List of Authors:Strauer,Bodo-Eckehard; Yousef, Muhammad; Schannwell, Christiana,M.
Abstract:
Despite accumulated evidence that intracoronary bone marrow cell (BMC) therapy may be beneficial in acute myocardial infarction, there are only limited data available on the effectiveness of BMCs in chronic heart failiure.The aim of this study was to quantitatively investigate ventricular hemodynamics, geometry, and contractility as well as the long-term clinical outcome of BMC treated patients with reduced left ventricular ejection fraction (LVEF) due to chronic ischemic cardiomyopathy.
Patients (n=391, LVEF<35%) with chronic ischemic cardiomyopathy were enrolled in the present study. Of these, 191 patients (mean NYHA class 3.22) underwent intracoronary BMC therapy. The control group (mean NYHA class 3.06) consisted of 200 patients with comparable LVEF. Assessment of hemodynamics at rest and exercise, quantitative ventriculography, spiroergometry, 24h Holter ECG, late potentials, and heart rate variability were analysed. Over 3 months to 5 years after intracoronary BMC therapy there was a significant improvement in hemodynamics (e.g. LVEF, cardiac index), exercise capacity, oxygen uptake, and LV contractility. Importantly, there was a significant decrease in long-term mortality in the BMC treated patients compared with the control group.
Intracoronary BMC therapy improves ventricular performance, quality of life and survival in patients with heart failure. The effects were present when BMC were administered in addition to standard therapeutic regimen. No side effects were observed.
Report:
The field of cardiac stem cell (SC) therapy has emerged as a new alternative for patients with heart failure and has made rapid progress.
Preclinical studies have demonstrated that the regeneration capability of the mammalian heart can be enhanced by transplantation of SCs. Pluripotent embryonic SCs home and fully regenerate cardiac tissue in big animal models of myocardial infarction. Adult SCs have proven to repair infarcted myocardium, ameliorating left ventricular remodelling in animal models. Moreover, using postnatal endothelial and cardiac SCs, functioning hearts can be created after decellularization and recellularization of cadaveric heart matrixes. It is predictable that this field will advance enormously with the new generation of induced pluripotent adult stem cells (iPSCs), which are genetically reprogrammed adult SCs with embryonic-like plasticity. This revolutionary approach provides an alternative source from which to generate cell lines with cardiogenic potential without the use of eggs or embryos and with no risk of immune rejection.
Human research with SCs for cardiac application has been almost limited to coronary heart disease. In patients with STEMI, early intracoronary transplantation of bone marrow derived stem cells (BMSCs) has demonstrated a favourable risk-benefit ratio and fulfils the strictest criteria for large-scale clinical trials. The experience in chronic ischemic patients is much more immature, and have included different clinical scenarios (pure chronic myocardial ischemia and left ventricular dysfunction with and without viability), where different of types of SCs (myoblasts, BMSCs, adipose SC) have safely produced a modest but significant benefit on left ventricular performance, myocardial perfusion or clinical status after their transplantation using different methods of delivery.
In the STAR trial, 391 patients with heart failure (LVEF <35%, NYHA class 3) due to healed infarction (interval from infarction to inclusion 8.5+3.2 years) were followed for 5 years using a comprehensive clinical and physiological assessment. 191 patients underwent intracoronary infusion of autologous BMSCs (6.6+3.3 x 107 per patient) after ischemic preconditioning. 200 patients with comparable conditions that refused the use of cells but accepted identical follow-up acted as control group. Despite the limited amount of transplanted cells, over 3 months to 5 years after transplantation there was a significant functional improvement in functional parameters and clinical outcome in BMSCs patients as compared to controls. This open label, non-randomized clinical trial is the largest study exploring the acute and long-term effect of stem cell transplantation in this setting. Its contribution to the field is relevant for several reasons.
First, its results strongly suggest that BMSCs safely benefit the outcome of patients with post-infarction heart failure, indicating the need to conduct double-blind randomized clinical trials to confirm this possibility and to explore different types of cells in this setting.
Second, if its results are confirmed, the simple, cheap, elegant and reproducible method used for stem cell delivery after preconditioning will become the preferred technique for cell transplantation in the heart.
Therefore, further studies are warranted to compare the efficacy of intracoronary delivery versus intramyocardial delivery.
Finally and very important, the amount of transplanted cells in this trial is not enough to produce the observed benefit in left ventricular performance through transdifferentiation into cardiomyocytes, supporting the hypothesis that, in humans and big animal models of infarction, the main mechanism of benefit of stem cells on remodelling are scaffolding effect and paracrine activation of resident cardiac stem cells.