Safety and efficacy of intracoronary artery administration of human bone marrow-derived mesenchymal stem cells in STEMI of Lee-Sung pigs—A preclinical study for supporting the feasibility of the OmniMSC-AMI phase I clinical trial

BackgroundThis study tested whether early left intracoronary arterial (LAD) administration of human bone marrow-derived mesenchymal stem cells (hBMMSCs, called OmniMSCs) in acute ST-segment elevation myocardial infarction (STEMI) of Lee-Sung pigs induced by 90 min balloon-occluded LAD was safe and effective.Methods and resultsYoung male Lee-Sung pigs were categorized into SC (sham-operated control, n = 3), AMI-B (STEMI + buffer/21 cc/administered at 90 min after STEMI, n = 6), and AMI-M [acute myocardial infarction (AMI) + hBMMSCs/1.5 × 107/administered at 90 min after STEMI, n = 6] groups. By 2 and 5 months after STEMI, the cardiac magnetic resonance imaging demonstrated that the muscle scar score (MSS) and abnormal cardiac muscle exercise score in the infarct region were significantly increased in the AMI-B than in the SC group that were significantly reversed in the AMI-M group, whereas the left ventricular ejection function by each month (from 1 to 5) displayed an opposite pattern of MSS among the groups (all p < 0.001). By 5 months, histopathological findings of infarct and fibrosis areas and isolectin-B4 exhibited an identical pattern, whereas the cellular expressions of troponin-I/troponin-T/von Willebrand factor exhibited an opposite pattern of MSS among the groups (all p < 0.001). The ST-segment resolution (>80%) was significantly earlier (estimated after 6-h AMI) in the AMI-M group than in the AMI-B group (p < 0.001). The protein expressions of inflammation (IL-1β/TNF-α/NF-κB)/oxidative stress (NOX-1/NOX-2/oxidized protein)/apoptosis (cleaved caspase-3/cleaved PARP)/DNA damage (γ-H2AX) displayed an identical pattern to MSS among the groups, whereas the protein expressions of angiogenesis factors (SDF-1α/VEGF) were significantly and progressively increased from SC, AMI-B, to AMI-M groups (all p < 0.001).ConclusionEarly intra-LAD transfusion of OmniMSC treatment effectively reduced the infarct size and preserved LV function in porcine STEMI

tPA-MMP-9 Axis Plays a Pivotal Role in Mobilization of Endothelial Progenitor Cells from Bone Marrow to Circulation and Ischemic Region for Angiogenesis

We examined the role of tissue plasminogen activator- (tPA-) matrix metalloproteinase- (MMP-) 9 in mobilizing endothelial progenitor cells (EPCs) from bone marrow to circulation and critical limb ischemia (CLI) region. Male C57BL/6J mice having been irradiated were categorized into wild-type mice (WT) receiving WT bone marrow cell (BMC) transfusion (group 1), WT mice receiving MMP-9 knockout (MMP-9−/−) BMC (group 2), MMP-9−/− receiving MMP-9−/− BMC (group 3), and MMP-9−/− receiving WT BMC (group 4), each of which was subdivided into sham control (SC), CLI, SC-tPA, and CLI-tPA. In groups 1 and 4, by post-CLI 18 h and day 14, circulating EPC (C-kit+/CD31+, Sca-1+/KDR+) levels were highest in CLI-tPA subgroup. In groups 2 and 3, EPC levels did not differ among all subgroups. The EPC levels in bone marrow were higher in groups 2 and 3 than those in groups 1 and 4. By day 14, in animals with CLI, expression levels of proangiogenic factors (CXCR4, SDF-1α, and VEGF) showed similar trends as circulating EPC levels. Moreover, the number of infiltrated neutrophils and macrophages in quadriceps was higher in groups 1 and 4 than groups in 2 and 3. In conclusion, tPA-MMP-9 axis plays a crucial role in EPC mobilization and angiogenesis in experimental CLI

Routinely transradial arterial approach for extra-cranial carotid stenting

BackgroundThe purpose of this study is to report a single center experience with its safety and feasibility of transradial arterial (TRA) approach in extra-cranial carotid artery (ECCA) stenting.Methods and results74 patients were consecutively enrolled in this study. A retrograde-engagement technique, involving looping 6-F Kimny guiding catheter, was utilized for ECCA angiographic study. For ECCA stenting, the 6-F Kimny guiding catheter was replaced with a 7-F Kimny guiding catheter and the procedure was performed as the follows. First, a 0.035-in. Teflon wire was carefully advanced into the common CA. Second, a PercuSurge GuardWire was inserted into the external CA, followed by distal balloon inflation for an anchoring support. Third, the 6-F guiding catheter was removed, followed by exchanging a 7-F kimny guiding catheter which was advanced along the 0.035-in. Teflon wire and the PercuSurge GuardWire to proximal part of common CA. Distal protection device was then utilized to protect from distal embolization during the procedure. One procedure failed due to external CA did not provide an anchoring support. Thus, the procedure was successful in 74 (98.7%) patients. No vascular or bleeding complication was observed. Minor stroke occurred in 3 (4.0%) patients during the procedure. All of them were completely recovery within 1week.ConclusionsThe TRA approach for ECCA stenting is safe and feasible. This access may offer a last resort for patients with unsuited to femoral arterial access and endarterectomy

Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats

<p>Abstract</p> <p>Background</p> <p>The therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) was investigated.</p> <p>Methods</p> <p>Adult male Sprague-Dawley (SD) rats (n = 30) were divided into IS plus intra-venous 1 mL saline (at 0, 12 and 24 h after IS induction) (control group) and IS plus intra-venous ADMSCs (2.0 × 10⁶) (treated interval as controls) (treatment group) after occlusion of distal left internal carotid artery. The rats were sacrificed and brain tissues were harvested on day 21 after the procedure.</p> <p>Results</p> <p>The results showed that BIA was larger in control group than in treatment group (p < 0.001). The sensorimotor functional test (Corner test) identified a higher frequency of turning movement to left in control group than in treatment group (p < 0.05). mRNA expressions of Bax, caspase 3, interleukin (IL)-18, toll-like receptor-4 and plasminogen activator inhibitor-1 were higher, whereas Bcl-2 and IL-8/Gro were lower in control group than in treatment group (all p < 0.05). Western blot demonstrated a lower CXCR4 and stromal-cell derived factor-1 (SDF-1) in control group than in treatment group (all p < 0.01). Immunohistofluorescent staining showed lower expressions of CXCR4, SDF-1, von Willebran factor and doublecortin, whereas the number of apoptotic nuclei on TUNEL assay was higher in control group than in treatment group (all p < 0.001). Immunohistochemical staining showed that cellular proliferation and number of small vessels were lower but glial fibrillary acid protein was higher in control group than in treatment group (all p < 0.01).</p> <p>Conclusions</p> <p>ADMSC therapy significantly limited BIA and improved sensorimotor dysfunction after acute IS.</p

One-year cardiovascular outcomes of drug-eluting stent versus bare-metal stent implanted in diabetic patients with acute coronary syndrome

AbstractBackgroundThe outcomes of drug-eluting stent (DES) versus bare-metal stent (BMS) use in patients with diabetic mellitus (DM) and acute coronary syndrome (ACS) are rarely reported in Taiwan. This study aimed to investigate the 1-year cardiovascular outcomes of DESs versus BMSs implanted in Taiwanese patients with DM and ACS.MethodsFor this study, we collected and analyzed patient information from the database of the Taiwan ACS Full Spectrum registry regarding characteristics and cardiovascular events in participants with DM and ACS who received implantation of either BMS (BMS group) or DES (DES group) from October 2008 to January 2010.ResultsWe found that several characteristics significantly varied between the groups. Compared with the BMS group (n = 575), the DES group (n = 199) had significantly lower rates of in-hospital cardiogenic shock (1.5% vs. 4.9%, p = 0.037) and acute renal failure (0.5% vs. 4.5%, p = 0.008), all-cause mortality (5.0% vs. 8.9%, p = 0.048), and major adverse cardiac events (MACEs) at 1 year (11.1% vs. 18.6%, p = 0.006) with an identical target vessel revascularization (TVR) rate (6.0% vs. 7.3%, p = 0.395). The BMS group had significantly higher risk-adjusted all-cause mortality [hazard ratio (HR) = 2.4, 95% confidence interval (CI) 1.0–5.7; p = 0.048] and MACE (HR = 2.2, 95% CI 1.2–3.9; p = 0.011) at 1 year with identical risks of TVR (HR = 1.3, 95% CI 0.6–2.9; p = 0.505) and nonfatal myocardial infarction (HR = 1.5, 95% CI 0.5–4.4; p = 0.478).ConclusionThe results of this study support the use of DES over BMS in Taiwanese patients with DM and ACS, providing the clinical benefits of lower rates of total mortality and MACE, and without increased TVR at 1 year in a real-world setting

Myocardium-derived conditioned medium improves left ventricular function in rodent acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>We investigated whether myocardium-derived conditioned medium (MDCM) is effective in preserving left ventricular (LV) function in a rat acute myocardial infarction (AMI) model.</p> <p>Methods</p> <p>Adult male Sprague-Dawley (SD) rats (n = 36) randomized to receive either left coronary artery ligation (AMI induction) or thoracotomy only (sham procedure) were grouped as follows (n = 6 per group): Group I, II, and III were sham-controls treated by fresh medium, normal rat MDCM, and infarct-related MDCM, respectively. Group IV, V, and VI were AMI rats treated by fresh medium, normal MDCM, and infarct-related MDCM, respectively. Either 75 μL MDCM or fresh medium was administered into infarct myocardium, followed by intravenous injection (3 mL) at postoperative 1, 12, and 24 h.</p> <p>Results</p> <p>In vitro studies showed higher phosphorylated MMP-2 and MMP-9, but lower α-smooth muscle actin and collagen expressions in neonatal cardiac fibroblasts treated with MDCM compared with those in the cardiac fibroblasts treated with fresh medium (all p < 0.05). Sirius-red staining showed larger collagen deposition area in LV myocardium in Group IV than in other groups (all p < 0.05). Stromal cell-derived factor-1α and CXCR4 protein expressions were higher in Group VI than in other groups (all p < 0.05). The number of von Willebrand factor- and BrdU-positive cells and small vessels in LV myocardium as well as 90-day LV ejection fraction were higher, whereas oxidative stress was lower in Group VI than in Group IV and Group V (all p < 0.05).</p> <p>Conclusion</p> <p>MDCM therapy reduced cardiac fibrosis and oxidative stress, enhanced angiogenesis, and preserved 90-day LV function in a rat AMI model.</p

Levels and values of circulating endothelial progenitor cells, soluble angiogenic factors, and mononuclear cell apoptosis in liver cirrhosis patients

BACKGROUND: The roles of circulating endothelial progenitor cell (EPC) and mononuclear cell apoptosis (MCA) in liver cirrhosis (LC) patients are unknown. Moreover, vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α are powerful endogenous substances enhancing EPC migration into circulation. We assessed the level and function of EPCs [CD31/CD34 (E(1)), KDR/CD34 (E(2)), CXCR4/CD34 (E(3))], levels of MCA, VEGF and SDF-1α in circulation of LC patients. METHODS: Blood sample was prospectively collected once for assessing EPC level and function, MCA, and plasma levels of VEGF and SDF-1α using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, in 78 LC patients and 25 age- and gender-matched healthy controls. RESULTS: Number of EPCs (E(1), E(2), E(3)) was lower (all p < 0.0001), whereas SDF-1α level and MCA were higher (p < 0.001) in study patients compared with healthy controls. Number of EPCs (E(2), E(3)) was higher but MCA was lower (all p < 0.05) in Child's class A compared with Child's class B and C patients, although no difference in VEGF and SDF-1α levels were noted among these patients. Chronic hepatitis B and esophageal varices bleeding were independently, whereas chronic hepatitis C, elevated aspartate aminotransferase (AST), and decompensated LC were inversely and independently correlated with circulating EPC level (all p < 0.03). Additionally, angiogenesis and transwell migratory ability of EPCs were reduced in LC patients than in controls (all p < 0.001). CONCLUSION: The results of this study demonstrated that level, angiogenic capacity, and function of circulating EPCs were significantly reduced, whereas plasma levels of SDF-1α and circulating MCA were substantially enhanced in cirrhotic patients

Intra-coronary administration of tacrolimus markedly attenuates infarct size and preserves heart function in porcine myocardial infarction

BACKGROUND: We test the hypothesis that intra-coronary tacrolimus administration can limit infarct size and preserve left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) through ligating left anterior descending coronary artery (LAD) in mini-pigs. METHODS: Twelve male mini-pigs were randomized into AMI-saline (MI-only) group and AMI-tacrolimus (MI-Tac) group that received intra-coronary saline (3.0 mL) and tacrolimus (0.5 mg in 2.5 mL saline) injection, respectively, beyond site of ligation 30 minutes after LAD occlusion. RESULTS: Larger infarct area was noted in MI-only group (p < 0.001). Inflammatory biomarkers at protein [oxidative stress, tumor necrotic factor-α, nuclear factor-κB], gene (matrix metalloproteinase-9, plasminogen activator inhibitor-1), and cellular (CD40+, CD68+ inflammatory cells) levels were remarkably higher in MI-only animals (p < 0.01). Conversely, anti-inflammatory biomarkers at gene level (Interleukin-10), gene and protein level (endothelial nitric oxide synthase), and anti-oxidant biomarkers at both gene and protein levels [heme oxygenase 1, NAD(P)H:quinone oxidoreductase] were lower in MI-only group (p < 0.01). Number of apoptotic nuclei and apoptotic biomarkers expressions at gene and protein levels (Bax, caspase 3) were notably higher, whereas anti-apoptotic biomarkers at gene and protein levels (Bcl-2), LVEF, and fractional shortening were markedly lower in MI-only group (p < 0.001). CONCLUSION: Intra-coronary administration of tacrolimus significantly attenuated infarct size and preserved LV function

Early combined treatment with sildenafil and adipose-derived mesenchymal stem cells preserves heart function in rat dilated cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>We investigated whether early combined autologous adipose-derived mesenchymal stem cell (ADMSC) and sildenafil therapy offers an additive benefit in preserving heart function in rat dilated cardiomyopathy (DCM).</p> <p>Methods</p> <p>Adult Lewis rats (n = 8 per group) were divided into group 1 (normal control), group 2 (saline-treated DCM rats), group 3 [2.0 × 10⁶ADMSC implanted into left ventricular (LV) myocardium of DCM rats], group 4 (DCM rats with sildenafil 30 mg/kg/day, orally), and group 5 (DCM rats with combined ADMSC-sildenafil). Treatment was started 1 week after DCM induction and the rats were sacrificed on day 90.</p> <p>Results</p> <p>The results showed that mitochondrial protein expressions of connexin43 and cytochrome-C were lowest in group 2, and lower in groups 3 and 4 than in group 5 (p < 0.002). Conversely, oxidative index was highest in group 2, and also higher in groups 3 and 4 than in group 5 (p < 0.0003). The mRNA expressions of interleukin (IL)-10, Gro/IL-8, endothelial nitric oxide synthase, and Bcl-2 were lowest in group 2, and lower in groups 3 and 4 compared with group 5 (p < 0.0001). The mRNA expressions of matrix metalloproteinase-9, Bax, caspase 3, and stromal-cell derived factor-1α were highest in group 2, and higher in groups 3 and 4 than in group 5 (p < 0.0004). Apoptosis and fibrosis in LV myocardium were most prominent in group 2 and higher in groups 3 and 4 than in group 5, whereas angiogenesis and LV ejection fraction were lowest in group 2 and lower in groups 3 and 4 than in group 5 (p < 0.003).</p> <p>Conclusion</p> <p>Early combined ADMSC/sildenafil is superior to either treatment alone in preserving LV function.</p