Yonsei Med J.  2007 Oct;48(5):754-764. 10.3349/ymj.2007.48.5.754.

Bone Marrow Mononuclear Stem Cells Transplanted in Rat Infarct Myocardium Improved the Electrical Conduction without Evidence of Proarrhythmic Effects

• Joung B
• Kim IK
• Lee MH
• Yoo KJ
• Kim SS

• KMID: 1122611
• DOI: http://doi.org/10.3349/ymj.2007.48.5.754

Abstract

PURPOSE: The arrhythmogenic effect of stem cells transplantation (SCT) in an infarct myocardium is still unknown. We investigated arrhythmogenicity of SCT in rat cryo-infarct model. MATERIALS AND METHODS: In rat cryo-infarct model, bone marrow mononuclear stem cells (MNSC, 1 x 10(7) cells) were transplanted into the infarct border zone (BZ) of the LV epicardium. We compared the optical mapping and inducibility of ventricular tachycardia/fibrillation (VT/VF) among normal (n=5), cryo-infarct (n=6), and SCT rats (n=6). RESULTS: The VT/VF inducibility was higher in the cryo- infarct (47.2%, p=0.001) and SCT groups (34.6%, p=0.01) than in the normal group (12.8%). The induced VT/VF episodes persisted for more than 2 minutes in 4.3%, 26.4% and 17.3% in the normal, cryo-infarct and SCT group, respectively. In the SCT group, the action potential duration at 70% was shorter at the SCT site than the BZ during SR (75.2 +/- 8.1 vs. 145.6 +/- 4.4 ms, p=0.001) and VT (78.2 +/- 13.0 vs. 125.7 +/- 21.0 ms, p= 0.001). Conduction block was observed at the SCT site and BZ during VT. However, no reentry or ectopic foci were observed around the SCT sites. CONCLUSION: The electrical conduction was improved by SCT without evidence of augmentation of arrhythmia in the rat cryo-infarct model.

Keyword

Arrhythmogenicity; stem cell; optical mapping

MeSH Terms

Action Potentials
Animals
Arrhythmias, Cardiac/*etiology
Bone Marrow Transplantation/*adverse effects
Disease Models, Animal
Electric Conductivity
Heart Ventricles/pathology/transplantation
Hematopoietic Stem Cell Transplantation/*adverse effects
Myocardial Infarction/pathology/*surgery
Rats
Rats, Sprague-Dawley

Figure

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  Fig. 1 Comparison of the ventricular tachycardia or fibrillation (VT/VF) inducibility between the control, cryo-injury, and stem cell transplantation (SCT) groups. SCT indicates stem cell transplantation group. The inducibility of VT/VF was 12.8%, 34.6%, and 47.2% in control, cryoinjury, and stem cell transplantation group, respectively. Cryoinjury and STC group had higher VT/VF inducibility than control (p = 0.01).

• 

  Fig. 2 Optical mapping of the control rat hearts during normal sinus rhythm (B and D) and ventricular fibrillation (C and E). (A) Optical mapping was recorded from the epicardium of the left ventricle (box). The numbers 1 to 3 represent the sites where the optical signals were taken. (B and C) Pseudo color membrane voltage maps at certain times are presented. (D and E) Optical signals were recorded from sites 1 to 3. During sinus rhythm, the depolarization was initiated from the mid-LV (site 2) and spread to the rest of the heart (sites 1 and 3). During VF, multiple wavefronts meandered over the entire heart during VF with amorphorous optical signals recorded from sites 1 to 3.

• 

  Fig. 3 Optical mapping of cryo-infarct rat hearts during normal sinus rhythm (B and D) and ventricular fibrillation (C and E). (A) Optical mapping was recorded from the epicardium of the LV (box). The numbers 1 to 4 represent the sites where optical signals were taken. Sites 1 and 2 are normal myocardium, 3 a border zone, and 4 a cryo-infarct. (B and C) Pseudo color membrane voltage maps at certain times are presented. Depolarization was initiated from the mid-LV (site 2), and spread to the normal myocardium (site 1, 544 ms) and then to the border zone (site 3,564 ms). (D and E) Optical signals recorded from sites 1 to 4. During sinus rhythm, depolarization was initiated from the mid-LV (site 2) and spread to the rest of the heart (sites 1 and 3). However, no depolarization was observed in the cryo-infarct (site 4). During VF, amorphorous waves are observed in the normal myocardium and border zone (sites 1 to 3) but not in the cryo-infarct (site 4).

• 

  Fig. 4 Optical mapping of a cryo-infarct in stem cell transplanted rat hearts during normal sinus rhythm (B and D) and ventricular fibrillation (C and E). (A) Optical mapping was recorded on the anterior LV including the SCT site (Box). The numbers 1 to 3 represent the sites where optical signals were recorded. (B and C) Pseudo color membrane voltage maps at certain times are presented. (D and E) Optical signals were recorded from sites 1 (normal zone), 2 (stem cell transplanted site), and 3 (border zone) as marked in the first sub-panel of panels B and C (asterisk). The ventricular tachycardia terminated spontaneously.

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  Fig. 5 Microscopic appearance of a cryo-infarct in a stem cell transplanted rat heart (Fig. 4). (A) H & E staining revealed cells in the mononuclear stem cell implant site. (B) Magnified view of the box in A. The stem cell transplant site had a higher density of cells (arrow). (C) With Masson Trichrome staining, a huge amount of fibrosis was observed from 1 to 6 o'clock along the left ventricle after the cryo-infarction (blue color). The stem cell transplant site had a brown color (box). (D) Magnified view of the box in C. The stem cell transplant site had less fibrosis (brown color, arrow).

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  Fig. 6 Differentiation of transplanted MNSCs into cardiomyocytes. MNSCs transplanted in infarct border zone showed rich viable cells (blue color in A). Transplanted MNSCs were engrafted in the myocardium and stained for cardiac troponin I. Troponin I positive cells are presented with red color in B, green color in C, and yellow color in D.

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