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How to Stimulate Myocardial Regeneration in Adult Mammalian Heart: Existing Views and New Approaches
No full textStem cell-based therapy has been considered as a promising option in the treatment of ischemic heart disease. Although stem cell administration resulted in the temporary improvement of myocardial contractility in the majority of studies, the formation of new cardiomyocytes within the injured myocardium has not been conclusively demonstrated. Consequently, the focus of research in the field has since shifted to stem cell-derived paracrine factors, including cytokines, growth factors, mRNA, and miRNA. Notably, both mRNA and miRNA can enter into the extracellular space either in soluble form or packed into membrane vesicles. Stem cell-derived paracrine factors have been shown to suppress inflammation and apoptosis, stimulate angiogenesis, and amplify the proliferation and differentiation of resident cardiac stem cells (CSCs). Such features have led to exosomes being considered as potential drug candidates affording myocardial regeneration. The search for chemical signals capable of stimulating cardiomyogenesis is ongoing despite continuous debates regarding the ability of mature cardiomyocytes to divide or dedifferentiate, transdifferentiation of other cells into cardiomyocytes, and the ability of CSCs to differentiate into cardiomyocytes. Future research is aimed at identifying novel cell candidates capable of differentiating into cardiomyocytes. The observation that CSCs can undergo intracellular development with the formation of "cell-in-cell structure" and subsequent release of transitory amplifying cells with the capacity to differentiate into cardiomyocytes may provide clues for stimulating regenerative cardiomyogenesis.This work was supported by the grants from the Russian Foundation for Basic Research (Nos. 12-04-00941 and 16-04-01424) and Program of Presidium of Russian Academy of Sciences "Fundamental Sciences for Medicine" (2012-2014), by the state assignment of FASO of Russia ("The mechanisms of development of neuropsychic, metabolic, and hormonal dysfunctions in the nervous and endocrine diseases and the approaches for their correction"), and by the Government of Russian Federation, Grant 08-08.Belostotskaya, G (reprint author), Russian Acad Sci, Sechenov Inst Evolutionary Physiol & Biochem, Grp Cytoanalysis, St Petersburg, Russia; Almazov Natl Med Res Ctr, Inst Expt Med, St Petersburg, Russia.
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Midterm follow-up after off-pump versus on-pump coronary artery bypass grafting. Results from a case-matched study
No full textObjective - Early survival in off-pump coronary artery bypass (OPCAB) patients is reported to be as good as that of conventional coronary artery bypass grafting (CABG). However, it remains unknown whether midterm cardiac outcome after off-pump surgery is similar to that for the on-pump procedure. Methods and results - One hundred OPCAB patients (67.8 (9.3) y) were compared to a case-matched contemporary group of CABG patients (69.4 (8.8) y). In-hospital and midterm outcome data are presented. Follow-up was 100% complete. The mean number of distal anastomoses per patient was 1.9 (0.8) and 2.4 (1.0) in the OPCAB and CABG group, respectively. Grafting according to treatment plan was 100% in both groups. Peak creatine kinase muscle-brain and cardiac troponin I (cTnl) release were similar in the overall groups, but the cTnl release in the 25 most recently operated patients was significantly lower in the OPCAB group (4.8 (9.1) ng/ml vs. 14.0 (20.5) ng/ml, p = 0.04). Duration of mechanical ventilation, ICU stay and hospital stay were shorter in the OPCAB group. The incidence of atrial fibrillation was similar. There were no differences in in-hospital complications. The actuarial survival at 1, 3 and 5 years was 88% (C.I. 81.6 to 94.3), 78% (C.I. 66.1 to 90.2) and 78% (C.1. 66.1 to 90.2) in the OPCAB and 90% (C.I. 84.0 to 95.9), 84% (C.I. 74.6 to 92.5) and 68% (C.I. 44.7 to 90.6) in the CABG group (log rank p-value = 0.96). Event-free survival at 1, 3, 5 years was 85% (C.I. 77.8 to 91.9), 71 % (C.I. 57.4 to 84.2) and 71 % (C.I. 57.4 to 84.2) in the OPCAB and 85% (C.I. 77.8 to 91.9),72% (C.I. 61.1 to 82.7) and 58% (C.I. 37.2 to 78.8) in the CABG group (log rank p-value = 0.63). Recurrence of angina (3%) and need for reintervention (2%) in the OPCAB group were low. Conclusions - OPCAB surgery is a safe and reproducible technique, yielding short-and midterm outcomes comparable to conventional CABG
THE BEST OF BOTH WORLDS: IN VITRO EVALUATION OF COMBINING TWO STEM CELL TYPES FOR TRUE CARDIAC REPAIR
No full textINTRODUCTION: Bone healing can be augmented by pre-conditioning MSCs (pMSCs) with inflammatory cytokines. Another approach is timely resolution of inflammation using immunomodula-tory cytokines. We investigated the efficacy of pMSC and genetically modified MSCs that over-express IL-4 (IL4-MSCs) on early stage steroid-associated osteonecrosis of the femoral head (ONFH) in rabbits .METHODS: 36 male mature NZW rabbits received methylpred-nisolone acetate (20mg/kgIM) 4 weeks before surgery. There were 6 groups: 1. Core Decompress (CD) alone-a 3 mm drill hole+ injection of:2. hydrogel (HG)-200 ml of hydrogel carrier3. MSCs-1 million rabbit MSCs4. pMSC-LPS (20 mg/ml) + TNFa (20 ng/ml) precondi-tioned MSCs 5. IL4-MSCs-rabbit IL-4 over-expressing MSCs 6. IL4-pMSCs-preconditioned IL-4 over-expressing MSCsEight weeks after surgery, femurs were evaluated by microCT, biomechanical, and his-tological analyses.RESULTS: Bone mineral density (BMD) and bone volume fraction (BVF) increased outside the CD in the pMSC group compared to the CD and MSC groups (p < 0.05). IL4-pMSC group was increased compared to the CD group (p < 0.05). The percentage of empty lacunae in the IL4-MSC group was significantly less than other groups outside the CD (p < 0.05); however, IL4-MSC group had less trabecular bone formation inside the CD. DISCUSSION: pMSC increased new bone formation after CD in ONFH; IL4-MSCs decreased the number of empty lacunae. Immunomodulation of bone healing has the potential to improve bone healing after CD for early stage ONFH; these interventions must be applied in a temporally sensitive fashion
Combining stem cells in myocardial infarction: The road to superior repair?
No full textMyocardial infarction irreversibly destroys millions of cardiomyocytes in the ventricle, making it the leading cause of heart failure worldwide. Over the past two decades , many progenitor and stem cell types were proposed as the ideal candidate to regenerate the heart after injury. The potential of stem cell therapy has been investigated thoroughly in animal and human studies, aiming at cardiac repair by true tissue replacement, by immune modulation, or by the secretion of paracrine factors that stimulate endogenous repair processes. Despite some successful results in animal models, the outcome from clinical trials remains overall disappointing, largely due to the limited stem cell survival and retention after transplantation. Extensive interest was developed regarding the combina-tional use of stem cells and various priming strategies to improve the efficacy of regenerative cell therapy. In this review, we provide a critical discussion of the different stem cell types investigated in preclinical and clinical studies in the field of cardiac repair. Moreover, we give an update on the potential of stem cell combinations as well as preconditioning and explore the future promises of these novel regenerative strategies. Abbreviations: ALDH, aldehyde dehydrogenase; BM, bone marrow; BM-MNC, bone marrow mononuclear cell; CASC, cardiac atrial appendage stem cell; CDC, cardiosphere-derived cell; CPC, cardiac progenitor cell; CVD, cardiovascular disease; Cx43, connexin43; DMOG, dimethyloxalylglycine; EPC, endothelial progenitor cell; EV, extracellular vesicle; hESC, human embryonic stem cell; HIF, hypoxia-inducible factor; HSC, hematopoietic stem cell; iPSC, induced pluripotent stem cell; iPSC-CM, induced pluripotent stem cell-derived cardiomyocyte; Isl-1, islet-1; LAD, left anterior descending; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MI, myocardial infarction; MSC, mesenchymal stem cell; Sca-1, stem cell antigen-1.Fonds Wetenschappelijk Onderzoek, Grant/Award Number: 1154120N; Bijzonder Onderzoeksfonds, Grant/Award Numbers: Universiteit Hasselt 16NI05BOF, Universiteit Hasselt BOF20TT04
Figures were created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http:// smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This study is supported by an aspirant PhD mandate to H.B. (Grant no. 1154120 N) from the “Research Foundation‐Flanders” (“Fonds Wetenschappelijk Onderzoek Vlaanderen”—FWO) as well as a Special Research Fund (BOF) of Hasselt University (Reference number BOF20TT04) to A.B. L.E. benefits from a “Bijzonder Onderzoeksfonds” (BOF) grant from Hasselt University (Grant no. 16NI05BOF)
Echocardiography-guided Injection for Targeted and Reliable Intramyocardial Stem Cell Delivery in a Rat Model of Myocardial Infarction
No full textEchocardiography-guided intramyocardial injection (EGI) is a minimally invasive technique for delivering stem cell therapies in preclinical myocardial infarction (MI) models. Compared to traditional open-chest approaches, EGI offers improved clinical translatability, reduced invasiveness, and minimized physiological impact on the animal. While EGI is well established in murine models, its application in rats remains limited due to anatomical and technical challenges. In particular, thinning of the left ventricular anterior wall (LVAW) in infarcted and peri-infarct regions complicates safe and accurate myocardial delivery, as wall thickness can fall below the needle bevel size of commonly used 27 G or 28 G needles, increasing the risk of ventricular perforation or failed delivery. To address this limitation, we optimized a protocol for EGI in rat MI models using 29 G Spinocan needles. The smaller-diameter, longer needle enables precise targeting of thin myocardial tissue, minimizing damage and enhancing injection accuracy, independent of LVAW thickness. This technique is compatible with standard transthoracic echocardiography platforms and eliminates the need for thoracotomy, allowing longitudinal studies in the same animal. Our refined method enables robust, reproducible delivery of therapeutic agents into viable myocardium adjacent to the infarct zone, where regenerative therapies are most effective. By improving safety and targeting precision, this approach increases the translational relevance of preclinical cardiac research and supports the development of standardized protocols across laboratories.We thank Kim Nijsten for assistance with fluorescence imaging. This work was financially supported by a Flanders Innovation & Entrepreneurship (VLAIO) Baekeland Mandate (HBC.2021.0811)
Release of cardiac troponin I in antegrade crystalloid versus cold blood cardioplegia
No full textObjective: The purpose of this study was to assess the efficacy of myocardial protection, comparing antegrade crystalloid cardioplegia with cold blood cardioplegia, in patients with preserved left ventricular function who were undergoing elective first coronary artery bypass grafting, Release of cardiac troponin I was used as a marker for the effectiveness of myocardial protection, Methods: A consecutive series of 62 patients were randomly assigned to receive crystalloid or blood cardioplegia, Cardiac troponin I concentrations were determined in venous blood samples before the operation, immediately after unclamping, at 6, 9, 12, and 24 hours, and daily thereafter for 5 days, Results: Rising levels of troponin I were found in all patients. The time course and peak release were similar in the crystalloid cardioplegia and the blood cardioplegia groups. No patients in either group had electrocardiographic evidence of perioperative myocardial infarction, Cardiac troponin I was able to detect small areas of myocardial damage, not revealed by electrocardiography or creatine kinase MB release, Aprotinin administration was associated with lower cardiac troponin I release in both groups, Cardiac troponin I was lower in patients whose conditions did not require electrical defibrillation after aortic unclanlping, irrespective of cardioplegia type. The presence of a main stem lesion was associated with higher cardiac troponin I release only in the crystalloid cardioplegia group. Conclusions: Antegrade cold blood cardioplegia is equally effective as antegrade crystalloid cardioplegia in a randomized group of patients with preserved left ventricular function who were undergoing elective first coronary artery bypass grafting, Aprotinin administration resulted in lower cardiac troponin I release, whereas electrical defibrillation was related to a higher release irrespective of cardioplegia type, The presence of a main stem lesion resulted in higher cardiac troponin I release in the crystalloid cardioplegia group
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