Pre-Operative Cytokine-Induced Mobilization of Bone Marrow-Derived Cells, Followed by Revascularization Surgery: Early and Long-Term Results of a Prospective Study in Patients with End-Stage Ischemic Cardiac Disease
Authors: Dato Guglielmo M Actis , Sansone Fabrizio , Zingarelli Edoardo , Flocco Roberto , Punta Giuseppe , Parisi Francesco , Forsennati Pier Giuseppe , Bardi Gian Luca , del Ponte Stefano , Casabona Riccardo , Tarella Corrado 
Published: October 2019

Abstract
Abstract 318
Introduction Coronary artery disease (CAD), along with its main complications, acute myocardial infarction (AMI) and congestive heart failure (CHF), remains a serious worldwide problem. Despite advances in medical and surgical treatments, CAD is still associated with a high mortality rate and markedly affects the quality of life of patients. The possibility to replace the scarring by inducing neoangiogenesis and possibly regeneration of injured myocardium is an attractive option to improve the prognosis of CAD patients. For this purpose, cytokine-induced mobilization of bone marrow stem cells (BMCs) into the peripheral blood might represents a potential pathway to activate the regenerative process. Some observations suggest that circulating BMCs may lodge in non-hematopoietic tissues such as muscle, liver and myocardium where the tissue injury or the local inflammation may promote stem cells migration. Thus, the association between cytokine induced BMCs migration and tissue injury, may induce tissue repair since the stem cells are usually attracted from the inflamed tissues. A phase II prospective study was performed combining BMCs migration, obtained by cytokines, and cardiac inflammation, induced by myocardial punctures. Results at early and long-term follow-up are here reported. Patients and methods BMCs mobilization was performed in 15 patients undergoing surgery for coronary artery bypass grafting (CABG) and/or mitral valve surgery and/or ventricular remodeling combined to multiple trans-myocardial punctures (Sen technique) in ungraftable non-viable fibrotic areas. BMC mobilization was induced by granulocyte colony stimulating factor (G-CSF) (Lenogastrim) given at 5 μgr/kg s.c. b.i.d. for 5 to 6 consecutive days, starting on day-3 before surgery along with granulocyte-macrophage colony stimulating factor (GM-CSF) (Molgramostim) at 2.5 μgr/kg s.c./day. Patients entered the study protocol on the basis of the following inclusion criteria: i. severe heart failure with left ventricular ejection fraction (EF) < 35%; ii. ineligibility to cardiac transplantation; iii. widespread myocardial ischemia with at least one area of akinetic and nonviable myocardium, detected by cardiac stress scintigraphy with Thallium; iv. presence of other combined surgical indications, including the requirement of surgery for CABG on areas other than nonviable scars; v. one or more previous myocardial infarction. The study protocol was approved by our local Institutional Review Board and Ethics Committee and all patients signed the informed written consent. Results Cytokine administration induced a variable increase in circulating CD34+ve cells in all patients, with peak values recorded between day +4 and day +6. There were no in hospital (0–30 days) deaths. All 15 patients were discharged from the ICU after a median of 2 days, while the overall in hospital stay was 10.5+4.2 days (range 7–21) and all patients were discharged in good clinical condition. There were two sudden deaths over the mid-term, at postoperative day +32 and +45: both patients had troublesome ECC weaning without other postoperative complications. Presently, at a median follow-up of 48 mos, four patients died, 11 patients are alive, one of them after heart transplantation. Among the 10 non-transplanted long-term survivors, there was a significant improvement of the NYHA class from 2,1±0,8 to 1,3±0,5 (p<0,005) and of the Canadian Class score from 2,6±0,5 to 1,0±0,0 (p<0,005); moreover, a significant increase of the ejection fraction from 31,4±7,3% to 41,7±12,6% (p<0,05) was documented. Conclusions The study suggests that cytokine-induced BMC mobilization combined to CABG along with multiple trans-myocardial punctures: i. is an innovative and safe procedure; ii. offers some clinical benefits in patients with end-stage CAD requiring cardiac surgery. Based on these results, a randomized trial has been launched, with the aim to define the beneficial effect of pre-operative cytokine-induced BMC mobilization in patients undergoing cardiac surgery.

Disclosures:
Off Label Use: G-CSF + GM-CSF in CAD.