Sitagliptin therapy enhances the number of circulating angiogenic cells and angiogenesis-evaluations in vitro and in the rat critical limb ischemia model.

BACKGROUND AIMS: We tested the hypothesis that sitagliptin is capable of increasing blood flow in the rat critical limb ischemia (CLI) model by enhancement of angiogenesis. METHODS: Adipose tissue from adult-male Fischer 344 rats (n = 6) were cultured in endothelial progenitor cell culture medium for 14 d with (25 µmol/L) or without sitagliptin. CLI was induced by ligation of the left femoral artery. Rats (n = 32) were equally separated into four groups: untreated controls (group 1), sitagliptin (4 mg/kg per day; group 2), CLI (group 3) and CLI with sitagliptin (group 4). RESULTS: In vitro, 7 and 14 d after cell culture, endothelial progenitor cell biomarkers assessed by flow cytometry (Sca-1/CD31+, CXCR4+, c-kit+ and CD34+ cells) and Western blot (vascular endothelial growth factor, CXCR4 and stromal-derived factor [SDF]-1α) were remarkably higher in group 4 than in the other groups (all P < 0.01). In vivo, 2 and 14 d after the CLI procedure, circulating angiogenic cell (Sca-1/CD31+, Sca-1+ and CD31+) numbers were significantly higher in group 4 than in the other groups (all P < 0.001). Additionally, the messenger RNA and protein expression of angiogenic biomarkers (CXCR4, SDF-1α and vascular endothelial growth factor), immunofluorescent staining of angiogenic cells (CXCR4+, SDF-1α+, CD31+, von Willebrand factor + cells) and immunohistochemical staining of small vessel numbers in the ischemic area were significantly higher in group 4 than in the other groups (all P < 0.01). Furthermore, laser Doppler showed that the ratio of ischemic/normal blood flow was remarkably higher group 4 than in group 3 by days 14 and 28 after the CLI procedure (all P < 0.01). CONCLUSIONS: Sitagliptin therapy enhances circulating angiogenic cell numbers, angiogenesis and blood flow in the CLI area.

Melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia-reperfusion injury.

This study investigated whether melatonin-treated adipose-derived mesenchymal stem cells (ADMSC) offered superior protection against acute lung ischemia-reperfusion (IR) injury. Adult male Sprague-Dawley rats (n = 30) were randomized equally into five groups: sham controls, lung IR-saline, lung IR-melatonin, lung IR-melatonin-normal ADMSC, and lung IR-melatonin-apoptotic ADMSC. Arterial oxygen saturation was lowest in lung IR-saline; lower in lung IR-melatonin than sham controls, lung IR-melatonin-normal ADMSC, and lung IR-melatonin-apoptotic ADMSC; lower in lung IR-melatonin-normal ADMSC than sham controls and lung IR-melatonin-apoptotic ADMSC; lower in lung IR-melatonin-apoptotic ADMSC than sham controls (P < 0.0001 in each case). Right ventricular systolic blood pressure (RVSBP) showed a reversed pattern among all groups (all P < 0.0001). Changes in histological scoring of lung parenchymal damage and CD68+ cells showed a similar pattern compared with RVSBP in all groups (all P < 0.001). Changes in inflammatory protein expressions such as VCAM-1, ICAM-1, oxidative stress, TNF-α, NF-κB, PDGF, and angiotensin II receptor, and changes in apoptotic protein expressions of cleaved caspase 3 and PARP, and mitochondrial Bax, displayed identical patterns compared with RVSBP in all groups (all P < 0.001). Numbers of antioxidant (GR+, GPx+, NQO-1+) and endothelial cell biomarkers (CD31+ and vWF+) were lower in sham controls, lung IR-saline, and lung IR-melatonin than lung IR-melatonin-normal ADMSC and lung IR-melatonin-apoptotic ADMSC, and lower in lung IR-melatonin-normal ADMSC than lung IR-melatonin-apoptotic ADMSC (P < 0.001 in each case). In conclusion, when the animals were treated with melatonin, the apoptotic ADMSC were superior to normal ADMSC for protection of lung from acute IR injury.

Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.

BACKGROUND: Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1α in CKD patients. METHODS: The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects. RESULTS: CKD patients had significantly lower numbers of EPCs (p < 0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p < 0.001). Compared with patients with early CKD (stages I-III), patients with late CKD [stage IV-V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1α (all p < 0.01). Serum VEGF level but not MCA or SDF-1α was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p < 0.04). CONCLUSION: Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs.

Benefit of combined extracorporeal shock wave and bone marrow-derived endothelial progenitor cells in protection against critical limb ischemia in rats.

OBJECTIVES: We hypothesized that combined treatment with extracorporeal shock wave and bone marrow-derived endothelial progenitor cells might exert enhanced protection against critical limb ischemia in rats. METHODS: Male Sprague-Dawley rats (n = 9 for laser Doppler study and n = 6 for laboratory examinations in each group) were divided into group 1 (sham control), group 2 (critical limb ischemia treated with culture medium), group 3 (critical limb ischemia treated with intramuscular bone marrow-derived endothelial progenitor cells [2.0 × 10 cells]), group 4 (critical limb ischemia treated with extracorporeal shock wave [280 impulses at 0.1 mJ/mm]), and group 5 (combined bone marrow-derived endothelial progenitor cell-extracorporeal shock wave) after critical limb ischemia induction. RESULTS: By day 21, laser Doppler showed substantially lower ratios of ischemic/normal blood flow in group 2 compared with other groups (p < .001). The protein expressions of mitochondrial cytochrome c, stromal cell-derived factor-1, C-X-C chemokine receptor type 4, vascular endothelial growth factor, and endothelial nitric oxide synthase were remarkably higher in group 5 than in groups 2 to 4, and notably higher in groups 3 and 4 than in group 2 (all p < .01). The messenger RNA expressions of proinflammatory and apoptotic biomarkers and oxidative stress were reduced in group 5 compared with groups 2 to 4, and notably lower in groups 3 and 4 than in group 2 (all p < .01). The messenger RNA expressions of anti-inflammatory and antiapoptotic biomarkers were lower in group 2 than in other groups (all p < .01). Immunofluorescent staining showed higher numbers of CD31+ stromal cell-derived factor-1+, chemokine receptor type 4+, and von Willebrand factor+ cells, and vessels in the ischemic area in group 5 than in groups 2 to 4, and in groups 3 and 4 than in group 2 (all p < .04). CONCLUSION: Combined treatment with bone marrow-derived endothelial progenitor cells and extracorporeal shock wave is superior to either bone marrow-derived endothelial progenitor cells or extracorporeal shock wave alone in improving ischemia in rodent critical limb ischemia.

Comparison of acute versus convalescent stage high-sensitivity C-Reactive protein level in predicting clinical outcome after acute ischemic stroke and impact of erythropoietin.

BACKGROUND AND AIM: Currently, no data on the optimal time point after acute ischemic stroke (IS) at which high-sensitivity C-reactive protein (hs-CRP) level is most predictive of unfavorable outcome. We tested the hypothesis that hs-CRP levels during both acute (48 h after IS) and convalescent (21 days after IS) phases are equally important in predicting 90-day clinical outcome after acute IS. We further evaluated the impact of erythropoietin (EPO), an anti-inflammatory agent, on level of hs-CRP after acute IS. METHODS: Totally 160 patients were prospectively randomized to receive either EPO therapy (group 1, n = 80) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or placebo (group 2, n = 80). Serum level of hs-CRP was determined using ELISA at 48 h and on day 21 after IS and once in 60 healthy volunteers. RESULTS: Serum level of hs-CRP was substantially higher in all patients with IS than in healthy controls at 48 h and day 21 after IS (all p < 0.001). Levels of hs-CRP did not differ between group 1 and 2 at 48 h and day 21 after IS (all p > 0.5). Multivariate analysis showed that hs-CRP levels (at 48 h and day 21) were independently predictive of 90-day major adverse neurological event (MANE) (defined as recurrent stroke, NIHSS≥8, or death) (all p < 0.03), whereas EPO therapy was independently predictive of reduced 90-day MANE (all p < 0.02). CONCLUSION: EPO therapy which was independently predictive of freedom from 90-day MANE did not alter the crucial role of hs-CRP levels measured at 48 h and 21-day in predicting unfavorable clinical outcome after IS.

Impact of obesity control on circulating level of endothelial progenitor cells and angiogenesis in response to ischemic stimulation.

BACKGROUND AND AIM: We tested the hypothesis that obesity reduced circulating number of endothelial progenitor cells (EPCs), angiogenic ability, and blood flow in ischemic tissue that could be reversed after obesity control. METHODS: 8-week-old C57BL/6J mice (n=27) were equally divided into group 1 (fed with 22-week control diet), group 2 (22-week high fat diet), and group 3 (14-week high fat diet, followed by 8-week control diet). Critical limb ischemia (CLI) was induced at week 20 in groups 2 and 3. The animals were sacrificed at the end of 22 weeks. RESULTS: Heart weight, body weight, abdominal fat weight, serum total cholesterol level, and fasting blood sugar were highest in group 2 (all p<0.001). The numbers of circulating EPCs (C-kit/CD31+, Sca-1/KDR + and CXCR4/CD34+) were lower in groups 1 and 2 than in group 3 at 18 h after CLI induction (p<0.03). The numbers of differentiated EPCs (C-kit/CD31+, CXCR4/CD34+ and CD133+) from adipose tissue after 14-day cultivation were also lowest in group 2 (p<0.001). Protein expressions of VCAM-1, oxidative index, Smad3, and TGF-ß were higher, whereas the Smad1/5 and BMP-2, mitochondrial cytochrome-C SDF-1α and CXCR4 were lower in group 2 than in groups 1 and 3 (all p<0.02). Immunofluorescent staining of CD31+ and vWF + cells, the number of small vessel (<15 µm), and blood flow through Laser Doppler scanning of ischemic area were lower in group 2 compared to groups 1 and 3 on day 14 after CLI induction (all p<0.001). CONCLUSION: Obesity suppressed abilities of angiogenesis and recovery from CLI that were reversed by obesity control.

Outcomes of patients with Killip class III acute myocardial infarction after primary percutaneous coronary intervention.

OBJECTIVES: Little is known about the outcomes of patients with Killip class III acute ST-segment elevation myocardial infarction in the reperfusion era. This study investigated the short- and long-term outcomes of these patients who underwent primary percutaneous coronary intervention. METHODS: Between January 2002 and November 2009, a total of 1,278 consecutive patients with acute ST-segment elevation myocardial infarction underwent primary percutaneous coronary intervention. Of these patients, 230 (17.0%) with Killip III, 216 (16.9%) with Killip II, and 832 (65.1%) with Killip I upon presentation were prospectively recruited. RESULTS: Angiographic study showed significantly lower final thrombolysis in myocardial infarction 3 flow in patients with Killip III compared with those with Killip II and I (83.5% vs. 94.9% vs. 95.7%, p<.0001). The incidence of multiple vessel disease was also notably higher in Killip III than in Killip II and I (65.7% vs. 13.9% vs. 53.8%, p<.001). Besides, the incidence of advanced congestive heart failure (defined as greater than or equal to New York Heart Association functional class 3) during hospitalization was remarkably higher in Killip III compared to Killip II and I (71.3% vs. 13.9% vs. 6.6%, p<.001). Furthermore, the 30-day mortality and 1-yr cumulative mortality were notably higher in Killip III than in Killip II and I (20.0% vs. 4.2% vs. 1.7%, p<.001 and 31.7% vs. 7.9% vs. 4%, p<.001, respectively). Multivariate analysis showed that Killip III was independently predictive of 30-day and 1-yr mortality (all p < .04). CONCLUSION: Killip III remains strongly and independently predictive of 30-day and 1-yr mortality in ST-segment elevation myocardial infarction patients even undergoing primary percutaneous coronary intervention.

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

BACKGROUND: We investigated whether myocardium-derived conditioned medium (MDCM) is effective in preserving left ventricular (LV) function in a rat acute myocardial infarction (AMI) model. METHODS: 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. RESULTS: 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). CONCLUSION: MDCM therapy reduced cardiac fibrosis and oxidative stress, enhanced angiogenesis, and preserved 90-day LV function in a rat AMI model.

The prognostic value of atrial fibrillation on 30-day clinical outcome in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

This study evaluated the association between atrial fibrillation (AF) and 30-day clinical outcome in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Between January 2005 and October 2009, 783 consecutive patients with acute STEMI undergoing primary PCI were enrolled. Of these patients, 85 (10.9%) with AF during admission were categorized into group 1, while the remaining 698 (89.1%) with sinus rhythm during admission served as group 2. The results demonstrated that the incidence of advanced Killip score (defined as ≥ score 3) and advanced congestive heart failure (defined as ≥ NYHA class 3) were significantly higher, whereas the left ventricular ejection fraction (LVEF) was notably lower in group 1 than in group 2 (all P < 0.003). Additionally, the normal blood flow in the infarct-related artery was notably lower in group 1 than in group 2 (P = 0.003). Moreover, the incidences of new-onset stroke and 30-day mortality were remarkably higher in group 1 than in group 2 (all P < 0.003). Furthermore, Kaplan-Meier analysis demonstrated that the 30-day survival rate was markedly lower in AF patients than in those with sinus rhythm. However, multivariate stepwise Cox regression analysis demonstrated that the advanced Killip score and low LVEF were significantly and independently predictive of 30-day mortality (all P < 0.004). In conclusion, AF was significantly associated with 30-day mortality.

Impact of electrocardiographic morphology on clinical outcomes in patients with non-ST elevation myocardial infarction receiving coronary angiography and intervention: a retrospective study.

BACKGROUND: The impact of electrocardiography (ECG) morphology on clinical outcomes in patients with non-ST segment elevation myocardial infarction (NSTEMI) receiving percutaneous coronary intervention (PCI) is unknown. This study investigated whether different ST morphologies had different clinical outcomes in patients with NSTEMI receiving PCI. METHODS: This retrospective study analyzed record-linked data of 362 patients who had received PCI for NSTEMI between January 2008 and December 2010. ECG revealed ST depression in 67 patients, inverted T wave in 91 patients, and no significant ST-T changes in 204 patients. The primary endpoint was long-term all-cause mortality. The secondary endpoint was long-term cardiac death and non-fatal major adverse cardiac events. RESULTS: Compared to those patients whose ECG showed an inverted T wave and non-specific ST-T changes, patients whose ECG showed ST depression had more diabetes mellitus, advanced chronic kidney disease (CKD) and left main artery disease, as well as more in-hospital mortality, cardiac death and pulmonary edema during hospitalization. Patients with ST depression had a significantly higher rate of long-term total mortality and cardiac death. Finally, multiple stepwise Cox regression analysis showed that an advanced Killip score, age, advanced CKD, prior percutaneous transluminal coronary angioplasty and ST depression were independent predictors of the primary endpoint. CONCLUSIONS: Among NSTEMI patients undergoing coronary angiography, those with ST depression had more in-hospital mortality and cardiac death. Long-term follow-up of patients with ST depression consistently reveals poor outcomes.

EPO-cyclosporine combination therapy reduced brain infarct area in rat after acute ischemic stroke: role of innate immune-inflammatory response, micro-RNAs and MAPK family signaling pathway.

This study tested the hypothesis that erythropoietin (EPO) and cyclosporine (CsA) could effectively reduce brain infarct area (BIA) in rat after acute ischemic stroke (AIS) through regulating inflammation, oxidative stress, MAPK family signaling and microRNA (miR-223/miR-30a/miR-383). Adult male Sprague-Dawley rats (n = 48) were equally divided into group 1 (sham control), group 2 (AIS), group 3 [AIS+EPO (5,000 IU/kg at 0.5/24/48 h, subcutaneous)] and group 4 [AIS+CsA (20.0 mg/kg at 0.5/24/48 h, intra-peritoneal)]. By 72 h, histopathology showed that BIA was largest in group 2 and smallest in group 1, and significantly larger in group 4 than group 3 (all P<0.0001). The three microRNAs expressed were higher in group 2 than in the other three groups (all P<0.04); between these three latter groups there were no significant differences. The protein expressions of MAPK family [phosphorylated (p)-ERK1/2, p-p38/p-JNK], inflammatory (iNOS/MMP-9/TNF-α/NF-κB/IL-12/MIP-1α/CD14/CD68/Ly6g), apoptotic (caspase-3/PARP/mitochondrial-Bax), oxidative-stress (NOX-1/NOX-2/oxidized protein) and mitochondrial-damaged (cytosolic cytochrome-C) biomarkers exhibited an identical pattern to BIA findings (all P<0.0001). The cellular expressions of brain edema (AQP4+), inflammation (CD11+/glial-fibrillary-acid protein+), and cellular damage (TUNEL assay/positive Periodic acid-Schiff stain) biomarkers exhibited an identical pattern, whereas the cellular-integrity markers (neuN+/MAP2+/doublecorin+) exhibited an opposite pattern to BIA (all P value <0.001). EPO-CsA therapy markedly reduced BIA mainly by suppressing the innate immune response to inflammation, oxidative stress, microRNAs (miR-223/miR-30a/miR-383) and MAPK family signaling.

Impact of clopidogrel on suppression of circulating levels of soluble CD40 ligand in patients with unstable angina undergoing coronary stenting.

This study investigated whether a regimen that comprised a loading dose of 300 mg of clopidogrel followed by 75 mg/day could significantly suppress circulating levels of soluble CD40 ligand (sCD40L) in patients who had unstable angina and underwent coronary stenting. Study results showed that the clopidogrel loading dose substantially decreased the circulating level of sCD40L at 24 hours after stenting (p <0.0001). Combined with aspirin, 75 mg/day of clopidogrel continuously decreased sCD40L levels after coronary stenting.

Percutaneous transluminal mitral valvuloplasty reduces circulating soluble CD40 ligand in rheumatic mitral stenosis.

BACKGROUND: Recent data suggest that the pathogenesis of vascular inflammation and thrombosis involves CD40 ligand (CD40L), which is mostly derived from platelets. Previous studies have demonstrated that platelet activation occurs in peripheral blood of patients with rheumatic mitral stenosis (MS). However, in patients with MS, the plasma level of soluble CD40L has never been investigated. METHODS AND RESULTS: Seventeen patients with symptomatic MS undergoing percutaneous transluminal mitral valvuloplasty were studied (group 1, 11 patients in permanent atrial fibrillation and 6 patients in sinus rhythm). Solid-phase, sandwich enzyme-linked immunosorbent assay determined the plasma levels of soluble CD40L in the femoral vein and artery, and right and left atria before valvuloplasty, and those in the peripheral venous blood obtained 10 min after valvuloplasty, and at the 4-week follow-up after valvuloplasty. The Doppler pressure half-time method was used to calculate the mitral valve area. Additionally, plasma concentrations of soluble CD40L in the peripheral venous blood obtained from 17 control patients were measured (including nine healthy volunteers in sinus rhythm [group 2] and eight patients in permanent lone atrial fibrillation [group 3]). Plasma levels of soluble CD40L were significantly elevated in group 1 patients (437.6 +/- 370.2 pg/mL) [mean +/- SD] compared with group 2 (203.8 +/- 218.0 pg/mL) and group 3 patients (173.5 +/- 105.0 pg/mL) [p < 0.05]. The area of mitral valve increased significantly after valvuloplasty (1.10 +/- 0.20 cm(2) vs 1.47 +/- 0.29 cm(2), p < 0.0001). The mean left atrial pressure fell significantly and immediately after valvuloplasty (22.8 +/- 4.9 mm Hg vs 17.6 +/- 5.5 mm Hg, p = 0.0004). The peripheral venous plasma levels of soluble CD40L obtained before valvuloplasty significantly fell after valvuloplasty (before, 437.6 +/- 370.2 pg/mL; vs 10 min after, 215.4 +/- 113.9 pg/mL; vs 4 weeks after, 217.5 +/- 111.9 pg/mL; p < 0.02). CONCLUSIONS: Patients with moderate-to-severe MS had higher venous plasma levels of soluble CD40L than healthy volunteers or patients with lone atrial fibrillation. Additionally, the elevated venous plasma levels of soluble CD40L fell significantly following valvuloplasty.

Atrial pacemaker complex preserved radiofrequency maze procedure reducing the incidence of sick sinus syndrome in patients with atrial fibrillation.

BACKGROUND: The Cox maze III procedure can effectively restore sinus rhythm in most patients with permanent atrial fibrillation (AF). However, previous studies have shown that the maze procedure results in significant sinus node dysfunction, and, consequently, a considerable number of patients required postoperative pacemaker implantation. HYPOTHESIS: This study investigates the hypothesis that the modification of the Cox III maze procedure, to avoid injuring the sinus node and the atrial physiologic pacemaker complex, will reduce the incidence of sick sinus syndrome following surgery. METHODS AND RESULTS: This study investigated 71 patients with permanent AF and mitral valve disease who were undergoing concomitant open-heart surgery. Most atrial incisions in the Cox maze III procedure were replaced with radiofrequency ablation, and the intercaval counterablation was moved posterolaterally to avoid injury to the sinus node and atrial pacemaker complex. At a mean (+/- SD) follow-up time of 46.5 +/- 24 months, 59 patients (83.1%) regained sinus rhythm without receiving antiarrhythmic drug therapy or undergoing electrical cardioversion. The transmitral atrial wave was observed in 44 patients (62%), and the transtricuspid atrial wave was also observed in 53 patients (74.6%). Late sinus node dysfunction developed in only two patients (2.8%), who received permanent pacemaker implantation. CONCLUSION: This modified radiofrequency maze procedure produces few patients with sick sinus syndrome and effectively restores sinus rhythm and atrial transport function in most patients with permanent AF undergoing concomitant open-heart surgery.

Adipose-derived mesenchymal stem cells embedded in platelet-rich fibrin scaffolds promote angiogenesis, preserve heart function, and reduce left ventricular remodeling in rat acute myocardial infarction.

OBJECTIVE: This study tested the hypothesis that autologous adipose-derived mesenchymal stem cells (ADMSCs) embedded in platelet-rich fibrin (PRF) can significant promote myocardial regeneration and repair after acute myocardial infarction (AMI). SUMMARY BACKGROUND: With avoiding the needle-related complications, PRF-embedded autologous ADMSCs graft provides a new effective stem cell-based therapeutic strategy for myocardial repair. METHODS: Adult male Sprague-Dawley rats were equally divided (n = 8 per group) into group 1 (sham-operated), group 2 (AMI by ligating left coronary artery), group 3 (AMI+ PRF), and group 4 (AMI+PRF-embedded autologous ADMSCs). RPF with or without ADMSCs was patched on infarct area 1h after AMI induction. All animals were sacrificed on day 42 after echocardiography. RESULTS: Left ventricular (LV) dimension and infarct/fibrotic areas were lowest in group 1, highest in group 2, in group 3 higher than in group 4, whereas LV performance and wall thickness exhibited a reversed pattern in all groups (all p < 0.001). Protein expressions of inflammatory (MMP-9, IL-1ß), oxidative, apoptotic (Bax, cleaved PARP), fibrotic (Smad 3, TFG-ß), hypertrophic (ß-MHC), and heart failure (BNP) biomarkers displayed an identical pattern in infarct/fibrotic areas, whereas the protein expressions of anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), anti-fibrotic (Smad1/5, BMP-2) biomarkers and α-MHC showed an opposite pattern (all p < 0.01). Angiogenic activities (c-Kit+, Sca-1+, CD31+, SDF-1α+, CXCR4+ cells; protein expressions of SDF-1α, CXCR4, VEGF) were highest in group 4 and lowest in group 1 (all p < 0.001). CONCLUSION: ADMSCs embedded in PRF offered significant benefit in preserving LV function and limiting LV remodeling after AMI.

Levels and values of serum high-sensitivity C-reactive protein within 6 hours after the onset of acute myocardial infarction.

BACKGROUND: C-reactive protein (CRP), which has been suggested to directly enhance inflammation in plaques, is rapidly synthesized and secreted in the liver 6 h after an acute inflammatory stimulus. Therefore, serum levels of CRP within 6 h after the onset of acute myocardial infarction (AMI) merely reflect a chronic and persistent inflammatory process and are not due to acute myocardial damage. We hypothesized that the serum CRP level, which would abnormally elevate thereafter, is followed by a plaque rupture in the clinical setting of AMI. METHODS AND RESULTS: CRP was prospectively measured by high-sensitivity CRP assay (hs-CRP) in 157 consecutive patients (106 patients within 6 h, and 51 patients >/= 6 h but < 12 h after the onset of AMI) with ST-segment elevation AMI undergoing primary percutaneous coronary intervention (PCI). Serum levels of hs-CRP were also measured in 30 patients with stable angina undergoing elective PCI and in 30 healthy control subjects. The serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 +/- 2.3 mg/L vs 1.4 +/- 0.7 mg/L, p < 0.0001 [mean +/- SD]) and in healthy subjects (2.7 +/- 2.3 mg/L vs 1.0 +/- 0.6 mg/L, p < 0.0001). There were no significant differences in serum levels of hs-CRP in patients with an onset of AMI 3 h but < 6 h (2.7 +/- 2.5 mg/L vs 2.7 +/- 2.2 mg/L, p = 0.87). However, the serum level of hs-CRP was significantly higher in patients with an onset >/= 6 h than in patients with an onset < 6 h (14.1 +/- 16.5 mg/L vs 2.7 +/- 2.3 mg/L, p < 0.0001). CONCLUSIONS: Serum levels of hs-CRP were significantly higher in patients with an onset of AMI < 6 h than in healthy subjects and in patients with angina pectoris undergoing PCI. The inflammatory process has been proved as one of the mechanisms causing plaque rupture. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.

The potential impact of primary percutaneous coronary intervention on ventricular septal rupture complicating acute myocardial infarction.

BACKGROUND: Recent data suggest that the risk of acquired ventricular septal defect (VSD), a complication of acute myocardial infarction (AMI), could be reduced using thrombolytic therapy. There are, however, still no available data regarding the potential impact of primary percutaneous coronary intervention (PCI) on AMI-related VSD in a clinical setting. The purposes of this study were to delineate the incidence and the potential risk factors of AMI-related VSD in the Chinese population, and to determine whether primary PCI could reduce such risk. METHODS AND RESULTS: From May 1993 through March 2003, a total of 1,321 patients with AMI (for < 12 h) underwent primary PCI in our hospital. Of these 1,321 patients, 3 patients (0.23%) developed VSD after undergoing a primary PCI, with a mean (+/- SD) time of occurrence of 25.3 +/- 12.2 h. During the same period, a total of 616 consecutive, unselected patients with early AMI [ie, > 12 h and < or = 7 days] or recent myocardial infarction (MI) [ie, > or = 8 days and < 30 days] who had not received thrombolytic therapy underwent elective PCI. Of these 616 patients, 18 (2.9%) had VSD either on presentation or during hospitalization, with a mean time of occurrence of 71.1 +/- 64.2 h. Clinical variables were utilized to statistically analyze the potential risk factors. Univariate analysis demonstrated that the enrollment variables strongly related to this complication were advanced age, hypertension, nonsmokers, anterior infarction, female gender, and lower body mass index (BMI) [all p < 0.005]. Using multiple stepwise logistic regression analysis, the only variables independently related to VSD were advanced age, female gender, anterior infarction, and low BMI (all p < 0.05). The in-hospital mortality rate was significantly higher in patients with this complication than in patients without this complication (47.6% vs 8.0%; p < 0.0001). The incidence of this complication was significantly lower in patients with AMI who underwent primary PCI than in those with early or recent MI who underwent elective PCI (3.0% vs 0.23%, respectively; p = 0.0001). CONCLUSION: Primary PCI had a striking impact on reducing the incidence of VSD after AMI compared to elective PCI in patients who did not receive thrombolytic therapy. Advanced age, female gender, anterior infarction, and low BMI had potentially increased the risk of this catastrophic complication after AMI in this Chinese population.

Clinical features and outcome of patients with direct percutaneous coronary intervention for acute myocardial infarction resulting from left circumflex artery occlusion.

BACKGROUND: Little is known about the clinical features and outcome of patients with left circumflex artery (LCX) infarct-related acute myocardial infarction (AMI). This study was conducted to investigate the clinical features and outcome of patients who underwent direct percutaneous coronary intervention (d-PCI) for AMI caused by LCX occlusion, and to discover prognostic determinants in this clinical setting. METHODS AND RESULTS: Between May 1993 and October 2000, a total of 819 patients with AMI underwent d-PCI in our hospital. Sixty-seven patients (8.2%) who had LCX infarct-related AMI constituted the population of this study. Ten of 67 patients (14.9%) were in cardiogenic shock. Angiographic findings demonstrated that the incidences of triple-vessel disease, reference lumen diameter (RLD) of the LCX > or = 4.0 mm, and LCX as the dominant artery in these patients were 26.9%, 22.4%, and 34.3%, respectively. Sixteen patients (23.9%) had unsuccessful reperfusion (defined as Thrombolysis in Myocardial Infarction flow < or = 2). Univariate analysis showed that dominant LCX, RLD of the LCX > or = 4.0 mm, cardiogenic shock, precordial ST-segment depression, and complete atrioventricular block were significantly related to unsuccessful reperfusion. Multiple stepwise logistic regression analysis demonstrated that dominant LCX and cardiogenic shock were significant independent predictors of unsuccessful reperfusion. The 30-day mortality rate in the 67 patients was 14.9%. Univariate analysis demonstrated that triple-vessel disease, dominant LCX, cardiogenic shock, poor left ventricular ejection fraction, and unsuccessful reperfusion were significantly associated with 30-day mortality. By multiple stepwise logistic regression analysis, dominant LCX, cardiogenic shock, and triple-vessel disease were significant independent predictors of increased 30-day mortality. CONCLUSIONS: LCX infarct-related AMI has its unique clinical features. The presence of dominant LCX and cardiogenic shock were independent determinants of unsuccessful reperfusion, and the presence of dominant LCX, cardiogenic shock, and triple-vessel disease were independent determinants of increased 30-day mortality in this clinical setting.

Acute myocardial infarction with simultaneous ST-segment elevation in the precordial and inferior leads: evaluation of anatomic lesions and clinical implications.

BACKGROUND: Simultaneous ST-segment elevation in the precordial and inferior leads is a rare ECG finding in patients with acute myocardial infarction (AMI) and its clinical implications rarely have been reported. The purpose of this study was to evaluate the clinical features of this distinctive ECG manifestation and its impact on clinical outcome. METHODS AND RESULTS: Between May 1993 and July 2001 in our hospital, direct percutaneous coronary intervention (dPCI) was performed in 924 patients with AMI. Of these 924 consecutive patients, 37 patients (4.0%) who had simultaneous ST-segment elevation (> or = 1 mm) in the precordial and inferior leads were retrospectively analyzed. Eight of these 37 patients who had a wrapped left anterior descending artery (LADA) occlusion were placed into group 1 (ie, wrapped LADA). Twenty-nine of the 37 patients who had anatomic lesions other than a wrapped LADA in the coronary arteries were placed into group 2 (ie, "nonwrapped" LADA). Group 2 patients had significantly higher incidences of cardiogenic shock (58.6% vs 0%, respectively; p = 0.004), pulmonary edema (43.8% vs 0%, respectively; p = 0.02), and sustained sudden cardiac death due to malignant ventricular tachyarrhythmias (44.8% vs 0%, respectively; p = 0.03) than did group 1 patients. Group 1 patients usually had ST-segment elevations of < 2 mm the inferior leads. However, group 2 patients always had ST-segment elevations of > or = 2 mm in the inferior leads. Univariate analysis demonstrated that the mean (+/- SD) ST-segment elevation in the inferior leads was significantly higher in group 2 patients than in group 1 patients (11.08 +/- 4.18 vs 2.95 +/- 0.92 mm, respectively; p = 0.0001). Coronary angiography demonstrated that the incidence of multivessel disease (93.1% vs 37.5%, respectively; p = 0.002) and the incidence of severe obstructive two-vessel disease (ie, stenosis of > 85%) [93.1% vs 0%, respectively; p = 0.0001] were significantly higher in group 2 than in group 1 patients. Although there was no significant difference in the rate of unsuccessful reperfusion (24% vs 13%, respectively; p = 0.38) between group 2 and group 1 patients, the 30-day mortality rate was significantly higher in group 2 patients than in group 1 patients (48.3% vs 0%, respectively; p = 0.015). CONCLUSIONS: AMI with ECG manifestation of simultaneous ST-segment elevation in precordial and inferior leads can be caused by either a wrapped LADA occlusion or a nonwrapped LADA occlusion. While patients with wrapped LADA occlusions usually have favorable clinical outcomes, patients with nonwrapped LADA occlusions usually have serious clinical presentations and unfavorable clinical outcomes. Specific clinical and ECG features identifying high-risk patients in this clinical setting would be extremely important for early, aggressive, and appropriate management.

Comparison of baseline characteristics, clinical features, angiographic results, and early outcomes in men vs women with acute myocardial infarction undergoing primary coronary intervention.

BACKGROUND: Women have had a higher early mortality rate than men after acute myocardial infarction (AMI) in the prethrombolytic and thrombolytic eras. Primary percutaneous coronary intervention (PCI) has been shown to significantly improve survival of patients with AMI, and to be superior to thrombolytic therapy in terms of immediate restoration of normal flow in the infarct-related artery and reduction of recurrent ischemic events. However, the effect of primary PCI on early outcomes of women vs men remains unknown. Therefore, we examined whether there was any difference in term of 30-day mortality between women and men after primary PCI. METHODS AND RESULTS: Between May 1993 and April 2002, primary PCI was performed in 1,032 consecutive patients (15.3% women and 84.7% men) with AMI. The overall successful reperfusion (final Thrombolysis in Myocardial Infarction grade 3 flow) and 30-day morality rates were 84.0% and 8.5%, respectively. The rate of successful reperfusion did not differ between women and men (84.8% vs 83.9%, p = 0.77). However, mortality at 30 days was significantly higher in women than in men (14.6% vs 7.4%, p = 0.003). In comparison with men, women were older; had significantly higher incidences of hypertension, diabetes mellitus, complete atrioventricular block, and right ventricular infarction; and had longer times of reperfusion (all p values < 0.05). During hospitalization, advanced congestive heart failure (New York Heart Association class 3 or greater), free wall rupture, and major bleeding complications were more likely to occur in women than in men (all p values < 0.05). Compared with men, the unadjusted odds ratio for 30-day death among women was 2.12 (95% confidence interval [CI], 1.27 to 3.53). After adjusting for age, the odds ratio was substantially reduced to 1.66 (95% CI, 0.98 to 2.79). Further adjustment for age and other variables further reduced the odds ratio to 1.06 (95% CI, 0.53 to 2.14). CONCLUSIONS: A gender gap of 30-day mortality existed between women and men with AMI that could not be altered by primary PCI. However, this gap was only an apparent one, and was not truly related to gender alone. In comparison with men, women were older, had significantly higher incidences of comorbidities and major untoward clinical events, and had longer times of reperfusion, which could help explain why the 30-day mortality rate was higher in women than in men.