPqP::B!2222ޥޥޥޥ$<4J___73939393939393$6h8r]3m@_mm]322!V4---m ,2873-m73--j> p̫착ޥ",l404d9td9DB d9(_]l-ɰ$___]3]3___4mmmmPzYdLzY222222 INDICAZIONI AL TRAPIANTO DI CUORE G Romano, C Maiello, M Cotrufo Il trapianto di cuore attualmente considerato il trattamento gold standard per la terapia della insufficienza cardiaca terminale. La continua disponibilit di enormi messe di dati comparativi fra i trattamenti cosiddetti convenzionali ed il trapianto di cuore rende merito e conferma che questultimo garantisce i migliori risultati clinici sia a breve che a medio e lungo termine. Sebbene in questi ultimi anni vi sia la generale tendenza ad estendere i benefici di questo trattamento ad un numero sempre maggiore di pazienti, questa tendenza deve essere contro-bilanciata dalla chiara consapevolezza sia che il numero dei donatori utilizzabili rimane ad oggi ampiamente insufficiente rispetto alla domanda e sia che lesponenziale aumento dei potenziali riceventi provoca inevitabilmente un progressivo allungamento dei tempi di attesa individuali, fatto non certamente auspicabile per pazienti a bassa aspettativa di vita, con conseguente incremento della mortalit in lista. Ci produce anche un danno indiretto poich limmagine pubblica che si potrebbe ricavare dellattivit di trapianto sarebbe quella di una terapia elitaria, costosa ed inefficace sul piano della generale domanda di salute e possibile fonte di speculazioni. Inoltre se la sopravvivenza dopo trapianto di cuore, con gli attuali protocolli in uso, pu essere predetta con ragionevole accuratezza sino al quinto anno post-operatorio, la qualit di vita dopo trapianto osservata in gruppi molto eterogenei di pazienti od in specifici subsets clinici non ha dimostrato in realt decisivi miglioramenti complessivi tenendo conto del frequente e rapido peggioramento a medio termine di patologie associate pre-esistenti, del rischio di patologie correlate al regime immunosoppressivo e che linevitabile ed in alcuni casi accelerata vasculopatia del graft conduce circa l80% dei pazienti trapiantati a morte od al re-trapianto in un tempo variabile tra i 10 ed i 15 anni. Se a questo elevato costo morale ed etico del ruolo del trapianto di cuore nel trattamento di tale patologia, soprattutto nel caso dei pazienti di giovane et o di quelli affetti da cardiopatie congenite complesse, si aggiunge lalto costo economico e sociale sostenuto per lorganizzazione ed il mantenimento di infrastrutture dedicate e quelli correlati alla procedura chirurgica e alla durata a vita di terapie specifiche, si comprende perch lattivit di trapianto in genere, e specificatamente quella di cuore, necessiti in maniera costante di una razionalizzazione rivolta da un lato alla ottimizzazione dei risultati e dallaltro alla chiara definizione ed alla gestione di priorit cliniche (listing criteria) che le non illimitate risorse disponibili possano soddisfare. Pertanto il trapianto di cuore genericamente indicato in qualsiasi forma di cardiomiopatia allo stadio terminale in cui i risultati attesi sia in termini di miglioramento della qualit che della aspettativa di vita risultino maggiormente soddisfacenti da quelli osservati nella storia naturale della patologia o con altre appurate forme alternative di terapia. La patogenesi di una cardiomiopatia generalmente riconducibile a molteplici cause distinte primariamente in primitive od idiopatiche e secondarie (Tabella 1); necessario per sinteticamente specificare che non tutte le forme classificate evolvono verso quadri clinici terminali di insufficienza cardiaca od a chiara indicazione chirurgica: alcune forme, come le metaboliche o le tossiche, se adeguatamente trattate presentano un decorso clinico benigno, reversibile e con una completa o parziale restetutio ad integrum; altre forme, e ci particolarmente vero per le forme secondarie a patogenesi sistemica cronica su base infiltrativa, ematologica o neuromuscolare, non vengono ritenute una accettabile indicazione al trapianto, neanche in condizioni di scompenso cardiaco conclamato, se la prognosi della patologia di base da considerarsi comunque infausta a breve o medio termine. Ciononostante dal punto di vista epidemiologico le forme pi frequentemente osservate sono le idiopatiche e le secondarie post-ischemiche che comprendono insieme circa l80% dei casi ad indicazione chirurgica. Linquadramento patogenetico delle varie forme quindi (il cui aspetto clinico evolutivo non oggetto di questa trattazione) una condizione necessaria ma non sufficiente a porre indicazione per il trapianto di cuore e riveste invece maggiore rilievo in termini di stratificazione prognostica durante le fasi di screening pre-trapianto sulla valutazione del rischio chirurgico perioperatorio e della prognosi a lungo termine. In altri termini, considerato il fattore patogenetico, il fattore che riveste la maggiore importanza la stadiazione della patologia e dei sintomi laddove possibile individuare una serie di quadri clinici tipici comuni che caratterizzano la chiara irreversibilit o la evidente progressione della patologia. Sul piano logistico tali criteri di generalizzazione si sono rilevati pi funzionali nelle scelte morali, nella gestione terapeutica e nellapproccio chirurgico (Tabella 2) anche se il crescente stato dellarte medica richiede periodicamente critiche rivisitazioni. Allo stato attuale lindicazione pi chiara e frequente tra le quelle riportate, con una definizione alternativa rispettivamente all aspetto etiopatogenetico precedentemente enunciata, la severa disfunzione mono- o bi-ventricolare che appare irreversibile e non trattabile con altri mezzi terapeutici e che causa acutamente o cronicamente una scadente qualit di vita o sintomi di tale severit da mettere il paziente in imminente pericolo di vita od in un periodo di tempo stimabile tra i tre ed i dodici mesi. Tale indicazione diventa mandatoria in assenza di controindicazioni specifiche in quei pazienti il cui grado di scompenso richiede ripetute ospedaliz-zazioni, luso prolungato o ripetuto di terapia infusionale con inotropi per via endovenosa o ladozione di sistemi di assistenza ventricolare meccanica (VAD) per il supporto di circolo per un periodo superiore a 60 giorni. Sul piano pratico perci necessario chiarire alcuni punti di critica rilevanza nella oggettiva stadiazione della patologia e che solo inizialmente pu avvalersi dellausilio di metodi non invasivi: Classificazione NYHA (New York Heart Association). La ben nota classificazione clinica di sintomi e del grado di dispnea ormai considerata un metodo di screening di massa che conserva un valore prognostico valido ma non sempre efficiente. Tale criterio di classificazione infatti fortemente dipen-dente dalla tendenza alla soggettivazione dei sintomi da parte del paziente ed in funzione diretta del grado di decondizionamento fisico, di obesit e di compliance terapeutica. Spesso una improvvisa acutizzazione dei sintomi dovuta allinsorgere di aritmie ipercinetiche sopraventricolari o ventricolari che possono essere adeguatamente controllate con un trattamento farmacologico mirato. Inoltre la recente applicazione di tecniche di resin-cronizzazione cardiaca, mediante limpianto di pace-maker bi-ventricolari, ha dimostrato effettiva validit nel miglioramento dei sintomi in una percentuale significativa di pazienti con ritardo elettrico di conduzione inter- od intra-ventricolare ma senza peraltro, ad oggi, modificarne significativamente la prognosi a lungo termine. Al contrario pazienti che lamentano solo sintomi di classe II ma che presentano un pattern di flusso ematico trans-mitralico di tipo restrittivo non reversibile allesame ecocardiografico seriato hanno di frequente la medesima prognosi a lungo termine dei pazienti con sintomi di classe III o IV ma con pattern restrittivo reversibile. Per tali motivi la semplice classificazione dei sintomi NYHA da considerarsi un metodo sintetico di approccio clinico il cui uso pu essere utile solo dopo personalizzazione ed ottimizzazione della terapia medica e come tecnica di monito-raggio clinico ambulatoriale. Classificazione HFSS (Heart Failure Survival Score). E un modello matematico predittivo di mortalit a 12 mesi che stato individuato e poi separatamente validato in serie distinte di ampie coorti di pazienti affetti da scompenso cardiaco cronico non sottoposti a trapianto cardiaco. Assegna un coefficiente matematico a sette variabili cliniche in unequazione di regressione (Patologia di tipo ischemico, frequenza cardiaca a riposo, pressione arteriosa media, stima della frazione di eiezione allecocardio-gramma, presenza di un ritardo di conduzione intra od inter ventricolare allECG basale, dosaggio ematico della sodiemia, valore misurato della VO2 al picco) che con formula di tipo additivo calcola uno score di rischio racchiuso in tre classi (Basso e"8.1, medio da 7.2 a 8.1 ed alto <7.2). E in uso un modello matematico ad otto variabili che aggiunge alla formula il valore della pressione di incuneamento capillare polmonare media che ne implementa laccuratezza ma presuppone lesecuzione di una metodica invasiva come il cateterismo cardiaco destro. I pazienti che sono racchiusi nella classe di alto rischio avrebbero una aspettativa di vita a dodici mesi inferiore al 50% e sono quelli che quindi maggiormente si avvantaggiano in termini prognostici del programma trapianto di cuore. Tale modello matematico ha il vantaggio di essere un metodo di screening efficiente ed applicabile anche a livello ambulatoriale ma risente per della terapia medica imposta al paziente in termini di uso dei farmaci -bloccanti e dei diuretici, che influenzano rispettivamente la frequenza cardiaca basale e la sodiemia, e dell impiego, oramai esteso, di pace-maker per la resin-cronizzazione cardiaca che annullano o riducono i difetti di conduzione elettrica ed impongono frequenze fisse di stimolazione determinate dalloperatore in caso di aritmie sopraventricolari persistenti: si pu quindi verificare una sottostima dello score, non validato tenendo conto di questi parametri, con un conseguente errore di classificazione. Di recente si rilevata una buona correlazione tra lo score di rischio HFSS e il valore misurato del BNP che, non risentendo di effetti farmacologici, pu essere dausilio nel processo di verifica. I pazienti che quindi totalizzano uno score ad alto rischio vanno inseriti al pi presto nel programma di trapianto se non sono presenti contro-indicazioni; pi dubbia la scelta per i pazienti a rischio medio o basso per i quali sar necessario un follow-up clinico serrato od uno studio invasivo della funzione cardiaca. Allo stato attuale altri modelli matematici sono in corso di validazione (SEATTLE, ADHF, ADHERE, ecc.) e sar possibile, in futuro, disporre di questi altri strumenti di previsione statistica pi accurata. Tutti gli algoritmi di calcolo sono facilmente reperibili nel web. Test del cammino per 6 minuti (Six minute walking test). Di semplice esecuzione ed ampiamente validato in letteratura, il test impone al paziente 6 minuti di cammino sul tappeto rotante con andatura volontaria ed a minima resistenza e quindi a costante basso carico di lavoro. La prova consente di monitorare in continuo la pressione arteriosa, lossimetria percutanea e il tracciato elettro-cardiografico; viene misurata la distanza totale in metri percorsa durante i 6 minuti e registrati i parametri vitali e/o i sintomi oggettivi di affaticamento. Al termine della prova il paziente esprime un giudizio soggettivo sulla difficolt incontrata durante il test che viene graduata su una scala di 10 gradi di libert denominata Indice di Borg. Una distanza percorsa inferiore ai 300-400 m che si accompagna ad ipotensione, ad irregolare incremento cronotropo ed a dispnea con consistente desaturazione ossi-metrica considerata chiaramente positiva ed impone un approfondimento diagnostico in quanto il test non in grado di differenziare la dispnea di origine cardiaca da quella polmonare. Il test non dovrebbe risentire del grado di decondizionamento fisico e di obesit se non allo stato avanzato. E utile per evidenziare sintomi iniziali di grave scompenso e per monitorare nel tempo ed in modo semplice ed oggettivo lefficacia della terapia medica imposta al paziente. ECG basale e dinamico delle 24 ore (Holter). L esame di base utile nel documentare la frequenza cardiaca a riposo e le alterazioni della conduzione atriale e ventricolare destra e sinistra. I soggetti con durata del QRSe"120 ms e bassa frazione d eiezione (<30%) dovrebbero essere valutati per il programma di resincronizzazione cardiaca. Lesame dinamico di sicura utilit per classificare le aritmie, che talvolta sono il sintomo dominante, stabilirne la gravit e landamento clinico in funzione della terapia intrapresa. E uno dei test necessari previsti dalle linee guida internazionali per limpianto di un defibrillatore automatico. Ecocardiogramma mono e bidimensio-nale con integrazione di analisi doppler e color-doppler. E lesame diagnostico che, allo stato attuale, se ben condotto, fornisce le informazioni pi utili sia di carattere anatomico che funzionale a riposo (possono essere inoltre applicate varie metodiche di analisi che con sempre maggiore accuratezza descrittiva ne implementano la capacit di approfondimento durante stress) ed oggi di sicuro la metodica di imaging cardiologico in pi tumultuoso sviluppo. In questa sede, per brevit, ci limiteremo a fornire dei punti di riferimento generali che possano guidare correttamente il lettore nellinterpretazione dellesame, singolo o seriato, in funzione di una patologia cronica come lo scompenso cardiaco e del timing chirurgico. In primo luogo vanno tenuti in considerazione i parametri anatomici generali ottenuti con misure monodimensionali ovvero dimensioni, volumi e spessori delle cavit, massa miocar-dica totale; lanalisi bidimensionale esamina anche la struttura e le dimensioni degli apparati valvolari e la cinetica segmentaria: ci fornir informazioni di carattere generico ma che orienteranno sul tipo di cardiomio-patia in oggetto. Dal punto di vista funzionale sono disponibili una serie di parametri dei quali, la frazione di eiezione del ventricolo sinistro (FE-Vs), riveste la maggiore impor-tanza. In un recente passato il riscontro di una FEd"25% costituiva una sufficiente condizio-ne clinica per porre indicazione al trapianto cardiaco. Allo stato attuale non si ritiene che tale cut-off sia sufficiente o meglio generaliz-zabile per tutte le cardiomiopatie. La FE-Vs un indice di funzione sistolica e non dello stato contrattile globale dal quale, come ovvio, direttamente dipende. Esprime in percentuale la frazione di volume ematico complessivo espulso per singolo stroke, cio il risultato di un semplice rapporto matematico tra il volume telesistolico ed il volume telediastolico ventricolare sinistro. In un individuo sano, con normali dimensioni cardiache in rapporto alla massa ematica circolante e quindi con normali volumi di riempimento diastolico (50-90 ml/m2), la FE-Vs a riposo del 60-65% che corrisponde ad un volume di stroke di 35-55 ml/m2 e ad un indice cardiaco normale compreso tra i 2.7 ed i 3.3 L/min/m2. In condizioni di stress, quindi di maggiori richieste metaboliche, un aumento della contrattilit intrinseca e della frequenza cardiaca garantisce lincremento dellindice cardiaco sino allo stato iper-dinamico poich ad un incremento del volu-me telediastolico corrisponde un incremento del volume di eiezione; in tal modo il rapporto tra volumi resta pressoch costante. Nel caso ad esempio delle cardiomiopatie ad evoluzione dilatativa, per cause intrinseche od estrinseche al tessuto miocardico, le cavit cardiache aumentano il loro volume (fino a 200 ml/m2 ed oltre) e la loro massa modificando la geometria delle fibre e delle cavit (ipertrofia eccentrica); anche se ci comporta una riduzione dello stato contrattile, i ben noti meccanismi fisiologici di compenso permettono per lungo tempo di sostenere una gittata sistolica lievemente subnormale ma sufficiente, almeno a riposo. La conseguenza di ci che il rapporto matematico della frazione di eiezione si riduce anche se il volume di stroke a riposo non si modifica in modo sostanziale. Al contrario nelle cardiomiopatie di tipo restrittivo od ipertrofico (riduzione primitiva dellelastanza o incremento abnorme della massa di tipo concentrico), dove si verifica una netta riduzione della compliance o capacitanza del ventricolo sinistro (pattern restrittivo), il volume telediastolico solitamente ridotto mentre la funzione sistolica rimane a lungo normale, per cui la frazione di eiezione pu risultare solo lievemente ridotta, nella norma od addirittura aumentata. Nelle forme post-ischemiche acute invece, ovvero in tutte quelle forme in cui non ancora evidente un rimodellamento della geometria ventricolare, la frazione di eiezione invece associabile al reale stato contrattile globale poich coincide realmente con una riduzione del volume di stroke e quindi della portata cardiaca. Altro parametro da tenere in considerazione la frazione di accorciamento del Vs (shortening fraction) che anchesso un indice di funzione sis-tolica ed esprime la capacit di accorcia-mento longitudinale delle miofibrille. Lesame doppler e color-doppler e quello che dal punto di vista emodinamico fornisce le maggiori informazioni per quanto riguarda la funzione valvolare e dei flussi ematici intracavitari (di enorme importanza nelle cardiopatie congenite complesse). In mani esperte possibile calcolare lo stroke volume, lindice cardiaco, la pressione telediastolica del Vs e verificare con esattezza la presenza e lentit di un eventuale rigurgito valvolare o di uno shunt. In altri termini lesame ecocardiografico fonte preziosa di informazioni che spesso, da sole, possono condurre allindicazione al trapianto ma una tecnica di imaging che si basa su di una serie di assunzioni geometriche e derivate matematiche che costituiscono comunque solo una valida approssimazione del reale stato contrattile ed emodinamico. E per uno strumento insostituibile nel pilotare scelte terapeutiche adeguate e nel monitoraggio e la stadiazione della cardiomiopatia nel tempo. Lanalisi in 3D migliora molto la sua capacit diagnostica e la precisione ma una metodica ancora in parte sperimentale e che purtroppo non ha ancora larga diffusione sul territorio. Dosaggio ematico del frammento NT-terminale del pro-ormone BNP (Brain Natriuretic Peptide). Lormone BNP viene prodotto dalle cellule cerebrali in condizioni patologiche e dalle fibrocellule muscolari miocardiche soprattutto ventricolari. Viene ri-lasciato in forma di pro-ormone in risposta ad un incremento della tensione transmurale di parete ovvero in tutti i casi di sovraccarico di volume o di pressione endocavitario. A causa del lento metabolismo dellormone attivo, che provoca fenomeni di accumulo, si preferisce dosare nel sangue il frammento NT-terminale lisato dal pro-ormone che pi fedelmente corrisponde alla quota istantanea di ormone attivo prodotta dalle miocellule cardiache. Il range di normalit varia molto sia in funzione del sesso che dellet del soggetto. E un test estremamente sensibile ma a bassa specificit che pu risultare falsamente positivo nei casi di cardiopatie valvolari, nella ipertensione polmonare primitiva e secondaria o nella ipertensione arteriosa essenziale non trattata. Il motivo di interesse sta nel fatto che in letteratura stato dimostrato non solo il suo consistente incremento nello stato di scompenso cardiaco cronico ma che vari livelli di cut-off (superiori a 500 e a 1000 pg/L) correlano strettamente sia con lo score HFSS che con il valore del VO2-max misurato. Gli stato attribuito quindi un valore di surrogato prognostico in luogo soprattutto del VO2 essendo questultimo un test prezioso e preciso ma non sempre eseguibile o ripetibile in larga scala. Pi prudentemente va considerato un test utile se accoppiato al valore del VO2-max nei pazienti borderline tenuti in follow-up clinico sia come tecnica di monitoraggio del grado di compenso emodinamico e sia come strumento di verifica oggettiva della efficacia a lungo termine della terapia medica. Test cardiopolmonare da sforzo con valutazione dei gas espirati (VO2-max o Test di Bruce). E un test che valuta in modo indiretto lefficienza complessiva sia della funzione cardiovascolare, centrale e perife-rica, sia di quella respiratoria e muscolare. Il massimo consumo di ossigeno, indicato con la formula VO2max, la quantit massima (max) in volume (V) di ossigeno (O2) che l'organismo in grado di estrarre e quindi utilizzare nell'unit di tempo per la contrazione muscolare e per produrre lavoro. Questo valore un flusso per cui pu essere espresso in l/min, ottenendo un dato assoluto, oppure in ml/kg/min ottenendo un valore indicizzato per il peso corporeo. Maggiore il VO2max raggiunto e maggiore sar la potenza aerobica del soggetto. Questa potenza aerobica in gran parte determinata da fattori genetici e solo in minima parte (fino al 20-30%) migliorabile con un appropriato allenamento fisico. Semplice-mente si pu paragonare il VO2max alla cilindrata del motore aerobico: a parit di componente muscolare, maggiore la cilindrata e minori saranno i "giri" a cui si sottopone il motore per mantenere una determinata velocit (carico di lavoro) rispetto ad un altro di cilindrata inferiore. In condizioni di riposo il VO2 ammonta mediamente a 3.5 ml/kg/min, quantit che viene definita come equivalente metabolico, mentre in corso di attivit fisica strenua corrisponde alla capacit aerobica massima di un individuo e raggiunge di solito valori oltre i 20 ml/kg/min in funzione dellet e del sesso (range di normalit 25-55 ml/kg/min). Il calcolo esatto del VO2 a riposo si ottiene con metodo invasivo secondo la nota formula di Fick per cui VO2= GC x O2 (aO2-vO2). Il fattore O2 la differenza artero-venosa, cio la differenza di ossigeno contenuta nel sangue arterioso e in quello venoso che rappresenta la quantit totale di ossigeno estratto dai tessuti. In 100 ml di sangue arterioso sono contenuti circa 20 ml di ossigeno, mentre in quello venoso circa 15 ml, cio in condizioni di riposo 5 ml vengono ceduti ai tessuti. All'aumentare dello sforzo e quindi del consumo d'ossigeno la differenza aumenta e si giunge ad una estrazione massima di circa 17 ml in condizioni di massimo consumo d'ossigeno e nei soggetti allenati. Ma pi importante invece capire da un punto di vista metabolico cos' il massimo consumo di ossigeno. Si consideri quindi un soggetto che inizia a correre: partendo da una condizione basale di riposo, lorganismo mette subito in moto meccanismi energetici anaerobici, pi rapidi di quelli aerobici, per sopperire all'iniziale carenza energetica. Dopo qualche minuto (da 2 a 4 a seconda del grado di condizionamento fisico del soggetto) i meccanismi aerobici si sono adeguati alla richiesta energetica e inizia lo stato d'equilibrio dove la iniziale produzione di lattati dal metabolismo anaerobico cessa. Durante questo stato il soggetto consuma ossigeno e tale consumo costante. Se lo sforzo aumenta (come si pu rilevare facendo correre il soggetto su un tapis roulant con inclinazioni crescenti della pendenza) aumenta di pari passo anche il consumo d'ossigeno. A un certo punto il meccanismo aerobico non sar in grado di fornire lenergia richiesta in maniera sufficiente e inizier di nuovo la produzione di acido lattico (soglia anaerobica). Il consumo d'ossigeno del sog-getto aumenter comunque ancora finch a un aumento della richiesta energetica non ci sar pi ulteriore incremento: a questo stadio il paziente ha raggiunto il massimo consumo d'ossigeno (VO2max). La soglia anaerobica anche una stima della capacit del paziente di sostenere un esercizio prolungato. Il suo valore indica la massima intensit di esercizio corrispondente ad un livello costante nella concentrazione ematica di lattato (circa 4mmoli/litro). Oltre questo punto la produzione di anidride carbonica (CO2), la ventilazione (atti respiratori al minuto), ed il livello di acido lattico prodotto crescono rapidamente. Nei soggetti non allenati, se rapportata con il massimo consumo di ossigeno, la soglia anaerobica coincide approssimativamente con il 55% del valore del VO2max. Attraverso il VO2max quindi misuriamo la capacit intrinseca della cellula di estrarre dallambiente esterno la massima quantit di O2 e di utilizzarla per la produzione di ATP e quindi indirettamente valutare lefficienza del sistema trasportoutilizzo dellossigeno dallo ambiente esterno sino alla sede cellulare in grado di utilizzarlo per produrre energia (mitocondri), fenomeno noto come capacit ossidativa dei muscoli: il valore massimo teorico di consumo di ossigeno per in funzione dell'et (si ritiene che lo zenit sia espresso allet di 25 anni cui segue una perdita progressiva pari all1% per ogni anno di vita) e della massa corporea anche se si possono derivare i valori normali di VO2max in funzione della massa magra. Qualsiasi patologia che coinvolga i fattori centrali di captazione e trasporto (polmoni, cuore e sangue) o che coinvolga i fattori periferici (cellule muscolari) in grado di influenzare il valore del VO2max. In condizioni normali quindi, dato che la capacit di estrazione di O2 cellulare in grado di desaturare le capacit di trasporto dei sistemi deputati ad esso, lincremento del consumo di ossigeno sotto stress legato per gran parte allincre-mento della portata cardiaca e quindi alleffi-cienza della funzione di pompa. Per questo motivo il valore di VO2max ha assunto una importanza sempre maggiore nello studio delle cardiomiopatie: allo stadio iniziale ed avanzato della patologia i fenomeni di rimo-dellamento ventricolare, sia in senso concen-trico che eccentrico, consentono di mantenere una adeguata gittata sistolica a riposo ma non consentono un adeguamento della portata in condizioni di stress fisico prolungato. Il risultato che il massimo consumo di ossi-geno raggiunge un valore ridotto rispetto al normale inversamente proporzionale al grado di deficit di pompa e precocemente sar rag-giunta la soglia dei lattati per la produzione di energia. Numerosi studi in letteratura hanno chiaramente documentato che il valore di VO2max ha un elevato potere prognostico positivo per mortalit a 12 mesi dei pazienti affetti da scompenso cardiaco cronico non sottoposti a trapianto cardiaco. Il valore soglia di criticit posto a 10 ml/kg/min lad-dove la probabilit di evento cardiaco fatale a 12 mesi superiore al 70%. Il chiaro vantag-gio clinico in termini di sopravvivenza a breve termine rende, per questi pazienti, lindicazione al trapianto ormai indiscutibile. Dati non concordanti sono stati ottenuti per i pazienti nella fascia compresa tra 10 e 14 ml/kg/min per i quali, in caso di trapianto, si dimostrato solo un vantaggio in termini di miglioramento della qualit di vita. Allo stato attuale quindi e secondo le linee guida accreditate ogni paziente in terapia medica ottimizzata che al test cardiopolmonare massimale non supera il valore soglia di 14 ml/kg/min viene incluso nel programma di trapianto di cuore. Per la determinazione indiretta non invasiva di questo indice metabolico, viene utilizzato come supporto per lo stress il treadmill (o ergometro trasportatore). I parametri venti-latori vengono elaborati da un analizzatore di gas (ergo-spirometro) a circuito chiuso tarato e collegato al paziente mediante boccaglio o mascherina a tenuta. I volumi di ossigeno vengono calcolati, respiro per respiro, per sottrazione misurando i parametri ventilatori ed i volumi di ossigeno presenti nellaria inspirata ed espirata. Lintero sistema gestito da software in PC. Si procede alla registrazione in continuo dei parametri cardiaci, ossia della frequenza cardiaca e della pressione arteriosa, e dellanidride carbonica prodotta. La frequenza cardiaca viene rapportata di continuo al lavoro eseguito ed alla misurazione dei gas espirati. Mediante il rapporto, calcolato respiro per respiro, tra consumo di ossigeno (VO2) e produzione di anidride carbonica (VCO2), messi in relazione tra loro (analisi V-Slope) ed il rapporto tra Ventilazione (VE) e VO2, lapparecchio in grado di fornire al termine del test i risultati corrispondenti ai valori della soglia anaerobica e del massimo consumo di ossigeno: -VO2max (protocollo massimale) Il soggetto esegue uno sforzo massimale su di un cicloergometro o un treadmill ad un carico progressivamente crescente durante il quale vengono misurati il consumo di ossigeno (VO2), i parametri respiratori e la frequenza cardiaca. Il massimo consumo di ossigeno (VO2 max) raggiunto durante l'esercizio considerato l'indice del fitness cardiorespira-torio (CFR). -Sub-max VO2 (protocollo sub-massimale) Analogo al test massimale, il test sottomassimale viene interrotto prima che il soggetto arrivi ad esaurimento e non appena viene raggiunta una percentuale 80-85 % della massima frequenza cardiaca (FC) teorica, in questo modo si evitano situazioni potenzialmente pericolose per il soggetto. Estrapolando la relazione tra VO2 e FC fino alla massima frequenza cardiaca si ottiene una stima molto precisa ed accurata del VO2 max. Le stesse estrapolazioni consentono una stima dello VO2 per prove precocemente interrotte per linsorgere di dispnea, angor od aritmie. Cateterismo cardiaco destro. E il test invasivo di maggiore importanza dal punto di vista emodinamico e che costituisce il punto di arrivo per tutti i candidati al programma di trapianto durante la fase clinica di screening. Consiste nel posizionare un catetere flottante cavo, provvisto di un palloncino distale, nelle cavit cardiache destre del paziente mediante la incannulazione percutanea di una vena di grosso calibro periferica (giugulare, succlavia o femorale). Collegando il catetere ad un trasduttore per il monitoraggio continuo pressorio, progressivamente potranno essere registrate le pressioni endocavitarie in atrio (PVC) e ventricolo destro (PVdx), e successi-vamente nel tronco dellarteria polmonare (PAP) e nei suoi rami periferici distali fino a registrare infine la pressione polmonare bloccata o pressione di incuneamento capil-lare polmonare (PCW). La progressione del catetere attraverso le cavit assicurata dal gonfiaggio della cuffia distale che in siffatto modo viene trasportato dalla normale dire-zione di flusso del torrente ematico sino allincuneamento finale. Con lapplicazione del principio di Fick (metodo ossimetrico) o della metodica della termodiluizione pos-sibile calcolare con accuratezza lindice cardiaco (CI), il lavoro cardiaco ed il consumo totale e cardiaco di ossigeno. Un rapido calcolo consentir poi di quantificare il gradiente trans-polmonare (GTP= PAP PCW) e di ottenere la stima delle resistenze vascolari polmonari indicizzate per la superfice corporea del soggetto (RVPI [Unit Wood]= GTP/CI). Lo scopo del test duplice. In primo luogo quello di verificare lo stato di ridotta portata cardiaca a riposo che in questi pazienti di solito presente in grado variabile: un indice cardiaco compreso tra i 2.5-3.0 L/min/m2 indicativo di uno stato di compenso emodinamico a riposo ancora sufficiente per cui lindicazione al trapianto potr essere posta in modo precoce solo sulla scorta dei dati provenienti dai test da stress od in base al tipo di cardiopatia ed alla evolutivit dei sintomi; viceversa un indice cardiaco al di sotto dei 2.5 L/min/m2 rappresenta un chiaro segno di compro-missione emodinamica che, in rapporto alla cardiomiopatia in oggetto, pu essere consi-derata non reversibile anche se i sintomi lamentati dal paziente spesso non esprimono alcuna urgenza clinica. Nei casi pi gravi e di solito con quadro clinico eclatante, lindice cardiaco pu essere estremamente ridotto (<1.5 L/min/m2) ed in genere laspettativa di vita a 30 giorni di questi pazienti inferiore al 30%. In questi casi utile fornire senza indugio al paziente un supporto emodinamico con inotropi per via endovenosa continua allo scopo di preservare una buona funzionalit degli organi periferici nellattesa di un organo compatibile e prendere in considerazione la possibilit di un impianto chirurgico di un sistema meccanico di assistenza al circolo a lungo termine. Il secondo aspetto da prendere in considera-zione che il test consente la stima dellentit delle pressioni vascolari polmonari e della loro eventuale reversibilit. E probabilmente il fattore di maggiore importanza durante il processo di screening poich lipertensione polmonare non reversibile ancora oggi considerata una delle principali cause della disfunzione primaria e della failure precoce del graft impiantato. Lo scompenso cardiaco cronico solo una delle cause secondarie di ipertensione polmonare conosciute ed in genere questultima viene descritta con il termine di postcapillare: in condizioni di insufficienza cardiaca terminale la gittata sistolica, per esaurimento delle scarse riserve contrattili governate dalla ben nota legge di Frank-Starling, dipende unicamente dalla entit delle resistenze periferiche ovvero dal post-carico. In queste condizioni si verifica un incremento della pressione telediastolica del Vs che impedisce il normale svuotamento atriale per annullamento del gradiente pres-sorio tra le cavit. Ci provoca stasi ematica nel circolo polmonare con conseguente incremento pressorio dapprima esclusiva-mente postcapillare e successivamente anche precapillare in funzione dellincremento di lavoro e della progressiva capacit di adat-tamento trofico del ventricolo destro al nuovo regime pressorio. Questa condizione persiste indefinitamente a causa della incapacit del muscolo cardiaco nativo ad adattare il proprio volume di stroke in modo da riportare il regime pressorio alla normalit ed inoltre aggravata dalla eventuale coesistenza di un certo grado di rigurgito dalle valvole atrio-ventricolari; il trapianto di cuore quindi rimuovendo la causa primaria di insufficienza di circolo dovrebbe consentire il ripristino di una normale funzione di pompa e quindi una normalizzazione del regime pressorio trans-polmonare. In realt per questo alterato stato di ipertensione polmonare, se di grado molto severo, persiste nelle immediate fasi post-operatorie sottoponendo il ventricolo destro del cuore trapiantato ad un lavoro che non anatomicamente in grado di sostenere in quanto proveniente da un donatore sano e quindi sottoposto a normali regimi pressori trans-polmonari. Questa nuova condizione emodinamica comporta una disfunzione acuta del graft che con gradi diversi di severit pu produrre uno stato di bassa portata post-operatoria sino alla failure completa e la morte del paziente. Ci avviene inevitabil-mente se lo stato di ipertensione polmonare non reversibile come avviene in tutte le forme primarie idiopatiche ed in quelle secondarie precapillari su base tromboembo-lica, ipossica cronica o da alterazione della architettura anatomica polmonare. La forma postcapillare quindi v attentamente differen-ziata dalle altre forme di ipertensione tenendo conto del fatto che nelle cardiomiopatie con lunga storia di malattia le resistenze vascolari polmonari passano da uno stato di reversi-bilit a quello della completa o parziale irreversibilit durante il decorso della pato-logia: il regime di ipertensione polmonare infatti rappresenta un noto e potente stimolo alla proliferazione delle cellule muscolari lisce della lamina basale dei capillari polmo-nari (vasi di resistenza). La conseguente iperplasia intimale dei capillari comporter la progressiva riduzione del loro diametro ed un incremento della resistenza basale al flusso con un incremento della rigidit di parete causata anche da una ridotta risposta e sensibilit allo stimolo chimico endogeno locale di massima vasodilatazione. Durante la procedura di cateterismo utile quindi testare dinamicamente il grado di reversibilit delle resistenze vascolari polmonari con un artificio farmacologico cio somministrando al paziente per via endovenosa un farmaco vasodilatatore periferico sistemico selettivo ad azione fasica (es. nitroprussiato sodico): la brusca caduta delle resistenze vascolari periferiche sistemiche produrr un fugace ma netto incremento della gittata sistolica e dellindice cardiaco con conseguente ridu-zione o normalizzazione delle pressioni polmonare bloccata, della polmonare media, del gradiente trans-polmonare e delle resistenze complessive del circolo. In alternativa si pu testare la riserva polmonare somministrando per via inalatoria farmaci vasodilatatori selettivi polmonari ad azione fasica (es. ossido nitrico ed epoprosterenolo) che per non producono un reale incremento di gittata sistolica ma anzi possono provocare un brusco e rischioso innalzamento della PAP e della pressione di incuneamento capillare e conseguentemente la comparsa di un improvviso edema polmonare. Le diverse metodiche in realt si integrano poich consentono di differenziare le forme di scompenso cardiaco mono-ventricolare destro e sinistro da quelle a componente bi-ventricolare; i test possono essere infatti eseguiti anche in successione valutando la risposta emodinamica sul singolo caso. E ancora oggetto di discussione quale sia il valore limite superiore accettabile delle resistenze vascolari polmonari per il trapianto di cuore: le recenti linee guida suggeriscono che il limite di 6 unit Wood (UW) totali non dovrebbe essere superato nel test basale ma molto pi utile fare riferimento al calcolo delle resistenze dopo aver eseguito i test di vasodilatazione. Un valore delle RVPI>3 UW durante i test soprattutto se accompagnato ad una elevata PAP >60 mmHg ed un incremento del GTP >15 mmHg esprimono di solito uno stato di ipertensione polmonare irreversibile che controindica il trapianto. Per questi pazienti dobbligo prendere in considerazione luso di sistemi di assistenza ventricolare attiva (VAD, cuore artificiale) come bridge temporanei al trapianto poich si osservato in alcuni casi un drop delle PVRI verso la reversibilit dopo alcuni mesi di assistenza meccanica al circolo. In sintesi, lindicazione al trapianto di cuore nasce dallevidenza clinica di un substrato anatomico spesso tipico ma subisce comunque e sempre un severo e continuo processo di verifica dello stato emodinamico e delle potenzialit di recupero funzionale con la terapia farmacologica o la chirurgia cardiaca convenzionale. Il definitivo giudizio clinico di idoneit al trapianto invece potr essere elaborato dalla valutazione critica delle condizioni generali del paziente e delle sue comorbidit. Controindicazioni Dopo le prime fallimentari esperienze degli anni 60 e superate le barriere tecnologiche e farmacologiche iniziali che avevano impedito il diffondersi del trapianto di cuore come terapia definitiva dello scompenso cardiaco, dai primi anni 80 ad oggi si ritiene sino stati eseguiti nel mondo circa 100.000 trapianti. LInternational Society of Heart and Lung Transplantation stata promotrice e garante della pi vasta raccolta di dati clinici sullintero fenomeno sin dal 1995 ed attualmente la maggiore fonte di informazioni disponibile per gli operatori del settore con un data set clinico composto da dati costantemente aggiornati su circa 70.000 procedure eseguite in ogni continente; risulta chiaro ed evidente a tutti che nonostante gli enormi progressi compiuti lesito di un trapianto di cuore dipende ancor oggi da una serie numerosa di fattori legati non solo alla procedura chirurgica, oramai standardizzata, ma anche da variabili relative alle condizioni cliniche generali del ricevente e del donatore, alla logistica ed alla procedura di accoppiamento biometrico ed immunologico fra donatore e ricevente (matching). Argomentare sulle varie eventualit possibili in termini predittivi di morbilit e mortalit sul singolo paziente virtualmente impossibile per una serie di ragioni ma ladozione di una serie di criteri di selezione generalizzabili sia del ricevente che del donatore necessaria per ridurre il rischio procedurale al minimo possibile e soddisfare il fine ultimo a cui tale complessa terapia si propone di raggiungere ovvero al miglioramento della aspettativa e della qualit di vita per un numero ragionevole di pazienti. Diverse organizzazioni professionali internazionali ed italiane quindi hanno recentemente emanato linee guida di riferimento per la appropriata selezione dei candidati allo scopo di garantire che il trapianto di cuore sia evitato o ritardato nei pazienti che presentano ancora un buon compenso funzionale, incoraggiando ad un management terapeutico standard ottimale, e scoraggiato nei pazienti che presentano un elevato rischio di peggior outcome a breve o medio termine nel tentativo di assistere gli operatori da un lato a soddisfare le logiche aspettative dei pazienti ed dallaltro ad ottemperare allobbligo istituzionale del miglior uso possibile delle scarse risorse di donazioni di cuore. Nella tabella 3 sono elencati i fattori clinici legati al ricevente che pi frequentemente sono associati ad un incremento del rischio di morbilit e mortalit; fatta eccezione per rarissimi casi in cui si presenta limpossibilit tecnica di eseguire lintervento chirurgico per motivi anatomici, solo alcuni tra questi sono da considerarsi ancora oggi come controindicazioni assolute al trapianto come let avanzata, le infezioni acute e croniche in fase attiva o persistente (infezioni da HIV, epatiti HCV/HDV correlate, TBC in stadio avanzato, ecc.), le neoplasie con metastasi sistemiche in atto, le malattie sistemiche con interessamento di pi organi a scadente prognosi quod vitam a breve termine. Le altre sono da ritenersi controindica-zioni relative poich se presenti singolarmente nel contesto clinico, sebbene alcune di queste possano incrementare il rischio in maniera considerevole, date le attuali possibilit terapeutiche della medicina generale e specialistica in costante miglioramento, ed in presenza di una buona compliance del paziente al programma di trapianto, raramente possono condurre ad un estemporaneo giudizio definitivo di non idoneit. Ad esempio in una selezionata serie di candidati pu essere presa in considerazione la soluzione di un trapianto combinato in quei casi in cui vi sia un danno s irreversibile ma isolato della funzione epatica, renale o polmonare. In genere per la contemporanea presenza di due o pi contro-indicazioni relative costituisce criterio di non idoneit, soprattutto quando si rilevano patologie ad interessamento sistemico di grado avanzato di tipo metabolico o con consistente interessamento multiorgano. Esaminiamo brevemente ora i singoli fattori di maggiore rilevanza clinica tenendo conto del fatto che per la valutazione del rischio individuale in fase di screening si predilige redigere una stima reale del rischio a breve termine (12 mesi), fase in cui le comorbidit del paziente hanno il massimo impatto sullesito chirurgico dellintervento e nell induzione ed il mantenimento di una adeguata immunomodulazione (Tabella 4): Ipertensione polmonare irreversibile: Nella sezione dedicata al cateterismo cardiaco destro abbiamo gi discusso della patogenesi della forma postcapillare e delle sue implicazioni cliniche nella fase chirurgica e postchirurgica. In questa sede vale la pena ricordare che le forme primitive di ipertensione polmonare e quelle secondarie a patologie specifiche polmonari costituiscono, salvo rare eccezioni, controindicazioni assolute al trapianto di cuore isolato. La diagnosi differenziale si avvarr quindi, oltre che del criterio anamnestico, di tutti i mezzi diagnostici necessari a chiarire il quadro clinico sia dal punto di vista anatomico che funzionale. I pazienti affetti da patologie polmonari con possibilit di guarigione a breve o medio termine possono essere rivalutati successivamente a stabilizzazione raggiunta. Et: Nella maggior parte dei centri di trapianto il limite di et fissato a 65 anni. Attualmente per pazienti di et superiore e compresa tra i 66 ed i 70 anni vengono considerati candidati accettabili se non sono presenti altre controindicazioni. Ci nasce dallosservazione che in limitate serie di pazienti la sopravvivenza globale comparata a breve termine risultata simile. Rispetto ai pi giovani infatti i pazienti in et pi avanzata hanno una pi bassa probabilit di eventi di rigetto acuto fatale nel primo anno dopo il trapianto a causa di una minore efficienza del sistema immunitario. Tale fattore per, e per la stessa causa, controbilanciato da una maggiore predisposizione alle infezioni post-operatorie ed alle neoplasie che sono le prime cause di morte di questi pazienti. Sebbene quindi il numero di questi potenziali candidati sia, dal punto di vista epidemiologico, in costante ascesa in questi ultimi anni, solo in casi selezionati il trapianto di cuore nellanziano produce un chiaro e soddisfacente miglioramento della qualit di vita tale da giustificare un ulteriore innalzamento della soglia di et come riferimento generale. Obesit patologica: I pazienti obesi (BMI >30 kg/m2) sono a rischio di morbidit e mortalit post-operatoria con un valore pari al doppio rispetto ai pazienti non obesi. Le cause di questo fenomeno sono molteplici e non tutte note: i soggetti obesi sono spesso affetti da alterazioni del metabolismo glucidico e questo predispone genericamente ad una ritardata guarigione delle ferite chirurgiche con un rischio pi elevato di infezioni dei tessuti molli. Si osservano inoltre con maggiore incidenza infezioni polmonari gravi ed episodi di rigetto acuto letali entro il primo anno dal trapianto. Inoltre la probabilit di un adeguato size matching con il donatore ridotta e ci introduce un elemento di criticit immediata di elevata performance emodinamica del cuore trapiantato non sempre ottenibile sin dalle prime fasi post-operatorie. Per tali motivi i pazienti affetti da obesit grave (BMI >35 kg/m2) non vengono di solito considerati candidati idonei al trapianto di cuore mentre quelli affetti da gradi meno severi di obesit (BMI e"30 - <35 kg/m2) possono essere considerati idonei con riserva. Diabete mellito: Il registro ISHLT dimostra che i pazienti affetti da diabete mellito hanno un rischio di mortalit a 12 mesi aumentato rispetto ai pazienti non diabetici in misura superiore al 20% anche se attentamente selezionati ed in assenza di danno dorgano dimostrabile (retinopatia, neuropatia, nefropatia). Sino a qualche anno orsono il diabete mellito era considerato da molti una controindicazione assoluta al trapianto mentre oggi si tende a valutarlo in forma relativa in base al danno dorgano oggettivabile (soprattutto per quanto riguarda la funzione renale) ed in base allefficienza del controllo farmacologico ottenibile. Ci nonostante non possibile prevedere la risposta metabolica del paziente nel post-operatorio data la intensa stimolazione glicolitica dovuta prima dallo stress chirurgico e poi dalla induzione farmacologica immunosoppressiva con alte dosi di corticosteroidi. Lesposizione ai farmaci inibitori della calcineurina nellattuale protocollo immunosoppressivo (Ciclosporina e Tacrolimus), dati i noti effetti nefro- e neuro-tossici di questi farmaci, pu far rapidamente peggiorare la funzione renale e la neuropatia diabetica con gravi effetti invalidanti sulla riabilitazione e la qualit di vita del paziente. Inoltre i pazienti con uno scarso controllo farmacologico dei valori glicemici hanno una maggiore predisposizione alle infezioni che si quantifica in una maggiore incidenza di gravi infezioni polmonari e delle ferite chirurgiche. Gli effetti del diabete sul metabolismo lipidico possono provocare una precoce comparsa od un rapido peggioramento di una vasculopatia periferica cerebrale o degli arti inferiori ed espongono il paziente ad un rischio di accelerata vasculopatia del graft. In fase di screening quindi il paziente che presenta segni clinici di resis-tenza periferica allinsulina, di retinopatia proliferativa o di nefroangiosclerosi con proteinuria spesso non ritenuto idoneo al trapianto di cuore ancora oggi in circa il 50% dei centri di trapianto di tutto il mondo. Funzione renale: Il danno renale irreversibile che si manifesta con una clearance della crea-tinina <50 ml/min od un valore stimato del filtrato glomerulare <40 ml/min considerato un criterio secondario di esclusione al trapianto cardiaco isolato. La ridotta funzione renale espone il paziente cardochirurgico ad un rischio di mortalit operatoria e a 12 mesi circa tre volte pi elevato rispetto ai pazienti con normale funzione renale ed un rischio indi-viduale in alcuni casi superiore al 50%. La semplice determinazione della creatinina serica non ha dimostrato di possedere un adeguato potere prognostico positivo per individuare i pazienti a maggior rischio di danno dorgano irreversibile e pertanto sono spesso necessarie molte indagini diagnostiche per chiarire il tipo ed il grado di cronicit della malattia renale e le reali possibilit di compenso ottenibili con il miglioramento esclusivo della fase emodinamica. I pazienti con malattia renale intrinseca possono comunque essere selezionati per un trapianto combinato cuore-rene. Diverso e latteggiamento clinico di fronte ad un danno renale non di grado severo (GFR compresa tra 40 e 60 ml/min); i farmaci attualmente in uso nei protocolli immunosoppressivi provocheranno inevitabilmente un deterioramento pro-gressivo della funzione renale sino alla necessit in diversi casi (circa il 10-15% dopo 10 anni dal trapianto) di trattamenti sostitutivi che incideranno non poco sulla qualit di vita e sulla mortalit a lungo termine di questi pazienti. Sebbene il rischio di mortalit e di morbilit sia quindi chiaramente pi elevato anche in questo subset esso non allo stato attuale considerato virtualmente inaccettabile e costituisce pertanto criterio di controindicazione relativa. Funzione epatica: E un fattore di rilevanza importante nei pazienti con lunga storia di malattia cardiaca e maggiormente rilevante nei casi con scompenso biventricolare o con prevalente disfunzione destra. Sebbene il quadro clinico della cirrosi cardiaca sia divenuto ormai una rarit clinica nellera moderna, abbastanza frequente invece rilevare un certo grado di insufficienza epatica che si manifesta o con una alterazione degli indici di sintesi proteica (che peggiora molto la sindrome ede-migena sino a quadri di anasarca inveterato) o con alterazione transitoria dei parametri della coagulazione ematica o con un incremento lieve-moderato delle transaminasi e della bilirubina. Questultima considerato il marker pi sensibile di disfunzione epatica ed stato rilevato che valori della bilirubinemia totale costantemente superiori a 3.0 mg/dl sono di solito associati ad una pessima prognosi chirurgica, con un incremento del rischio individuale che cresce proporzionalmente ai valori di bilirubinemia riscontrati nella fase pre-operatoria. Queste alterazioni corrispondono dal punto di vista anatomico ad un avanzato stato di fibrosi epatica secondaria allinsulto cronico dellipossia causata dallo stato di ridotta portata cardiaca associata al danno provocato dal regime di ipertensione venosa del distretto cavale e portale. La presenza di un avanzato grado di fibrosi nelle biopsie epatiche, anche in assenza del quadro di sovvertimento strutturale dellarchitettura lobulare epatica tipica della cirrosi, fornisce levidenza di un consistente danno dorgano non reversibile che pu rendersi acutamente e drammaticamente manifesto nella immediata fase post-operatoria innescando dal principio sindromi emorragiche difficilmente dominabili e persistendo successivamente nel complesso quadro clinico della insufficienza multiorgano che quasi inevitabilmente condurr il paziente a morte. Sebbene il trapianto di cuore sia lunica strada percorribile per interrompere il circolo vizioso che sostiene ed aggrava tale insulto epatico, ogni sforzo deve essere posto in atto per identificare i pazienti a rischio pi elevato di contrarre tale temibile complicanza anche se stabilire lentit e la natura del danno epatico spesso compito difficile che richiede lausilio di competenze specialistiche esperte: la valutazione della funzione epatica infatti particolarmente complessa quando in aggiunta al fattore emodinamico si sovrappone il danno generato da infezioni croniche di natura virale (Epatite B e C, infezioni da virus Delta) che devono essere quindi sempre attentamente ricercate ed identificate anche se in fase di quiescenza e compenso clinico. In questi casi il rischio concreto coincide con linduzione della terapia immunosoppressiva che abbattendo le difese naturali del paziente dar nuovo vigore alla replicazione virale con quadri di epatite acuta a decorso non prevedibile ed a volte ad evoluzione fulminante. Funzione polmonare: E piuttosto frequente rilevare allindagine spirometrica una sindro-me disventilatoria di tipo restrittivo di grado variabile dovuta allimbibizione edemigena causata dallo stato di ipertensione capillare. Essendo un quadro clinico collegato alla cardiomiopatia questo si risolve completamente nalla fase di riabilitazione del paziente dopo il trapianto. Maggior attenzione v posta invece per le sindromi croniche di tipo ostruttivo: quando si rileva allesame spirometrico una cospicua riduzione della capacit vitale (<50%) od, in particolare, una riduzione del volume espiratorio forzato (FEV1) al di sotto del 40% del volume teorico predetto, il paziente a forte rischio di insorgenza di una grave forma di insufficienza respiratoria acuta nella immediata fase post-operatoria il cui trattamento necessiter di un lungo periodo di assistenza ventilatoria meccanica con grave rischio di infezioni polmonari gravi anche da batteri opportunisti. Le stesse considerazioni vanno fatte anche per le gravi forme di insuf-ficienza respiratoria su base neuro-muscolare e quelle secondarie a tromboembolia polmonare o ad infarto polmonare. Vasculopatia periferica: E considerata una controindicazione relativa o temporanea. La revisione retrospettiva dei dati acquisiti sulle procedure effettuate ha rivelato che il circa 10% dei pazienti trapiantati sviluppa nel follow-up una vasculopatia periferica sintomatica e che i pazienti con anamnesi positiva per diabete mellito, fumo di sigaretta e cardiomiopatia di tipo ischemico sono quelli maggiormente esposti a questa complicanza. Nella fase di screening v posta particolare attenzione alla sede ed alla pluridistrettualit delle lesioni soprattutto nei pazienti gi sottoposti a chirurgia cardiaca in cui pu essere necessaria la disponibilit di un accesso vascolare periferico perfettamente pervio (femorale od ascellare) per la manovra di cannulazione arteriosa necessaria a connettere il paziente alla circolazione extracorporea. Altrettanto importante il riscontro di una patologia aterosclerotica dei tronchi sovra aortici e del circolo cerebrale nel tratto intracranico: il rischio di ictus ischemico e/o di disfunzione neurologica permanente nel periodo peri-procedurale chirurgico particolarmente elevato in questi pazienti e di ci v tenuto debito conto. Le attuali tecniche di chirurgia vascolare consentono una risoluzione chirurgica della patologia vascolare obliterante nella maggior parte dei casi per cui lindicazione al trapianto attualmente sconsigliata solo nei casi con severa patologia (lesioni pluri-distrettuali del circolo cerebrale extra od intracranico, arteropatie degli arti inferiori allo stadio di Fontaine III/IV) a mancata risoluzione chirurgica. Rischio neoplastico: I pazienti affetti da qual-siasi tipo di neoplasia in fase attiva non sono ritenuti candidati idonei al trapianto di cuore fatta eccezione per le neoplasie della cute non metastatizzate ed aggredibili chirurgicamente con exeresi completa. Candidati accettabili a rischio aumentato sono i pazienti in fase di remissione clinica da almeno 5 anni o quelli affetti da neoplasie a basso grado di invasivit con elevata probabilit di guarigione completa. Bisogna per tener conto che il limite con-sigliato dei 5 anni di remissione clinica un limite arbitrario che pu variare in base al tipo di neoplasia preesistente. Sebbene siano stati riportati casi sporadici di pazienti neoplastici trapiantati di cuore con normale sopravvivenza a distanza senza recidiva del tumore primitivo, persiste levidenza di unelevata incidenza di neoplasie nei pazienti soggetti a terapie immunosoppressive e ci rappresenta una delle principali cause di morte nel lungo termine dopo trapianto (>20%). Rischio infettivologico: Le infezioni rappre-sentano la prima causa di morte entro il primo anno dal trapianto di cuore. La valutazione del rischio infettivologico individuale la componente pi delicata nel processo di selezione dei candidati e deve essere affrontata con estrema attenzione e con esperta competenza. Nel paziente immunodepresso, nonostante le profilassi antibiotiche e le misure di asepsi adottate, qualsiasi infezione localizzata si propaga con facilit e rapidamente al torrente ematico realizzando quadri di sepsi generalizzata a decorso talvolta in shock fulminante (<24 ore). Particolarmente temibili sono le infezioni da batteri Gram negativi: la sede di partenza solitamente localizzata a livello addominale o nelle vie urinarie e quindi sono particolarmente a rischio i pazienti con difetti anatomici o funzionali dellapparato urinario, affetti di sovente da cistiti ricorrenti, e quelli affetti da patologie della colecisti e del colon-retto. Le infezioni delle basse vie respiratorie, sia da Gram positivi che da Gram negativi, sono le pi frequenti nellimmediato post-operatorio e non infrequente imbattersi nel breve termine nella nocardiosi, nella legionellosi o nella aspergillosi polmonare. Frequente la polmonite da pneumocistis carinii. Particolarmente a rischio di complicanze polmonari sono i pazienti defedati, gli obesi, i diabetici e quelli affetti da patologie polmonari croniche come la broncopatia cronica ostruttiva o le sindromi da apnea notturna (OSAS). Da segnalare il potenziale pericolo nei soggetti asintomatici portatori del bacillo tubercolare che pu riacquisire lesivit e provocare re-infezioni a diffusione sistemica. Non meno importanti sono le infezioni di natura virale ed in primo luogo, come gi accennato in precedenza, sono da considerare i virus delle epatiti B e C in fase attiva o cronicizzata. I pazienti portatori del virus HIV non sono in alcun caso considerati idonei al trapianto di cuore. Rilevanti, soprattutto in ambito pediatrico, sono le associazioni tra riattivazioni asintomatiche del virus di Epstein-Barr e sindromi mieloproliferative nel follow up breve. Il ruolo del virus citomegalico nella patogenesi della vasculopatia precoce del graft verr invece ampiamente discusso nella sezione risultati di questo capitolo. Stato psico-sociale ed abuso di sostanze voluttuarie: In linea generale il paziente deve dimostrare una adeguata compliance al programma di trapianto ed essere in grado di comprendere ed assolvere autonomamente ed in modo esatto le istruzioni terapeutiche fornite dalla equipe medica. E infatti dimostrato che una scarsa compliace terapeutica un fattore di rischio per ripetuti episodi di rigetto acuto nei primi mesi dopo lintervento. Per i pazienti affetti da demenza, schizofrenia, anoressia o ritardo mentale lidoneit ovviamente subordinata ad un ottimale supporto parentale ed al parere positivo di un consulente esperto. I pazienti che fanno uso attivo di sostanze stupefacenti od abuso di alcool non sono considerati candidati idonei al trapianto poich generalmente non sono complianti ad alcun regime terapeutico. Diversamente vengono considerati idonei con riserva e previo valutazione psicologica positiva i pazienti con anamnesi positiva per abuso di sostanze psicotrope ma con dimostrata sospensione del consumo attivo per un periodo continuato di almeno 24 mesi. Da tutto ci si evince che tutti i candidati al programma trapianto vengono inizialmente e periodicamente sottoposti ad una intensa attivit di screening e monitoraggio clinico con approccio multidisciplinare col fine preciso di verifica della corretta indicazione, della stadiazione della patologia cardiaca e dello stato delle comorbidit: non infrequentemente infatti pazienti inizialmente ritenuti idonei presentano un rapido deterioramento delle condizioni generali tale da imporre una revisione negativa didoneit a distanza di tempo. Tale visione dinamica del management clinico risponde inoltre alla necessit di verifica periodica delle priorit in lista e costituisce la base informativa necessaria ad un adeguato matching donatore-ricevente ed alla scelta di un mirato protocollo immunosoppressivo nella fase chirurgica e post-chirurgica. In ultima analisi lindicazione al trapianto di cuore nasce dalla uguale compartecipazione di tutti i soggetti coinvolti nel processo decisionale che non pu non prescindere dalla storia clinica del soggetto e dal suo percorso patologico, terapeutico e sociale: ci richiede competenze specia-listiche dedicate, esperte ed integrate che nella loro autonomia possano gestire in modo consa-pevole e non compassionevole le limitate risorse disponibili nel miglior modo possibile, nel pieno rispetto delletica professionale e del diritto alla salute di ogni singolo individuo. Tecnica chirurgica LS De Santo, C Maiello, M Cotrufo Prelievo del cuore Valutazione preoperatoria del graft Giunti nella sede del prelievo si comunicano al centro trapianti i dati relativi ai tempi di viaggio ed un aggiornamento della situazione clinica ed emodinamica del donatore. Prima di procedere allintervento necessario revisionare lintera documentazione clinica per verificare la correttezza della procedura di accertamento di morte cerebrale, lespressione del consenso, lemogruppo, lassetto anticorpale e gli esami microbiologici, gli esami ematologici ed emogasanalitici, limaging e la storia clinica. Particolare attenzione verr posta alla radiografia del torace, allECG, allecocardiogramma ed allenzimogramma cardiaco specifico. A tale proposito vanno ricordate le principali indicazioni riportate dalla Consensus Conference on Maximizing use of organs recovered from the cadaver donor per una corretta interpretazione dei dati clinici e strumentali(1). Innanzitutto il ruolo dellecocardiografia, pur fondamentale nella valutazione della morfologia cardiaca va temperato: 1) dalla nozione della sua operatore dipendenza; 2) dalla intrinseca incapacit di fornire dati univoci sulla performance emodinamica (ampia dipendenza dal pre e postcarico). La presenza di fattori di rischio per coronaropatia aterosclerotica va computata insieme allet, alleventuale presenza di aree di dissinergia, ad alterazioni dellenzimogramma e/o dellECG nel determinare la necessit di un esame coronarografico. La tabella 1 riporta le attuali raccomandazioni sulluso della coronarografia nello screening del potenziale donatore cardiaco. La fattibilit di uno screening coronarografico tuttavia ampiamente limitata nella pratica clinica dalla mancanza di servizi di emodinamica nelle sedi periferiche e dalle condizioni di instabilit emodinamica di molti donatori. Metodiche alternative di screening della cardiopatia ischemica stanno recentemente entrando nella pratica clinica. Tra esse emerge lecocardiogramma da stress per le buone doti di sensibilit e specificit e, soprattutto, per la facilit di esecuzione al letto del donatore e la disponibilit anche nelle sedi di prelievo pi periferiche. Le alterazioni dellenzimogramma cardiaco vanno contestualizzate alla storia clinica, ai dati strumentali ed alla funzionalit dellemuntorio renale. Elevati valori degli enzimi cardiaci specifici sembrano associarsi a una maggiore incidenza di early graft failure e maggiore necessit di supporto inotropo post trapianto. Tuttavia, tali alterazioni, se disgiunte da alterazioni della cinetica globale e segmentaria e da alterazioni franche dellECG, non costituiscono di per s motivo di inidoneit dellorgano. Infine levidenza ecocardiografica di ipertrofia miocardica severa (>13 mm) associata a segni ecggrafici e alla previsione di un tempo di ischemia prolungato controindicano il prelievo. (1)Zaroff JG, Rosengard BR, Armstrong WF, Babcock WD, D'Alessandro A, Dec GW, Edwards NM, Higgins RS, Jeevanandum V, Kauffman M, Kirklin JK, Large SR, Marelli D, Peterson TS, Ring WS, Robbins RC, Russell SD, Taylor DO, Van Bakel A, Wallwork J, Young JB. Consensus Conference Report Maximizing Use of Organs Recovered From the Cadaver Donor: Cardiac Recommendations March 28-29, 2001, Crystal City, Va. Circulation 2002;106:836-841. Tecnica di prelievo La tecnica di prelievo ampiamente codificata, e con varianti minori applicata da tutta la comunit trapiantologica. Eseguita la sternotomia mediana si esplorano il mediastino e le cavit pleuriche. Si procede quindi allincisione del pericardio che viene sospeso. Si ispeziona il cuore alla ricerca di deficit contrattili, aree di cicatrizzazione e/o contusione. Si esegue poi la palpazione alla ricerca di fremiti valvolari e/o lesioni coronariche aterosclerotiche. Decretata e comunicata lidoneit al prelievo, si separa laorta dalla polmonare e la si circonda con un fettuccia ombelicale. Si espone la vena cava superiore e la si circonda al livello dellazygos. Terminata la preparazione degli organi addominali, si somministrano 30000 unit di eparina, si confeziona una borsa di tabacco sullaorta ascendente e si posiziona la cannula della cardioplegia cui si connette la linea di infusione opportunamente debollata. Rimossa la linea venosa centrale si lega la vena cava superiore e si incidono la vena polmonare superiore sinistra e la vena cava inferiore per ottenere un adeguato ventaggio delle cavit destre e sinistre. In caso di concomitante prelievo di polmone il venting sinistro viene eseguito incidendo la parete atriale al di sopra dello sbocco delle vene polmonari inferiori o, alternativamente, incidendo lauricola sinistra. Si clampa laorta, si somministra la cardioplegia (10-20mL/Kg, H" 150 mmHg) e si interrompe la ventilazione. Per completare la protezione miocardica, si sommerge il graft con soluzione salina fredda a 4C e si pone un aspiratore nella vena cava inferiore. Durante la perfusione bisogna osservare attentamente la pressione aortica ed il venting ventricolare. Terminata la cardioplegia si sezionano laorta ascendente allarco, larteria polmonare alla biforcazione e la cava superiore allazygos. Si solleva il cuore e si completa la sezione della vena cava inferiore e delle vene polmonari. In caso di concomitante prelievo di polmone si completa latriotomia sinistra lasciando una adeguata cuffia di tessuto intorno agli osti delle vene polmonari. Si pone quindi il graft in una bacinella contenente soluzione salina fredda e si procede alla separazione dellaorta dallarteria polmonare e della polmonare stessa dalla vena cava superiore e dal tetto dellatrio sinistro. Si apre quindi latrio sinistro congiungendo prima gli osti delle vene polmonari omolaterali e poi la linea di mezzo tra siffatte incisioni. Si ispezionano gli apparati valvolari, il setto interatriale, ed il seno coronarico. Terminato il backtable si conserva il cuore in una busta per trasporto dorgani riempita con soluzione cardioplegica che a sua volta inserita in altre due buste riempite di fisiologica fredda. Il tutto viene poi alloggiato in un icebox per il trasporto. Protezione miocardica Nonostante un significativo miglioramento globale degli outcomes posttrapianto, lincidenza della primary graft failure tuttora pari al 9% con una relativa costanza nellultimo decennio. Fattori che contribuiscono alla severit della disfunzione miocardica precoce includono: un errato management del donatore, lipotermia, il danno da ischemia-riperfusione e la deplezione delle riserve energetiche. Attualmente, il cold ischemic storage il metodo di protezione miocardica pi comunemente adottato; esso consiste in una singola somministrazione di soluzione cardioplegica seguita da un ipotermia statica a 4 - 10C. Tale strategia clinicamente efficace per ischemie fino a 4 - 6 ore. Nonostante lipotermia ritardi la morte cellulare, alcuni processi fisiopatologici permangono attivi e possono comunque danneggiare il graft. Questi includono: (a) edema cellulare, (b) edema extracellulare, (c) acidosi cellulare, (d) deplezione di substrati metabolici, (e) danno da riperfusione, (f) calcium overload, e (g) danno endoteliale. La formulazione delle soluzioni cardioplegie mira quindi a rispondere schematicamente a tre esigenze: (a) arresto ipotermico del metabolismo, (b) determinazione di un micro ambiente fisico e biochimico che preservi lintegrit morfofunzionale delle varie componenti tissutali ed intracellulari durante larresto ischemico ipotermico (c) minimizzazione del danno da riperfusione. Lampia variet di soluzioni cristalloidi attualmente disponibili pu essere classificata in base alla composizione ionica in intracellulari ed extracellulari. Le soluzioni intracellulari, caratterizzate da una concentrazione pi o meno elevata di potassio e da una bassa concentrazione di sodio, mirano a ridurre ledema indotto dallipotermia. Le soluzioni extracellulari, caratterizzate da basse concentrazioni di potassio ed elevate concentrazioni di sodio, mirano invece a prevenire il danno cellulare e laumento delle resistenze vascolari indotti dalliperkaliemia. Una pletora di agenti farmacologici aggiuntivi stata via via introdotta, tra essi quelli pi comunemente impiegati sono gli stabilizzanti di membrana, i free radical scavengers, i substrati metabolici e i buffers. Come riportato in una autorevole review, la letteratura sulla protezione miocardica durante trapianto cardiaco, sostanzialmente limitata negli ultimi venti anni e dominata dagli studi su modelli animali. Tali studi, se da un lato hanno consentito di implementare le conoscenze sui processi fisiopatologici di base, dallaltro, non hanno determinato consistenti innovazioni sul piano clinico. La scarsit e la esigua numerosit campionaria degli studi clinici umani sulle soluzioni cardioplegiche disponibili non consente di trarre conclusioni definitive. Appare tuttavia chiaro che il miglioramento della formulazione delle soluzioni cardioplegiche solo uno degli steps necessari per prevenire learly graft failure. Lottimizzazione della condotta chirurgica di prelievo ed impianto e del management anestesiologico globale appaiono infatti egualmente importanti. Recenti studi sperimentali su modelli animali e su piccole casistiche cliniche hanno infine questionato lutilizzo stesso dellipotermia statica. Lo sviluppo di nuovi sistemi di perfusione continua ex vivo del graft sembra infatti aprire nuove frontiere nella ricerca della strategia di protezione miocardica ottimale. In particolare stato recentemente sviluppato l Organ Care System (TransMedics, Inc. 200 Minuteman Road Suite 302, Andover, MA 01810 USA). Esso composto essenzialmente da due componenti integrati: un piattaforma portatile ed un sistema di perfusione. La console portatile alloggia una pompa ed un ossigenatore che provvedono al mantenimento di una perfusione a flusso pulsatile del graft cardiaco con sangue arricchito con una specifica soluzione nutriente. La console include inoltre delle batterie ricaricabili per il funzionamento durante il trasporto ed un sistema wireless di monitoraggio sia della funzionalit del sistema stesso che dei principali parametri del graft (pressione aortica, flusso coronarico, temperatura del sangue e frequenza cardiaca). Il sistema di perfusione una camera sterile trasparente che protegge il graft che viene mantenuto battente in condizioni ottimali di temperatura ed umidit. Il sistema consente la valutazione ecocardiografica sterile ed unanalisi metabolica mediante prelievo del sangue refluo dal seno coronarico. L Organ Care System, se validato dalla ricerca clinica, ha il potenziale di migliorare la protezione del graft estendendo il pool dei donatori e consentendone una pi accurata valutazione ex vivo. Il Matching donatore ricevente I criteri per il matching donatore ricevente sono fondamentalmente la compatibilit per emogruppo ABO e la compatibilit dimensionale. A tal proposito va ricordato che trapianti eseguiti senza compatibilit ABO determinano sempre rigetto iperacuto fatale. La compatibilit dimensionale ha una tolleranza allincirca del 30% eccetto i trapianti pediatrici dove il matching deve essere pi stringente. In caso di ipertensione polmonare severa nel ricevente (5 - 6 Wood units) raccomandabile un oversizing del donatore per scongiurare il rischio di una disfunzione ventricolare destra acuta precoce. In presenza di un positivit anticorpale per PRA (panel reactive antibody)> 10%, spia di una presensibilizzazione alloantigenica, assolutamente necessario eseguire cross-match preventivo. Trapianto cardiaco ortopico Come riportato dai dati del registro della UNOS la tecnica chirurgica originariamente codificata da Shumway and Lower tuttora la pi utilizzata (56%). Dopo accesso sternotomico ed incannulazione aortica e bicavale si istituisce una CEC ipotermica totale raffreddando il paziente a 28 C. Clampata laorta ascendente distale si pone un vent nella vena polmonare superiore destra e si procede alla cardiectomia. Il corretto timing delle cardiectomie sul donatore e sul ricevente uno step fondamentale nel minimizzare il tempo di ischemia del graft. La perfetta sincronizzazione dovrebbe ottenersi tramite un coordinamento serrato tra lequipe di prelievo ed il centro trapianti. Idealmente la procedura sul ricevente dovrebbe essere eseguita subito prima dellarrivo dellorgano. Una volta giunti in sala operatoria, il graft viene quindi rimosso dal frigo di trasporto e posto in una bacinella mentre lequip di impianto sezionate laorta e larteria polmonare a livello delle semilunari e poi separa luna dallaltra con lelettrobisturi ponendo attenzione a non danneggiare il ramo destro dellarteria polmonare. Gli atri vengono incisi lungo il solco atrioventricolare lasciando unadeguata cuffia posteriore contenente lo sbocco delle vene cave a destra e delle vene polmonari a sinistra. Limpianto inizia ponendo una sutura doppio ago in prolene 3-0 a livello della vena polmonare superiore sinistra nella cuffia del ricevente e poi alla base dellauricola sinistra nel graft. Lorgano viene quindi calato allinterno del torace e la sutura procede prima in senso cranio-caudale e poi medialmente verso il setto interatriale. Terminata la porzione posteriore della sutura si procede ad ipotermia topica tramite infusione di soluzione salina fredda ponendo il paziente in anti Trendelemburg e ruotandolo verso sinistra col duplice scopo di impedire che linfusato ostacoli la procedura chirurgica e raffreddare efficacemente le superfici ventricolari. Limpianto infatti un periodo di estrema vulnerabilit del graft tanto che fino al 50% dellinsulto ischemico si realizza in questa fase. Si completa quindi la sutura atriale sinistra lungo il tetto dellatrio e verso il setto interatriale ponendo particolare attenzione ad un corretto matching dimensionale. La sutura atriale destra viene confezionata in maniera simile alla precedente ponendo il primo punto nella porzione punto pi alta o in quella pi bassa del setto interatriale cos che i suoi estremi si incontrino nel mezzo della parete anterolaterale. Per un corretto matching dimensionale lorificio della vena cava inferiore viene opportunamente inciso in direzione dellauricola destra, come originariamente suggerito da Barnard, per evitare danni al nodo seno atriale. Si confeziona poi lanastomosi termino-terminale dellarteria polmonare in prolene 4-0 iniziando dallinterno sulla parete posteriore, completando dallesterno sullanteriore e repertando gli estremi della sutura al di fuori del torace. E fondamentale un corretto trimming dei monconi per evitare il kinking dellarteria pomonare da eccessiva lunghezza. Si completa la procedura avviando il riscaldamento del paziente e sospendendo il raffreddamento topico mentre si procede alla confezione dellanastomosi termino-terminale dellaorta nella quale opportuno un certo grado di ridondanza per consentire lispezione del margine posteriore di sutura. Si procede quindi ad un accurata purga dellaria dalle cavit destre e sinistre, ponendo il paziente in Trendelemburg e lasciando una linea di aspirazione in aorta ascendente. Dopo aver somministrato lidocaina (100 200 mg ev) si rimuove il clamp aortico e se necessario si procede alla defibrillazione. Lemostasi delle linee di sutura viene ispezionate con cura e si procede allo svezzamento dalla circolazione extracorporea. Generalmente si somministrano farmaci inotropi e cronotropi positivi e vasodilatatori polmonari secondo protocolli che variano da istituzione ad istituzione e se necessario si ricorre al pacing epicardico. Si termina la procedura con la consueta ricostruzione a strati su drenaggi. Tecniche alternative di trapianto ortotopico La tecnica anastomotica bicavale la alternativa pi frequentemente adottata. Essa prevede la completa escissione dellatrio destro lasciando oltre la consueta cuffia atriale sinistra una cuffia di tessuto intorno agli osti cavali. Completata lanastomosi atriale sinistra secondo la tecnica di Shumway si procede alla due anastomosi termino-terminali delle vene cave inferiore e superiore. E stata infine codificata la tecnica del Total heart transplantation che prevede lanastomosi separata degli osti delle vene polmonari di destra e sinistra oltre alla doppia anastomosi termino-terminale delle vene cave. La maggior complessit tecnica di queste procedure sarebbe giustificata sul piano teorico da una minore incidenza di insufficienza delle valvole atrio-ventricolari e di disturbi di conduzione. Una recente analisi del database della United Network for Organ Sharing (UNOS) su un campione di 14,418 trapianti cardici primari ha valutato gli outcomes della tecnica tradizionale e di quella bicavale(2). Pur avendo evidenziato una significativa riduzione dei tempi di ospedalizzazione e una minor incidenza di impianto di pacemakers definitivi nei pazienti sottoposti a trapianto con la tecnica bicavale non si dimostrato alcun beneficio in termini di sopravvivenza precoce e a distanza. (2) Weiss ES, Nwakanma LU, Russell SB, Conte JV, Shah AS. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant. 2008 Feb;27(2):178-83 Trapianto cardiaco eterotopico Il trapianto cardiaco eterotopico fu introdotto nella pratica clinica nel 1974 da Barnard and Losman quale sistema di assistenza circolatoria biologica in unepoca in cui le limitate conoscenze in materia di immunosoppressione e sorveglianza del rigetto acuto rendevano lincidenza della early graft failure estremamente elevata. La procedura di prelievo del graft non differisce in caso di trapianto eterotopico. Il ricevente viene posto in circolazione extracorporea totale mediante incannulazione aortica e bicavale, si clampa laorta ascendente distale ed il cuore nativo viene protetto mediante cardioplegia ematica. Per limpianto sono disponibili due tecniche chirurgiche: una di assistenza ventricolare sinistra isolata e unaltra mirata ad una assistenza bi ventricolare. In caso di assistenza sinistra, posto il graft nellemitorace destro, si procede allanastomosi diretta latero-laterale dei due atri sinistri e termino-laterale delle due aorte. Il ritorno dal seno coronarico del donatore viene garantito mediante lanastomosi dellarteria polmonare del graft con latrio destro del ricevente. In caso di assistenza bi ventricolare, terminata lanastomosi atriale sinistra, viene confezionata una anastomosi diretta a diamante dei due atri destri. Le arterie polmonari e le aorte vengono anastomizzate con tecnica termino laterale mediante interposizione di tubi protesici di dimensioni tali da prevenire il kinking dellanastomosi atriale destra. Il riempimento atriale e ventricolare del graft sar quindi determinato dalla pressione telediastolica del cuore nativo, ed il contributo relativo dei due cuori posti in parallelo alla gittata globale dipender dalle resistenze intracardiache. Le complicanze maggiori del trapianto cardiaco eterotopico sono: 1) la compressione diretta del graft sui lobi polmonari medio ed inferiore destro che determina disventilazione ed infezioni, 2) difficolt di sincronizzazione delle due attivit contrattili, 3) precoce e severo deterioramento della funzione del cuore nativo che, quando aggravato da insufficienza aortica e mitralica massiva, determina flusso retrogrado, 4) tromboembolismo e 5) presenza di un tubo protesico in un paziente immunodepresso. In caso di trapianto etero topico pediatrico stata infine segnalata la cosiddetta big heart syndrome caratterizzata da convulsioni e coma dovuti ad iperafflusso cerebrale. La complessit tecnica della procedura e del management perioperatorio ne hanno limitato grandemente la diffusione. Le attuali indicazioni alla procedura sono lipertensione polmonare irreversibile e il severo mismatch dimensionale donatore-ricevente in pazienti ad alto rischio. Taluni centri hanno esteso le indicazioni anche alla presenza di donatori marginali per cinesi e/o tempo di ischemia estremamente prolungato. RISULTATI DEL TRAPIANTO DI CUORE C Amarelli, C Maiello, M Cotrufo Lepoca pionieristica dei trapianti di cuore, dal primo trapianto (Cape Town, 1967) allintroduzione delluso della ciclosporina (Stanford, primi anni 80) stata gravata da un numero elevatissimo di insuccessi. Nellepoca pre-ciclosporinica la sopravvivenza ad 1 anno di un trapiantato di cuore raggiungeva in centri ad alto volume di interventi il 30%. Lesperienza sperimentale di quei trapianti ha lasciato un enorme patrimonio di conoscenze sulle complicanze precoci e tardive dei trapianti di cuore che ha consentito di ottimizzarne i risultati a breve e medio termine. Il progressivo miglioramento dei risultati del trapianto di cuore ha fatto s che divenisse la terapia di scelta per il paziente con scompenso cardiaco terminale. Nonostante il recente miglioramento dei risultati della terapia medica dello scompenso cardiaco cronico (blocco dellattivazione neurormonale) abbia modificato il pool dei pazienti sottoposti a trapianto di cuore (incremento dellet media, peggioramento delle condizioni cardiache e del numero di comorbidit, aumento del numero di pazienti gi sottoposti a chirurgia cardiaca) i risultati a breve, medio e lungo termine del trapianto di cuore hanno avuto un costante trend in miglioramento. La mortalit ospedaliera del trapianto di cuore si mantenuta negli anni attorno all8-10% e dipende fortemente dalle condizioni preoperatorie del ricevente. Secondo le casistiche internazionali i pazienti a maggior rischio chirurgico sono i pazienti in status I, i pazienti gi sottoposti a pregressa chirurgia, i pazienti con ipertensione polmonare severa o disfunzione epatica e renale preoperatoria. La sopravvivenza ad un anno si approssima al 90% e dipende dalla presenza/assenza di fattori di rischio riconosciuti del paziente ed in maniera continua dalla et del donatore, dal tempo di ischemia del donatore e dalla esperienza del centro (volume di trapianti annui). La sopravvivenza a 5 anni del 70% sulla coorte generale ed significativamente superiore a quella dei pazienti con scompenso cardiaco cronico con indicazione accertata al trapianto che non riescono ad esser trapiantati. Se si estrapolano pazienti di giovane et, non operati precedentemente che ricevano un organo da un donatore di giovane et tale sopravvivenza supera l80% (Dati ISHLT 2006, fig. 1 a). La sopravvivenza del paziente anziano viene modificata in maniera ancora pi significativa dalla qualit dellorgano attribuito (fig. 1 b). Circa il 50 % dei riceventi raggiungono i 13 anni dal trapianto di cuore (Dati ISHLT 2007, fig. 2a) e questa durata progressivamente e costantemente aumentata negli anni. (Dati ISHLT 2007, fig. 2b). Il traguardo del trapianto di cuore oggi non tanto il miglioramento dei risultati a lungo termine della procedura (fatta eccezione la prevenzione del rigetto cronico) ma il miglioramento della qualit di vita del paziente, la riduzione della incidenza delle complicanze post trapianto e del loro impatto economico ed organizzativo. Le complicanze a distanza del trapianto di cuore sono distinte in complicanze immunologiche e complicanze non immunologiche. Negli anni sono state chiaramente evidenziate le relazioni tra i farmaci immunosoppressori utilizzati e le complicanze immunologiche e non immunologiche osservate. La scelta dello schema immunosoppressivo in relazione alle caratteristiche preoperatorie del paziente (fattore scarsamente modificabile se non mediante la assistenza meccanica del circolo) pertanto lo strumento pi idoneo a ridurre lincidenza delle complicanze precoci e tardive del trapianto di cuore ed ad ottimizzarne i risultati in termini di sopravvivenza e qualit di vita. Mortalit ospedaliera Il 50 % circa della mortalit ospedaliera (fig. 3) ancora oggi rappresentata da graft failure postoperatoria i cui determinanti fondamentali sono la qualit dellorgano prelevato, la qualit della protezione dellorgano, il matching dimensionale tra donatore e ricevente (<10 % del peso, sovradimensionamento in caso di riceventi ad alto rischio per PVRI) e la reversibilit della ipertensione polmonare del ricevente. Ancora nel 2001, nonostante lincrementata esperienza nella valutazione della idoneit dellorgano e nel trattamento postoperatorio, lUK Registry segnalava un 10% di graft failure legate allipertensione polmonare del ricevente. La seconda causa di morte ancora oggi nei registri internazionali rappresentata dalle infezioni postoperatorie e dalla MOF postoperatoria. Management emodinamico e graft failure non immunologica La fase di arresto cardioplegico dellorgano ottenuta mediante la somministrazione delle apposite soluzioni iperpotassiche in grado di bloccare il metabolismo miocardico (arresto miocardio diastolico) e di proteggere lintegrit dellendotelio coronarico rappresenta di per se una potenziale causa di danno miocardico perioperatorio. Laddove la qualit del graft ed il matching dimensionale tra donatore e ricevente siano adeguate alle condizioni preoperatorie del ricevente (relativamente alle PVRI) i determinanti di una insoddisfacente ripresa emodinamica dellorgano sono: -inadeguata protezione miocardica -durata del tempo di ischemia (ischemia fredda ed ischemia calda) -et del donatore -uso di amine del donatore. Alla ripresa della perfusione coronarica, che si verifica al declampaggio aortico, inizia la fase detta di riperfusione calda dellorgano; durante questa fase il cuore ancora collegato alla macchina cuore polmone ma parzialmente bypassato dalla circolazione extracorporea. Ci mantiene il cuore decompresso in maniera dipendente dai flussi di pompa e dal volume ematico circolante. La sola decompressione del cuore in assistenza di circolo in grado di ridurre del 50 % il consumo di O2 e substrati del miocardio. La fase di riperfusione calda la fase durante la quale lorgano, dopo la fase di arresto cardioplegico in cui ha consumato lentamente substrati energetici, vede reintegrare le proprie riserve energetiche (ATP) e pu riparare i minimi danni verificatisi durante la fase di arresto. La durata della riperfusione calda deve dunque tener conto delle variabili su esposte per permettere pertanto di ripristinare il quoziente energetico del graft (rapporto ATP/AMP) e garantire quindi un rapido svezzamento dellorgano dalla circolazione extracorporea. Durante questa prima fase i farmaci inotropi dovrebbero essere utilizzati con parsimonia per non aumentare il metabolismo miocardico ed ottimizzare il successivo svezzamento dalla macchina cuore-polmone. Di grandissima importanza nella gestione non-immunologica del paziente trapiantato di cuore luso dei farmaci vasodilatatori necessari per la dipendenza dal postcarico del cuore subito dopo la fase di arresto. Se in origine il farmaco di scelta era senza dubbio il Nitroprussiato sodico per la sua capacit di vasodilatazione polmonare e sistemica, non si pu probabilmente dire lo stesso oggi. La maggiore incidenza di pazienti con ipertensione polmonare moderata o severa nelle casistiche mondiali, la maggiore vulnerabilit del ventricolo destro alla ischemia perioperatoria e quindi alla disfunzione precoce (Right Ventricular Failure), il maggiore uso preoperatorio di vasodilatatori periferici ha spostato la pratica clinica verso luso di farmaci vasodilatatori polmonari selettivi (NO), o parzialmente selettivi (alprostadil, prostaciclina). Negli ultimi 2 anni sempre maggiori evidenze sono state raccolte sulluso perioperatorio degli inibitori delle fosfodiesterasi 5 come terapia o come profilassi primaria e secondaria nei pazienti a rischio di right ventricular failure. Luso ed il dosaggio dei farmaci vasodilatatori polmonari guidato nella maggior parte dei centri dal monitoraggio emodinamico con catetere di Swan-Ganz. b) Graft failure immunologica Il rischio di graft failure immunologica il rischio che maggiormente decrementato negli anni con la maggiore esperienza e con la disponibilit di nuovi farmaci. Le possibili forme di rigetto immunomediato verso lorgano impiantato sono: -Rigetto iperacuto -Rigetto acuto cellulare -Rigetto acuto umorale -Rigetto cronico (CAV, chronic allograft vasculopathy ) Il rigetto iperacuto una forma di rigetto caratterizzata dalla necrosi fibrinoide intravascolare dei vasi dellorgano trapiantato, determinata dalla attivazione del complemento da parte di anticorpi preformati contro gli antigeni espressi sulle cellule endoteliali dellorgano e compare generalmente sul tavolo operatorio o nelle prime 24 ore dal trapianto. Tale forma generalmente imputabile alla preesistenza di anticorpi diretti verso lHLA del donatore o verso gli antigeni del gruppo sanguigno (incompatibilit di gruppo ABO); virtualmente scomparso con lo studio dei pannelli anticorpali preoperatori del ricevente e la pratica del cross-match preoperatorio dei pazienti a rischio. In alcuni setting clinici (trapianto pediatrico o in emergenza di pazienti immunizzati o con gruppo sanguigno raro) stato sperimentalmente effettuato il trapianto di cuore con organi di gruppo non compatibile. La plasmaferesi completa o metodiche di immunoassorbimento sono state sperimentalmente utilizzate con successo per prevenire la graft failure primaria. I risultati a medio e lungo termine non sono per al momento conosciuti e limpiego di tale tecniche da considerare aneddotico. Il rigetto acuto cellulare la forma pi comune di risposta immunologica al graft, caratterizzata sul piano anatomopatologico dalla comparsa di una infiltrazione linfocitaria parcellare o diffusa, che si pu associare alla comparsa di edema interstiziale del miocardio sino alla necrosi miocardica. Compare classicamente dopo la prima settimana dal trapianto non appena si raggiunge la fase di mantenimento della terapia immunosoppressiva. Lincidenza del rigetto acuto cellulare stata notevolmente ridotta dai progressi della terapia immunosoppressiva (inibitori delle calcineurine, micofenolato mofetile). Questi trattamenti infatti sono selettivi sulla funzione attivatrice della risposta immunitaria del Linfocita T. Nei primi anni 80 tra il 70 e l85% dei pazienti trapiantati sviluppavano un episodio di rigetto acuto cellulare durante i primi 6 mesi. Lincidenza attuale tra il 20 ed il 40% e riguarda per lo pi pazienti che hanno necessitato di riduzione della terapia immunosoppressiva per effetti collaterali dei trattamenti o per infezioni intercorrenti; la non compliance rimane ancora oggi una causa non infrequente di rigetto acuto cellulare. La classificazione dei rigetti acuti classica quella ISHLT(1990), recentemente rivisitata da una consensus conference nel 2004 (Tabella. 2). Generalmente vengono trattati solo i rigetti maggiori di 2 o i rigetti di qualsiasi grado con compromissione emodinamica, i rigetti >1A sono trattati con un incremento dei dosaggi dellimmunosoppressione in corso. Secondo la nuova classificazione si trattano solo i rigetti di grado severo, o i rigetti di grado moderato con compromissione emodinamica. Il rigetto acuto viene generalmente trattato in prima linea con 3 boli di corticosteroidi (Metil Prednisolone Solfato) da 1 grammo in tre giorni. Tale trattamento sufficiente a risolvere levento nella maggior parte dei casi. Nei restanti casi il trattamento si modifica da paziente a paziente e da centro a centro. Strategie comuni sono: nuovo trattamento con farmaci utilizzati nella fase di induzione (ATG, ALG, Anticorpi monoclonali), fotoaferesi, cambio del farmaco utilizzato nella prevenzione primaria del rigetto (CSA( Tacrolimus o viceversa), decalage di corticosteroidi orali prolungato nel tempo. I pazienti trattati in maniera pi aggressiva necessitano di una attenta sorveglianza infettivologica per evitare il rischio che una over-immunosoppressione sfoci in una infezione potenzialmente letale. Il rigetto acuto umorale compare generalmente nei primi mesi postoperatori. La sua incidenza del 7% circa. La causa sono anticorpi anti HLA o anticorpi che riconoscono antigeni dellendotelio coronarico del graft. Tale forma pi frequente nei pazienti con pannello di reattivit anticorpale positivo e con seropositivit al CMV. Leffetto pi comune e temibile del rigetto umorale la brusca riduzione della riserva coronaria di flusso. La diagnosi istochimica (ricerca delle immunoglobuline e dei frammenti C4d del complemento su frammenti bioptici) entrata nella pratica clinica di molti centri come routine nei pazienti che effettuano la biopsia endomiocardica. Il rigonfiamento delle cellule endoteliali alle colorazioni con ematossilina-eosina pu indurre la ricerca di un rigetto umorale. La ridotta incidenza in termini numerici di tale forma di rigetto per fa ritenere che in termini costi benefici e per evitare falsi negativi tale ricerca vada fatta solo nei pazienti con impairment emodinamico in assenza di un rigetto acuto cellulare. La terapia del rigetto umorale basata sullincremento dei dosaggi della terapia immunosoppressiva ed eventualmente sulla plasmaferesi. Negli ultimi anni lassociazione della metodica di immunoassorbimento e dellanticorpo monoclonale anti-CD20 (rituximab) stata segnalata per la sua efficacia nel trattamento del rigetto umorale. Il ruolo del rigetto acuto umorale nella genesi del rigetto cronico vascolare (CAV) attualmente oggetto di studio. Il rigetto cronico sar trattato tra le complicanze tardive del trapianto di cuore. c) Management immunologico e rischio infettivo. Gli schemi di immunosoppressione sono cambiati notevolmente dai primi trapianti effettuati da Barnard sino ad oggi. Le maggiori innovazioni nella gestione dellimmunosoppressione sono dovute a Shumway ed alla equipe multidisciplinare da egli creata per rendere clinicamente possibile il trapianto di cuore. Il primo trapianto di cuore stato effettuato da Barnard a Cape Town nel 1967 ed i trapianti di cuore si sono succeduti velocemente nel mondo per linteresse verso una procedura nuova, affascinante e potenzialmente risolutiva per il trattamento dello scompenso cardiaco cronico. I risultati dei trapianti effettuati nei primi anni furono per assolutamente deludenti in relazione alla difficolt della gestione immunologica dei pazienti trapiantati. Nel 1971 su 170 trapianti di cuore effettuati nel mondo solo 30 erano vivi. Il rischio di infezioni potenzialmente letali da un lato e quello di graft failure secondarie a rigetto acuto condizionarono un verticale decremento dei numeri dei trapianti nel mondo e se nel 1968 nel mondo furono eseguiti 100 trapianti, nel 1970 ne furono effettuati solo 18. Solo il gruppo di Stanford e di Parigi continuarono con la loro attivit alla ricerca di strategie di gestione e di farmaci per il controllo della difesa immunitaria. Il miglioramento dei risultati del trapianto di cuore si deve alla invenzione della metodica della biopsia endomiocardica (fig.4) per la diagnosi del grado di risposta immunologica verso il graft ed alla introduzione della Ciclosporina A nellarmamentario terapeutico della medicina dei trapianti. Dalla introduzione della Ciclosporina in poi in tutto il mondo fiorirono centri trapianti di cuore ed in brevissimo tempo si raggiunsero i 1000 trapianti di cuore nel mondo. Grazie ad un azione immunosoppressiva selettiva sui linfociti T la ciclosporina infatti ha portato nei primi anni 80 la sopravvivenza ad un anno del trapianto di cuore dal 30% al 70%. La comprensione dei meccanismi della reazione immunomediata alla base del rigetto acuto, la disponibilit di farmaci immunosoppressori pi selettivi, la identificazione di trough levels dei farmaci immunosoppressori in grado di ottimizzare il rischio di infezioni rigetti acuti e comorbidit, hanno permesso di migliorare i risultati a breve e lungo termine dei trapianti di cuore. La strategia di immunosoppressione di basa sulluso di una terapia di induzione (non effettuata da tutti i centri trapianto), e una terapia di mantenimento da proseguire a vita. La terapia di induzione (tab 3) ha la finalit di ridurre sensibilmente le difese immunitarie durante la fase precoce del decorso postoperatorio in cui il rischio di rigetto acuto massimo (fig.5) e lassorbimento, il numero e la gravit delle reazioni avverse dei farmaci immunosoppressori sono scarsamente prevedibili. stato dimostrato che la terapia di induzione con ATG (sieroantitimocitario) o con ALG (siero antilinfocitario) o con anticorpi monoclonali (anti CD4, anti CD3, anti CD 25) non migliora la sopravvivenza dei trapianti di cuore ma sposta temporalmente la reazione immunitaria a quando la funzione emodinamica e renale si sono stabilizzate. I sostenitori della inutilit della terapia di induzione evidenziano una maggiore incidenza di infezioni virali e di PTLD (Post Transplant Linfoproliferative Disorders) nei pazienti trattati con terapie di induzione. Tale obiezione seppure realistica sembra essere legata alla preparazione utilizzata ed al dosaggio inserito nel complessivo schema immunosoppressivo (linserimento di nuove e pi potenti molecole nella terapia di mantenimento ha portato a rivedere il dosaggio delle terapie di induzione). Lelevata frequenza del numero di PTLD nei trapianti pediatrici fa invece ritenere che la mancanza di dati a favore dellutilit clinica della terapia di induzione non giustifichi il maggiore rischio oncologico del paziente. Per tale motivo luso in et pediatrica si notevolmente ridotto negli anni. Il potenziale beneficio in termini di libert da rigetto cronico riferibile alluso della terapia di induzione e della minore incidenza di rigetti acuti ancora oggetto di studio. La terapia di mantenimento (tab 4) ha la finalit di mantenere un potere immunologico globale (bersaglio di numerose ricerche per poter ottimizzare la terapia long-term del paziente trapiantato) tale da prevenire il rigetto acuto ed il rigetto cronico con il numero ed i dosaggi minimi di farmaci immunosoppressori. Ci nellinteresse di ridurre le comorbidit (ed il costo) dei trapiantati di cuore. Lelevato numero di comorbidit della popolazione dei trapiantati determina infatti la necessit di politerapie estremamente complesse e di gruppi multidisciplinari per la gestione di questi pazienti. Il disconfort legato alla complessit degli schemi terapeutici tuttora un problema in relazione alla compliance al trattamento di pazienti cos delicati. Se per anni il protocollo di immunosoppressione pressoch uniformemente in uso in Europa era Ciclosporina/Azatioprina/Steroidi, gli schemi terapeutici attualmente in uso prevedono la combinazione di un inibitore della calcineurina (Ciclosporina A, Tacrolimus), un inibitore della proliferazione cellulare (Azatioprina, Micofenolato Mofetile, Rapamicina, Everolimus) e il cortisone (Prednisone). In tabella sono riportati il razionale per luso e gli svantaggi dei singoli farmaci. La conoscenza su larga scala dei benefici e gli svantaggi dei singoli farmaci sta lentamente conducendo verso una immunosoppressione sempre pi ragionata e indirizzata alle caratteristiche cliniche del singolo paziente (tailored therapy). La sospensione dello steroide argomento estremamente dibattuto. Lo steroide la principale causa delle comorbidit non immunologiche del paziente trapiantato (eccesso ponderale, disturbi comportamentali, dislipidemia, diabete mellito, ipertensione arteriosa, ritenzione idrica, osteoporosi etc.), la sua sospensione fattore di rischio riconosciuto per lo sviluppo di rigetto acuto nellimmediato periodo dopo la sospensione ed a distanza. Un aumento del rischio di rigetto cronico stato segnalato ma non univocamente dimostrato, ma laumento del richio di CAV nei pazienti con pregresso rigetto acuto chiaramente dimostrato. Le associazioni immunoppressive maggiormente utilizzate a livello mondiale nella immunosoppressione de novo sono attualmente Ciclosporina/ MMF/ Steroide e Tacrolimus /MMF /Steroide, la prima pi frequente in Europa la seconda in USA. I centri che utilizzano Tacrolimus sono pi inclini alla sospensione precoce dello steroide. In tabella 5 sono riportati i dosaggi ed i TL, in uso presso il nostro centro, dei singoli farmaci immunosoppressori nei diversi schemi di immunosoppressione. Leverolimus per la maggiore maneggevolezza rispetto al suo precursore (la rapamicina) ha un ampio potenziale di impiego nella immunosoppressione del long-term. Le resistenze riguardo allimpiego del farmaco nel de novo sono attualmente rappresentate dal rischio di ritardo della guarigione delle ferite chirurgiche e di infezioni batteriche precoci. Il forte razionale sperimentale, i dati dalle prime sperimentazioni cliniche e le esperienze provenienti dagli altri trapianti dorgano (utilizzo in monoterapia nel trapianto di rene) pur in mancanza di dati inequivocabili sulla efficacia in termini di libert da rigetto cronico ha fatto si che il farmaco entrasse nel mantenimento del long-term in associazione con gli inbitori delle calcineurine nellottica di una minimizzazione del loro uso (e quindi degli effetti collaterali). Il monitoraggio del rigetto acuto viene ancora oggi effettuato mediante la biopsia endomiocardica, tale procedura viene effettuata secondo schemi di follow-up differenti da centro a centro ma che prevedono una sorveglianza estremamente frequente (settimanale) durante i primi 2 mesi e successivamente mensile. Dopo il sesto mese il numero di procedure si riduce notevolmente ed in alcuni centri la biopsia viene effettuata solo in caso di sospetto clinico. Ci in quanto la bassa probabilit a priori del test non giustifica il rischio della procedura. Il rischio di infezioni postoperatorie del trapianto di cuore si ridotto grazie alla migliore conoscenza dei meccanismi e dei germi coinvolti nello sviluppo delle stesse. La sorveglianza infettivologica ha permesso di anticipare la diagnosi e la terapia delle infezioni ed in tal modo di migliorarne loutcome. Durante le prime 4-6 settimane dal trapianto il paziente a rischio di infezioni batteriche potenzialmente letali. Tale rischio connesso in particolare modo alla necessit di intubazione prolungata perioperatoria (Ventilator Associated Pneuomonia). Tali polmoniti sono infatti spesso sostenute da germi nosocomiali ed ancora oggi costituiscono causa di mortalit ospedaliera. Il rischio di infezioni batteriche acute incrementato nei pazienti trattati con Everolimus rispetto a quelli trattati con Micofenolato. Le infezioni virali postoperatorie sono per lo pi sostenute dalla riattivazione di virus (in particolar modo quelli erpetici). I pi comunemente osservati sono: CMV, VZV, HSV 1, EBV, HSV-8, Parvovirus B19. Il micofenolato incrementa il rischio di infezioni virali in misura maggiore rispetto allEverolimus. I pazienti positivi per i virus HBV e HCV preoperatoriamente vengono monitorizzati mediante il periodico monitoraggio quantitativo alla PCR della attivit di replica del virus e trattati su tale base. In tutti i centri trapianto di cuore abitudine effettuare la profilassi farmacologica con aciclovir orale per i primi 2 mesi per lHSV 1. La sorveglianza dellinfezione da citomegalovirus di particolare importanza relativamente al ruolo della viremia da citomegalovirus nello sviluppo delle opportunistiche postoperatorie e al probabile coinvolgimento nella coronaropatia cronica del graft. I centri trapianto si distinguono relativamente allapproccio alla infezione da CMV in centri che effettuano profilassi primaria (profilassi ai pazienti con Mismatch sierologico per CMV particolarmente D+/R-) e centri che effettuano profilassi secondaria (strategia di terapia preemptive). Tale strategia consiste nel trattare con antivirali (o antivirali + Immunoglobuline specifiche per CMV) i pazienti che positivizzino un test di riattivazione virale. I vari centri adottano tests diversi e diversi cut-off per il trattamento dei pazienti. I tests maggiormente utilizzati sono la PCR (su siero o su sangue) ed il dosaggio della pp65 su sangue. Attualmente in investigazione la espressione delle immediate early (IE)-1 proteins, la cui espressione in cellule CD8+ sarebbe altamente protettiva dalla infezione da CMV. La soglia per il trattamento in preemptive varia da centro a centro per trattare il massimo numero di pazienti a rischio di infezione e ridurre il numero di pazienti trattati. Presso il nostro centro trapianti il cut-off > 5 cellule per campo. Con questo cut-off un solo paziente (D+/R-) non trattato ha sviluppato malattia da CMV e il numero dei pazienti trattati contenuto tra il 5 ed il 45% a seconda dello schema di immunosoppressione adottato (incremento del rischio in pazienti trattati con MMF e che ricevono terapia di induzione con ATG). La immunosoppressione da infezione da CMV responsabile di un incremento del rischio di infezioni batteriche e protozoarie durante i primi 6 mesi dal trapianto cardiaco. I meccanismi di tale immunosoppressione in relazione alla ricostituzione delle difese T CMV specifiche attualmente oggetto di studio. Il virus EBV si replica nel 30-70% dei soggetti sieropositivi preoperatoriamente e nel 100% di quelli sieronegativi con donatore sieropositivo. Linfezione attiva da EBV spesso si traduce nella sviluppo di PTLD (Post Transplant Linfoproliferative Disease). La riattivazione del virus HHV-8 invece la principale causa del sarcoma di Kaposi. Le infezioni opportunistiche compaiono generalmente tra il 2 ed il 6 mese post-operatorio. Le pi comuni sono rappresentate da Pneumocystis Carinii, Nocardia, Aspergillus, Criptococco. La diagnostica generalmente complicata per la paucisintomaticit legata alla terapia immunosoppressiva (cortisonici) ed alla variegata presentazione radiografica che spesso ritarda la diagnosi. I test immunologici si positivizzano tardivamente per effetto dellimmunosoppressione e per tale motivo si privilegiano test di ricerca dellagente infettivo su materiali o tessuti o di antigeni prodotti dallorganismo ricercato (galattomannani sierici nella Aspergillosi). Altra patologia che pu avere un decorso subdolo la tubercolosi. Non infrequente la riattivazione della crescita del micobatterio in corrispondenza della induzione della immunosoppressione. I pazienti che presentano una positivit al test alla tubercolina preoperatorio necessitano di un attento monitoraggio clinico. Complicanze tardive del trapianto di cuore Complicanze non immunologiche (tab 6) Le complicanze non immunologiche del trapianto di cuore sono da riferire in maniera diretta allo schema immunosoppressivo in uso presso i singoli centri ed alle caratteristiche preoperatorie dei pazienti sottoposti a trapianto cardiaco. Non pertanto possibile definire una incidenza univoca per le principali complicanze post trapianto. Le complicanze pi comuni della terapia immunosoppressiva sono: insufficienza renale cronica, ipertensione arteriosa, dislipidemia, diabete mellito di nuova insorgenza (NODM), eccesso ponderale, ritenzione idrosalina, osteoporosi, miopatie. In tabella sono riportate lincidenza ad 1, 5, 10 anni delle principali complicanze non immunologiche nel database dellISHLT. Linsufficienza renale cronica ha diversa incidenza in base al tipo di inibitore della calcineurina (Tacrolimus < Ciclosporina A), al farmaco associato agli inibitori della calcineurina (Micofenolato Mofetile < Azatioprina), ai trought level in uso presso i singoli centri, alla et media dei pazienti, alluso di ACE inibitori. Lincidenza di ipertensione arteriosa, ritenzione idrica, osteoporosi e obesit strettamente correlata alluso a lungo termine degli steroidi. Lincidenza precoce del diabete mellito (NODM) correlata al dosaggio totale di steroidi impiegata ed alluso del Tacrolimus; lincidenza dopo il quinto anno dal trapianto di cuore simile tra i pazienti in Ciclosporina e in Tacrolimus. Lincidenza di dislipidemia dipende in maniera diretta dallinibitore della calcineurina utilizzato (incidenza maggiore con la ciclosporina), dal farmaco associato (incidenza maggiore con Everolimus), dal pool dei pazienti trapiantati (maggiore per pazienti affetti da cardiomiopatia ischemica), dalluso di steroidi e dalla politica del centro relativamente alluso delle statine. Complicanze immunologiche (infezioni, rigetto cronico e neoplasie) Il rischio infettivo oltre il primo anno rimane solo incrementato rispetto alla popolazione generale in relazione alla riduzione della intensit della immunosoppressiva. Il rischio di mortalit per cause infettive raggiunge infatti un plateau dopo i primi mesi dal trapianto. (fig 5) Il rigetto cronico (CAV, chronic allograft vasculopathy) oggi il problema maggiore delloutcome a distanza del trapianto di cuore ed considerato la nemesi della procedura. Compare generalmente dopo il primo anno dal trapianto, classicamente diagnosticato in emodinamica con metodiche IVUS tra il 3 ed il 5 anno dal trapianto. E la prima causa di mortalit dopo il primo anno dal trapianto. Si manifesta come una aterosclerosi diffusa (le differenze con la aterosclerosi sono riportate in tabella 7 ed in fig 7) con proliferazione miointimale nei vasi coronarici epicardici ed intramiocardici e con un trend temporale molto pi aggressivo della classica aterosclerosi coronarica (fig.6). La natura diffusa del danno coronarico la rende scarsamente suscettibile a terapia endovascolare e terapia chirurgica. Il tratto prossimale del vaso epicardico interessato da una fibrosi intimale concentrica che il segno caratteristico ricercato allIVUS (incremento dello spessore intimale allecografia intravascolare). Tale segno stato da molti messo in relazione con eventi cardiovascolari e con un peggioramento della prognosi a breve e medio termine. Non per infrequente il trattamento in emodinamica delle lesioni coronariche da passenger atherosclerosis, fenomeno che si embrica trettamente con la CAV classicamente definita. Il meccanismo patogenetico ancora oggetto di studio anche se sono oramai ben noti i fattori di rischio del donatore, del ricevente, della procedura e del decorso postoperatorio che giocano un ruolo nel determinismo di tale complicanza. I fattori di rischio pre-harvesting del cuore sono: et del donatore, causa del decesso del donatore, modalit di esordio della morte cerebrale (la cosiddetta morte esplosiva), uso di inotropi e vasocostrittori del donatore, fattori di rischio cardiovascolari del donatore (peso, diabete, aterosclerosi extracardiaca). Molti dei fattori succitati in realt sono tra di loro in sovrapposizione: il donatore anziano infatti spesso il donatore che decede pi frequentemente per emorragia cerebrale (o ictus ischemico) che ha gi una ipertensione arteriosa in trattamento e dunque fattori di rischio cardiovascolari riconosciuti dallOMS. I fattori di rischio relativi allaccoppiamento donatore ricevente sono: stato sierologico del CMV del donatore e del ricevente (maggiore rischio nel donatore sieropositivo in ricevente sieronegativo), tempo di ischemia (dipendente dalla sede del prelievo ed dalle modalit di spostamento dellequipe), accoppiamento degli HLA ( chiaramente dimostrata una maggiore incidenza di rigetti cronici in pazienti con mismatch dellHLA- DR). I fattori di rischio relativi al ricevente (pre e postoperatori) sono: et del ricevente, malattia di base, fattori di rischio cardiovascolari (diabete, insulinoresistenza, iperlipidemia, obesit, ipertensione arteriosa, insufficienza renale, iperomocisteinemia), reattivit anticorpale preoperatoria numero di rigetti acuti cellulari postoperatori, riattivazione/reinfezione da CMV. In tal senso la scelta del trattamento immunosoppressore condizionando la comparsa di alcuni dei fattori di rischio riconosciuti per la patologia in grado di interagire con le caratteristiche preoperatorie del paziente nel determinare linsorgenza del rigetto cronico. Il ruolo dellinibizione di mTOR in termini di prevenzione del rigetto cronico oggi il maggiore campo oggetto di studio e di speranze degli addetti al settore. Sul piano patogenetico (fig. 8) le determinanti del rigetto cronico sono il danno endoteliale e la esposizione della matrice extracellulare al flusso ematico. Lendotelio ha un ruolo regolatore importante nel determinismo del tono vasomotore, della coagulazione e della risposta infiammatoria. Il danno endoteliale si traduce in una ridotta produzione di fattori antitrombogeni (PAI, eparani, NO, trombomodulina) che pu spiegare i fenomeni di microtrombosi intravascolare. Il danno endoteliale pu essere di tipo non denudante o di tipo denudante. Il danno non denudante caratterizzato da una rapida sostituzione delle cellule endoteliali che porta una temporanea disfunzione endoteliale. Le cause sono sia immunologiche che non immunologiche. Il dannno denudante invece si verifica per danno da ischemia/riperfusione nella fase chirurgica e durante gli episodi di rigetto acuto cellulare. Il danno denudante espone la matrice extracellulare e le fibrocellule muscolari al flusso ematico spostando la bilancia emocoagulativa in senso pro coagulante. Ci determina un incremento delle resistenze intravascolari ed una ischemia cronica. La riduzione del flusso coronarico diagnosticabile in maniera non invasiva mediante metodiche ecocardiografiche o mediante RMN stata dimostrata predittiva di una riduzione della FE e di eventi cardiaci maggiori. Il danno denudante incrementa la permeabilit vascolare permettendo lingresso di un gran numero di lipoproteine nello spazio subendoteliale. Tale evento accelera ulteriormente levoluzione della patologia mediante il richiamo di macrofagi. La terapia oggi non esiste. Grandissimo risalto viene oggi dato ai farmaci inibitori del complesso mTor (everolimus e rapamicina) per il loro potenziale antiproliferativo dimostrato in vitro ed in vivo. Molti dati fanno ritenere che la migliore prevenzione del rigetto acuto cellulare ottenuta con lMMF,la migliore protezione dorgano ottenuta con le moderne soluzioni cardioplegiche ed il trattamento precoce della reinfezione/riattivazione del CMV possano sortire leffetto di ridurre lincidenza del rigetto cronico. Le statine, luso dellASA ed il controllo dei fattori di rischio per cardiopatia ischemica potrebbero giocare un ulteriore ruolo nel frenare la progressione della patologia. Il rischio neoplastico dopo trapianto cardiaco forse il rischio cui, negli anni, stato dato meno risalto. Limmunosoppressione si associa ad un incremento del rischio neoplastico (fig 9) anche se limmunosoppressione si sviluppata negli anni nel senso di una maggiore selettivit dei meccanismi di azione. Il rischio neoplastico stato riportato dall ISHLT (fig.10) e dal CTS di Opelz in cui sono state riportate lincidenza del problema neoplastico e limpatto sulla prognosi a breve e medio termine. Pochi studi per lo pi monocentrici hanno messo in correlazione il rischio neoplastico con il regime immunosoppressivo utilizzato; i dati non sono univoci e talora sono addirittura contrastanti. Un recente studio di registro spagnolo evidenziato un incremento della incidenza soprattutto di PTLD con luso di OKT3 e ATG, un minore rischio di neoplasie cutanee con lMMF, una riduzione dellincidenza di neoplasie collegate ad oncovirus (Sarcoma di Kaposi, PTLD, tumori cellulari squamosi associati al papilloma virus), nei pazienti che effettuavano terapia con antivirali profilassi delle infezioni virali. I tumori della popolazione dei trapiantati si distinguono in tumori cutanei, linfomi (PTLD), e tumori solidi. Lincidenza di 19 pazienti/pazienti/anno durante il primo anno ed aumenta con laumentare della lunghezza del follow-up. I pi frequenti sono i tumori cutanei con una frequenza relativa del 50% e con una prognosi sovrapponibile a quella della popolazione generale. Le PTLD rappresentano il 10% delle neoplasie posttrapianto ma sono le neoplasie con il decorso pi aggressivo (circa 50% di sopravvivenza a 1 anno). I tumori solidi hanno incidenze estremamente variabili da casistica a casistica e rispetto alla popolazione generale (fig.11) in ragione prevalentemente dei fattori di rischio della popolazione trapiantata e delle modalit di screening preoperatorio. Il ruolo della et in relazione allo sviluppo delle neoplasie molto modificato rispetto alla popolazione generale per effetto di una dipendenza dallet giovane delle PTLD. 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HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/15596559?ordinalpos=26&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" Drug therapy in the heart transplant recipient: part I: cardiac rejection and immunosuppressive drugs.Circulation. 2004 Dec 14;110(24):3734-40 Lindenfeld J, Miller GG, Shakar SF, Zolty R, Lowes BD, Wolfel EE, Mestroni L, Page RL 2nd, Kobashigawa J.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/15611389?ordinalpos=25&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation. 2004 Dec 21;110(25):3858-65. Lindenfeld J, Page RL 2nd, Zolty R, Shakar SF, Levi M, Lowes B, Wolfel EE, Miller GG.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/15630040?ordinalpos=24&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" Drug therapy in the heart transplant recipient: Part III: common medical problems. Circulation. 2005 Jan 4;111(1):113-7. Crespo-Leiro MG, Alonso-Pulpn L, Arizn JM, Almenar L, Delgado JF, Palomo J, Manito N, Rbago G, Lage E, Diaz B, Roig E, Pascual D, Blasco T, de la Fuente L, Camprecis M, Vzquez de Prada JA, Muiz J. Influence of induction therapy, immunosuppressive regimen and anti-viral prophylaxis on development of lymphomas after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry. J Heart Lung Transplant. 2007 Nov;26(11):1105-9. Opelz G, Wujciak T.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/8068075?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" The influence of HLA compatibility on graft survival after heart transplantation. The Collaborative Transplant Study. N Engl J Med. 1994 Mar 24;330(12):816-9. Kaczmarek I, Deutsch MA, Rohrer ME, Beiras-Fernandez A, Groetzner J, Daebritz S, Schmoeckel M, Spannagl M, Meiser B, Reichart B. HLA-DR matching improves survival after heart transplantation: is it time to change allocation policies? J Heart Lung Transplant. 2006 Sep;25(9):1057-62. Epub 2006 Aug 8 Aranda JM Jr, Hill J. Cardiac transplant vasculopathy. Chest. 2000 Dec;118(6):1792-800. Mehra MR.. Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. Am J Transplant. 2006 Jun;6(6):1248-56. Maziar Rahmani, Rani P. Cruz, David J. Granville and Bruce M. McManus. Allograft Vasculopathy Versus Atherosclerosis. Circ. Res. 2006;99;801-815 Valantine HA.. HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/14974936?ordinalpos=37&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" The role of viruses in cardiac allograft vasculopathy. Am J Transplant. 2004 Feb;4(2):169-77. Crespo-Leiro MG, Alonso-Pulpn L, Vzquez de Prada JA, Almenar L, Arizn JM, Brossa V, Delgado JF, Fernandez-Yaez J, Manito N, Rbago G, Lage E, Roig E, Diaz-Molina B, Pascual D, Muiz J. Malignancy after heart transplantation: incidence, prognosis and risk factors. Am J Transplant. 2008 May;8(5):1031-9. Tabella 1: Cause riconosciute di cardiomiopatia Forme primitive od idiopatiche: Cardiomiopatia dilatativa idiopatica Cardiomiopatia restrittiva idiopatica Cardiomiopatia ipertrofica idiopatica Displasia aritmogena del ventricolo destro Forme secondarie: Infiammatorie Infettive Virus Rickettsie Micobatteri Spirochete Miceti Parassiti Non infettive Collagenopatia Granulomatosi Morbo di Kawasaki Metaboliche Cause nutrizionali Tiamina Kwashiorkor Pellagra Scorbuto Ipervitaminosi D Carenza di Selenio Carenza di Carnitina Endocrine Acromegalia Tireotossicosi Mixedema Uremia Morbo di Cushing Feocromocitoma Diabete mellito Cataboliche Gotta Ossaluria Porfiria Tossiche Cobalto Alcol Bleomicina Adriamicina Fenotiazine ed antidepressivi Composti antimoniali Monossido di carbonio Piombo Emetina e diidroemetina Clorochina Litio Ciclofosfamide Idrocarburi Amine sintetiche Fosforo Mercurio Punture di insetto (Morbo di Chagas) Morsi di serpente Paracetamolo Reserpina Corticosteroidi Cocaina MetilsergideInfiltrative Amiloidosi Emocromatosi Neoplasie Tesaurismosi glicogeniche Sarcoidosi Mucopolisaccaridosi Malattia di Fabry Malattia di Whipple Malattia di Gaucher Sfingolipidosi Fibroplastiche Fibrosi endomiocardica Fibroelastosi endomiocardica Endocardite di Lffler Carcinoide Ematologiche Anemia drepanocitica Morbo di Vasquez Porpora trombotica trombocitopenica Leucemia Da ipersensibilit Metildopa Antibiotici (penicilline, tetracicline, sulfamidici) Farmaci antitubercolari Miocardite a cellule giganti Rigetto acuto persistente di trapianto cardiaco Neuromuscolare Distrofia muscolare di Duchenne Distrofia muscolare facio-scapolo-omerale Distrofia braccio-scapolare di Erb Miotonia distrofica Atassia di Friedrich Sindrome di Kearns-Sayre Generiche acquisite Post-ischemica Post-valvulopatia Ipertrofica non ostruttiva Da cardiopatia congenita complessa Post-partum Cardiomiopatia dellobeso Da agenti fisici Colpo di calore Ipotermia Radiazioni (post-attiniche) Tabella 2: Indicazioni a trapianto cardiaco: Shock cardiogeno o stato di bassa portata cardiaca (Indice cardiaco <2.0 L/m2/min) con danno dorgano reversibile che necessita dellimpiego di un device di assistenza meccanico (Respiratore automatico, contropulsazione aortica, VAD, cuore artificiale totale). Scompenso cardiaco cronico con stato di bassa portata che richiede luso di supporto farmacologico inotropo continuo per via endovenosa. Classe funzionale NYHA III/IV (con rischio elevato allo score HFSS) con accentuato e progressivo deterioramento emodinamico in corso di terapia medica ottimizzata con importante limitazione funzionale e scadente prognosi a 12 mesi (VO2 max d"14 ml/kg/min o superiore con decremento progressivo). Insufficienza cardiaca con ricorrenti episodi di scompenso acuto non responsiva al dosaggio ottimale di diuretici e vasodilatatori. Severa cardiomiopatia ipertrofica o restrittiva con sintomi di IV classe funzionale NYHA. Angina instabile refrattaria a terapia medica massimale non suscettibile di trattamento chirurgico od endovascolare di rivascolarizzazione miocardica dovuta al diffuso o distale interessamento dellalbero coronarico o che si accompagni a severa disfunzione ventricolare sinistra con segni obiettivi di ischemia miocardica ai test funzionali. Aritmie ventricolari ricorrenti refrattarie al trattamento medico ottimale non suscettibili di ablazione chirurgica. Tumori del cuore chirurgicamente non aggredibili a bassa probabilit di metastasi. Sindrome del cuore sinistro ipoplasico. Cardiopatie congenite complesse con segni progressivi di insufficienza cardiaca non correggibili con la chirurgica cardiaca convenzionale o palliativa (Per i pazienti in et scolare o prescolare particolare attenzione va posta nel rilevare segni di insufficiente incremento ponderale dovuta allavanzato stato di scompenso o al progressivo incremento delle resistenze vascolari polmonari che si ritengano possano precludere al trapianto di cuore in et adulta). Tabella 3: Fattori clinici del ricevente associati ad un incremento del rischio di morbilit e mortalit Ipertensione polmonare irreversibile (e"6 unit Wood indicizzate non responsive ai test con vasodilatatori o con parziale reversibilit con resistenze residue >3 UW, pressione sistolica polmonare > 60 mmHg e gradiente trans- polmonare e"15 mmHg). Sepsi da qualsiasi causa o infezione cronica persistente con danno dorgano. Patologie croniche epatiche, renali e polmonari con danno dorgano non reversibile. Embolia polmonare od infarto polmonare recente. Et >65 anni. Diabete mellito con danno dorgano non reversibile (rischio aumentato anche senza danno dorgano). Patologia aterosclerotica obliterante degli arti inferiori e/o vasculopatia cerebrale (rischio relativo al grado di severit della patologia ed alla pluridistrettualit). Patologie gastrointestinali (Diverticolite o poliposi del colon, ulcera peptica con recenti segni di sanguinamento). Obesit patologica (peso corporeo >120% del peso ideale). Neoplasie in atto o recenti (alto rischio di recidiva entro i 5 anni dalla remissione, rischio minore se follow up >5 anni). Osteoporosi di grado avanzato. Disordini della sfera psichica di tipo affettivo o schizofrenico e pi in generale disturbi della personalit conpreso atteggiamenti di non compliance terapeutica. Abuso di sostanze voluttuarie (fumo di sigaretta attivo, alcol, stupefacenti). Assenza di supporto psico-sociale. Tabella 4: Cause di morte dei pazienti trapiantati secondo la ISHLT  Tabella 5  From Zaroff JG, Rosengard BR, Armstrong WF, Babcock WD, D'Alessandro A, Dec GW, Edwards NM, Higgins RS, Jeevanandum V, Kauffman M, Kirklin JK, Large SR, Marelli D, Peterson TS, Ring WS, Robbins RC, Russell SD, Taylor DO, Van Bakel A, Wallwork J, Young JB. Consensus Conference Report Maximizing Use of Organs Recovered From the Cadaver Donor: Cardiac Recommendations March 28-29, 2001, Crystal City, Va. Circulation 2002;106:836-841. Tabella 6 Fattori di rischio per decesso a 1 anno VARIABLENRelative RiskP-value95% Confidence IntervalTemporary circulatory support*523.38<0.00012.11-5.42Diagnosis: Congenital vs. cardiomyopathy1702.130.00011.47-3.10VAD (unknown type)571.990.02031.11-3.55Recipient history of insulin-dependent diabetes621.870.04241.02-3.41Recipient on ventilator at time of transplant2031.830.00011.36-2.46Recipient history of dialysis2171.560.001"A  7TKa!_ Z !!*!7!L!##n''''''''깮voo h2H5h:Zhhhh:ZmH sH h2H5h:Z5mH sH  h h:Z h%vh:Zh:ZmH sH hVh:ZmH sH h h:ZmH sH hIh:Z56mH sH  h&ih:Zhxh:Z6 h:Z6hh:Z6 h'Fh:Zh:Zh:Z6OJQJh*Ih:Z5+"AB W n'|49b=OQQS[\lw| $^a$gd:Z $ & Fa$gd:Z $`a$gd:Z$a$gd:Z $dha$gd:Z$a$gd:Z''%,,{4|444T7b79:b==lCCFFGGWGXGIIIRRS:TUT[W[\E\P\\]]]$]8]G]T]]]]]] ^^$^n^hM&h:Z6\ hZh:Z h:Z\hZh:Z\ hAh:Zh  h:ZH*hMih:ZH* h&ih:Zh.h:Z5h0h:Z5hgoh:Z6h:Zh:ZmH sH h:Zh:Z5mH sH  hO!h:Zh:Z h2H5h:Z3n^^^^^^___A`W`7a8a"b4b*\h ~h:Z\h<#h:Z6\ h:Z\h3h:Z\<|#~~Ԥդ֤Rb=Huy $ & Fa$gd:Z$a$gd:Z $`a$gd:Z $ & Fa$gd:Z $^a$gd:Z@DM^_;Cأ>֤KSU<5Rv6a"A -MN-Lvx.MXwRhDyh:ZH*h$h:Z56>* hPGh:ZhPh:Z6hw<h:Z5 h:Z5h hiMh:Z6 hn8h:Z h,Fh:Zhwh:Z6 h:Z6h:ZARq#-L% bq(Gf4o-=M[z}~w+,EdH_5T3Rrh ,=\6uchL#h:ZH* hAsh:Zh$h:Z56>* hch:Zh:Zh Tc9X`lmtby]|qMlHJ]yz8f z **...A>n>\D{D|OOh"L/h-5hh-56h<| hh-h-6OJQJhMhx6OJQJhh-56OJQJ^Jh:Z56OJQJ^Jh:Z56>*h$h:Z56>*h th:Z6h:Zhy=6y H]   e z yz{|~$a$gdy=gdy=dhgd- $dha$gdx $dha$gdM $`a$gd:Z $ & Fa$gd:Z*****...@>n>CCC[D{D|DzO|OOOORRT$a$gd"L/$a$gd- $dha$gdM$a$gdM $dha$gd-$a$gdy=OOOOOOPPPPRGR^RRRRRRRRS5S6S:SES[SgSzS T4T;TcTrT{TTTTTTTTTTTTTT2UXUUUU'V(VVVVVVVVVW̵ԱԱԱԩ̥̥ԥԝhah6h1hO|h&h'P hlh9hhLhUhBhSh|.h9hR>h_hdhYh@l hM5hM6OJQJ h_5=T(V7W]Y&Zt[^-^`EaFaHaabcc'd9dUdZfhMilm$a$gd $ & Fa$gdb $h^ha$gdWd$a$gdiS$a$gd9@$a$gd"L/W6W7WpWtWWWWXXX^XXXXXXXXXXRYXY\Y]YYYY!Z"Z#Z$Z%Z&Z2ZOZSZUZ]ZZZZ[*[J[X[t[[[[[[[[[[[[𱥡𙥙h8hmhL?5h-h9hh3ShJhyh(9huh9@ hQzhyX hQzh1hyX hQzh9@ hQzhQz hQzh/hRh1h6hah/9[\\\\Q]R]S]\]]]j]s]]]]]]^^^^^,^-^V^_^{^^^u_________`.`U`\`]```````DaEaFaHaƹ hWd5hhHvhdhh_h\-h: hlhiShl56OJQJ^JhiS56OJQJ^Jhv#56OJQJ^JhY56OJQJ^Jh9h hCh hQvwh8hqhT=C4Haaa*bIbbb c|cc9dUdJee=f>fYfZfxfzfffffffffgsgg+h5ht?tOtYtZt[t\tltvtwttt u!uKujuruvvv۾۶۶۲›ێhnfBh h6 hiS56hRFh$~hhdhp*hh#hhw 9hiShiS56 hThThThhiSh- h5h/h5 hS}5 hb5 hw 958vvvvw0wxy#y)yEyhyjysytyuyvywy4{9{:{F{G{M{||||}}~~~R~s~t~~~~~~~~5QRS  0(Ľ hr^h(9h(9 hr^hr^ hr^hThr^hbhA h! hA hA  h 356hiSh 356hl jh 3hzh1Lh6Wh 3hhThnfBhiS:(nr;<=@KlmŅ[eqhňmn F h"6hoho6h"h h1ehoh8>?hj~Y h/Jhh>h3h>hP4hX" hL<5h/hS}5 hS}5 hnY(5hb hbhbhbhb56h 3hMh}XhihT2nF~0rƐj-͞-:xv:c$a$gdr$a$gdKz$a$gdW׌#$0GHPr hȔ͗Q]sDEzWgij8ucs ,ZžϺϮޮh6$VhKRhh6hhh -h h)F56h)Fh)F56h)FhR. hR.huPh8>?h:h)FhuP56huPhoh hl>Z[\|˞̞͞$ 3"!(:RwxF{#Il(9ͺͯͨ~y~ hDZ}\ hKz\ h~\hKzhKz\hKzh:QhWYhWY6hq&hWY hWY56hvg h=Rh=R h=R56h=h=Rh=R6h=RhJa hJa56hv9\h ph p6h ph6$VhhqJh8>?h^,9:`ab  ¶öĶŶK[\{ڹ۹Կzvrvnvjfjfj_ h*ahcnhhcnh 'hQh*a h 5 h+5 hY5hiShL<56OJQJ^J h)FhL<hL<56OJQJ^Jhr56OJQJ^J hL<5 h=R56 hrhr hr56h=Rh=R56 hWYhrhrh|hvgh)h:Q hKzhKz%¶\۹%&')l1$a$gd|q$a$gdcn$a$gd*a $ & Fa$gdL<$a$gdL<$a$gdPS$a$gdW$a$gdr۹̺$%JQ 4:%&'()ltf9A>cdxyĪĢh;h/h[~h h!h h2ChQ=h4h0:56hS}h+=h-h0: hL<5 h15 h 5 h+5h+hhcnh=hQh '6hQh%Eh '8z01z5`s=U u|  #{yUsu ÿh}X5mH sH hCqhiohWhthz3h69 hz356 h h h h;huhhh!hlheha h0:B1;@U kUv  %\  $ & Fa$gd:Z $h^ha$gd:Z$a$gd}X$a$gdz3$a$gdW%^  /@\yOdk޸ϧϧϧϧϧϜϜϧτyh:Zh:ZCJaJh;]h:ZCJaJh:gh:Z0JCJaJh:gh:ZCJaJ h:gh:Z0JCJaJmH sH h:gh:ZmH sH h:ZCJaJmH sH h:gh:ZCJaJmH sH h:gh:Z6CJaJmH sH h:Zh:Z6hr|5mH sH *k  _a=c!QRV_`ʺ٩ٺٚٚzjajzjYTY h9D6h:Zh:Z6h!A6CJaJh!Ah!A6CJaJmH sH h!Ah!ACJaJmH sH h!Ah!A6CJaJ h:Z6h:gh:ZCJaJmHsH h:gh:Z0JCJaJmH sH h:gh:Z6CJaJmH sH h:Zh:ZCJaJmH sH h:gh:ZCJaJmH sH h:Zh:ZCJaJh:Zh:Z0JCJaJQRSTUV`|BX $ & Fa$gd? 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Tabella 8 Schemi di immunosoppressione SchemaDose iniziale CSADose iniziale Antiproliferativo AZA/MMF/EVEI-VI meseVI-XII meseDopo 1annoSospensione CortisoniciCSA/AZA3 mg/Kg1-4 mg/kg250-350200-300150-250RARACSA/MMF3 mg/Kg1-3 g/die250-350200-300150-250FrequenteCSA/EVE (o RAPA)3 mg/Kg0,01-0,02 mg/kg150-250100-20080-150FrequenteTAC/AZA0,1 mg/Kg1-4 mg/kg10-205-155-10FrequenteTAC/MMF0,1 mg/Kg1-3 g/die8-155-105-10ComuneTAC/EVE (o RAPA)0,1 mg/Kg0,01-0,02 mg/kg5-155-105-10? Tabella 9 Incidenza di complicanze non immunologiche ad 1 anno, 5 e 10 anni OutcomeWithin 1 YearWithin 5 YearsWithin 10 YearsHypertension74.4%93.8%98.5%Renal Dysfunction30.4%32.6%38.7% Abnormal Creatinine < 2.5 mg/dl22.4%21.2%24.4% Creatinine > 2.5 mg/dl5.9%8.4%8.2% Chronic Dialysis1.6%2.5%4.9% Renal Transplant0.4%0.5%1.2%Hyperlipidemia67.8%87.1%93.3%Diabetes31.5%34.8%36.7%Cardiac Allograft Vasculopathy7.1%31.5%52.7% Tabella 10 Caratteristiche comparative della CAV dalla aterosclerosi.  Fig Xa. Effetto del matching donatore ricevente sul ricevente giovane.  EMBED PowerPoint.Slide.8  Fig Xb. Effetto del matching donatore ricevente sul ricevente anziano.  EMBED PowerPoint.Slide.8  Fig Xa. Curva di sopravvivenza del trapianto di cuore.  EMBED PowerPoint.Slide.8  Fig Xb. Curva di sopravvivenza del trapianto di cuore. Stratificazione per Era.  EMBED PowerPoint.Slide.8  Fig X Tecnica della Biopsia endomiocardica.  SHAPE \* MERGEFORMAT  Fig. X Trend temporale del rigetto acuto.  EMBED PowerPoint.Slide.8  Fig X Decorso temporale della aterosclerosi e della CAV a confronto.  Fig. XCaratteristiche comparative della CAV dalla aterosclerosi.  Fig X Patogenesi della CAV  Fig X Fattori di rischio della cancerogenesi nel trapianto di cuore.  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