Rony Atoui

Concise Review: Immunomodulatory Properties of Mesenchymal Stem Cells in Cellular Transplantation: Update, Controversies, and Unknowns

Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage, for which the use of autologous donor cells has been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stem cells have been reported to be uniquely immune‐tolerant, in both in vitro and in vivo transplant models. In this review, we explore in detail the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as “universal donor cells” with fascinating clinical implications.

Myocardial Regenerative Therapy: Immunologic Basis for the Potential “Universal Donor Cells”

Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage for which use of autologous donor cells have been preferred to avoid immune rejection. Recently however, rodent, porcine, and even human bone marrow stromal cells have been reported to be uniquely immune tolerant, both in the in vitro mixed lymphocyte co-culture studies and in the in vivo allo-transplant and xeno-transplant models. In this review, we explore the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as universal donor cells with fascinating therapeutic implications.

Marrow Stromal Cells as Universal Donor Cells for Myocardial Regenerative Therapy: Their Unique Immune Tolerance

BACKGROUNDnRecently rodent and porcine bone marrow stromal cells (MSCs) have been reported to be uniquely immune tolerant. To confirm these findings in human cells, we tested whether human MSCs are also immune tolerant, such that they can be used as universal donor cells for myocardial regenerative therapy.nnnMETHODSnImmunocompetent female rats underwent coronary ligations (n = 90). In group I, lacZ-labeled male human MSCs were implanted into the peri-infarcted area. In groups II, III, and IV, isogeneic rat MSCs, culture medium, or human fibroblasts were injected, respectively. Echocardiography was carried out to assess cardiac function, and the specimens were examined serially for up to 8 weeks with immunohistochemistry, fluorescent in situ hybridization, and polymerase chain reaction to examine MSCs survival and differentiation.nnnRESULTSnHuman MSCs survived within the rat myocardium for more than 8 weeks without immunosuppression. Furthermore, the implanted MSCs significantly contributed to the improvement in ventricular function and attenuated left ventricular remodeling. No cellular infiltration characteristic of immune rejection was noted in contrast to group IV.nnnCONCLUSIONSnHuman MSCs survived within this xenogeneic environment, and contributed to the improvement in cardiac function. Our findings support the feasibility of using these cells as universal donor cells for xenogeneic or allogeneic cell therapy, as they can be prepared and stored well in advance for urgent use. Allogeneic MSCs from healthy donors may be particularly useful for severely ill or elderly patients whose own MSCs could be dysfunctional.

Intra-atrial implantation of a mitral valve prosthesis in a heavily calcified mitral annulus

Extensive annular calcification of the mitral valve can make anatomic implantation of a prosthesis extremely difficult and challenging. We herein describe a surgical technique of mitral valve replacement in a 78-year-old man with multiple medical co-morbidities suffering from severe mitral regurgitation with extensive circumferential calcification of the mitral annulus. The pertinent literature is reviewed and the technical steps and clinical presentation are discussed.

Biventricular pacing for end-stage heart failure: early experience in surgical vs. transvenous left ventricular lead placement.

Transvenous coronary sinus lead placement is currently the standard approach for left ventricular pacing. The aim of this study is to assess whether a mini-thoracotomy approach would be feasible and safe when used for cases in which transvenous procedures were ineffective or judged unlikely to succeed. Biventricular pacing was performed in 138 consecutive patients with 47 patients undergoing a mini-thoracotomy procedure. NYHA status, quality of life, electrical and echocardiographic data were assessed in the two groups over a follow-up period of 17.6+/-4.2 weeks. There was no significant difference in the preoperative characteristics in both groups other than a greater prevalence of renal failure and previous cardiac surgery among the surgical patients. The mean procedure time was significantly longer in the transvenous group. No significant differences were noted in the immediate or long-term pacing parameters. Two mortalities were observed in the surgical group >2 weeks following the procedure. During the follow-up period, we noted a comparable improvement in the echocardiographic parameters, QRS duration and NYHA status with both approaches. Our results suggest that even when performed on high-risk patients, epicardial lead placement through a mini-thoracotomy is beneficial and feasible as a rescue procedure after a failed transvenous approach.

On-pump beating heart mitral valve repair in patients with patent bypass grafts and severe ischemic cardiomyopathy

Re-operative mitral valve surgery in patients with poor ventricular function can be challenging especially in the presence of patent bypass grafts. We report the case of 11 patients with severe ischemic cardiomyopathy who underwent reoperative mitral valve repair through a limited right thoracotomy approach, on a non-fibrillating beating heart. All patients had their valves successfully repaired with no operative mortality and minimal morbidity. The technical aspects of the procedure are discussed, and the pertinent literature reviewed.

Bronchopulmonary carcinoid tumor associated with Cushing syndrome.

Cushing syndrome due to adrenocorticotropic hormone secretion by a bronchial carcinoid tumor is rare. The present study reports a case of a bronchopulmonary carcinoid presenting with Cushing syndrome in a 24-year old man who was successfully treated with a right middle lobectomy. The pertinent literature is reviewed, and the pathology and clinical presentation are discussed.

Transcatheter Aortic Valve Implantation: State of the Art

In the last century, medical innovation has revolutionized human lives and the management of medical diseases. Conditions which were once considered untreatable are now managed and even cured. Consequently, life expectancy has dramatically increased. The aging population brings about new challenges and pathologies that must be addressed with different approaches. As the body ages, so does the heart, bringing aortic stenosis to the forefront of valvular heart disease. It is estimated that 4.6% of patients over the age of 75 years old suffer from aortic stenosis (Nkomo et al., 2006). Traditionally, there were three modalities of treatment: conservative medical management, balloon valvuloplasty, and surgical aortic valve replacement (AVR). Long considered to be the gold-standard for aortic valve stenosis, surgical intervention provided a functional valve with acceptable mortality rates. However, the risks of surgical intervention increase dramatically depending on a patient’s comorbidities. Accordingly, high-risk patients were often relegated to medical management or balloon valvuloplasty. Conservative management has yielded extremely disappointing results. Patients who underwent balloon valvuloplasty in conjunction with medical treatment had a 44-37.2% mortality rate within a year. In addition, conservative management is associated with a high rate of restenosis. Medical management alone resulted in an unacceptable 25% mortality in one year (Nkomo et al., 2006; Ben-Dor et al., 2010). Despite these staggering statistics, the Euro Heart Survey suggested that approximately 30% of patients suffering from severe aortic stenosis were not treated with surgical intervention (Lung et al., 2003). A significant portion of these patients are refused surgery because they are deemed to have elevated surgical risks. Considering the natural history of the pathology, patients who were refused for surgery suffer considerable morbidity and mortality. Even with maximum medical therapy, the future for these patients appeared bleak. Fortunately, the advent of transcatheter aortic valve implantation (TAVI), has led to new options for non-surgical candidates. As early as 1965, an article describing a cathetermounted valve replacement for temporary relief of aortic insufficiency in an animal (Davies H., 1965). After more than three decades of development, Cribier et al. (2002) successfully implanted a percutaneous prosthetic heart valve in a 57-year-old man. The patient, who was moribund due to numerous medical conditions, showed significant clinical and echocardiographic improvement after the valve had been implanted. Although he eventually

Repair of chronic ischemic mitral regurgitation with posterior leaflet extension.

We read with great interest the review article ‘Chronic ischaemic mitral regurgitation — current treatment results and new mechanism-based surgical approaches’ by Bouma and colleagues in a past issue of this journal [1]. Management of severe ischaemic mitral regurgitation remains challenging with disappointing long-term surgical results. Furthermore, despite the increasing popularity of valve repair, its longterm durability in chronic ischaemic mitral regurgitation continues to be uncertain. In this article, the authors worked in an excellentmanner to review the different mechanisms of ischaemic mitral regurgitation, and to describe the variety of surgical approaches used to deal with this entity. To address leaflet tethering commonly observed in these patients, our group had recently reported the midterm results of posterior leaflet extension with a bovine pericardium, coupled with remodelling annuloplasty [2]. After extending the posterior leaflet height by about 1 cm from the medial half of P2 to the end of P3 in 44 consecutive patients with type IIIb ischaemic mitral regurgitation, the observed actuarial freedom from recurrent mitral regurgitation was 90% at 2 years. This also correlated with 90% of patients remaining in the New York Heart Association class I at 2 years. We believe that this is a relatively easy technique, safely reproduced, which can lead to good midterm results. Longer follow-up is necessary to assess the competency of the mitral valve and confirm the effectiveness of this approach.