title: Safety, feasibility and effectiveness of first in-human administration of muscle-derived stem/progenitor cells modified with connexin-43 gene for treatment of advanced chronic heart failure.
abstract: To assess the safety and efficacy of transendocardial delivery of muscle-derived stem/progenitor cells with connexin-43 overexpression (Cx-43-MDS/PC) in advanced heart failure (HF).
  
  
  
  Thirteen subjects with advanced HF, New York Heart Association (NYHA) class II-III were enrolled and treated with targeted injection of Cx-43-MDS/PCs and then monitored for at least 6 months. Overexpression of Cx43 (Cx43+) was significantly higher in all but one subject (Cx43-). Injection of MDS/PCs was associated with significant improvement of exercise capacity: NYHA (3 ± 0 vs. 1.8 ± 0.7, P = 0.003), exercise duration (388.69 ± 141.83 s vs. 462.08 ± 176.69 s, P = 0.025), peak oxygen consumption (14.38 ± 3.97 vs. 15.83 ± 3.74 ml/kg.min, P = 0.022) and oxygen pulse (10.58 ± 2.89 vs. 18.88 ± 22.63 mLO2/heart rate, P = 0.012). Levels of BNP, left ventricular (LV) ejection fraction and LV end-diastolic volumes tended to improve. There was a significant improvement of the mean unipolar voltage amplitudes measured for the injected segments and the entire left ventricle (9.62 ± 2.64 vs. 11.62 ± 3.50 mV, P = 0.014 and 8.83 ± 2.80 vs. 10.22 ± 3.41 mV, P = 0.041, respectively). No deaths were documented, Cx43+ (n = 12) subjects presented no significant ventricular arrhythmia; one Cx43- subject suffered from ventricular tachycardia (successfully treated with amiodarone).
  
  
  
  Injection of Cx-43-MDS/PCs in patients with severe HF led to significant improvement in exercise capacity and myocardial viability of the injected segments while inducing no significant ventricular arrhythmia. This may arise from improved electrical coupling of the injected cells and injured myocardium and thus better in-situ mechanical cooperation of both cell types. Therefore, further clinical studies with Cx43+ MDS/PCs are warranted.
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gwizdala
authors.affiliation: Department of Reproductive Biology and Stem Cells, Institute of Human Genetics Polish Academy of Sciences, ul. Strzeszynska 32, 60-479, Poznan, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rozwadowska
authors.affiliation: Department of Reproductive Biology and Stem Cells, Institute of Human Genetics Polish Academy of Sciences, ul. Strzeszynska 32, 60-479, Poznan, Poland.
authors.forename: Tomasz Jan
authors.initials: TJ
authors.lastname: Kolanowski
authors.affiliation: Department of Reproductive Biology and Stem Cells, Institute of Human Genetics Polish Academy of Sciences, ul. Strzeszynska 32, 60-479, Poznan, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Malcher
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Cieplucha
authors.affiliation: Poznan University of Medical Sciences, Department of Cardiac Surgery, Poznan, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Perek
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Seniuk
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Straburzynska-Migaj
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Oko-Sarnowska
authors.affiliation: Greater Poland Cancer Centre, Nuclear Medicine Department, Poznan, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Cholewinski
authors.affiliation: Poznan University of Medical Sciences, Department of Statistics, Poznan, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Michalak
authors.affiliation: Poznan University of Medical Sciences, 1st Department of Cardiology, Poznan, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grajek
authors.affiliation: Department of Reproductive Biology and Stem Cells, Institute of Human Genetics Polish Academy of Sciences, ul. Strzeszynska 32, 60-479, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kurpisz
mesh_terms: D000368:Aged; D018929:Cell Culture Techniques; D002908:Chronic Disease; D018031:Connexin 43 / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology*; D032446:Myoblasts / Q000637:transplantation*; D009206:Myocardium; D010865:Pilot Projects; D011446:Prospective Studies; D012038:Regeneration; D012720:Severity of Illness Index; D033581:Stem Cell Transplantation / Q000379:methods*; D014162:Transfection; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human
keywords: Connexin-43; Heart failure; Muscle-derived stem cells; Transendocardial injection