Document Detail


Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction.
MedLine Citation:
PMID:  21445273     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Leonardo Bocchi; Monia Savi; Gallia Graiani; Stefano Rossi; Aldo Agnetti; Francesca Stillitano; Costanza Lagrasta; Silvana Baruffi; Roberta Berni; Caterina Frati; Mario Vassalle; Umberto Squarcia; Elisabetta Cerbai; Emilio Macchi; Donatella Stilli; Federico Quaini; Ezio Musso
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-18
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-03-29     Completed Date:  2011-08-02     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e17750     Citation Subset:  IM    
Affiliation:
Dipartimento di Biologia Evolutiva e Funzionale, Università di Parma, Parma, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / etiology,  physiopathology,  prevention & control*
Disease Models, Animal*
Electrocardiography
Immunohistochemistry
Intercellular Signaling Peptides and Proteins / pharmacology*
Male
Myocardial Infarction / complications*,  physiopathology
Myocardium / cytology*
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells / cytology*
Chemical
Reg. No./Substance:
0/Intercellular Signaling Peptides and Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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