• cardiac cell therapy
• meta-analysis
• mouse
• myocardial infarction

The long‐term outcomes of the intracoronary delivery of autologous bone marrow‐derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE‐AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo.

A 5 year follow‐up of major adverse cardiac events (defined as the composite of all‐cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC‐treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non‐cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group.

This 5 year follow‐up analysis of the REGENERATE‐AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.

• Cell- and Tissue-Based Therapy/methods
• Cell- and Tissue-Based Therapy/trends
• Heart Failure/mortality
• Heart Failure/therapy
• Hospitalization
• Humans
• Myocardial Infarction/therapy
• Observer Variation
• Quality of Life
• Randomized Controlled Trials as Topic
• Research Design
• Stroke Volume
• Systematic Reviews as Topic
• Treatment Outcome
• Ventricular Function, Left

• cardiomyopathy
• diabetes
• metformin
• stem cells

• AMP-Activated Protein Kinases/metabolism
• Animals
• Blood Glucose/drug effects
• Blood Glucose/metabolism
• Cell Movement/drug effects
• Cell Survival/drug effects
• Cells, Cultured
• Diabetes Mellitus, Experimental/blood
• Diabetes Mellitus, Experimental/chemically induced
• Diabetes Mellitus, Experimental/drug therapy
• Diabetes Mellitus, Experimental/metabolism
• Diabetic Cardiomyopathies/blood
• Diabetic Cardiomyopathies/etiology
• Diabetic Cardiomyopathies/pathology
• Diabetic Cardiomyopathies/surgery
• Disease Models, Animal
• Fibrosis
• Glycated Hemoglobin/metabolism
• Hypoglycemic Agents/toxicity
• Insulin/blood
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Metformin/toxicity
• Myocardium/metabolism
• Myocardium/pathology
• Neovascularization, Physiologic/drug effects
• Rats, Wistar
• Recovery of Function
• Streptozocin
• Rats

• 142265 Canadian Institute of Health Research
• MOP142265 CIHR

• cell transplantation
• heart failure
• meta-analysis
• myocardial infarction
• randomized controlled trials

• Angiogenesis
• Exosomes
• Ischemic heart diseases
• Microvesicles
• Non-ischemic heart diseases
• Stem cells

• Cardiac imaging techniques
• Cardiac regeneration
• End-points
• Ischemic cardiac disease
• Stem cell therapy

Several cell-based therapies for adjunctive treatment of acute myocardial infarction have been investigated in multiple clinical trials, but the timing of transplantation remains controversial. We conducted a meta-analysis of randomized controlled trials to investigate the effects of timing on bone marrow-derived cell (BMC) therapy in acute myocardial infarction (AMI).

A systematic literature search of PubMed, MEDLINE, and Cochrane Evidence-Based Medicine databases from January 2000 to June 2017 was performed on randomized controlled trials with at least a 3-month follow-up for patients with AMI undergoing emergency percutaneous coronary intervention (PCI) and receiving intracoronary BMC transfer thereafter. The defined end points were left ventricular (LV) ejection fraction, LV end-diastolic and end-systolic index. The data were analyzed to evaluate the effects of timing on BMC therapy.

Thirty-four RCTs comprising a total of 2,307 patients were included; the results show that, compared to the control group, AMI patients who received BMC transplantation showed significantly improved cardiac function. BMC transplantation 3–7 days after PCI (+3.32%; 95% CI, 1.91 to 4.74; P < 0.00001) resulted in a significant increase of left ventricular ejection fraction (LVEF). As for the inhibitory effect on ventricular remodeling, BMC transplantation 3–7 days after PCI reduced LV end-diastolic indexes (–4.48; 95% CI, −7.98 to –0.98; P = 0.01) and LV end-systolic indexes (–6.73; 95% CI, –11.27 to –2.19; P = 0.004). However, in the groups who received BMC transplantation either within 24 hours or later than 7 days there was no significant effect on treatment outcome. In subgroup analysis, the group with LVEF ≤ 50% underwent a significant decrease in LV end-diastolic index after BMC transplantation (WMD = –3.29, 95% CI, –4.49 to –2.09; P < 0.00001); the decrease was even more remarkable in the LV end-systolic index after BMC transplantation in the group with LVEF ≤ 50% (WMD = –5.25, 95% CI, –9.30 to –1.20; P = 0.01), as well as in patients who received a dose of 10^7–10^8 cells (WMD = –12.99, 95% CI, –19.07 to –6.91; P < 0.0001). In the group with a follow-up of more than 12 months, this beneficial effect was significant and increased to a more pronounced effect of +3.58% (95% CI, 1.55 to 5.61; P = 0.0006) when compared with control.

In this meta-analysis, BMC transfer at 3 to 7 days post-AMI was superior to transfer within 24 hours or more than 7 days after AMI in improving LVEF and decreasing LV end-systolic dimensions or LV end-diastolic dimensions. It is more effective in patients with lower baseline LVEF (≤50%) and the effect can last more than 12 months.

The online version of this article (doi:10.1186/s13287-017-0680-5) contains supplementary material, which is available to authorized users.

• Acute myocardial infarction (AMI)
• Bone marrow-derived cells (BMCs)
• Cell therapy
• Cells
• Meta-analysis

• Acute myocardial infarction
• Bone marrow stem cells
• Cardiac regeneration
• Cell therapy
• Remodeling

Standardization of stem cell therapy requires application of appropriate methods to evaluate safety and efficacy, including long‐term pharmacovigilance. To accomplish this objective, a long‐term registry programme was installed.

We analysed 150 patients with ischemic cardiomyopathy, who received intramyocardial CD133+ bone marrow mononuclear stem cell treatment combined with coronary artery bypass grafting (CABG) or CABG alone. The mortality rate, major adverse cerebral and cardiac events, and functional outcome parameters were evaluated for the time period up to 14 years follow‐up. As a result, we have stratified the patient population (96 patients) into responders and non‐responders. Furthermore, the analysis of relevant predictors of good response to CD133+ bone marrow mononuclear stem cell treatment was performed. Several positive tendencies related to stem cells transplantation were demonstrated. First, no significant difference in major adverse cardiovascular and cerebral events was observed between stem cell and control group up to 14 years follow‐up. Second, an improvement of left ventricle ejection fraction (LVEF) in stem cell group retained for 5 years in contrast with CABG‐only group, where no significant changes in LVEF after 2 years were observed. In addition, LVEF under 30% and left ventricle end diastolic diameter above 60 mm were independent predictors of functional response to CD133+ cell therapy.

Participants with overt heart failure benefit most from CABG combined with intramyocardial injection of CD133+ bone marrow mononuclear cell within the group. An improvement LVEF in stem cell group remained for 5 years in contrast with the CABG‐only group. The patients, in whom the improvement of both LVEF and LVED was observed, have benefited by increased life expectancy.

• CABG
• CD133+
• intramyocardial injection
• register
• responder
• stem cells

• Cardiovascular complications
• Diabetes mellitus
• Risk factors
• Sex-gender differences
• Therapeutic approaches

Mesenchymal stromal cells (MSCs) are considered to have a modest benefit on left ventricular ejection fraction (LVEF) in patients with acute myocardial infarction (AMI). However, the optimal injection timing and dose needed to induce beneficial cardiac effects are unknown. The purpose of this meta-analysis was to identify an optimal MSC transplantation time and cell dose in the setting of AMI to achieve better clinical endpoints.

The authors conducted a systematic review of studies published up to June 2016 by searching PubMed, EMBASE, MEDLINE, and the Cochrane Library for relevant randomized controlled trials (RCTs).

Eight prospective RCTs with 449 participants were included. The pooled results revealed that patients in the MSC group had no significant increase in LVEF from baseline compared with that in the control group (1.47% increase, 95% confidence interval (CI) −4.5 to 7.45; I² = 97%; P > 0.05). A subgroup analysis was conducted to explore the results according to differences in transplantation time and dose of MSCs injected. For transplantation timing, the LVEF of patients accepting a MSC infusion within 1 week was significantly increased by 3.22% (95% CI 1.31 to 5.14; I² = 0; P < 0.05), but this increase was insignificant in the group that accepted an MSC infusion after 1 week (−0.35% in LVEF, 95% CI −10.22 to 9.52; I² = 99%; P > 0.05). Furthermore, patients accepting a MSC dose of less than 10⁷ cells exhibited an LVEF improvement of 2.25% compared with the control (95% CI 0.56 to 3.93; I² = 9%; P < 0.05). Combining transplantation time and cell dose indicates that a significant improvement of LVEF of 3.32% was achieved in the group of patients injected with <10⁷ MSCs within 1 week (95% CI 1.14 to 5.50; I² = 0; P = 0.003).

Transplantation time and injected cell dose are key factors that determine the therapeutic effect of stem cell therapy. The injection of no more than 10⁷ MSCs within 1 week for AMI after percutaneous coronary intervention might improve left ventricular systolic function. Further studies on the mechanism and the effectiveness of MSCs for long-term therapy are warranted.

• Acute myocardial infarction
• Cell dose
• Mesenchymal stromal cell
• Transplantation timing

• Bone marrow-derived stem cell therapy
• Cardiac systolic function
• Follow-up
• Mortality rate
• Non-ischaemic dilated cardiomyopathy

• Adult Stem Cells/cytology
• Bone Marrow/physiology
• Bone Marrow Transplantation/methods
• Cardiomyopathy, Dilated/therapy
• Female
• Humans
• Male
• Middle Aged
• Randomized Controlled Trials as Topic
• Stem Cell Transplantation/methods
• Stroke Volume/physiology
• Ventricular Function, Left/physiology

• National Natural Science Foundation of China
• Shanghai Med-X Foundation

• heart failure
• meta-analysis
• myocardial infarction
• outcome measures
• stem cells

• Animals
• Clinical Trials as Topic
• Diabetes Complications/pathology
• Disease Models, Animal
• Humans
• Myocardial Ischemia/complications
• Myocardial Ischemia/therapy
• Risk Factors
• Stem Cell Transplantation/adverse effects

• Bone marrow cell
• Cell therapy
• Chronic ischemia
• Intramyocardial injection

• Aged
• Angina Pectoris/diagnosis
• Angina Pectoris/epidemiology
• Angina Pectoris/therapy
• Bone Marrow Transplantation/methods
• Cohort Studies
• Double-Blind Method
• Female
• Follow-Up Studies
• Humans
• Male
• Middle Aged
• Myocardial Ischemia/diagnosis
• Myocardial Ischemia/epidemiology
• Myocardial Ischemia/therapy
• Myocardium/pathology
• Predictive Value of Tests
• Treatment Outcome

• Cardiovascular Diseases/therapy
• Cell- and Tissue-Based Therapy/methods
• Diabetes Complications/therapy
• Humans

• Animals
• Blood Cells/cytology
• Blood Cells/physiology
• Cell Lineage/genetics
• Cell Lineage/physiology
• Endothelial Cells/cytology
• Endothelial Cells/physiology
• Hematopoiesis/genetics
• Hematopoietic Stem Cells/cytology
• Humans
• Mice
• Neovascularization, Physiologic/genetics
• Stem Cells/cytology
• Stem Cells/physiology

• R01 HL109602 NHLBI NIH HHS

• Aged
• Angina Pectoris/prevention & control
• Bone Marrow Cells
• Chronic Disease
• Coronary Circulation
• Cross-Over Studies
• Female
• Heart Function Tests
• Humans
• Injections
• Leukocytes, Mononuclear
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Myocardial Ischemia/diagnosis
• Myocardial Ischemia/physiopathology
• Myocardial Ischemia/therapy
• Myocardium
• Quality of Life
• Research Design
• Severity of Illness Index
• Tomography, Emission-Computed, Single-Photon
• Treatment Outcome
• Ventricular Function, Left

Cardiovascular disease remains the primary cause of death worldwide. In the US, deaths due to cardiovascular disease for women exceed those of men. While cultural and psychosocial factors such as education, economic status, marital status and access to healthcare contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored.

This article describes concepts, methods and procedures to assist in the design of animal and tissue/cell based studies of sex differences in cardiovascular structure, function and models of disease.

To address knowledge gaps, study designs must incorporate appropriate experimental material including species/strain characteristics, sex and hormonal status. Determining whether a sex difference exists in a trait must take into account the reproductive status and history of the animal including those used for tissue (cell) harvest, such as the presence of gonadal steroids at the time of testing, during development or number of pregnancies. When selecting the type of experimental animal, additional consideration should be given to diet requirements (soy or plant based influencing consumption of phytoestrogen), lifespan, frequency of estrous cycle in females, and ability to investigate developmental or environmental components of disease modulation. Stress imposed by disruption of sleep/wake cycles, patterns of social interaction (or degree of social isolation), or handling may influence adrenal hormones that interact with pathways activated by the sex steroid hormones. Care must be given to selection of hormonal treatment and route of administration.

Accounting for sex in the design and interpretation of studies including pharmacological effects of drugs is essential to increase the foundation of basic knowledge upon which to build translational approaches to prevent, diagnose and treat cardiovascular diseases in humans.

Faced with the end stage of heart disease, the current treatments only slow worsening of heart failure. Stem cells have the potential of self-renewal and differentiation. It is expected to replace and repair damaged myocardium. But many clinical trials have shown that the stem cell therapy of heart failure is modest or not effective. The possible causes for the limited effects of stem cell in curing heart failure are the stem cells which have been transplanted into the ischemic heart muscle may suffer low survival rate, affected by inflammatory molecules, proapoptotic factor, and lack of nutrients and oxygen, and then the stem cells which home and have been completely transplanted to the site of myocardial infarction become very small. Therefore, through preconditioning of stem cells and appropriate choice of genes for mesenchymal stem cell modification to improve the survival rate of stem cells, ability in homing and promoting angiogenesis may become the newly effective strategies for the application of stem cells therapy in heart failure.