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Introduction Cardiovascular diseases are the primary cause of death in Europe and the United States (Bleumink et al. 2004; Lloyd-Jones et al. 2009). The World Health Organization reported that the [...], Recent increase in the interest in stem and progenitor cells may be attributed to their behavioural characteristics. A consensus has been reached that embryonic or adult stem cells have therapeutic potential. As cardiovascular health issues are still the major culprits in many developed countries, stem and progenitor cell driven approaches may give the clinicians a new arsenal to tackle many significant health issues. However, stem and progenitor cell mediated cardiovascular regeneration can be achieved via complex and dynamic molecular mechanisms involving a variety of cells, growth factors, cytokines, and genes. Functional contributions of transplanted cells on target organs and their survival are still critical problems waiting to be resolved. Moreover, the regeneration of contracting myocardial tissue has controversial results in human trials. Thus, moderately favourable clinical results should be interpreted carefully. Determining the behavioural programs, genetic and transcriptional control of stem cells, mechanisms that determine cell fate, and functional characteristics are the primary targets. In addition, ensuring the long-term follow-up of cells with efficient imaging techniques in human clinical studies may provide a resurgence of the initial enthusiasm, which has faded over time. Here, we provide a brief historical perspective on stem cell driven cardiac regeneration and discuss cardiac and vascular repair in the context of translational science. Key words: cardiac stem cell, progenitor cell, cytotherapy, cardiac regeneration, angiogenesis. Le regain d'interet recent pour les cellules souches et progenitrices peut etre attribue aux caracteristiques de leur comportement. Un consensus a ete obtenu sur le fait que les cellules souches embryonnaires ou adultes possedaient un potentiel therapeutique. Puisque les questions de sante cardiovasculaire constituent toujours un probleme majeur de plusieurs pays developpes, les approches basees sur les cellules souches et progenitrices peuvent fournir aux cliniciens un arsenal nouveau permettant de s'attaquer a plusieurs problemes de sante importants. Cependant, la regeneration cardiovasculaire par les cellules souches et progenitrices peut etre realisee via des mecanismes moleculaires complexes et dynamiques impliquant une variete de cellules, de facteurs de croissance, de cytokines et de genes. Les contributions fonctionnelles des cellules transplantees dans les organes cibles et leur survie constituent toujours un probleme critique qui attend d'etre resolu. De plus, la regeneration du tissu contractile du myocarde a conduit a des resultats controverses lors d'essais chez l'humain. Ainsi, des resultats cliniques moderement favorables doivent etre interpretes prudemment. La programmation du comportement, le controle genetique et transcriptionnel des cellules souches, les mecanismes qui determinent la destinee des cellules et les caracteristiques fonctionnelles constituent des cibles majeures. De plus, si l'on s'assure d'un suivi a long terme des cellules a l'aide de techniques d'imagerie efficaces applicables chez l'humain, il sera possible de raviver l'enthousiasme initiale qui s'est attenue au cours du temps. Nous presentons ici un bref regard historique sur la regeneration cardiaque determinee par les cellules souches, et nous discutons de la reparation cardiaque et vasculaire dans le contexte de la science translationnelle. Mots-cles : cellules souches cardiaques, cellules progenitrices, cytotherapie, regeneration cardiaque, angiogenese. [Traduit par la Redaction]

Mesenchymal stem cells (MSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes, and cardiomyocytes. Several established methods are presently available for in vitro isolation of MSCs from bone marrow. However, the duration necessary to culture them can be a major handicap to cell-based therapies needed for such urgent cardiovascular conditions as acute myocardial infarction and acute hindlimb ischemia. The best timing of cardiomyocyte differentiation induction after MCS isolation and expansion is still an unresolved issue. Our goal was to investigate the possibility of obtaining functional cardiomyocytes from rat MSC within a shorter time period. We examined MSCs' colony-forming capacity, CD90 and CD34 immunoreactivity during the 14 days of culturing. Cardiomyocyte differentiation was induced by 5-azacytidine. Immunohistochemic staining, together with intracellular [Ca.sup.2+] measurement experiments, revealed that MSCs do not differentiate into any specific cell lineage but show the characteristics of MSCs on both the 9th and 14th days of the culture. To check the potential for differentiation into cardiomyocytes, experiments with caffeine application and depolarization with KCl were performed. The cells possessed some of the specific biochemical features of contracting cells, with slightly higher capacities on the 14th day. Cells from 9th and 14th days of the culture that were treated with 5-azacytidine had a higher expression of cardiac-specific markers such as troponin I, α-sarcomeric actin, and MEF2D compared with the control groups. This study illustrates that it is possible to get functional cardiomyocytes from in vitro MSC culture in a shorter time period than previously achieved. This reduction in time may provide emergency cases with access to cell-based therapies that may have previously been unavailable. Key words: mesenchymal stem cells, cardiomyocytes, differentiation, rat, in vitro, gene expression. Les cellules souches mesenchymateuses (CSM) ont la capacite de se differencier en osteoblastes, chondrocytes, adipocytes, myocytes et cardiomyocytes. Plusieurs methodes eprouvees permettent d'isoler in vitro les CSM de la moelle osseuse. Toutefois, la duree requise pour leur culture pourrait etre un desavantage majeur pour la therapie cellulaire d'urgences cardiovasculaires comme l'infarctus du myocarde et l'ischemie des membres inferieurs. Le meilleur moment de l'induction de la differenciation des cardiomyocytes apres l'isolement et l'expansion des CSM n'a toujours pas ete determine. Nous avons etudie la possibilite d'obtenir des cardiomyocytes fonctionnels de CSM de rats sur une courte periode de temps. Nous avons examine la capacite de formation de colonies des CSM et l'immunoreactivite a CD90 et CD34 durant les 14 jours de culture. La differenciation en cardiomyocytes a ete induite par la 5-azacytidine. La coloration immuno-histochimique ainsi que des mesures du [Ca.sup.2+] intracellulaire ont revele que les CSM ne se differencient pas en une lignee cellulaire specifique, mais montrent les caracteristiques des CSM lors des 9e et 14' jours de culture. Pour verifier le potentiel de differenciation en cardiomyocytes, nous avons fait des experiences avec application de cafeine et depolarisation au KCl. Les cellules possedaient certaines des caracteristiques biochimiques specifiques des cellules pouvant se contracter, avec des capacites legerement superieures le quatorzieme jour. Les cellules des 9e et 14e jours de culture traitees avec la 5-azacytidine ont montre une plus grande expression de marqueurs specifiques du cour, tels que la troponine I, l'actine α-sarcomerique et MEF2D, comparativement a celles des groupes temoins. Cette etude montre qu'il est maintenant possible d'obtenir des cardiomyocytes fonctionnels d'une culture in vitro de CSM dans une courte periode de temps. Cette reduction de temps pourrait fournir aux cas d'urgence un acces a des therapies cellulaires jusqu'alors inaccessibles. Mots-cles : cellules souches mesenchymateuses, cardiomyocytes, differenciation, rat, in vitro, expression genique. [Traduit par la Redaction], Introduction Stem cell research has gained tremendous interest in the past two decades because it provides opportunities to develop new strategies for debilitating diseases. Stem, or progenitor, cells have the [...]

Abstract Background Coronary artery bypass grafting (CABG) with cardioplegic cardiac arrest and cardiopulmonary bypass (CPB) is associated with myocardial injury. The aim of this study was to investigate whether a modified mechanical post-conditioning (MMPOC) technique has a myocardial protective effect by enhancing early metabolic recovery of the heart following revascularization. Methods A prospective, randomized trial was conducted at a single-center university hospital performing adult cardiac surgery. Seventy-nine adult patients undergoing first-time elective isolated multivessel coronary artery bypass grafting were prospectively randomized to MMPOC or control group. Anesthetic, cardiopulmonary bypass, myocardial protection, and surgical techniques were standardized. The post reperfusion cardiac indices, inotrope use and biochemical-electrocardiographic evidence of myocardial injury were recorded. The incidence of postoperative complications was recorded prospectively. Results Operative characteristics, including CPB and aortic cross-clamp time, were similar between the two groups (p>0.05). The MMPOC group had lower troponin I and other cardiac biomarkers level post CPB and postoperatively, with greater improvement in cardiac indices (p Conclusions MMPOC technique promotes early metabolic recovery of the heart during elective CABG, leading to better myocardial protection and functional recovery.

Abstract Background Bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with coronary heart disease are impaired with respect to number and functional activity. However, the relation between the functional activity of BM-CPCs and the number of diseased coronary arteries is yet not known. We analyzed the influence of the number of diseased coronary arteries on the functional activity of BM-CPCs in peripheral blood (PB) in patients with ischemic heart disease (IHD). Methods The functional activity of BM-CPCs was measured by migration assay and colony forming unit in 120 patients with coronary 1 vessel (IHD1, n = 40), coronary 2 vessel (IHD2, n = 40), coronary 3 vessel disease (IHD3, n = 40) and in a control group of healthy subjects (n = 40). There was no significant difference of the total number of cardiovascular risk factors between IHD groups, beside diabetes mellitus (DM), which was significantly higher in IHD3 group compared to IHD2 and IHD1. Results The colony-forming capacity (CFU-E: p Conclusions The functional activity of BM-CPCs in PB is impaired in patients with IHD. This impairment increases with the number of diseased coronary arteries. Moreover, the regenerative capacity of BM-CPCs in ischemic tissue further declines in IHD patients with DM. Furthermore, monitoring the level of BM-CPCs in PB may provide new insights in patients with IHD.

Abstract Background Emerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG). Methods A total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes. Results Among 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (p = 0.002). ACE D/D genotype was associated with hypertension (p = 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (p = 0.007). Conclusions FVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.

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Objective: We investigated the long-term results of autologous bone marrow mononuclear cells (ABMMNCs) implantation in patients with Buerger's disease (BD). Methods: Twenty-eight patients (25 males and 3 females) who had BD and critical unilateral limb ischemia were investigated between April 2003 and August 2005. The patients were administered multiple injections of CD34+ and CD45+ positive ABMMNCs into the gastrocnemius muscle, the intermetatarsal region, and the dorsum of the foot (n=26) or forearm (n=2) and saline injection into the contralateral limb. Results: The mean follow-up time was 139.6±10.5 months. No complication related to stem cell therapy was observed during the follow-up. The ankle-brachial pressure index evaluated at 6 months and 120 months was compared to the baseline scores (p<0.001 and p=0.021, respectively). Digital subtraction angiography (DSA) was performed for all patients at baseline, 6 months, and 120 months. The angiographic improvement was 78.5% and 57.1% at 6 and 120 months, respectively. Patients demonstrated a significant improvement in the quality of life parameters at 6 months compared to baseline (p=0.008) and 120 months compared to the baseline (p=0.009). The 10-year amputation-free rate was 96% (95% CI=0.71-1) in ABMMNC-implanted limbs and 93% (95% CI=0.33-0.94) in saline-injected limbs (p=1). Conclusion: Autologous stem cell therapy could be an alternative therapeutic method for BD at long-term follow-up. [ABSTRACT FROM AUTHOR]

Background To evaluate the results of patients with chronic hepatitis C virus (HCV) following cardiac surgery in the TurcoSCORE (TrS) database. Methods Sixty patients with HCV who underwent cardiac surgery between 2005 and 2016 in our clinic out of a total 8,018 patients from the TrS database were included in the study. The perioperative morbidity and mortality rates in these patients were compared with a matched cohort. Results The mean follow-up time was 96.6 ± 12.3 months. Hospital mortality rates (HCV group 5% vs. control group 1.7%, p = 0.61) were similar between the groups. No significant difference was found in the duration of cardiopulmonary bypass (HCV 79.1 ± 12.3 vs. control 82.6 ± 11.8, p = 0.88) and cross clamps (HCV 33.4 ± 6.9 vs control 33.8 ± 7.2 p = 0.76) between the two groups. The rate of patients who were revised due to postoperative hemorrhage was significantly higher in the HCV arm compared with the matched cohort (HCV 13.3% vs. control 1.7%, p < 0.05). Although the measured prothrombin time (PT) and international normalized ratio (INR) in the postoperative 24th hour were in normal ranges in both arms, they were significantly higher in the HCV arm (HCV 11.2 ± 1.2 vs. control 10.5 ± 0.8, p < 0.05; HCV 0.99 ± 0.06, vs. control 0.92 ± 0.03, p < 0.0001). Conclusion The presence of HCV can be an important prognostic factor formorbidity in patients undergoing cardiac surgery. It can also play an important role in the risk models generated for cardiac surgery. [ABSTRACT FROM AUTHOR]

Objective: We aimed to identify characteristics differentiating patients undergoing mitral valve replacement versus valve repair for mitral regurgitation (MR) and to investigate retrospectively mid-term clinical and functional outcomes. Methods: From January, 2004 to January, 2009 146 patients underwent mitral valve surgery (62 male / 84 female; age: 55.9±13.6 [18-80] years) by one surgical team. Mitral valve replacement was performed in 101 patients (69.2%) and valve repair was performed in 45 patients (30.8%). Mean follow-up time was 586±413 days. Life tables were constructed for the analysis of 5-year complication free survival and comparisons were performed between the groups using Log-rank test within 95%CI. Results: The choice of surgical technique depended on the etiology of MR. Degenerative (p<0.001) and ischemic (p=0.014) MR were more common in patients undergoing repair whereas patients with complex rheumatic mitral valve disease (p<0.001) with subvalvular involvement commonly underwent replacement. Overall 30-day mortality was 3.2% (replacement, 3.96%vs repair, 2.22%, p=0.59). Although there was no significant difference between the groups regarding baseline left ventricular ejection fraction (EF) (ischemic p=0.61; non-ischemic p=0.34), improvement was more pronounced in the repair group for both etiologies (ischemic MR, p=0.001; non- ischemic MR p=0.002). Survival at 5-years was 91.7±4.7% after repair and 83.5±9.2% after replacement, respectively (p=0.83). Freedom from grade 2 or more mitral regurgitation, reoperation, endocarditis, and thromboembolism were 95±5% vs 97±3% (p=0.71); 95±4% vs 98±2% (p=0.98); 94±4% vs 100% (p=0.16); and 85±8% vs 100% (p=0.095) in replacement and repair groups, respectively. Conclusion: This study demonstrates that mitral valve repair is associated with an acceptable operative mortality, satisfactory mid-term survival and better preservation of left ventricular function. Significant differences in favor of repair are expected in long-term follow-up particularly regarding freedom from thromboembolism and endocarditis. [ABSTRACT FROM AUTHOR]

In the era of proton-antiproton collisions, stem cell field has emerged as the newly recognized protons of regenerative medicine. Great interest and enthusiasm were depending on their behavioral difference such as self-renewal, clonogenicity and differentiation into functional progeny that may become vehicles for regenerative medicine. Although progress has evolved dramatically strategies using stem-cell-driven cardiac regeneration involve extremely complex and dynamic molecular mechanisms. Cell death in transplanted heart continues to be a significant issue. Every step from stem cell homing, and migration to retention, engraftment, survival and differentiation in cardiac cytotherapy deserves intense research for optimum results. Furthermore, regeneration of contractile tissue remains controversial for human studies and careful interpretation is warranted for modest benefit in clinical trials. Currently, the only realistic approach to replace the damaged cardiomyocytes is cardiac transplantation for patients with end-stage heart failure. Ultimately, the giant footsteps in cell-based cardiac repair can only be achieved by an enthusiastic but also skeptical teams adhering to good manufacturing practices. Better understanding of cell-fate decisions and functional properties in cardiac cytotherapy may change the erosion of initial enthusiasm and may open new prospects for cardiovascular medicine. [ABSTRACT FROM AUTHOR]

The present review addresses the issues related to innovative contributions in biotechnology and their potential role in stem cell research at present and in the future. We can expect that future developments and applications in biotechnological sciences and industry will effect the direction of emerging cellular therapies. The use of these advances may offer a unique opportunity to investigate the mechanisms related to the journey from embryonic cells or bone-marrow derived stem/progenitor cells to cardiomyocytes or endothelial cells and the molecular regulators of cell differentiation. [ABSTRACT FROM AUTHOR]