Published online Oct 26, 2019. doi: 10.4252/wjsc.v11.i10.831
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
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.
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.
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).
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).
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%).
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.
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.