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Rigato, Mauro (2018) CIRCULATING PROGENITOR CELLS: A NOVEL BIOMARKER OF MICROVASCULAR AND MACROVASCULAR DISEASE IN TYPE 2 DIABETIC PATIENTS. [Ph.D. thesis]

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Abstract (english)

Objective. We evaluated the ability of circulating stem cell levels to predict future micro and macrovascular complications in patients with type 2 diabetes. We further investigate the prognostic value of stem cells in a wide and heterogeneous cohort of patients, using a meta-analytic approach.
Research design and methods. A cohort of 187 patients with type 2 diabetes was followed-up for a median of 3.3 years and 6.1 years for the evaluation of microvascular and macrovascular outcomes, respectively. The primary outcomes were onset or progression of any microangiopathy, and time to a first cardiovascular event. In addition, we meta-analysed all studies reporting the prognostic role of the CPC/EPC measure on cardiovascular outcomes and death in a heterogeneous population of 4451 patients at high cardiovascular risk.
Results. New onset or progression of microangiopathy occurred in 70 patients (9.5% per year). After controlling the false discovery rate (FDR), baseline CD34+ CPCs and EPCs were significantly lower in patients with onset/progression of microalbuminuria and any microangiopathy. Patients with baseline CD34+ CPC or CD133+KDR+ EPC levels below median were more likely to experience worsening microangiopathy than those with high cell levels. In FDR-fully-adjusted analysis, CD34+ cells predicted onset/progression of microalbuminuria, retinopathy, and any microangiopathy. A first cardiovascular event occurred in 48 patients (4.5% per year). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Patients with below median levels of CD34+ and CD34+CD133+ cells experienced higher rates of cardiovascular events. In Cox proportional hazard regression analyses, a reduced CD34+ and CD34+CD133+ cell count independently predicted future events. Addition of the CD34+ cell count to the UKPDS risk engine model improved C-statistics, continuous NRI and/or IDI. In the meta-analysis, reduced CPC/EPC levels were associated with a ~2 fold increased risk of future cardiovascular events and cardiovascular death and the most predictive phenotypes were CD34+ and CD34+CD133+.
Conclusions. In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts worsening of microangiopathy and cardiovascular events up to 6 years later, and improves risk stratification. The meta-analysis suggests that prognostic impact of reduced stem cell levels was similar in diabetic and non-diabetic patients.

Abstract (italian)

Obiettivi. Il presente studio è stato finalizzato a valutare l’abilità delle cellule progenitrici endoteliali nel predire le complicanze croniche micro a macro-vascolari dei pazienti affetti da diabete mellito di tipo 2.
Metodi. Una coorte di 187 pazienti affetti da diabete di tipo 2 è stata seguita durante un follow-up mediano di 3.3 e 6.1 anni per la valutazione delle complicanze micro e macro-vascolari, rispettivamente. L’outcome primario era rappresentato dalla nuova insorgenza o dalla progressione di una qualsiasi forma di microangiopatia o dal tempo al primo evento cardiovascolare (CV). Inoltre, abbiamo meta-analizzato tutti gli studi che riportavano il ruolo prognostico dei livelli di CPC/EPC nel predire lo sviluppo di eventi CV o la morte, in una coorte eterogenea di 4451 pazienti ad alto rischio CV.
Risultati. Settanta pazienti hanno sperimentato l’insorgenza o la progressione della microangiopatia (9.5% per anno). Dopo l’aggiustamento per il false discovery rate (FDR), il livello basale di CD34+ CPCs e di EPCs era significativamente inferiore nei pazienti che andavano incontro ad insorgenza o progressione di microalbuminuria o dell’end point composito di una qualsiasi forma di microangiopatia. I pazienti con valori basali di CD34+ CPC o CD133+KDR+ EPC inferiori alla mediana presentavano un rischio più elevato di peggioramento della microangiopatia, rispetto a quelli con valori più elevati di cellule. Nell’analisi statistica multivariata, i livelli di CD34+ erano in grado di predire lo sviluppo/progressione di microalbuminuria, retinopatia e dell’end point costituito da una qualsiasi forma di microangiopatia. Quarantotto pazienti hanno sviluppato un evento CV durante il periodo di follow-up (4.5% per anno). I pazienti con evento CV avevano livelli di cellule CD34+ e CD34+CD133+ significativamente più bassi rispetto ai pazienti senza eventi. I pazienti con livelli basali di CD34+ e CD34+CD133+ inferiori al valore mediano, presentavano un maggior rischio di eventi CV. Nell’analisi di sopravvivenza di Cox, un ridotto numero di CD34+ e CD34+CD133+ rappresentava un predittore indipendente di futuri eventi CV. L’inserimento dei livelli di CD34+ all’interno dell’UKPDS risk engine model, migliorava significativamente la capacità predittiva del modello. Nella meta-analisi, un ridotto livello di CPC/EPC era associato ad un raddoppio del rischio di sviluppare futuri eventi CV e di morte CV, e i fenotipi cellulari maggiormente predittivi erano il CD34+ e il CD34+CD133+.
Conclusioni. Nei pazienti con diabete mellito di tipo 2, un ridotto livello basale di cellule progenitrici CD34+, è in grado di predire a lungo termine la progressione della microangiopatia e lo sviluppo di eventi CV. La meta-analisi suggerisce che l’impatto prognostico del ridotto numero di cellule progenitrici sembra essere simile nei pazienti diabetici e non diabetici.

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EPrint type:Ph.D. thesis
Tutor:Avogaro, Angelo
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA SPECIALISTICA "G.B. MORGAGNI"
Data di deposito della tesi:11 January 2018
Anno di Pubblicazione:05 January 2018
Key Words:progenitor cell, cardiovascular disease, microangiopathy, diabetes
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/13 Endocrinologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:10687
Depositato il:15 Nov 2018 12:31
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