• Acute myocardial infarction
• Cell therapy
• Systematic review

• Humans
• Myocardial Infarction/physiopathology
• Myocardial Infarction/therapy
• Randomized Controlled Trials as Topic
• Stem Cell Transplantation/adverse effects
• Stem Cell Transplantation/methods
• Stroke Volume/physiology
• Treatment Outcome
• Ventricular Function, Left/physiology

• Innovative Regenerative Medicine Clinical Research Support Program the Ministry of Health and Welfare

• Adult
• Aged
• Female
• Humans
• Male
• Middle Aged
• Angina Pectoris/therapy
• Bone Marrow Transplantation/methods
• Quality of Life
• Transplantation, Autologous
• Treatment Outcome
• Clinical Trials, Phase II as Topic
• Randomized Controlled Trials as Topic

• Biological sciences
• Developmental biology
• Molecular biology

• cardiovascular therapeutics
• cell-based therapy
• extracellular vesicles
• mesenchymal stem cells (MSCs)
• regenerative medicine

• Humans
• Mesenchymal Stem Cells/cytology
• Cardiovascular Diseases/therapy
• Mesenchymal Stem Cell Transplantation/methods
• Animals
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/transplantation
• Cell- and Tissue-Based Therapy/methods

• 940594 / Narasimman Gurusamy / 2022 American Heart Association

• Acute myocardial infarction
• CD14++CD16+ monocytes
• Collateral circulation
• Left ventricular remodeling
• Vascular endothelial growth factor

• Endothelial cell
• Macrophage
• Mesenchymal cell
• Myocardial ischemia/reperfusion injury
• Single-cell RNA sequencing

• Mice
• Animals
• Humans
• Endothelial Cells
• Ventricular Remodeling
• Heart
• Reperfusion Injury
• Antigens, CD34
• Ischemia

• National Natural Science Foundation of China

• heart failure
• inflammation
• left ventricular remodeling
• myocardial infarction
• neurohormonal activation
• wall stress

• Exosomes
• Mesenchymal stem cells (MSCs)
• Skin photoaging
• Skin rejuvenation
• Stem cell therapy

• Fibroblasts
• Humans
• Mesenchymal Stem Cells
• Skin
• Skin Aging
• Ultraviolet Rays/adverse effects

• Acute myocardial infarction
• Bone marrow mesenchymal stem cells
• Bone marrow mononuclear cells
• Cardiac function
• Muse cells

• CD34 antigens
• RNA sequence analysis
• endothelial cells
• fluorescent antibody technique
• microRNAs
• smad proteins
• vascular system injuries

• Autologous stem cells
• Cell therapy
• Diabetes
• Ischemic heart disease
• Microvessicles
• Regenerative potential

• Extracellular matrix
• Injectable hydrogels
• Myocardial infarction
• Translational studies

• adult stem cells
• bone marrow cells
• cell therapies
• heart failure
• pluripotent cells (Min5–Max 8)

• angiogenesis
• ischemic heart disease
• mesenchymal stem cells
• neovascularization
• vasculogenesis

Background: The aim of this study was to investigate the effectiveness of bone marrow-derived cells (BMC) technology in patients with heart failure and compare it with alternative therapies, including drug therapy, cardiac resynchronization therapy pacemaker (CRT-P), cardiac resynchronization therapy defibrillator (CRT-D).

Methods: A systematic review study was conducted to identify all clinical studies published by 2017. Using keywords such as "Heart Failure, BMC, Drug Therapy, CRT-D, CRT-P" and combinations of the mentioned words, we searched electronic databases, including Scopus, Cochrane Library, and PubMed. The quality of the selected studies was assessed using the Cochrane Collaboration's tool and the Newcastle-Ottawa. The primary and secondary end-points were left ventricular ejection fraction (LVEF) (%), failure cases (Number), left ventricular end-systolic volume (LVES) (ml), and left ventricular end-diastolic volume (LVED) (ml). Random-effects network meta-analyses were used to conduct a systematic comparison. Statistical analysis was done using STATA.

Results: This network meta-analysis covered a total of 57 final studies and 6694 patients. The Comparative effectiveness of BMC versus CRT-D, Drug, and CRT-P methods indicated the statistically significant superiority of BMC over CRT-P (6.607, 95% CI: 2.92, 10.29) in LVEF index and overall CRT-P (-13.946, 95% CI: -18.59, -9.29) and drug therapy (-4.176, 95% CI: -8.02, -.33) in LVES index. In addition, in terms of LVED index, the BMC had statistically significant differences with CRT-P (-10.187, 95% CI: -18.85, -1.52). BMC was also dominant to all methods in failure cases as a final outcome and the difference was statistically significant i.e. BMC vs CRT-D: 0.529 (0.45, 0.62) and BMC vs Drug: 0.516 (0.44, 0.60). In none of the outcomes, the other methods were statistically more efficacious than BMC. The BMC method was superior or similar to the other methods in all outcomes.

Conclusion: The results of this study showed that the BMC method, in general, and especially in terms of failure cases index, had a higher level of clinical effectiveness. However, due to the lack of data asymmetry, insufficient data and head-to-head studies, BMC in this meta-analysis might be considered as an alternative to existing treatments for heart failure.

• Bone marrow cell
• CRT-D
• CRT-P
• Drug
• Heart failure
• Network meta-analysis

Aging increases risk for ischemic vascular diseases. Bone marrow–derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. Activation of either the Mas receptor (MasR) by angiotensin-(1-7) (Ang-(1-7)) or angiotensin-converting enzyme-2 (ACE2) stimulates vasoreparative functions in HSPCs. This study tested if aging is associated with decreased ACE2 expression in HSPCs and if Ang-(1-7) restores vasoreparative functions. Flow cytometric enumeration of Lin⁻CD45^lowCD34⁺ cells was carried out in peripheral blood of male or female individuals (22–83 years of age). Activity of ACE2 or the classical angiotensin-converting enzyme (ACE) was determined in lysates of HSPCs. Lin⁻Sca-1⁺cKit⁺ (LSK) cells were isolated from young (3–5 months) or old (20–22 months) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7), and mobilization of HSPCs was determined following ischemia induced by femoral ligation. A laser Doppler blood flow meter was used to determine blood flow. Aging was associated with decreased number (Spearman r = − 0.598, P < 0.0001, n = 56), decreased ACE2 (r = − 0.677, P < 0.0004), and increased ACE activity (r = 0.872, P < 0.0001) (n = 23) in HSPCs. Migration or proliferation of LSK cells in basal or in response to stromal-derived factor-1α in old cells is attenuated compared to young, and these dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in young mice, and blood flow to ischemic areas was recovered. These responses were impaired in old mice but were restored by treatment with Ang-(1-7). These results suggest that activation of ACE2 or MasR would be a promising approach for enhancing ischemic vascular repair in aging.

• ACE2
• Aging
• Angiotensin-(1-7)
• Hematopoietic stem/progenitor cells
• Ischemia

• Advanced heart failure
• Chronic heart failure
• LVAD
• Stem cell therapy

• cell therapy
• ischemic cardiomyopathy
• non-ischemic cardiomyopathy
• stem cells

• O-hMSC transplantation
• SIRT3
• aging
• gene modification
• myocardial infarction
• myocardial repair

• MAPK/ERK signaling
• PI3K/Akt signaling
• cardiac c-Kit+ progenitor cells
• cardiac dysfunction
• cardiomyocyte differentiation
• cardiomyocyte renewal
• heart failure
• mesenchymal stem cells
• myocardial regeneration potential
• stem cell-based therapy

• Cardiac surgical procedures
• Fibrotic scar
• Myocardial infarction
• Stem cell transplantation

• controlled release
• drug delivery
• exosomes
• extracellular vesicles
• injectable hydrogels

• Acute myocardial infarction
• Atorvastatin
• Mesenchymal stem cells
• Multiple administrations
• Timing

• Acute Disease
• Animals
• Atorvastatin/pharmacology
• Atorvastatin/therapeutic use
• Disease Models, Animal
• Humans
• Male
• Mesenchymal Stem Cells/metabolism
• Myocardial Infarction/drug therapy
• Rats
• Time Factors

• R03 AA020101 NIAAA NIH HHS

• cell- and tissue-based therapy
• clinical trial
• heart diseases
• heart failure

The epicardial surface of the heart is readily accessible during cardiac surgery and presents an opportunity for therapeutic intervention for cardiac repair and regeneration. As an important anatomic niche for endogenous mechanisms of repair, targeting the epicardium using decellularized extracellular matrix (ECM) bioscaffold therapy may provide the necessary environmental cues to promote functional recovery. Following ischemic injury to the heart caused by myocardial infarction (MI), epicardium derived progenitor cells (EPDCs) become activated and migrate to the site of injury. EPDC differentiation has been shown to contribute to endothelial cell, cardiac fibroblast, cardiomyocyte, and vascular smooth muscle cell populations. Post-MI, it is largely the activation of cardiac fibroblasts and the resultant dysregulation of ECM turnover which leads to maladaptive structural cardiac remodeling and loss of cardiac function. Decellularized ECM bioscaffolds not only provide structural support, but have also been shown to act as a bioactive reservoir for growth factors, cytokines, and matricellular proteins capable of attenuating maladaptive cardiac remodeling. Targeting the epicardium post-MI using decellularized ECM bioscaffold therapy may provide the necessary bioinductive cues to promote differentiation toward a pro-regenerative phenotype and attenuate cardiac fibroblast activation. There is an opportunity to leverage the clinical benefits of this innovative technology with an aim to improve the prognosis of patients suffering from progressive heart failure. An enhanced understanding of the utility of decellularized ECM bioscaffolds in epicardial repair will facilitate their growth and transition into clinical practice. This review will provide a summary of decellularized ECM bioscaffolds being developed for epicardial infarct repair in coronary artery bypass graft (CABG) surgery.

• biomaterials
• bioscaffold
• cardiac surgery
• epicardium
• extracellular matrix
• heart failure
• myocardial infarction

• cardiovascular disease
• cardiac fibrosis
• fibrosis
• therapeutics
• therapies

• granulocyte colony-stimulating factor
• left ventricular remodeling
• myocardial infarction
• percutaneous coronary intervention
• standard of care

• ACE2
• CD34+ cells
• Mas receptor
• hypoxia

• cardiovascular diseases
• cell therapy
• regeneration
• scaffolds

• Bioprinting
• Humans
• Immunomodulation
• Printing, Three-Dimensional
• Regeneration/physiology
• Tissue Engineering/methods
• Tissue Scaffolds/chemistry

It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia.

This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3‑month and P = 0.15 at 12-month follow-up).

Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia.

Clinical Trial Registration: NTR2516

The online version of this article (10.1007/s12471-018-1213-2) contains supplementary material, which is available to authorized users.

• Bone marrow cells
• Chronic heart failure
• Ischaemia

• Bone marrow mononuclear cells
• Cardiac stem cells
• Heart failure

• Cell therapy
• Extracellular vesicle
• Glycolysis
• Heart failure
• Metabolism
• Mitochondria

• Animals
• Diabetes Mellitus, Experimental
• Female
• Male
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction
• Myocardium/metabolism
• Myocardium/pathology

• P50 HL120163 NHLBI NIH HHS
• R01 ES028268 NIEHS NIH HHS
• U54 HL120163 NHLBI NIH HHS
• P30 GM127607 NIGMS NIH HHS
• R01 ES019217 NIEHS NIH HHS
• R01 HL130174 NHLBI NIH HHS
• UM1 HL113530 NHLBI NIH HHS
• P20 GM103492 NIGMS NIH HHS
• P01 HL078825 NHLBI NIH HHS
• R01 HL055477 NHLBI NIH HHS
• R56 HL122580 NHLBI NIH HHS

Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.

• cardiac clinical trials
• cardiac regeneration
• cell therapy
• heart dysfunction
• heart failure
• stem cells
• translational medicine

• Angiogenesis
• Ischaemic heart disease
• LncRNAs
• Therapeutic angiogenesis

Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. However, the possible mechanisms underlying its influence are unknown. We hypothesized that SIRT3 increases the antioxidant capacity of aged cells and improves the efficacy of human mesenchymal stem cell (hMSC) therapy for ischaemic heart diseases in aged patients. In vitro, the antioxidant capacity of old hMSCs (O‐hMSCs) was increased after SIRT3 overexpression using a gene transfection technique, while the antioxidant capacity of young hMSCs (Y‐hMSCs) was decreased by SIRT3 silencing. The levels of forkhead box O3a (FoxO3a) in the nucleus, and antioxidant enzymes Mn‐superoxide dismutase (MnSOD) and catalase (CAT) increased in SIRT3‐overexpressed O‐hMSCs while they decreased in SIRT3‐silenced Y‐hMSCs after oxidative stress. Following myocardial infarction in adult rats in vivo, infarct size decreased and cardiac function was significantly enhanced after cell transplantation with SIRT3 overexpressed O‐hMSCs. The number of apoptotic cells decreased and the survival rate of transplanted cells increased following SIRT3 overexpression in O‐hMSCs. SIRT3 protects aged hMSCs against oxidative stress by positively regulating antioxidant enzymes (MnSOD and CAT) via increasing the expression of FoxO3a in the nucleus. The efficacy of aged hMSC transplantation therapy for ischaemic heart diseases can be improved by SIRT3 overexpression.

• ageing
• antioxidant capacity
• cell transplantation
• gene modification
• human mesenchymal stem cells

• Editorials
• endothelial progenitor cells
• mesenchymal stromal cells
• mortality
• regeneration

• Cardiomyocyte proliferation
• Dynamics of renewal
• Retrospective radiocarbon dating

• Schwann cell
• nerve conduction velocity
• signaling

• Cardiovascular diseases
• aptamers
• exosomes
• immunotherapy
• nanomedicine
• stem cells
• treatment modalities

Coronary artery disease (CAD) is one of the most common causes of death worldwide. In the last decade, significant advancements in CAD treatment have been made. The existing treatment is medical, surgical or a combination of both depending on the extent, severity and clinical presentation of CAD. The collaboration between different science disciplines such as biotechnology and tissue engineering has led to the development of novel therapeutic strategies such as stem cells, nanotechnology, robotic surgery and other advancements (3-D printing and drugs). These treatment modalities show promising effects in managing CAD and associated conditions. Research on stem cells focuses on studying the potential for cardiac regeneration, while nanotechnology research investigates nano-drug delivery and percutaneous coronary interventions including stent modifications and coatings. This article aims to provide an update on the literature (in vitro, translational, animal and clinical) related to these novel strategies and to elucidate the rationale behind their potential treatment of CAD. Through the extensive and continued efforts of researchers and clinicians worldwide, these novel strategies hold the promise to be effective alternatives to existing treatment modalities.

• heart
• stem cells
• surgery
• treatment modality

• Animals
• Biotechnology
• Cell- and Tissue-Based Therapy
• Coronary Artery Disease/drug therapy
• Coronary Artery Disease/surgery
• Coronary Artery Disease/therapy
• Drug Delivery Systems
• Humans
• Nanotechnology
• Stem Cells
• Stents
• Tissue Engineering

It is postulated that the ability of dipeptidyl peptidase-4 inhibitors (DPP-4-i) to increase circulating endothelial progenitor cells (EPCs) may be at least partly mediated by active stromal cell–derived factor 1α (SDF-1α) (a pivotal mediator of stem cell mobilization from the bone marrow). As other DPP-4-i were demonstrated to increase EPC concentrations, in this study, we sought to investigate the ability of the DPP-4-i alogliptin in modifying EPCs and SDF-1α, in patients with good and poor diabetes control.

Two groups of diabetic patients on metformin were divided by hemoglobin A_1c (HbA_1c): Group A—those with HbA_1c ≤6.5% (28 patients) and Group B—those with HbA_1c 7.5% to 8.5% (31 patients). Both groups received alogliptin 25 mg/daily for 4 months. At baseline and 4 months later, clinical, laboratory parameters, EPCs, and active SDF-1α were determined.

After 4-month treatment with alogliptin, either Group A or Group B showed reduced HbA_1c levels and concomitant similar increase in EPCs and active SDF-1α.

Alogliptin showed significant benefits in increasing EPCs and active SDF-1α either in good or poor diabetes control. The study demonstrated that similar to other DPP-4-i, also alogliptin is able to increase EPC concentrations, suggesting the existence of a class effect mediated by SDF-1α. The extent of increase in EPCs is independent from baseline diabetes control.

• DPP-4 inhibitors
• Diabetes
• SDF-1α
• alogliptin
• endothelial progenitor cells
• metformin