Comparison of Second-Generation Cryoballoon Ablation and Quantitative Radiofrequency Ablation Guided by Ablation Index for Atrial Fibrillation.

We compared the efficacy and complication rates of quantitative radiofrequency ablation guided by ablation index (RFCA-AI) with those of second-generation cryoballoon ablation (CBA-2). Consecutive patients (n = 230) with symptomatic atrial fibrillation (AF) undergoing a first ablation CBA-2 (92 patients) or RFCA-AI (138 patients) procedure were enrolled in this study. The late recurrence rate in the CBA-2 group was higher than that in the RFCA-AI group (P = .012). Subgroup analysis showed the same result in patients with paroxysmal AF (PAF) (P = .039), but no difference was found in patients with persistent AF (P = .21). The average operation duration in the CBA-2 group (85 [75-99.5] minutes) was shorter than that in the RFCA-AI group (100 [84.5-120] minutes) (P < .0001), but the average exposure time (17.36(13.87-22.49) vs 5.49(4.00-8.24) minutes) in the CBA-2 group and X-ray dose (223.25(149.15-336.95) vs 109.15(80.75-168.7) mGym) were significantly longer than those in RFCA-AI group (P < .0001). Multivariate logistic regression analysis showed that left atrial diameter (LAD), early recurrence, and methods of ablation (cryoballoon ablation) were independent risk factors for late recurrence after AF ablation. Early recurrence of AF and LAD were independent risk factors for predicting late recurrence after AF ablation.

Release characteristics and toxicity assessment of micro/nanoplastics from food-grade nonwoven bags.

Micro/nanoplastic (M/NP) contamination in food has become a global concern. Food-grade polypropylene (PP) nonwoven bags, which are widely used to filter food residues, are considered environmentally friendly and nontoxic. However, the emergence of M/NPs has forced us to re-examine the use of nonwoven bags in cooking as plastic contact with hot water leads to M/NP release. To evaluate the release characteristics of M/NPs, three food-grade PP nonwoven bags of different sizes were boiled in 500 mL water for 1 h. Micro-Fourier transform infrared spectroscopy and Raman spectrometer confirmed that the leachates were released from the nonwoven bags. After boiling once, a food-grade nonwoven bag can release 0.12-0.33 million MPs (>1 µm) and 17.6-30.6 billion NPs (<1 µm), equivalent to a mass of 2.25 - 6.47 mg. Number of M/NPs released is independent of nonwoven bag size; however, it decreases with increasing cooking times. M/NPs are primarily produced from easily breakable PP fibers, and they are not released into the water at once. Adult zebrafish (Danio rerio) were cultured in filtered distilled water without released M/NPs and in water containing 14.4 ± 0.8 mg L-1 released M/NPs for 2 and 14 days, respectively. To evaluate the toxicity of the released M/NPs on the gills and liver of zebrafish, several oxidative stress biomarkers (i.e., reactive oxygen species, glutathione, superoxide dismutase, catalase, and malonaldehyde) were measured. The ingestion of the released M/NPs by zebrafish induces oxidative stress in the gills and liver, depending on the exposure time. Food-grade plastics, such as nonwoven bags, should be used with caution in daily cooking because they release large amounts of M/NPs when heated, which can threaten human health.

Responses of cherry radish to different types of microplastics in the presence of oxytetracycline.

Croplands have become a hotspot for antibiotic and microplastic (MP) pollution. However, little is known regarding their combined effects on crops. In this study, the individual and combined effects of oxytetracycline (OTC) and three MPs (i.e., polypropylene (PP), polyamide (PA), and polyvinylchloride (PVC)) on cherry radish were investigated using pot experiments. Individually, OTC (50 mg kg-1), PA (2%, w/w), and PP (2%, w/w) induced negligible effects on cherry radish biomass and the root/shoot ratio. However, PVC (2%, w/w) significantly inhibited cherry radish growth; that is, its shoot and root fresh weight decreased by 46.2% and 81.1%, respectively. In the combined exposure groups, OTC alleviated the adverse effects of PVC on the cherry radish leaf number and shoot fresh weight. This was linked to that OTC increased the content of photosynthetic pigments. Superoxide dismutase activity in cherry radish roots was inhibited to different extents in all treatment groups except for the PA and PVC treatments. Malondialdehyde (MDA) content in cherry radish roots increased in all treatment groups, suggesting that both OTC and MPs caused oxidative damage to cherry radish root cells, therefore inhibiting cherry radish root growth. However, the presence of OTC non-significantly changed the effects of MPs on cherry radish roots. Irrespective of OTC presence, MPs induced a reduction in the root/shoot ratio of cherry radish, suggesting that the inhibitory effect of MPs on cherry radish roots was stronger than that on shoots. These findings contribute to the evaluation of the phytotoxicity of antibiotics and MPs in soil-vegetable systems.

The Effect of the Enhanced Endpoint of Pulmonary Vein Isolation on the Long-Term Success Rate of Radiofrequency Ablation for Atrial Fibrillation.

OBJECTIVE: This study aimed to investigate whether the enhanced endpoint of pulmonary vein isolation (PVI; intravenous injection of adenosine-triphosphate [ATP] + pacing capture + supplemental ablation) after initial PVI can reduce the long-term recurrence rate of atrial fibrillation (AF) after PVI. METHODS: Patients with paroxysmal or persistent AF undergoing catheter ablation treatment were enrolled in this study and divided into three groups according to the surgical endpoint: (1) group 1 (n = 92), in which patients were observed for 30 minutes after the initial PVI and pulmonary vein-left atrium (PV-LA) electrical conduction had not recovered; (2) group 2 (n = 99), in which patients were observed for 30 minutes after the initial PVI, then intravenously injected with ATP, and PV-LA electrical conduction had not recovered; and (3) group 3 (n = 102), in which patients were observed for 30 minutes after the initial PVI, then intravenously injected with ATP + treated with ablation line pacing, and the atrium could not be captured. RESULTS: Patients were followed up for 12 months after the operation. Twenty-eight patients in group 1 (30.4%), 19 patients in group 2 (19.2%), and 10 patients in group 3 (9.8%) developed a recurrence of AF. The difference between groups 1 and 3 was statistically significant (p < 0.001). At 12 months after the operation, the thickness of the left atrium, the posterior wall of the left ventricle, and the ventricular septum of the three groups of patients were significantly thinner than before the operation. Furthermore, the left ventricular ejection fraction had increased (p < 0.05 for all), and the pulmonary artery pressure had decreased (p < 0.001). CONCLUSION: For patients with paroxysmal AF or persistent AF, the enhanced endpoint of PVI after the initial PVI can reduce the long-term recurrence rate of AF after PVI.

Site-specific metastases of gallbladder adenocarcinoma and their prognostic value for survival: a SEER-based study.

BACKGROUND: Gallbladder cancer is a rare but highly malignant cancer, which often progresses to a metastatic stage when diagnosed because of its asymptomatic manifestation. In this study, we intended to analyze the prognostic value of metastatic gallbladder adenocarcinoma (GBA) with site-specific metastases. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, GBA patients diagnosed with metastases between 2010 and 2016 were selected to identify the prognosis according to the isolated metastatic sites, including liver, lung, bone, brain and distant lymph nodes (DL). Kaplan-Meier methods were used for survival comparisons and multivariable Cox regression models were constructed to find out independent factors that associated with survival. RESULTS: Data from 1526 eligible patients were extracted from the SEER database. Among the patients, 788 (51.6%) had isolated liver metastases, 80 (5.2%) had isolated distant nodal involvement, 45 (2.9%) had isolated lung metastases, 21 (1.4%) had isolated bone metastases, 2 (0.1%) had isolated brain metastases and 590 (38.7%) had multiple metastases. No significant survival difference was shown between patients with single or multisite metastases (P > 0.05). Patients with isolated lung or DL metastases had significant better survival outcomes than those with isolated bone metastases (P < 0.05). Multivariate analysis showed that performing surgery at primary site, receiving chemotherapy were associated with better OS and CSS for patients with isolated liver or DL metastases. CONCLUSIONS: The study showed that different metastatic sites affect survival outcomes in metastatic GBA patients. Highly selected subset of patients with liver or DL metastases might benefit from surgery at primary site.

Phosphorylation of Yes-associated protein impairs trophoblast invasion and migration: implications for the pathogenesis of fetal growth restriction†.

Fetal growth restriction (FGR) is a condition in which a newborn fails to achieve his or her prospective hereditary growth potential. This condition is associated with high newborn mortality, second only to that associated with premature birth. FGR is associated with maternal, fetal, and placental abnormalities. Although the placenta is considered to be an important organ for supplying nutrition for fetal growth, research on FGR is limited, and treatment through the placenta remains challenging, as neither proper uterine intervention nor its pathogenesis have been fully elucidated. Yes-associated protein (YAP), as the effector of the Hippo pathway, is widely known to regulate organ growth and cancer development. Therefore, the correlation of the placenta and YAP was investigated to elucidate the pathogenic mechanism of FGR. Placental samples from humans and mice were collected for histological and biomechanical analysis. After investigating the location and role of YAP in the placenta by immunohistochemistry, we observed that YAP and cytokeratin 7 have corresponding locations in human and mouse placentas. Moreover, phosphorylated YAP (p-YAP) was upregulated in FGR and gradually increased as gestational age increased during pregnancy. Cell function experiments and mRNA-Seq demonstrated impaired YAP activity mediated by extracellular signal-regulated kinase inhibition. Established FGR-like mice also recapitulated a number of the features of human FGR. The results of this study may help to elucidate the association of FGR development with YAP and provide an intrauterine target that may be helpful in alleviating placental dysfunction.

Relationship between the site of thrombosis and the prevalence of pulmonary embolism in acute lower extremity deep venous thrombosis.

OBJECTIVE: Lower extremity deep venous thrombosis (LEDVT) is common and can lead to pulmonary embolism (PE). Currently, the mechanism of how LEDVT causes PE is unclear. The aim of this study was to explore the relationship between the thrombus sites and PE in LEDVT patients. METHODS: A retrospective study that included the medical data of 3101 patients aged >18 years who were diagnosed with LEDVT by duplex ultrasound was performed at The First Affiliated Hospital of Wenzhou Medical University from 2008 to 2017. The clinical information of the patients was collected. According to the thrombosis sites, the patients were divided into three groups. We determined the cumulative prevalence and prevalence rate of PE between the groups and used Cox proportional hazard regression models, which were stratified on matched sets, to calculate the hazard ratios (HRs) for all of the outcomes of interest. We focused on the relationship of proximal or isolated distal LEDVT with PE and also analyzed the relationship of the left side or right side of LEDVT with PE. RESULTS: A total of 1629 (52.5%) patients had left LEDVT (group 1), 912 (29.4%) patients had right LEDVT (group 2), and 560 (18.1%) patients had bilateral LEDVT (group 3). The rate of PE was higher in group 2 than in group 1, although there were more patients suffering from LEDVT in group 1 than in group 2 (P < .001). The patients with proximal LEDVT in group 3 exhibited a greater risk of PE compared with those with isolated distal LEDVT (adjusted HR, 2.79; 95% confidence interval, 1.42-5.49). We also observed that the proportion of patients with proximal LEDVT who were receiving treatment was much higher than that of patients with distal LEDVT (P < .05). The patients with right LEDVT had a higher risk of PE than the patients with left LEDVT (adjusted HR, 1.60; 95% confidence interval, 1.15-2.21), and the patients with right LEDVT had more comorbidities, such as malignant neoplasms, hypertension, and diabetes (P < .001). CONCLUSIONS: Patients with proximal bilateral LEDVT had a higher likelihood for development of PE than did patients with distal LEDVT, which may be associated with inadequate therapy for proximal bilateral LEDVT. PE was more likely to develop with right-sided LEDVT because these patients had more comorbidities in our study.

Trophoblastic proliferation and invasion regulated by ACTN4 is impaired in early onset preeclampsia.

Successful pregnancy requires normal placentation, which largely depends on the tight regulation of proliferation, invasion, and migration of trophoblast cells. Abnormal functioning of trophoblast cells may cause failure of uterine spiral artery remodeling, which may be related to pregnancy-related disorders, such as preeclampsia. Here, we reported that an actin-binding protein, α-actinin (ACTN)4, was dysregulated in placentas from early onset preeclampsia. Moreover, knockdown of ACTN4 markedly inhibited trophoblast cell proliferation by reducing AKT membrane translocation. Furthermore, E-cadherin regulated ACTN4 and ß-catenin colocalization on trophoblast cell podosomes, and ACTN4 down-regulation suppressed the E-cadherin-induced cell invasion increase via depolymerizing actin filaments. Moreover, loss of ACTN4 recapitulated a number of the features of human preeclampsia. Therefore, our data indicate that ACNT4 plays a role in trophoblast function and is required for normal placental development.-Peng, W., Tong, C., Li, L., Huang, C., Ran, Y., Chen, X., Bai, Y., Liu, Y., Zhao, J., Tan, B., Luo, X., Wang, H., Wen, L., Zhang, C., Zhang, H., Ding, Y., Qi, H., Baker, P. N. Trophoblastic proliferation and invasion regulated by ACTN4 is impaired in early onset preeclampsia.

Luteolin inhibits angiogenesis of the M2­like TAMs via the downregulation of hypoxia inducible factor­1α and the STAT3 signalling pathway under hypoxia.

The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour­associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2­like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia­inducible factor­1α (HIF­1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase­9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF­1 and phosphorylated­signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2­like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF­1α and STAT3 signalling pathways.

Telmisartan reduces atrial arrhythmia susceptibility through the regulation of RAS-ERK and PI3K-Akt-eNOS pathways in spontaneously hypertensive rats.

Telmisartan is an angiotensin II receptor blocker that displays unique PPAR-γ modulating activity. PPAR-γ agonists have been shown to decrease susceptibility to atrial fibrillation through their antioxidant and antiapoptotic effects. The aim of this study was to determine whether telmisartan would have a greater effect on susceptibility to atrial arrhythmia in a hypertensive rat model than valsartan, which is a traditional angiotensin II receptor blocker. In this study, spontaneously hypertensive rats were treated with 10 mg·(kg body mass)(-1)·d(-1) telmisartan (TEL group), 10 mg·(kg body mass)(-1)·d(-1) valsartan (VAL group), or vehicle (saline; SHR group) for 4 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. After 4 weeks of treatment, we performed echocardiographic assessment, electrophysiological analysis, histological evaluation, and Western blot analysis. Telmisartan decreased systolic blood pressure to a similar extent as valsartan. Relative to the WKY controls, atrial arrhythmia susceptibility was significantly increased in the SHR group, and was significantly decreased by both telmisartan and valsartan, albeit to a greater extent with telmisartan. Arrhythmogenic atrial remodeling, including enlargement of the left atrium, myocyte hypertrophy, interstitial fibrosis, and myocyte apoptosis, was observed in the SHR group, and was accompanied by activated RAS-ERK signaling and suppressed PI3K-Akt-eNOS signaling. The results suggest that telmisartan reduced susceptibility to atrial arrhythmia to a greater extent than valsartan, ameliorated atrial remodeling, and reversed imbalances in the RAS-ERK and PI3K-Akt-eNOS pathways.

In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions.

BACKGROUND: Hepatocyte growth factor (HGF) is reported to protect the heart against ischemia-reperfusion injury. However, whether in vivo adenovirus-mediated HGF gene transfer before ischemia is protective against ischemia-reperfusion and its precise mechanisms are still unknown. METHODS AND RESULTS: By using a rabbit model of ischemia-reperfusion injury, we demonstrate that HGF gene transfer is cardioprotective through its multiple beneficial actions, such as angiogenesis, Bcl-2 overexpression, and decreasing hydroxyl radicals, deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL)-positive myocytes, and fibrotic area. After HGF gene transfer, the rabbits underwent 30 minutes of coronary occlusion and 30 minutes, 4 hours, 48 hours, and 14 days of reperfusion. The infarct size at 48 hours of reperfusion was significantly reduced in the HGF group (13.4% +/- 2.3%) compared with that in the LacZ group (36.5% +/- 2.0%) and saline group (40.3% +/- 3.2%). At 14 days of reperfusion, HGF gene transfer improved left ventricular ejection fraction and fractional shortening, reduced the fibrotic area, and increased the capillary density in the risk area. At 4 hours of reperfusion, Bcl-2 protein was overexpressed and the incidence of TUNEL-positive myocytes was significantly decreased in the risk area in the HGF group compared with the LacZ and saline groups. The myocardial interstitial 2,5-dihydroxybenzoic acid level, an indicator of hydroxyl radical, increased during 30 minutes of ischemia and 30 minutes of reperfusion in the LacZ and saline groups, and was significantly inhibited in the HGF group. CONCLUSION: HGF gene therapy may be a novel therapeutic strategy against unstable angina pectoris or severe angina pectoris, which may progress to acute myocardial infarction.

Autologous bone marrow cell transplantation improves left ventricular function in rabbit hearts with cardiomyopathy via myocardial regeneration-unrelated mechanisms.

Recent studies suggest transplanted bone marrow cells (BMCs) can be used to reconstitute coronary vessels and myocardium following acute myocardial infarction, thereby improving cardiac function. We sought to investigate the therapeutic potential of BMC transplantation in the treatment of nonischemic cardiomyopathy. Experimental cardiomyopathy was produced by treating rabbits for 8 weeks with doxorubicin (2 mg/kg per week). Two weeks after the treatment was finished, freshly aspirated BMCs or an equivalent volume of phosphate-buffered saline was injected directly into the left ventricular free wall. Four weeks later, heart function was examined during perfusion on a Langendorff apparatus. Left ventricular developed pressure and +/-dp/dt were significantly better in the transplantation group, among which echocardiography also showed significantly better ejection fractions. In addition, left ventricular weights as a fraction of body weight and left ventricular wall thicknesses were both lower in rabbits transplanted with BMCs than in controls. Immunohistochemical analyses carried out 2 weeks after transplantation showed no new myocardium and a very small number of endothelial cells originating from BMCs. On the other hand, immunoblotting revealed upregulated expression of transforming growth factor-beta1 and downregulated expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha following BMC transplantation. In conclusion, autologous BMC transplantation into cardiomyopathic rabbit hearts ameliorates the decline in ventricular function without regenerating cardiomyocytes, most likely by altering expression of various cytokines.

[Study on effect of ginsenoside Rg1 in promoting myocardiac vascular endothelial cell regeneration through induction on bone marrow stem cell's migration and differentiation in rabbits of myocardial infarction].

OBJECTIVE: To observe whether ginsenoside Rg1 could reduce the infarcted area and improve the heart function by path of promoting bone marrow stem cells differentiated to vascular endothelial cells (VECs). METHODS: Bone marrow was drawn from rabbit's ilium and labelled with red fluorochrome DiI, then it was transferred again into the rabbit's body. The rabbits was then made into myocardiac infarction model. The model rabbits were divided into the control group and the ginsenoside Rgl treated group (treated group). The infracted area at two weeks, and the left ventricular function at one and two weeks after infarction were determined respectively. The DiI positive cell rate of myelogenetic cells in ischmia area and CD31 positive cell rate of VECs were determined by confocal microscopy. Myocardial interstitial granulocyte colony-stimulating factor(GCSF) levels during ischemia and reperfusion period were determined also. RESULTS: DiI positive rate of CD31 staining positive cells in the treated group was obviously increased, and the concentration of G-CSF in myocardium interstitial obviously increased, accompanied with obviously improving of heart function and obviously reducing of infarcted area. CONCLUSION: Ginsenoside Rgl could stimulate the G-CSF secretion in local myocardiac tissues, thus to induce bone marrow mononuclear cells migrate to myocadial tissue and further differentiate to VECs. The regeneration of endothelium cells show certain direct action in promoting capillary regeneration of infarcted myocardium tissue and maintaining the blood supply.

Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes.

Insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) are cardiogenic and cardiohypertrophic growth factors. Although the therapeutic effects of IGF and HGF have been well demonstrated in injured hearts, it is uncertain whether natural upregulation of HB-EGF after myocardial infarction (MI) plays a beneficial or pathological role in the process of remodeling. To answer this question, we conducted adenoviral HB-EGF gene transduction in in vitro and in vivo injured heart models, allowing us to highlight and explore the HB-EGF-induced phenotypes. Overexpressed HB-EGF had no cytoprotective or additive death-inducible effect on Fas-induced apoptosis or oxidative stress injury in primary cultured mouse cardiomyocytes, although it significantly induced hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. Locally overexpressed HB-EGF in the MI border area in rabbit hearts did not improve cardiac function or exhibit an angiogenic effect, and instead exacerbated remodeling at the subacute and chronic stages post-MI. Namely, it elevated the levels of apoptosis, fibrosis, and the accumulation of myofibroblasts and macrophages in the MI area, in addition to inducing left ventricular hypertrophy. Thus, upregulated HB-EGF plays a pathophysiological role in injured hearts in contrast to the therapeutic roles of IGF and HGF. These results imply that regulation of HB-EGF may be a therapeutic target for treating cardiac hypertrophy and fibrosis.

Antidiabetic drug miglitol inhibits myocardial apoptosis involving decreased hydroxyl radical production and Bax expression in an ischaemia/reperfusion rabbit heart.

1 We examined whether antidiabetic drug miglitol could reduce ischaemia/reperfusion-induced myocardial apoptosis by attenuating production. 2 Japanese white rabbits were subjected to 30-min coronary occlusion followed by 4-h reperfusion with miglitol (10 mg kg(-1), i.v., n=20) or saline (n=20). The infarct area was determined by myoglobin staining, and the infarct size (IS) was expressed as a percentage of the area at risk. DNA fragmentation was assessed by TUNEL method and DNA ladder formation. The expression of Bcl-XL and Bax was detected by immunohistochemical analysis and Western blot analysis. Myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, were measured during 30-min ischaemia and 30-min reperfusion in the absence (n=10) or presence of miglitol (10 mg kg(-1), i.v., n=10) using a microdialysis technique. 3 The IS was significantly reduced in the miglitol group (22.4+/-3.4%, n=10) compared to the control group (52.8+/-3.5%, n=10). Miglitol significantly decreased the 2,5-DHBA level during ischaemia and reperfusion and suppressed the incidence of TUNEL-positive myocytes in the ischaemic region (from 10.7+/-3.4 to 4.1+/-3.0%) and the intensity of DNA ladder formation. Miglitol significantly decreased the incidence of Bax-positive myocytes in the ischaemic region (7.4+/-1.7 vs 13.7+/-1.9% of the control) and significantly attenuated the upregulation of Bax protein in the ischaemic regions (from 179+/-17 to 90+/-12% of sham). There was no difference in the expression of Bcl-XL between the two groups. 4 These data suggest that miglitol reduces myocardial apoptosis by attenuating production of hydroxyl radicals and suppressing the upregulation of the expression of Bax protein.

Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment.

BACKGROUND: We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony-stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration. METHODS AND RESULTS: In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 microg x kg(-1) x d(-1) of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2+/-1.5/13.4+/-1.1, 0.4+/-0.1/1.8+/-0.5*, 0/0, and 0/0 mm2 x slice(-1) x kg(-1), granulation areas 0/0, 4.0+/-0.7/8.5+/-1.0*, 3.9+/-0.8/5.7+/-0.7,* and 0/0 mm2 x slice(-1) x kg(-1), and scar areas 0/0, 0/0, 0/0, and 4.2+/-0.5/7.9+/-0.9* mm2 x slice(-1) x kg(-1) in G and S, respectively (*P<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, surviving myocardial tissue areas within the risk areas were significantly increased in G despite there being no difference in LV weight, LV wall area, or cardiomyocyte size between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive 3,3,3',3'-tetramethylindocarbocyanine perchlorate and positive troponin I in G, suggesting enhanced myocardial regeneration by G. CONCLUSIONS: The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.

The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts.

OBJECTIVE: We aimed to clarify the relation between sarpogrelate (SG), a 5-hydroxytryptamine (5-HT)-2 receptor blocker, and myocardial interstitial serotonin or infarct size during ischemia and reperfusion. BACKGROUND: In cardiac tissues serotonin is rich in vascular platelets, mast cells, sympathetic nerve endings, and the receptors are present in platelets and cardiomyocytes. METHODS: The myocardial interstitial serotonin levels were measured using a microdialysis technique during 30-min ischemia with and without SG in in vivo as well as isolated rabbit hearts. Other rabbits underwent 30 min of ischemia and 48 h of reperfusion, and the effect of SG on the infarct size was investigated in the absence and presence of a selective protein kinase C (PKC) inhibitor, chelerythrine (5 mg/kg, intravenously), or a mitochondrial adenosine triphosphate sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate (5-HD) (5 mg/kg, intravenously). In another series, the effect of SG on PKC isoforms in cytosol and membrane fraction was assessed after a 20-min global ischemia in isolated rabbit hearts. RESULTS: Interstitial serotonin levels were markedly increased during 30-min ischemia in in vivo and isolated hearts, and the increases were inhibited by SG in each. The infarct size was reduced by SG (27 +/- 2% vs. 40 +/- 3% of control). This effect was blocked by chelerythrine and 5-HD, respectively. Sarpogrelate further enhanced the ischemia-induced translocation of PKC-epsilon to the membrane fraction. CONCLUSIONS: Sarpogrelate reduces the myocardial infarct size by inhibiting the serotonin release followed by enhancement of PKC-epsilon translocation and opening of the mitochondrial KATP channel in ischemic myocytes.