Tranexamic acid is associated with improved hemostasis in elderly patients undergoing coronary-artery surgeries in a retrospective cohort study.

Background: More elderly patients undergo coronary artery bypass surgery (CABG) than younger patients. Whether tranexamic acid (TA) is still effective and safe in elderly patients undergoing CABG surgeries is still unclear. Methods: In this study, a cohort of 7,224 patients ≥70 years undergoing CABG surgery were included. Patients were categorized into the no TA group, TA group, high-dose group, and low-dose group according whether TA was administered and the dose administered. The primary endpoint was blood loss and blood transfusion after CABG. The secondary endpoints were thromboembolic events and in-hospital death. Results: The blood loss at 24 and 48 h and the total blood loss after surgery in patients in the TA group were 90, 90, and 190 ml less than those in the no-TA group, respectively (p < 0.0001). The total blood transfusion was reduced 0.38-fold with TA administration compared to that without TA (OR = 0.62, 95% CI 0.56-0.68, p < 0.0001). Blood component transfusion was also reduced. High-dose TA administration reduced the blood loss by 20 ml 24 h after surgery (p = 0.032) but had no relationship with the blood transfusion. TA increased the risk of perioperative myocardial infarction (PMI) by 1.62-fold [p = 0.003, OR = 1.62, 95% CI (1.18-2.22)] but reduced the hospital stay time in patients who were administered TA compared to that of patients who did not receive TA (p = 0.026). Conclusion: We revealed that elderly patients undergoing CABG surgeries had better hemostasis after TA administration but increased the risk of PMI. High-dose TA was effective and safe compared with low-dose TA administration in elderly patients undergoing CABG surgery.

Impact of gender differences on hemostasis in patients after coronary artery bypass grafts surgeries in the context of tranexamic acid administration.

BACKGROUND: Sex differences present in the blood management of patients after coronary artery bypass grafts (CABG) surgeries. Tranexamic acid (TXA) performed well in maintaining hemostasis during and after surgeries. However, the impact of sex differences on blood control after CABG in patients who received TXA was not investigated. METHODS: Overall, 29,536 patients undergoing CABG with TXA administration from 2009 to 2019 in our hospital were included. Propensity score matching was performed. Finally, 6808 males and 6808 females were matched based on 23 covariates. RESULTS: Female patients had a 0.36-fold lower incidence of reoperations due to major hemorrhage or cardiac tamponade compared to males (1.3% vs. 2.0%, p = 0.001, OR = 0.64, 95%CI = 0.49-0.84). Females had a median of 100 ml less blood loss in 24 h (median 360 vs. 460 ml, p < 0.0001), 150 ml less in 48 h (median 580 vs. 730 ml, p < 0.0001), and 180 ml less in total (median 760 vs. 940 ml, p < 0.0001) than male patients. The red blood cell (RBC) transfusion rate in female was 1.53-fold higher than that in male (33.0% vs. 21.6%, OR = 1.53, 95% CI = 1.43-1.63, p < 0.0001). Females also had higher morbidities than males after CABGs. CONCLUSIONS: Females had less blood loss than males after CABG with the TXA treatment. Females still had a higher RBC transfusion rate after surgery. Morbidities in women were also higher than that in men.

Tranexamic Acid Administered During Off-Pump Coronary Artery Bypass Graft Surgeries Achieves Good Safety Effects and Hemostasis.

BACKGROUND: Tranexamic acid (TXA) administered during off-pump coronary artery bypass (OPCAB) surgeries has achieved good blood control in small cohorts. We aimed to investigate the safety issues and hemostasis associated with TXA administration during OPCAB in a large retrospective cohort study. METHODS: This study included 19,687 patients with OPCAB from 2009 to 2019. A total of 1,307 patients were excluded because they were younger than 18 years or certain values were missing. Among the remaining 18,380 patients, 10,969 were in the TXA group and 7,411 patients were in the no-TXA group. There were 4,889 patients whose TXA dose was ≥50 mg/kg, and the remaining 6,080 patients had a TXA dose of <50 mg/kg. Propensity score matching (PSM) was performed between the TXA and no-TXA groups and between the high-dose and low-dose groups, and statistical analysis was performed. RESULTS: Tranexamic acid administration did not increase the risk of hospital death or thromboembolic events. Patients who administered TXA had less blood loss at 24 h (478.32 ± 276.41 vs. 641.28 ± 295.09, p < 0.001) and 48 h (730.59 ± 358.55 vs. 915.24 ± 390.13, p < 0.001) and total blood loss (989.00 ± 680.43 vs. 1,220.01 ± 720.68, p < 0.001) after OPCAB than the patients with non-TXA. Therefore, the risk of total blood exposure [odds ratio (OR) = 0.50, 95% CI 0.47-0.54, p < 0.001] or blood component exposure (p < 0.001) was decreased significantly in the patients who administered TXA. The TXA dosage did not impact the patient survival, thromboembolic events, or blood management. CONCLUSIONS: The application of TXA was safe and provided blood control in patients with OPCAB, and the dosage did not affect these parameters.

Blood conservation outcomes and safety of tranexamic acid in coronary artery bypass graft surgery.

BACKGROUND: The safety and blood management effects of Tranexamic acid (TXA) and its dose effects in coronary artery bypass graft (CABG) were still ambiguous. This study aimed to analyze these TXA effects. METHODS: Overall, 42,010 patients undergoing CABG were enrolled in this retrospective cohort study. Patients were assigned to the TXA group (n = 29,536) and the no-TXA group (n = 12,474). Furthermore, the TXA group was divided into the high-dose (≥50 mg/kg) (16,488) and the low-dose (<50 mg/kg) (13,048) subgroup. Propensity score matching was performed in both groups respectively. The primary endpoint after CABG was composed of hospital death, perioperative myocardial infarction (PMI), stroke, acute kidney injury (AKI), and pulmonary embolism. The secondary endpoint included blood loss and blood transfusion after surgery. RESULTS: TXA led to a 1.40-fold risk of PMI (p < 0.001). Patients in the TXA group had fewer re-operations for bleeding or tamponade [Odd ratio (OR) = 0.82, p = 0.044], less blood loss after surgery (p < 0.001), and a lower risk for blood transfusion exposure (OR = 0.45, p < 0.001) than those in the no-TXA group. The high-dose TXA reduced blood loss after cardiac surgery compared to the low-dose TXA (p < 0.001) with no associations with blood exposure or adverse events. CONCLUSIONS: The use of TXA during CABG increased the risk of PMI despite better blood control after surgery. The high dose of TXA acquired better bleeding management. Meanwhile, it did not increase the risk of primary endpoint.

No-Touch Versus Conventional Vein Harvesting Techniques at 12 Months After Coronary Artery Bypass Grafting Surgery: Multicenter Randomized, Controlled Trial.

BACKGROUND: Vein graft occlusion is deemed a major challenge in coronary artery bypass grafting. Previous studies implied that the no-touch technique for vein graft harvesting could reduce occlusion rate compared with the conventional approach; however, evidence on the clinical benefit and generalizability of the no-touch technique is scare. METHODS: From April 2017 to June 2019, we randomly assigned 2655 patients undergoing coronary artery bypass grafting at 7 hospitals in a 1:1 ratio to receive no-touch technique or conventional approach for vein harvesting. The primary outcome was vein graft occlusion on computed tomography angiography at 3 months and the secondary outcomes included 12-month vein graft occlusion, recurrence of angina, and major adverse cardiac and cerebrovascular events. The generalized estimate equation model was used to account for the cluster effect of grafts from the same patient. RESULTS: During the follow-up, 2533 (96.0%) participants received computed tomography angiography at 3 months after coronary artery bypass grafting and 2434 (92.2%) received it at 12 months. The no-touch group had significantly lower rates of vein graft occlusion than the conventional group both at 3 months (2.8% versus 4.8%; odds ratio, 0.57 [95% CI, 0.41-0.80]; P<0.001) and 12 months (3.7% versus 6.5%; odds ratio, 0.56 [95% CI, 0.41-0.76]; P<0.001). Recurrence of angina was also less common in the no-touch group at 12 months (2.3% versus 4.1%; odds ratio, 0.55 [95% CI, 0.35-0.85]; P<0.01). Rates of major adverse cardiac and cerebrovascular events were of no significant difference between the 2 groups. The no-touch technique was associated with higher rates of leg wound surgical interventions at 3-month follow-up (10.3% versus 4.3%; odds ratio, 2.55 [95% CI, 1.85-3.52]; P<0.001). CONCLUSIONS: Compared with the conventional vein harvesting approach in coronary artery bypass grafting, the no-touch technique significantly reduced the risk of vein graft occlusion and improved patient prognosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03126409.

Ligustrazine Protects Homocysteine-Induced Apoptosis in Human Umbilical Vein Endothelial Cells by Modulating Mitochondrial Dysfunction.

Ligustrazine is one of the alkaloid compounds isolated from the traditional Chinese herb, which shows protective effects on cardiovascular disorders. High homocysteine (Hcy) level can predict cardiovascular-related events including death. In this study, we used Hcy to stimulate the human umbilical vein endothelial cells (HUVECs) and investigated the protective effect of ligustrazine on endothelial dysfunction by assessing the cell apoptosis, oxidative damage, mitochondrial dysfunction, and the potential molecular pathways. Our results clearly showed that ligustrazine increased HUVEC cell viability, decreased the dehydrogenase (LDH) level, and inhibited HUVEC apoptosis, which was associated with the attenuation of attenuated oxidative damage. The mitochondrial-dependent pathway was closely related in the regulation of ligustrazine, reflected by the attenuated mitochondrial membrane potential change and decreased cytochrome c release from the mitochondria to the cytosol. Ligustrazine may protect Hcy-induced apoptosis in HUVECs by attenuating oxidative damage and modulating mitochondrial dysfunction.

Minor alleles of genetic variants in second heart field increase the risk of hypoplastic right heart syndrome.

Hypoplastic right heart syndrome(HRHS) is characterized by hypoplastic right ventricle (RV); Numerous transcriptional cascades in the second heart field (SHF) regulate RVdevelopment. The relationship of SHF gene variants with human HRHS remains unknown. The whole lengths of 17 SHF genes were sequenced in 16 HRHS, and the selected single-nucleotide variants (SNVs) were then genotyped in HRHS, other congenital heart disease (CHD) and healthy control. Luciferase assay was performed to verify the effect of FOXC2: rs34221221A>GandTBX20: rs59854940C>Gat the transcription level. There were 151 (12.86%) novel SNVs after sequence analysis, of which three were in exons (one was synonymous SNV and two were nonsynonymous SNVs), two in promoter, and most SNVs (89.95%) were in intronic regions. Genotype analyses revealed that the minor alleles of FOXC2: rs34221221 A>G and TBX20: rs59854940 C>G could increase HRHS risk (P<0.05), but not in other CHD or healthy control. Luciferase assay showed that the minor G allele in rs34221221 significantly increased FOXC2 transcription while in rs59854940 it decreased TBX20 transcription significantly. Novel variants of SHF gene associated with HRHS were identified. Minor alleles in two variants from FOXC2 and TBX20 could increase the risk of HRHS.

Intronic Polymorphisms in Gene of Second Heart Field as Risk Factors for Human Congenital Heart Disease in a Chinese Population.

Transcriptional factors and signaling factors in the second heart field (SHF) contribute to cardiac development. However, the associations of intronic gene variants in the SHF with congenital heart disease (CHD) remain ununderstood. Ten single nucleotide polymorphisms (SNPs) from our previous sequencing data were selected and then genotyped in 383 CHD patients and 384 healthy controls in a Chinese population. Genotype analyses revealed that minor alleles in TBX1: rs12165908 C > G [odds ratio (OR) = 2.64; 95% confidence interval (CI) = 1.87-3.73, p = 3.03 × 10-8] and GATA6: rs143085291 C > T (OR = 2.49; 95% CI = 1.18-5.29, p = 0.01) increased CHD risk significantly. Meanwhile, FGF10: rs78454549 T > C and GATA4: rs13275657 A>G polymorphisms were significantly associated with increased risk of simple CHDs. The minor allele C in GATA4: rs17153694 T > C increased the risk of tetralogy of Fallot, whereas minor alleles in TBX1: rs41298006 G>A, FGF10: rs75629618 C>T, FGF10: rs10461755 G>A, FGF10: rs75632187 A>G, and FGF10: rs12518964 G > A were associated with increased risk of single ventricle. The minor allele T in rs143085291 in GATA6 enhancer decreased the transcription level in luciferase assay. Our findings suggest that intronic SNPs in transcriptional factors and signaling factors in the SHF are significantly associated with increased risk of different CHD types.

A Giant Right Coronary Artery Aneurysm Leading to Tricuspid Stenosis.

Giant coronary artery aneurysms (CAAs) are rare coronary artery anomalies. The management of CAAs is still controversial because of the different possible pathophysiologies. In our case, tricuspid stenosis resulting from compression of the giant CAA was successfully relieved by CAA repair. As far as we know, this is the first reported case of compression by a giant CAA resulting in tricuspid stenosis.

Surgical outcome after complete repair of tetralogy of Fallot with absent pulmonary valve: comparison between bovine jugular vein-valved conduit and monocusp-valve patch.

BACKGROUND: The prognosis of tetralogy of Fallot with absent pulmonary valve (TOF/APV) without operation is poor. We evaluated the surgical outcome of TOF/APV in a single center. METHODS: Twenty-two TOF/APV patients underwent complete surgical correction in our hospital. Right ventricular outflow tract reconstruction was performed using bovine jugular vein (BJV)-valved conduit implantation (n = 10), homograft-valved conduit implantation (n = 2), or monocusp-valve patch (n = 10). Health-related quality of life (QOL) was evaluated during follow-up. RESULTS: The overall survival at 5 and 10 years was 86.4 ± 7.3% (confidence interval 69.4-97.2%). The survival rates were significantly different between patients with and without bronchial stenosis (40 and 100%, P = 0.0003, log-rank test). The survival of patients aged > 6 months was higher than those ≤ 6 months (100 vs. 40%, P = 0.0003, log-rank test). Patients with BJV-valved conduits had higher systolic gradients from the right ventricle to the pulmonary artery (RV-PA) compared to those with monocusp-valve patches. BJV-valved conduit implantation was a risk factor for post-operative pulmonary-valve stenosis. The QOL score for patients with BJV-valved conduits was lower than those with monocusp-valve patches (P < 0.05). No reoperation was performed during follow-up. CONCLUSIONS: Bronchial stenosis and lower age (≤ 6 months) were the main factors influencing post-operative survival. The use of a BJV-valved conduit was a main reason for RV-PA restenosis; thus, the use of a BJV-valved conduit may increase the need for repeat intervention and decrease the post-operative quality of life.

Effect analysis of repeat sternotomy in pediatric cardiac operations.

BACKGROUND: Reoperation for congenital heart disease may be associated with cardiac or vascular injuries during repeat sternotomy, resulting in increased mortality and/or morbidity rates. The aim of this study was to determine the frequency of these cardiac injuries and the associated outcome. METHODS: Between January 2012 and December 2013, 4256 sternotomy procedures were performed at the Pediatric Cardiac Center in Fuwai Hospital, including 195 repeat sternotomy procedures (RS). We retrospectively studied the clinical data of 195 RS patients and 250 randomly selected primary sternotomy (PS) patients. Demographic and operative details, major injures (MI), and clinical outcomes were compared between the two groups. We also assessed the risk factors for major injury and in-hospital mortality and morbidity. RESULTS: Significant differences were observed between the RS and PS groups in terms of skin incision to cardiopulmonary bypass(CPB) time, overall CPB time, cross-clamp time and blood requirement, and ventilation time (p < 0.001). MI during RS occurred in 7 of the 195 patients (3.6 %), while operative mortality was 1.0 % (2/195). However, in the RS patients, mortality and morbidity rates were not significantly different between the MI subgroup and the non-MI subgroup (p = 1.000 and 0.556, respectively). Additionally, no significant difference was found between the RS and PS groups in terms of mortality (p = 1.000) and morbidity (p = 0.125). CONCLUSIONS: Both RS and MI are not associated with increased risk of operative mortality and morbidity. Outcomes for reoperative pediatric operations in contemporary practice are similar with those for primary operations.

Telocytes and putative stem cells in ageing human heart.

Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days-1 year), children (6-17 years) and adults (34-60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm(2) ) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52-62%; vascular smooth muscle cells and pericytes 22-28%, Schwann cells with nerve endings 6-7%, fibroblasts 3-10%, macrophages 1-8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults).

MicroRNA-21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs.

BACKGROUND: Coronary atherosclerotic unstable plaque is one of the leading causes of cardiovascular death. Macrophage-derived matrix metalloproteinase (MMP) 9 is considered for degrading extracellular matrix and collagen, thereby thinning the fibrous cap in plaques. miR-21 is implicated to play an important role in the progression of atherosclerosis. Nevertheless, miR-21 as the biomarker for coronary atherosclerotic unstable plaque remains unknown. We aimed to investigate the prediction role of miR-21 for unstable plaque by pathway study of miR-21 on MMPs and its inhibitor RECK in macrophages. METHODS: Expression of miR-21 in macrophages and serum miR-21 as well as MMP-9 was measured in patients with coronary non-calcified plaque, calcified plaque and controls. In vitro experiment was done in human macrophages by over-expressing miR-21 or down-regulating RECK. The regulation of RECK and MMP-9 by miR-21 was evaluated by western blotting and siRNA strategy. RESULTS: Patients with non-calcified coronary artery lesions had significantly higher miR-21 in macrophages and lower miR-21 serum levels compared to the control and calcified plaque patients. At the same time, the serum levels of MMP-9 were significantly elevated in non-calcified patients. Experiments in vitro indicated that over-expressing miR-21 could induce the expression and secretion of pro-MMP-9 and active-MMP-9 in human macrophages via targeting gene RECK, and knocking down RECK expression by specific siRNA can resemble that of miR-21 over-expression. CONCLUSIONS: miR-21 might be a biomarker for plaque instability by suppressing target gene RECK to promote the expression and secretion of MMP-9 in macrophages.

Polymorphisms of VEGF, TGFß1, TGFßR2 and conotruncal heart defects in a Chinese population.

Genetic variants may determine susceptibility of congenital heart disease (CHD). To evaluate the impact of transforming growth factor-ß1 (TGFß1), TGFß receptor II (TGFßR2) and vascular endothelial growth factor (VEGF) polymorphisms on conotruncal heart defects susceptibility, we genotyped six functional polymorphisms TGFß1 rs1800469 C>T, TGFßR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T in a hospital based case-control study of 244 conotruncal heart defects cases and 136 non-CHD controls in a Chinese population. Logistic regression analyses revealed that if the TGFß1 rs1800469 CC homozygote genotype was used as the reference group, subjects carrying the CT variant heterozygote had a significant 0.48-fold decreased risk of conotruncal heart defects [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.30-0.88], subjects carrying the TT variant homozygote had a significant 0.47-fold decreased risk of conotruncal heart defects (OR 0.53; 95% CI 0.28-1.00). In stratification analyses, the TGFß1 rs1800469 C>T genotype was associated with a decreased risk for tetralogy of fallot in homozygote comparisons (OR 0.47; 95% CI 0.22-0.99), a decreased risk for transposition of great artery in the dominant genetic model (OR 0.49; 95 % CI 0.28-0.87) and heterozygote comparisons (OR 0.45; 95% CI 0.24-0.83). Our findings suggest that TGFß1 rs1800469 C>T polymorphism was significantly associated with decreased risk of conotruncal heart defects. TGFßR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T polymorphisms may not play a role in the susceptibility of conotruncal heart defects.

Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation.

BACKGROUND: MicroRNAs (miRNAs) are short, single-stranded and non-coding RNAs, freely circulating in human plasma and correlating with vary pathologies. In this study, we monitored early myocardial injury and recovery after heart transplantation by detecting levels of circulating muscle-specific miR-133a, miR-133b and miR-208a. METHODS: 7 consecutive patients underwent heart transplantation in Fuwai hospital and 14 healthy controls were included in our study. Peripheral vein blood was drawn from patients on the day just after transplantation (day 0), the 1st, 2nd, 3rd, 7th and 14th day after transplantation respectively. Serum from peripheral blood was obtained for cardiac troponin I (cTnI) measurement. Plasma was centrifuged from peripheral blood for measuring miR-133a, miR-133b and miR-208a by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The plasma concentration of miRNAs were calculated by absolute quantification method. The sensitivity and specificity of circulating miRNAs were revealed by receiver operating characteristic curve (ROC) analysis. Correlations between miRNAs and cTnI / perioperative parameters were analyzed. RESULTS: Similar to cTnI, miR-133a, miR-133b and miR-208a all showed dynamic changes from high to low levels early after operation. The Sensitivity and specificity of miRNAs were: miR-133a (85.7%,100%), miR-208a (100%,100%), and miR-133b (90%,100%). Correlations between miRNAs and cTnI were statistically significant (p < 0.05), especially for miR-133b (R2 = 0.813, p < 0.001). MiR-133b from Day 0-Day 2 (r > 0.98, p < 0.01), and cTnI from Day 1- Day 3 (r > 0.86, p < 0.05) had strong correlations with bypass time, particularly parallel bypass time. Obviously, miR-133b had a better correlation than cTnI. Circulating miR-133b correlated well with parameters of heart function such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and inotrope support, while cTnI only correlated with 3 of the 4 parameters mentioned above. MiR-133b also had strong correlations with ventilation time (r > 0.99, p < 0.001) and length of ICU stay (r > 0.92, p < 0.05), both of which reflected the recovery after operation. The correlation coefficients of miR-133b were also higher than that of cTnI. CONCLUSIONS: The dynamic change in circulating muscle-specific miRNAs, especially miR-133b can reflect early myocardial injury after heart transplantation. And miR-133b may have advantages over cTnI in forecasting graft dysfunction and recovery of patients after operation.

Remote ischemic postconditioning enhances cell retention in the myocardium after intravenous administration of bone marrow mesenchymal stromal cells.

Efficacy of intravenous administration of mesenchymal stromal cells (MSCs) for myocardial infarction (MI) is limited by low cell retention in the damaged myocardium. Previous studies indicated that remote ischemic conditioning could protect against ischemia-reperfusion-induced injury by release of various cytokines including stromal cell derived factor-1 alpha (SDF-1α). However, whether remote ischemic postconditioning (RIPostC) can also enhance the retention of infused cells in the myocardium by activating MSC homing is unclear. In this study, RIPostC was induced with 4cycles of 5min occlusion and reperfusion of the abdominal aorta in female Sprague-Dawley (SD) rats which underwent ligation of the coronary artery 1week previously. Cytokine levels in serum and myocardium were evaluated by enzyme-linked immunosorbent assay (ELISA) at 1, 6, 24 and 48h after RIPostC. Then, a total of 4×10(6) male MSCs were infused intravenously at 24h after RIPostC. The number of survived cells in the myocardium was evaluated by real-time polymerase chain reaction analysis for Y chromosome and the heart function was evaluated by echocardiography at 1month after cell infusion. Furthermore, 10µg/kg rabbit anti-rat CXCR4 polyclonal antibody was injected intraperitoneally to prove the role of SDF-1α for RIPostC. RIPostC induced an increase in SDF-1α in serum at 1h and enhanced SDF-1α transcription and protein synthesis in the myocardium at 24h after the procedure. 1month after cell transplantation, RIPostC significantly increased MSC myocardial retention by 79.1±12.3% and thereby contributed to enhanced cardiac function in comparison with cell transplantation without RIPostC. Furthermore, blockade with a CXCR4-specific antibody after RIPostC markedly attenuated the enhancement of therapeutic efficacy. We conclude that RIPostC activated SDF-1α expression and enhanced retention of the infused MSCs in the injured myocardium. Priming of the heart with RIPostC might be a novel adjunctive approach for intravenous cell delivery.

Central zone of myocardial infarction: a neglected target area for heart cell therapy.

The purpose of this study was to investigate the fate of transplanted cells in the central zone of myocardial infarction (MI), and to clarify the relationship between the injection-site impact and the efficacy of cell therapy. MI was created by coronary ligation in female rats. Three weeks later, 3-million labelled male bone marrow mesenchymal stem cells (BMSCs) were directly injected into the border (BZC group) or central zone (CZC group) of MI area. As a control, culture medium was injected into the same sites. Cell survival was evaluated by quantitative real-time polymerase chain reaction, and apoptosis was assayed with TUNEL and caspase-3 staining. Four weeks after transplantation, heart function and cardiac morphometry were evaluated by echocardiography and Masson's Trichrome staining, respectively. Angiogenesis and myogenesis were detected by immunofluorescence staining. After cell transplantation into the border or central zone, there was no cell migration between the different zones of MI. BMSCs in the CZC group exhibited no difference in apoptotic percentage, in the long-term survival, when compared with those in the BZC group. However, they did effectively promote angiogenesis and cellular myogenic differentiation. Although cell delivery in the central zone of MI had no effect on the recovery of heart function compared with the BZC group, the retained BMSCs could still increase the scar thickness, and subsequently exhibit a trend in the reverse remodelling of ventricular dilation. Hence, we concluded that the central zone of MI should not be ignored during cell-based therapy. Multiple site injection (border+central zone) is strongly recommended during the procedure of cell transplantation.