Numerose evidenze dimostrano che il GLP-1 e i suoi analoghi hanno effetti benefici sulla pressione arteriosa, sul profilo lipidico e sul peso corporeo, che rappresenta-no tre tra i più importanti fattori di rischio cardiovasco-lare. È stato anche osservato che il GLP-1 e le molecole GLP-1-mimetiche possono migliorare i livelli di biomar-catori dell’infiammazione, contribuendo verosimilmen-te ad un profilo di espressione genica più favorevole a livello endoteliale(48). Anche in studi in vivo, condotti in soggetti con danno metabolico e vascolare (pazienti diabetici con coronaropatia documentata), l’infusione di GLP-1 ha migliorato l’attività contrattile dell’endo-telio, come dimostrato dall’aumento della dilatazione flusso-mediata (FMD), un importante indicatore della funzionalità endoteliale(49).
Di particolare interesse - per le potenziali ricadute fi-siopatologiche e terapeutiche – sono gli effetti diretti del GLP-1 sul miocardio. I recettori per il GLP-1 sono dimo-strabili e funzionali su tutte le cellule presenti nei tessu-ti cardiaci (miocardiocitessu-ti, cellule endocardiche, cellule endoteliali), sia nell’animale sperimentale, sia nell’uo-mo(48). La ablazione del recettore per il GLP-1 attraverso tecniche di ingegneria genetica nel topo si associa ad anomalie strutturali e funzionali del cuore(50). Per con-verso, è stata osservata una migliore resistenza al dan-no ischemico e una più prolungata sopravvivenza negli animali in cui i livelli circolanti di GLP-1 vengono au-mentati mediante l’inattivazione degli enzimi respon-sabili del catabolismo del GLP-1, a sottolineare il ruolo importante che questo ormone gioca fisiologicamente nello sviluppo e nella maturazione delle strutture car-diache(51). Nell’animale studiato in vivo, il GLP-1 agisce proteggendo direttamente le strutture cardiache: se si induce un infarto sperimentale, nell’animale pre-tratta-to con GLP-1 l’area dell’infarpre-tratta-to è più piccola rispetpre-tratta-to al non pre-trattato(52). Anche il trattamento con analoghi del GLP-1, in studi sperimentali su animali in cui viene indotta una ischemia coronarica, ha determinato una
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riduzione significativa dell’area infartuale e soprattutto un miglioramento della sopravvivenza dell’animale, sia rispetto al placebo sia rispetto ad altri farmaci ipoglice-mizzanti(53,54).
Questi effetti possono essere traslati sull’uomo? Non vi è ancora una risposta definitiva, ma alcuni stu-di pilota suggeriscono che l’attivazione del sistema del GLP-1 può effettivamente avere degli effetti benefici. Ad esempio, il trattamento con analoghi del GLP-1 in soggetti con scompenso cardiaco cronico migliora la fra-zione di eiefra-zione e le capacità contrattili del ventricolo sinistro(55), e tale effetto si osserva anche in pazienti con infarto recente e disfunzione ventricolare sinistra(56) (Fi-gura 1). Questa azione è rapida e diretta sulla cellula, non mediata da azioni metaboliche. Anche per gli ini-bitori della DPP-4 esistono evidenze di un potenziale effetto protettivo sulla funzione cardiaca nell’uomo. Ad esempio, in soggetti con cardiopatia ischemica è stato osservato che la somministrazione di una singola dose di sitaglitin si associa al miglioramento della perfor-mance del ventricolo sinistro, misurata con il test alla dobutamina(57). Inoltre, l’inibizione dell’enzima DPP-4 sembra modulare la mobilizzazione delle cellule pro-genitrici endoteliali, che giocano un ruolo importante nei processi di omeostasi e rigenerazione vascolare(58). Infine, una prospettiva recentissima, documentata per ora solo da studi sperimentali in vitro, suggerisce che il GLP-1 possa agire sulle cellule del miocardio proteg-gendole dall’apoptosi indotta da condizioni metabo-liche avverse(59). In conclusione, il GLP-1 mostra una serie di effetti cardioprotettivi, che sono legati da un lato agli effetti di miglioramento dei fattori di rischio cardiovascolare (glicemia, peso corporeo, pressione ar-teriosa, infiammazione), dall’altro a effetti biologici di-retti sulla funzione delle cellule endoteliali e verosimil-mente anche sulla performance e vitalità delle cellule
miocardiche. L’approfondimento sperimentale e clinico di queste risposte biologiche può aprire nuove vie nella prevenzione e gestione del rischio cardiovascolare nella persona con diabete tipo 2.
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