Boris Robic

The cardiac atrial appendage stem cell: a new and promising candidate for myocardial repair

AIMS Considerable shortcomings in the treatment of myocardial infarction (MI) still exist and therefore mortality remains high. Cardiac stem cell (CSC) therapy is a promising approach for myocardial repair. However, identification and isolation of candidate CSCs is mainly based on the presence or absence of certain cell surface markers, which suffers from some drawbacks. In order to find a more specific and reliable identification and isolation method, we investigated whether CSCs can be isolated based on the high expression of aldehyde dehydrogenase (ALDH). METHODS AND RESULTS An ALDH(+) stem cell population, the cardiac atrial appendage stem cells (CASCs), was isolated from human atrial appendages. CASCs possess a unique phenotype that is clearly different from c-kit(+) CSCs but that seems more related to the recently described cardiac colony-forming-unit fibroblasts. Based on immunophenotype and in vitro differentiation studies, we suggest that CASCs are an intrinsic stem cell population and are not mobilized from bone marrow or peripheral blood. Indeed, they possess a clonogenicity of 16% and express pluripotency-associated genes. Furthermore, compared with cardiosphere-derived cells, CASCs possess an enhanced cardiac differentiation capacity. Indeed, differentiated cells express the most important cardiac-specific genes, produce troponin T proteins, and have an electrophysiological behaviour similar to that of adult cardiomyocytes (CMs). Transplanting CASCs in the minipig MI model resulted in extensive cardiomyogenic differentiation without teratoma formation. CONCLUSION We have identified a new human CSC population able to differentiate into functional CMs. This opens interesting perspectives for cell therapy in patients with ischaemic heart disease.

Cardiac atrial appendage stem cells engraft and differentiate into cardiomyocytes in vivo: A new tool for cardiac repair after MI.

BACKGROUND This study assessed whether autologous transplantation of cardiac atrial appendage stem cells (CASCs) preserves cardiac function after myocardial infarction (MI) in a minipig model. METHODS AND RESULTS CASCs were isolated from right atrial appendages of Göttingen minipigs based on high aldehyde dehydrogenase activity and expanded. MI was induced by a 2h snare ligation of the left anterior descending coronary artery. Upon reperfusion, CASCs were intramyocardially injected under NOGA guidance (MI-CASC, n=10). Non-transplanted pigs (MI, n=8) received sham treatment. 3D electromechanical mapping (EMM) and cardiac MRI were performed to assess left ventricular (LV) function. MI pigs developed LV dilatation at 2 months (2M), while in the MI-CASC group volumes remained stable. Global LV ejection fraction decreased by 16 ± 8% in MI animals vs 3 ± 10% in MI-CASC animals and regional wall thickening in border areas was better preserved in the MI-CASC group. EMM showed decreased viability and wall motion in the LV for both groups POST-MI, whereas at 2M these parameters only improved in the MI-CASC. Substantial cell retention was accompanied by cardiomyogenic differentiation in 98±1% of the transplanted CASCs, which functionally integrated. Second harmonic generation microscopy confirmed the formation of mature sarcomeres in transplanted CASCs. Absence of cardiac arrhythmias indicated the safety of CASC transplantation. CONCLUSION CASCs preserve cardiac function by extensive engraftment and cardiomyogenic differentiation. Our data indicate the enormous potential of CASCs in myocardial repair.

From Bone Marrow to Cardiac Atrial Appendage Stem Cells for Cardiac Repair: A Review

Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells - CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%).

Compromised Cardiopulmonary Exercise Capacity in Patients Early After Endoscopic Atraumatic Coronary Artery Bypass Graft: Implications for Rehabilitation

Objective The purpose of this work was to test the hypothesis that cardiopulmonary exercise tolerance is better preserved early after endoscopic atraumatic coronary artery bypass graft (endo-ACAB) surgery versus coronary artery bypass graft (CABG) surgery. Design Twenty endo-ACAB surgery patients, 20 CABG surgery patients, and 15 healthy subjects executed a maximal cardiopulmonary exercise test, with assessment and comparison of cycling power output, O2 uptake, CO2 output, respiratory gas exchange ratio, end-tidal O2 and CO2 pressures, equivalents for O2 uptake and CO2 output, heart rate, O2 pulse, expiratory volume, tidal volume, respiratory rate, at peak exercise and ventilatory threshold. In patients, forced expiratory volume and forced vital capacity were measured. Results Oxygen uptake, CO2 output, expiratory and tidal volume, equivalents for O2 uptake and CO2 output, end-tidal O2 and CO2 pressures at peak exercise (matched peak respiratory gas exchange ratio between patient groups), and ventilatory threshold were significantly worse in patients versus healthy controls (P < 0.05; observed power, >0.80). All these parameters, and lung function, were, however, comparable between CABG and endo-ACAB surgery patients (P > 0.10). Conclusions Exercise tolerance and ventilatory function during exercise seems, in contrast to expectation, equally compromised early after endo-ACAB surgery as opposed to after CABG surgery. These data may signify the need for exercise-based rehabilitation intervention early after endo-ACAB surgery.

Possibilities and limitations for co-transplantation of cardiac atrial appendage stem cells and mesenchymal stem cells for myocardial repair

[Fanton, Yanick; Rummens, Jean-Luc; Daniels, Annick; Windmolders, Severina; Willems, Leen; Declercq, Jeroen; Hensen, Karen; Koninckx, Remco] Jessa Hosp, Lab Expt Hematol, Hasselt, Belgium. [Fanton, Yanick; Robic, Boris; Rummens, Jean-Luc; Windmolders, Severina; Willems, Leen; Notelaers, Kristof; Paesen, Rik; Ameloot, Marcel; Bito, Virginie; Declercq, Jeroen; Hensen, Karen; Koninckx, Remco; Hendrikx, Marc] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Robic, Boris; Mees, Urbain; Hendrikx, Marc] Jessa Hosp, Dept Cardiothorac Surg, Hasselt, Belgium. [Jamaer, Luc; Dubois, Jasperina] Jessa Hosp, Dept Cardiac Anesthesia, Hasselt, Belgium. [Bijnens, Eric; Heuts, Nic] Jessa Hosp, Dept Radiol, MRI Unit, Hasselt, Belgium. [Notelaers, Kristof; Paesen, Rik; Ameloot, Marcel; Bito, Virginie] Hasselt Univ, Biomed Res Inst, Hasselt, Belgium.

A comparison between minimized extracorporeal circuits and conventional extracorporeal circuits in patients undergoing aortic valve surgery: is ‘minimally invasive extracorporeal circulation’ just low prime or closed loop perfusion ?

Introduction: Even though results have been encouraging, an unequivocal conclusion on the beneficial effect of minimally invasive extracorporeal circulation (MiECC) in patients undergoing aortic valve surgery cannot be derived from previous publications. Long-term outcomes are rarely reported and a significant decrease in operative mortality has not been shown. Most studies have a limited number of patients and are underpowered. They merely report on short-term results of a heterogeneous intraoperative group using different types of ECC system in aortic valve surgery. The aim of the present study was to determine whether MiECC systems are more beneficial than conventional extracorporeal systems (CECC) with regard to mortality, hospital stay and inflammation and with only haemodilution and blood-air interface as differences. Methods: We retrospectively analysed data regarding mortality, hospital stay and inflammation in patients undergoing isolated aortic valve surgery. Forty patients were divided into two groups based on the type of extracorporeal system used; conventional (n=20) or MiECC (n=20). Results: Perioperative blood product requirements were significantly lower in the MiECC group (MiECC: 0.2±0.5 units vs CECC: 0.9±1.2 units, p=0.004). No differences were seen postoperatively regarding mortality (5% vs 5%, p=0.99), total length of hospital stay (10.6±7.2 days (MiECC) vs 12.1±5.9 days (CECC), p=0.39) or inflammation markers (CRP: MiECC: 7.09±13.62 mg/L vs CECC: 3.4±3.2 mg/L, p=0.89). Conclusion: MiECC provides circulatory support that is equally safe and feasible as conventional extracorporeal circuits. No differences in mortality, hospital stay or inflammation markers were observed.