title: Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
abstract: Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.
authors: Dipartimento di Biologia Evolutiva e Funzionale, Università di Parma, Parma, Italy.
authors: Leonardo
authors: L
authors: Bocchi
authors: Monia
authors: M
authors: Savi
authors: Gallia
authors: G
authors: Graiani
authors: Stefano
authors: S
authors: Rossi
authors: Aldo
authors: A
authors: Agnetti
authors: Francesca
authors: F
authors: Stillitano
authors: Costanza
authors: C
authors: Lagrasta
authors: Silvana
authors: S
authors: Baruffi
authors: Roberta
authors: R
authors: Berni
authors: Caterina
authors: C
authors: Frati
authors: Mario
authors: M
authors: Vassalle
authors: Umberto
authors: U
authors: Squarcia
authors: Elisabetta
authors: E
authors: Cerbai
authors: Emilio
authors: E
authors: Macchi
authors: Donatella
authors: D
authors: Stilli
authors: Federico
authors: F
authors: Quaini
authors: Ezio
authors: E
authors: Musso
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004562:Electrocardiography; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins