Brachial and central hypertension in relation to coronary stenosis in patients with coronary angiography.

The clinical significance of central beyond brachial blood pressure (BP) remains unclear. In patients who underwent coronary angiography, the authors explored whether elevated central BP would be associated with coronary arterial disease (CAD) irrespective of the status of brachial hypertension. From March 2021 to April 2022, 335 patients (mean age 64.9 years, 69.9% men) hospitalized for suspected CAD or unstable angina were screened in an ongoing trial. CAD was defined if a coronary stenosis of ≥50%. According to the presence of brachial (non-invasive cuff systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and central (invasive systolic BP ≥130 mmHg) hypertension, patients were cross-classified as isolated brachial hypertension (n = 23), isolated central hypertension (n = 93), and concordant normotension (n = 100) or hypertension (n = 119). In continuous analyses, both brachial and central systolic BPs were significantly related to CAD with similar standardized odds ratios (OR, 1.47 and 1.45, p < .05). While categorical analyses showed that patients with isolated central hypertension or concordant hypertension had a significantly higher prevalence of CAD and the Gensini score than those with concordant normotension. Multivariate-adjusted OR (95% confidence interval [CI]) for CAD was 2.24 (1.16 to 4.33, p = .009) for isolated central hypertension and 3.02 (1.58 to 5.78, p < .001) for concordant hypertension relative to concordant normotension. The corresponding OR (95% CI) of a high Gensini score was 2.40 (1.26-4.58) and 2.17 (1.19-3.96), respectively. In conclusion, regardless of the presence of brachial hypertension, elevated central BP was associated with the presence and severity of CAD, indicating that central hypertension is an important risk factor for coronary atherosclerosis.

Evaluation of metoprolol standard dosing pathway in Chinese patients with acute coronary syndrome: a prospective multicenter single-arm interventional study.

OBJECTIVE: To evaluate the feasibility and tolerability of metoprolol standard dosing pathway (MSDP) in Chinese patients with acute coronary syndrome (ACS). METHODS: In this multicenter, prospective, open label, single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals. A total of 998 hospitalized patients aged ≥ 18 years and diagnosed with ACS were included. The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines. The primary endpoint was the percentage of patients achieving the target dose at discharge (V2). The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge (V4), and percentage of patients experiencing bradycardia (heart rate < 50 beats/min), hypotension (blood pressure < 90/60 mmHg) and transient cardiac dysfunction at V2 and V4. RESULTS: Of the 998 patients, 29.46% of patients achieved the target dose (≥ 95 mg/d) at V2. The total population was divided into two groups: target group (patients achieving the target dose at V2) and non-target group (patients not achieving the target dose at V2). There was significant difference in the reduction of heart rate from baseline to discharge in the two groups (-4.97 ± 11.90 beats/min vs. -2.70 ± 9.47 beats/min, P = 0.034). There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2 (0 vs. 0, P = 1.000) and V4 (0.81% vs. 0.33%, P = 0.715). There was no significant difference in the proportion of hypotension between the two groups at V2 (0.004% vs. 0.004%, P = 1.000) and V4 (0 vs. 0.005%, P = 0.560). No transient cardiac dysfunction occurred in two groups during the study. A total of five adverse events (1.70%) and one serious adverse event (0.34%) were related to the pathway in target group. CONCLUSIONS: In Chinese ACS patients, the feasibility and tolerability of the MSDP have been proved to be acceptable.

Patients with comorbid coronary artery disease and hypertension: a cross-sectional study with data from the NHANES.

Background: Hypertension (HTN) and coronary artery disease (CAD), two common cardiovascular diseases, are often comorbid and interacted. The patients with comorbid CAD and HTN have worse outcomes and prognosis, however, the prevalence remains unclear. In the cross-sectional study, we aimed to explore the prevalence and influence factors of patients with comorbid CAD and HTN in the USA. Methods: Adult patients with comorbid CAD and HTN derived from the National Health and Nutrition Examination Survey (NHANES) database in the 1999-2000 and 2017-2018 cycles were included. Demographic data, physical examination results, laboratory data, and questionnaire data were collected and compared in the two cycles. Subgroup analyses were performed between the elder (≥65 years of age) and middle-young (18-65 years of age) populations. Results: The age-adjusted prevalence of patients with comorbid CAD and HTN increased from 4.22% [1999-2000] to 5.40% [2017-2018] (P=0.006) and the age decreased from 71 [63-79] to 69 [61-77] years (P=0.008). The HTN control rate, the low-density lipoprotein cholesterol (LDL-C) control rate, systolic blood pressure (SBP), and the levels of blood lipids, as well as the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), ß-blockers and statins improved in the 2017-2018 cycle as compared with the 1999-2000 (all P<0.05). On the other hand, the proportions complicated with diabetes mellitus (DM), obesity and chronic kidney disease (CKD), as well as the levels of serum glucose, glycohemoglobin and creatinine increased from the 1999-2000 to 2017-2018 (all P<0.01). Subgroup analyses revealed that the prevalence of middle-young patients with comorbid CAD and HTN increased more than their elder counterparts, while diastolic blood pressure (DBP), pulse, blood lipids and oral medication rates were inferior to the latter. Conclusions: The recent prevalence of patients with comorbid CAD and HTN increased than 20 years ago, mainly caused by more morbid middle-young population. For another, the control of blood pressure (BP) and lipids were favorably affected by increased use of statins, ACEIs/ARBs and ß-blockers in these patients. Nevertheless, there is still much room for strengthening medication utilization and intervention of risk factors in future.

Amphiregulin promotes cardiac fibrosis post myocardial infarction by inducing the endothelial-mesenchymal transition via the EGFR pathway in endothelial cells.

The endothelial-mesenchymal transition (EndMT) plays a key role in the development of cardiac fibrosis (CF) after acute myocardial infarction (AMI). The results of our previous study showed that amphiregulin (AR) expression was enhanced after MI. However, the role of AR on EndMT post MI remains unknown. This study aimed to elucidate the impact of AR on EndMT post MI and the associated molecular mechanisms. AR expression was markedly enhanced in infarct border area post MI, and endothelial cells were one of the primary cell sources of AR secretion. Stimulation with AR promoted endothelial cell proliferation, invasion, migration, collagen synthesis and EndMT. In addition, EGFR and downstream gene expression was significantly enhanced. In vivo, EndMT was significantly inhibited after lentivirus-AR-shRNA was delivered to the myocardium post MI. In addition, silencing AR ameliorated cardiac function by decreasing the extent of CF. Furthermore, the levels of EGFR pathway components in endothelial cells extracted from infarct border myocardium were all significantly decreased in lentivirus-AR-shRNA-treated MI mice. Our results demonstrate that AR induces CF post MI by enhancing EndMT in endothelial cells. Thus, targeting the regulation of AR may provide a potentially novel therapeutic option for CF after MI.

The CatLet score: a new coronary angiographic scoring tool accommodating the variable coronary anatomy for the first time.

BACKGROUND: The SYNTAX score for decision makings or outcome predictions in coronary artery disease does not account for the variations in the coronary anatomy, which is a clear fallacy for patients with less typical anatomy than suggested by the SYNTAX score. The current study aimed to derive a new coronary angiographic scoring system accommodating the variability in the coronary anatomy. METHODS: The 17-myocardial segment model and laws of competitive blood supply and flow conservation were utilized to derive this new scoring system. RESULTS: We obtained 6 types of RCA dominance, 3 types of diagonal size and 3 types of left anterior descending artery (LAD) length, which together resulted in a total of 54 patterns of coronary artery circulation to account for the variability in the coronary anatomy among individuals. A Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system has been designed based on the above-mentioned reclassification scheme (htpp://www.catletscore.com, IE browser is required to run this calculator). CONCLUSIONS: This new CatLet angiographic scoring system accommodated the variability in the coronary anatomy and standardized the collection of the coronary angiographic data, which could facilitate the comparison and exchange of these data between different catheter labs. Its utility for predicting the clinical outcomes and standardizing the angiographic data collection will be investigated in a series of clinical trials enrolling "all-comers" with coronary artery disease (CAD).

Amphiregulin enhances cardiac fibrosis and aggravates cardiac dysfunction in mice with experimental myocardial infarction partly through activating EGFR-dependent pathway.

Cardiac fibrosis (CF), a main process of ventricular remodeling after myocardial infarction (MI), plays a crucial role in the pathogenesis of heart failure (HF) post-MI. It is known that amphiregulin (AR) is involved in fibrosis of several organs. However, the expression of AR and its role post-MI are yet to be determined. This study aimed to investigate the impact of AR on CF post-MI and related mechanisms. Significantly upregulated AR expression was evidenced in the infarct border zone of MI mice in vivo and the AR secretion was enhanced in macrophages, but not in cardiac fibroblasts. In vitro, treatment with AR increased cardiac fibroblast migration, proliferation and collagen synthesis, and upregulated the expression of epidermal growth factor receptor (EGFR) and the downstream genes such as Akt, ERK1/2 and Samd2/3 on cardiac fibroblasts. All these effects could be abrogated by pretreatment with a specific EGFR inhibitor. To verify the functions of AR in MI hearts, lentivirus-AR-shRNA and negative control vectors were delivered into the infarct border zone. After 28 days, knock-down of AR increased the survival rate and improved cardiac function, while decreasing the extent of myocardial fibrosis of MI mice. Moreover, EGFR and the downstream genes were significantly downregulated in lentivirus-AR-shRNA treated MI mice. Our results thus indicate that AR plays an important role in promoting CF after MI partly though activating the EGFR pathway. Targeting AR might be a novel therapeutic option for attenuating CF and improve cardiac function after MI.

Exosomes Derived from Mesenchymal Stem Cells Rescue Myocardial Ischaemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy Via AMPK and Akt Pathways.

BACKGROUND/AIMS: Reperfusion after an ischaemic insult might cause infarct extension. Mesenchymal stem cell (MSC)-derived exosomes could attenuate myocardial remodelling in animal models of myocardial ischaemia reperfusion injury (MIRI), and the present study aimed to explore the related mechanisms. METHODS: In vitro, rat H9C2 cardiomyocytes (H9C2s) were exposed to H2O2. Cell viability was detected by the CCK-8 assay, apoptosis was detected by Annexin V-PE/7-AAD staining, ROS production was detected by fluorescence microscopy and flow cytometry, and apoptosis-related proteins and signalling pathway-related proteins were detected by western blot analysis. Autophagic flux was measured using the tandem fluorescent mRFG-GFP-LC3 assay. MSC-derived exosomes were extracted using the total exosome isolation reagent. Apoptosis, myocardial infarction size, heart function and myocardial LC3B expression were examined in an in vivo I/R model by the TUNEL assay, TTC/Evan blue staining, echocardiography and immunohistochemicalstaining, respectively. RESULTS: In vitro, H2O2 dose-dependently increased ROS production and cell apoptosis in H9C2s and blocked autophagic flux after 3 h of exposure; autophagy gradually decreased thereafter, and the lowest level was detected at 12 h after exposure. MSC-derived exosomes reduced H2O2-induced ROS production and cell apoptosis and enhanced autophagy at 12 h after exposure. In H9C2 cells exposed to H2O2 for 12 h, treatment with exosomes enhanced autophagy via the AMPK/mTOR and Akt/mTOR pathways. Likewise, in vivo exosome injections in rats that underwent I/R injury significantly reduced apoptosis and the myocardial infarct size and upregulated myocardial LC3B expression as well as improved heart function. CONCLUSIONS: Our results indicate that MSC-derived exosomes could reduce MIRI by inducing cardiomyocyte autophagy via AMPK/mTOR and Akt/mTOR pathways.

The role of miR-19b in the inhibition of endothelial cell apoptosis and its relationship with coronary artery disease.

The biological effects of microRNAs (miRNAs) and TNF-α in atherosclerosis have been widely studied. The circulating miR-17-92 cluster has been recently shown to be significantly downregulated in patients with injured vascular endothelium. However, it remains unclear whether the miR-17-92 cluster plays a significant role in vascular endothelial repair. The aim of this study was to investigate the relationship between the miR-17-92 cluster and TNF-α-induced endothelial cell apoptosis. We determined that the down-regulation of miR-19b level among patients with coronary artery disease was consistent with miRNA expression changes in endothelial cells following 24 h of TNF-α treatment. In vitro, the overexpression of miR-19b significantly alleviated the endothelial cells apoptosis, whereas the inhibition of miR-19b significantly enhanced apoptosis. The increased levels of Afap1 and caspase7 observed in our apoptosis model could be reduced by miR-19b, and this effect could be due to miR-19b binding 3'-UTRs of Afap1 and caspase7 mRNA. Therefore our results indicate that miR-19b plays a key role in the attenuation of TNF-α-induced endothelial cell apoptosis and that this function is closely linked to the Apaf1/caspase-dependent pathway.

The lncRNA MALAT1 protects the endothelium against ox-LDL-induced dysfunction via upregulating the expression of the miR-22-3p target genes CXCR2 and AKT.

CXCR2 plays a key role in protecting the integrity of the endothelium. Emerging evidence has demonstrated that the long ncRNAs (lncRNA) Human metastasis associated lung adenocarcinoma transcript 1 (MALAT1) participates in the regulation of the pathophysiological processes. However, whether there is crosstalk between CXCR2 and MALAT1 remains unknown. In this study, we demonstrated that MALAT1 was upregulated in patients with unstable angina. MALAT1 silencing significantly downregulated the expression of the miR-22-3p target gene CXCR2 via reversing the effect of the miR-22-3p, resulting in the aggravation of Oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury; this process was associated with the AKT pathway. Thus, MALAT1 protects the endothelium from ox-LDL-induced endothelial dysfunction partly through competing with miR-22-3p for endogenous RNA.

Hydrogen sulfide improves cardiomyocytes electrical remodeling post ischemia/reperfusion injury in rats.

Hydrogen sulfide (H2S), produced by cystanthionine-γ-lysase (CSE) in the cardiovascular system, is an endogenous gaseous mediator exerting pronounced physiological effects as the third gasotransmitter in addition to nitric oxide (NO) and carbon monoxide (CO). Accumulating evidence indicated that H2S could mediate the cardioprotective effects in myocardial ischemia model. Ventricular arrhythmia is the most important risk factor for cardiac mortality and sudden death after acute myocardial infarction (AMI). The potential impact of H2S on cardiomyocytes electrical remodeling post ischemic insult is not fully explored now. Present study investigated the role of H2S on cardiomyocytes electrical remodeling in rats with ischemia/reperfusion injury. H2S concentration was reduced and arrhythmia score was increased in this model. CSE mRNA level was also upregulated in the ischemic myocardium. Exposure to exogenous NaHS reduced the action potential duration (APD), inhibited L-type Ca(2+) channels and activated K(ATP) channels in cardiomyocytes isolated from ischemic myocardium Exogenous H2S application improves electrical remodeling in cardiomyocytes isolated from ischemic myocardium. These results indicated that reduced H2S level might be linked to ischemia/reperfusion induced arrhythmias.

Tissue kallikrein is related to the severity of coronary artery disease.

BACKGROUND: The impairment of the tissue kallikrein (KLK1)-kinin system (KKS) may result in atheroma development. However, it remains unclear if the KKS correlates with coronary artery disease (CAD). METHODS: KLK1, VEGF and hs-CRP plasma levels were measured in 100 patients newly diagnosed with CAD and 33 CAD-free controls. Patients were followed-up for the incidence of major adverse cardiovascular events (MACE) for 8months to 2y. Gene expression of KLK1, CD105 and CD68 was assessed in human coronary endarterectomy specimens. RESULTS: Patients with CAD and acute coronary syndrome (ACS) had significantly elevated KLK1 levels. In addition, the concentration of hs-CRP was increased in ACS patients. A strong positive correlation between plasma KLK1 and the severity of CAD was also demonstrated, suggesting that high KLK1 levels are an independent predictor for CAD. MACE during follow-up significantly correlated with KLK1 levels in the ACS group. Unstable coronary plaques demonstrated markedly increased KLK1 levels, macrophage infiltration and high microvessel density. Additionally, KLK1 staining primarily colocalized with macrophages. CONCLUSIONS: In the present study, plasma KLK1 levels were a useful predictor for the presence and extent of CAD. More extensive studies are, however, necessary in order to validate these findings.

Efficiently tracking of stem cells in vivo using different kinds of superparamagnetic iron oxide in swine with myocardial infarction.

BACKGROUND: Superparamagnetic iron oxide (SPIO) particles have shown much promise as a means to visualize labeled cells using molecular magnetic resonance imaging (MRI). Micrometer-sized superparamagnetic iron oxide (MPIO) particles and nanometer-sized ultrasmall superparamagnetic iron oxide (USPIO) are two kinds of SPIO widely used for monitoring stem cells migration. Here we compare the efficiency of two kinds of SPIO during the use of stem cells to treat acute myocardial infarction (AMI). METHODS: An AMI model in swine was created by 60 minutes of balloon occlusion of the left anterior descending coronary artery. Two kinds of SPIO particles were used to track after intracoronary delivered 10(7) magnetically labeled mesenchymal stem cells (MR-MSCs). The distribution and migration of the MR-MSCs were assessed with the use of 3.0T MR scanner and then the results were confirmed by histological examination. RESULTS: MR-MSCs appeared as a local hypointense signal on T2*-weighted MRI and there was a gradual loss of the signal intensity after intracoronary transplantation. All of the hypointense signals in the USPIO-labeled group were found on T2*-weighted MRI, contrast to noise ratio (CNR) decreased in the MPIO-labeled group (16.07 ± 5.85 vs. 10.96 ± 1.34) and USPIO-labeled group (11.72 ± 1.27 vs. 10.03 ± 0.96) from 4 to 8 weeks after transplantation. However, the hypointense signals were not detected in MPIO-labeled group in two animals. MRI and the results were verified by histological examination. CONCLUSIONS: We demonstrated that two kinds of SPIO particles in vitro have similar labeling efficiency and viability. USPIO is more suitable for labeling stem cells when they are transplanted via a coronary route.

Effects of heme oxygenase-1 gene modulated mesenchymal stem cells on vasculogenesis in ischemic swine hearts.

BACKGROUND: Mesenchymal stem cells (MSCs) transplantation may partially restore heart function in the treatment of acute myocardial infarction (AMI). The aim of this study was to explore the beneficial effects of MSCs modified with heme xygenase-1 (HO-1) on post-infarct swine hearts to determine whether the induction of therapeutic angiogenesis is modified by the angiogenic cytokines released from the implanted cells. METHODS: In vitro, MSCs were divided into four groups: (1) non-transfected MSCs (MSCs group), (2) MSCs transfected with the pcDNA3.1-Lacz plasmid (Lacz-MSCs group), (3) MSCs transfected with pcDNA3.1-hHO-1 (HO-1-MSCs group), and (4) MSCs transfected with pcDNA3.1-hHO-1 and pretreatment with an HO inhibitor, tin protoporphyrin (SnPP) (HO-1-MSCs + SnPP group). Cells were cultured in an airtight incubation bottle for 24 hours, in which the oxygen concentration was maintained at < 1%, followed by 12 hours of reoxygenation. After hypoxia/reoxygen treatment, ELISA was used to measure transforming growth factor (TGF-ß) and fibroblast growth factor (FGF-2) in the supernatant. In vivo, 28 Chinese mini-pigs were randomly allocated to the following treatment groups: (1) control group (saline), (2) Lacz-MSCs group, (3) HO-1-MSCs group, and (4) HO-1-MSCs + SnPP group. About 1 × 10(7) of autologous stem cells or an identical volume of saline was injected intracoronary into porcine hearts 1 hour after MI. Magnetic resonance imaging (MRI) assay and postmortem analysis were assessed four weeks after stem cell transplantation. RESULTS: Post hypoxia/reoxygenation in vitro, TGF-ß in the supernatant was significantly increased in the HO-1-MSCs ((874.88 ± 68.23) pg/ml) compared with Lacz-MSCs ((687.81 ± 57.64) pg/ml, P < 0.001). FGF-2 was also significantly increased in the HO-1-MSCs ((1106.48 ± 107.06) pg/ml) compared with the Lacz-MSCs ((853.85 ± 74.44) pg/ml, P < 0.001). In vivo, at four weeks after transplantation, HO-1 gene transfer increased the capillary density in the peri-infarct area compared with the Lacz-MSCs group (14.24 ± 1.66/HPFs vs. 11.51 ± 1.34/HPFs, P < 0.001). Arteriolar density was also significantly higher in HO-1-MSCs group than in the Lacz-MSCs group (7.86 ± 2.00/HPFs vs. 6.45 ± 1.74/HPFs, P = 0.001). At the same time, the cardiac function was significantly improved in the HO-1-MSCs group compared with the Lacz-MSCs group ((53.17 ± 3.55)% vs. (48.82 ± 2.98)%, P < 0.05). However, all these effects were significantly abrogated by SnPP. CONCLUSION: MSCs provided a beneficial effect on cardiac function after ischemia/reperfusion by the induction of therapeutic angiogenesis, and this effect was amplified by HO-1 overexpression.

[Effects of autologous mesenchymal stem cells transfected with heme oxygenase-1 gene transplantation on ischemic Swine hearts].

OBJECTIVE: To observe the effect of intracoronary transfer of autologous HO-1 overexpressed MSCs in porcine model of myocardial ischemia (1 h)/reperfusion. METHODS: Apoptosis was assayed and cytokine concentrations in supernatant were measured in cells exposed to hypoxia-reoxygen in vitro. In vivo, Chinese male mini-pigs were allocated to the following treatment groups: control group (saline), MSCs group (MSCs), MSCs transfected with pcDNA3.1-nHO-1 (HO-1-MSCs). 1 x 10(7) of autologous stem cells or identical volume of saline was injected intracoronary into porcine hearts 1 h after ischemia. MRI assay and postmortem analysis were assessed 3 months after stem cell transplantation. RESULTS: In vitro, cell apoptosis rate post hypoxia-reoxygen was significantly reduced in HO-1-MSCs group (30.30% +/- 7.64%) compared with that in MSCs group (56.93% +/- 4.68%, P < 0.001) and LacZ-MSCs group (55.88% +/- 4.38%, P < 0.001), VEGF was also significantly upregulated in HO-1-MSCs group [(768.44 +/- 78.38) pg/ml] compared with that in MSCs group [(555.27 +/- 67.67) pg/ml, P < 0.001] and LacZ-MSCs group [(522.97 +/- 71.45) pg/ml, P < 0.001]. In vivo, cardiac function was significantly improved in both MSCs transplantation groups compared to saline group (all P < 0.05 vs.saline) and the left ventricular ejection fraction was significantly higher in HO-1-MSCs group compared with that in MSCs group at 3 months after transplantation (53.50% +/- 2.09% vs. 49.54% +/- 2.74%, P = 0.017), capillary density in the peri-infarct area was also significantly higher in HO-1-MSC group than that in MSCs group [(14.59 +/- 2.39)/HPF vs. (11.78 +/- 2.48)/HPF, P = 0.033]. CONCLUSIONS: Efficacy of HO-1 overexpressed MSCs on improving cardiac function and promoting angiogenesis was greater than those by MSCs in this porcine ischemia/reperfusion model.

Identification and differentiation of magnetically labeled mesenchymal stem cells in vivo in swines with myocardial infarction.

We aim to track mesenchymal stem cells (MSCs) after magnetically labeling and test the ability of these cells differentiate into cardiomyocytes in vivo. Therefore, 20 swines were divided into four groups, sham-operated group (n=3); acute myocardial infarction (AMI) transplanted with PBS (n=3); labeled MSCs (n=7) and unlabeled MSCs (n=7) group. 10(7) labeled or unlabeled cells were intracoronary delivered after MI (4.8+/-1.3 days), and serial cardiac MR (3.0T) imaging studies were performed at 0, 4 and 8 weeks after transplantation, then the results were confirmed by histological and western blot analysis. We demonstrated that labeled MSCs can be reliably detected and tracked in vivo using MR imaging. In particular, we provided the evidence of regeneration of labeled MSCs in vivo by histological examination and western blot analysis.

[Therapeutic effects of magnetically labeled mononuclear and mesenchymal stem cells transplantation in a swine myocardial infarction model assessed by magnetic resonance imaging].

OBJECTIVE: To evaluate the therapeutic effects of magnetically labeled mononuclear stem cells (MR-MNC) and mesenchymal stem cells (MR-MSC) transplantation in a swine acute myocardial infarction (AMI) model by MR imaging. METHODS: AMI model was established in swines by balloon occlusion of the left anterior descending coronary artery, 10(7) autologous MR-MSC (n = 7), MR-MNC (n = 6) or PBS (n = 6) were delivered via intracoronary infusion within 1 week after AMI [(4.8 +/- 1.3) days]. Changes of infarct size and cardiac function were assessed with the use of 3.0T MR scanner before AMI, at 1 and 8 weeks post AMI. RESULTS: Magnetically labeled stem cells could be identified in the region of AMI by cardiac MR imaging. Eight weeks post transplantation, infarct size was significantly reduced in MR-MSC transplantation group (8.5% +/- 0.5% vs. 24.7% +/- 3.1%, P < 0.05) and in MR-MNC transplantation (12.3% +/- 1.5% vs. 26.1% +/- 1.5%, P < 0.05) while infarct size remained unchanged in PBS group (P > 0.05) compared to values at 1 week post AMI, left ventricular ejection fraction (LVEF) was also significantly higher in MR-MSC transplantation group (56.9% +/- 1.3% vs. 40.7% +/- 2.0%, P < 0.05) and MR-MNC transplantation group (52.8% +/- 1.4% vs. 41.9% +/- 3.3%, P < 0.05) compared to LVEF at 1 week post AMI. LVEF increase was more significant in swines received MR-MSC transplantation than MR-MNC transplantation (16.2% +/- 1.2% vs. 10.9% +/- 3.0%, P < 0.05). Prussian blue staining identified stem cells in corresponding myocardial regions with as by MRI. Western blot analysis demonstrated that cardiac expressions of myosin heavy chain (MHC) in MR-MSC group (100.3 +/- 5.5) and in MR-MNCs group (95.5 +/- 4.2) were significantly higher than that in PBS group (75.7 +/- 5.7, P < 0.05), myocardial troponin T (cTNT) expression in MR-MSC group (124.0 +/- 5.8) and MR-MNC group (118.4 +/- 4.4) were also significantly higher than in PBS group (93.3 +/- 3.9, P < 0.05) while MMP2/TIMP1 ratios in MR-MSC group (0.6 +/- 0.1) and MR-MNC group (0.6 +/- 0.1) were significantly lower than that in PBS group (4.2 +/- 0.2, P < 0.05). CONCLUSIONS: Magnetically labeled MR-MSC and MR-MNC homed to heart post myocardial infarction and reduced infarct size, improved cardiac function. MR-MSC is superior to MR-MNC on improving cardiac function.

Transplantation of magnetically labeled mesenchymal stem cells improves cardiac function in a swine myocardial infarction model.

BACKGROUND: Mesenchymal stem cells (MSCs) transplantation provides a new approach for myocardial repair. However, many important fundamental questions about MSCs transplantation remain unanswered. There is an urgent need to identify MSCs from the beating heart and analyze the efficacy of this new approach. This study aimed to localize the magnetically labeled MSCs (MR-MSCs) and monitor the restorative effects of MR-MSCs with magnetic resonance (MR) imaging. METHODS: Acute myocardial infarction (AMI) was created in swine by a balloon occlusion of the left anterior descending coronary artery. Cells were delivered via intracoronary infusion after myocardial infarction. Infarct size change and cardiac function were assessed with 3.0T MR scanner. The results were then confirmed by histological and western blot analysis. All statistical procedures were performed with Systat (SPSS version 12.01). RESULTS: A total of 26 swine were divided into four groups (sham-operated group, n=6; AMI group with PBS transplantation, n=6; labeled MSCs group, n=7; unlabeled MSCs group, n=7). MSCs, MR-MSCs (10(7) cells) or PBS were delivered by intracoronary injection after MI and serial cardiac MR imaging studies were performed at 0, 4 and 8 weeks after transplantation. MR imaging demonstrated MI size decreased after MSCs transplantation in labeled and unlabeled groups, however, increases were seen in the AMI group at 8 weeks after MI. The left ventricular ejection fraction (LVEF) was slightly increased in the AMI group ((41.87+/-2.45)% vs (39.04+/-2.80)%, P>0.05), but significantly improved in the MR-MSCs group ((56.85+/-1.29)% vs (40.67+/-2.00)%, P<0.05) and unlabeled group ((55.38+/-1.07)% vs (41.78+/-2.08)%, P<0.05) at 8 weeks after treatment. MR-MSCs were further confirmed by Prussian blue and immunofluorescent staining. Western blot analysis demonstrated that there was an increased expression of cardiomyocyte markers such as myosin heavy chain and troponin T in the MSCs treatment groups and the ratio of matrix metalloproteinase 2 to tissue inhibitor of metalloproteinase 1 decreased in the labeled group and unlabeled group compared with the AMI group and sham-operated group. CONCLUSION: Transplanted MR-MSCs can regenerate new myocardium and prevent remolding in an MI model at 2-month follow-up and represent a preferred method to better understand the mechanisms of stem cell therapy in future clinical studies.