Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Oct 26, 2019; 11(10): 831-858
Published online Oct 26, 2019. doi: 10.4252/wjsc.v11.i10.831
Unmodified autologous stem cells at point of care for chronic myocardial infarction
Alexander Haenel, Mohamad Ghosn, Tahereh Karimi, Jody Vykoukal, Dipan Shah, Miguel Valderrabano, Daryl G Schulz, Albert Raizner, Christoph Schmitz, Eckhard U Alt
Alexander Haenel, Tahereh Karimi, Eckhard U Alt, Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, United States
Alexander Haenel, Daryl G Schulz, Eckhard U Alt, The Methodist Hospital Research Institute, Houston, TX 77030, United States
Alexander Haenel, Department of Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, Lübeck D-23562, Germany
Mohamad Ghosn, Dipan Shah, Miguel Valderrabano, Albert Raizner, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, United States
Jody Vykoukal, Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, United States
Christoph Schmitz, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich D-80336, Germany
Eckhard U Alt, Isar Klinikum Munich, Munich D-80331, Germany
Author contributions: Raizner A and Alt EU substantially contributed to conception and design of the study; Haenel A, Ghosn M, Karimi T, Vykoukal J, Shah D, Valderrabano M, Schulz DG, Raizner A and Alt EU substantially contributed to acquisition of data; Haenel A, Ghosn M, Karimi T, Vykoukal J, Shah D, Schulz DG, Raizner A, Schmitz C and Alt EU substantially contributed to analysis and interpretation of data; Haenel A, Schmitz C and Alt EU drafted the article; Haenel A, Raizner A, Schmitz C and Alt EU made critical revisions related to important intellectual content of the manuscript; All authors approved the version of the article to be published.
Supported by Alliance of Cardiovascular Researchers (New Orleans, LA 70102, United States), No. 2013-AH-01 (to Haenel A)
Institutional review board statement: This study was approved by the Institutional Review Board of Houston Methodist Hospital (Houston, TX, United States).
Institutional animal care and use committee statement: The animal use protocol has been reviewed and approved by the Institutional Animal Care and Use Committee at Houston Methodist Hospital (Houston, TX, United States) (AUP-0910-0019).
Conflict-of-interest statement: Schmitz C has served as consultant of SciCoTec (Grünwald, Germany), the principal shareholder of InGeneron, Inc. (Houston, TX, United States). Alt EU is Chairman of the Board of Isar Klinikum and of InGeneron, Inc.
Data sharing statement: Requests for access to data should be addressed to the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Eckhard U Alt, MD, PhD, Professor of Medicine, Heart and Vascular Institute, Department of Medicine, Tulane University, Health Science Center, 1340 Tulane Ave., New Orleans, LA 70112, United States.
Telephone: +1-504-9883040
Received: February 18, 2019
Peer-review started: February 20, 2019
First decision: April 15, 2019
Revised: June 5, 2019
Accepted: August 26, 2019
Article in press: August 26, 2019
Published online: October 26, 2019
Research background

Cardiovascular diseases substantially contribute to morbidity and mortality worldwide. Myocardial infarction (MI) is one of the most common consequences of ischemic heart disease. Advanced medical treatments and device-based therapies have substantially improved the survival of patients with MI. However, these therapies can only rescue the remaining viable myocardial tissue within the damaged heart, but cannot replace lost myocardium. Accordingly, numerous studies have investigated cell-based therapies for MI. The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI.

Research motivation

Experimental studies on animal models (performed by ourselves and others) demonstrated the potential of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) for treating acute MI. In contrast, studies on the treatment of chronic MI (CMI; > 4 wk post-MI) with UA-ADRCs have not been published thus far. Our promising results from treating a porcine model with UA-ADRCs for the study of acute MI (Int J Cardiol 2010; 144: 26-35) motivated us to investigate the effectiveness and safety of UA-ADRCs for treating CMI in a porcine model. Besides this, as one of several methods for delivering cells to the myocardium, retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated to be an effective option.

Research objectives

Our study aimed to test (in a porcine model for the study of CMI) the following hypotheses: (1) Occlusion of the left anterior descending (LAD) coronary artery for three hours results in a clinically relevant reduction of the left ventricular ejection fraction (LVEF) to less than 40% on an average of 4 wk post-MI (demonstrating significance of the used animal model); (2) Delivery of UA-ADRCs into the LAD vein 4 wk post-MI in this model leads to improved LVEF by more than 15% (relative change) on an average of 10 wk post-MI (primary objective of this study); and (3) The same animal model shows improvements in cardiac structure 6 wk after the delivery of UA-ADRCs (i.e. 10 wk post-MI) (secondary objective of this study).

Research methods

The LAD coronary artery of pigs was blocked for 180 min at time point T0. Then, either 18×106 UA-ADRCs prepared at “point of care” or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0 (T1). Effects of cells or saline were assessed by cardiac magnetic resonance (CMR) imaging, late gadolinium enhancement CMR imaging and post mortem histologic analysis 10 wk after T0 (T2).

Research results

Unlike the delivery of saline, the delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1: increased mean LVEF (UA-ADRCs group: +18%; saline group: -4.2%), increased mean cardiac output (UA-ADRCs group: +41%; saline group: +5.9%), increased mean mass of the left ventricle (UA-ADRCs group: +29%; saline group: +8.2%) and reduced mean relative amount of scar volume of the left ventricular wall (UA-ADRCs group: -21%; saline group: +29%).

Research conclusions

The present study indicates that delivery of UA-ADRCs by a balloon-blocked retrograde venous injection 4 wk after MI is effective, producing a significant increase in cardiac output and significant reduction in the relative amount of scar volume of the left ventricular wall, without adverse effects occurring during the observation period.

Research perspectives

Our results justify the evaluation of a new combination of UA-ADRCs (including the isolation procedure), dose, delivery route and timing presented here in future clinical trials for treating CMI under strict criteria, as recently suggested by the European Society of Cardiology Working Group Cellular Biology of the Heart (Eur Heart J 2016; 37: 1789-1798), which includes the use of CMR imaging and clinically-relevant endpoints.