The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease.

BACKGROUND: To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m2. METHODS: In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m2 with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups. RESULTS: A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68-1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Incidence and risk factors of colonoscopic post-polypectomy bleeding and perforation in patients with end-stage renal disease.

BACKGROUND AND AIMS: Colonoscopic polypectomy in end-stage renal disease (ESRD) patients are at risks of post-polypectomy bleeding and perforation, but evidences are limited. This study aimed to determine the incident polypectomy complications among ESRD patients. METHODS: In the nationwide ESRD cohort, a propensity score matched case-control study design was conducted to assess risk associated with post-polypectomy bleeding and perforation using the Taiwanese National Health Insurance Research Database from 1997 to 2013 for adults aged 40 years and older; 7011 ESRD and 19 118 non-ESRD patients met the study criteria. A total of 5302 patients in each group were matched for further analyses. The primary endpoint was post-polypectomy bleeding or bowel perforation in 30 days. The secondary endpoint was mortality and length of hospital stay for the bleeding complications requiring hospitalization. RESULTS: Overall incidences of post-polypectomy bleeding or perforation in patients with ESRD was higher than the non-ESRD group (5.83% vs 1.78%, P < 0.0001) in the matched cohort. High risk of adverse outcomes was associated with ESRD (adjusted odds ratio [aOR], 2.38, 95% confidence interval [CI], 1.85-3.05), female patient (aOR, 1.7, 95% CI, 1.37-2.11), history of acute myocardial infarction (aOR, 1.91, 95% CI, 1.1-3.32), liver disease (aOR, 1.79, 95% CI, 1.37-2.34), diabetes (aOR, 1.45, 95% CI, 1.16-1.82), cancer (aOR, 1.4, 95% CI, 1.09-1.81), inpatient setting (aOR, 13.19, 95% CI, 9.73-17.88), and prior use of clopidogrel (aOR, 1.61, 95% CI, 1.03-2.52) and warfarin (aOR, 2.03, 95% CI, 1.21-3.41). CONCLUSIONS: End-stage renal disease was associated with approximately twofold higher risk of colonoscopic post-polypectomy bleeding or perforation and should be cautiously performed in this special population cohort.

The role of antibiotics in upper gastrointestinal bleeding among cirrhotic patients without major complications after endoscopic hemostasis.

BACKGROUND AND AIM: Antibiotic prophylaxis should be instituted for cirrhotic patients with upper gastrointestinal bleeding (UGIB), but the benefit on compensated patients remains undetermined. We aimed to compare the clinical outcomes between cirrhotic patients without major complications with UGIB with and without antibiotic prophylaxis. METHODS: We conducted this population-based cohort study by using Taiwanese Longitudinal Health Insurance Database 2000 (LHID2000, between 1997 to 2013), aged 18 years or older with a hospital discharge diagnosis of cirrhosis (n = 64,506), UGIB (n = 7,784), and endoscopic therapy (n = 2,292). After strict exclusions, 1205 patients were enrolled and were divided into antibiotic exposure (n = 558) and non-exposure (n = 647) groups. The outcomes were rebleeding and mortality. RESULTS: After completing the analysis adjusted by death, the rebleeding rates within 4 weeks were significantly lower in patients with antibiotic prophylaxis (3.05% versus 6.03%, P = 0.0142) and those with endoscopic therapy (0.72% vs 3.09%, P = 0.0033) but not significant after 3 months and onwards. Male patients aged > 55, high CCI score â‰§ 4, and UGIB of variceal etiologies were benefited from rebleeding. The use of antibiotics did not significantly impact 6-week mortality (adjusted hazard ratio: 1.07, 95%CI: 0.41~2.75; P = 0.8943). Old age, multiple comorbidities, and UGIB of variceal etiologies were risk factors of all-cause mortality. CONCLUSIONS: The current study suggested that cirrhotic patients without major complications who suffered from UGIB were benefited by the use of antibiotics to prevent rebleeding within 4 weeks after endoscopic treatment of UGIB especially for those with age > 55, high CCI score â‰§ 4, and UGIB of variceal etiologies.

Common pulmonary vein on the recurrence of atrial tachyarrhythmia after pulmonary vein isolation.

AIMS: Catheter ablation has become an effective treatment modality for atrial fibrillation (AF). However, the relationship between common pulmonary vein (PV) and recurrent atrial tachyarrhythmia (ATA) after PV isolation (PVI) remains controversial. This study aimed to explore the function of common PV on the risk of recurrent ATA after PVI. METHODS: We identified a total of 191 patients who received radiofrequency catheter ablation for paroxysmal AF at our hospital between July 2010 and December 2017 for retrospective chart review. We collected the following data for analysis: results of preprocedural computed tomography, including the anatomy of PV and left atrial (LA) volume; the incidence of early- and late-onset recurrence of ATA. We compared these characteristics between the two groups defined by the presence or absence of the late-onset recurrence of ATA. RESULTS: Compared to the no ATA recurrence group, the ATA recurrence group had larger LA size, larger LA end-diastolic and systolic volumes, larger maximal diameter of PV, higher prevalence of common PV, and higher incidence of early-onset recurrence of ATA. In multivariate logistic regression analyses, presence of common PV and early-onset recurrence were independently associated with late-onset recurrence of ATA. Compared to patients without common PV, patients with common PV had larger diameter of PV and higher incidence of late-onset recurrent ATA. CONCLUSION: In patients with paroxysmal AF, early-onset recurrence of ATA and the presence of common PV were independently associated with late-onset recurrent ATA after radiofrequency catheter ablation.

Additional cavotricuspid isthmus block ablation may not improve the outcome of atrial fibrillation ablation.

AIMS: Pulmonary vein isolation (PVI) is an effective procedure for atrial fibrillation (AF). The role of additional cavotricuspid isthmus (CTI) block ablation remains controversial in AF patients without atrial flutter (AFL). Therefore, this study aimed to explore the clinical outcome of additional CTI block ablation in patients without AFL. METHODS: Between January 2013 and December 2017, a total of 139 patients who did not have documented AFL and who underwent catheter ablation for AF were recruited. Fifty-seven patients were classified in additional CTI block ablation group and 82 patients were classified in without CTI group. The incidence of early-onset and late-onset atrial arrhythmia recurrence was compared between the two groups. RESULTS: The additional CTI group had a higher prevalence of persistent or long-standing AF and larger left atrial volume. The additional CTI group had a higher incidence of late-onset atrial arrhythmia recurrence (38.6% vs 12.2%; P < .001). When compared to without CTI group, additional CTI therapy did not have a better outcome in terms of freedom of atrial arrhythmia in subgroup analysis. The incidence of early-onset and late-onset atrial arrhythmia recurrence did not differ between additional CTI group and without CTI group in paroxysmal AF patients and nonparoxysmal AF patients after propensity scoring matching. CONCLUSION: CTI block ablation in addition to PVI for AF patients without a history of AFL or inducible AFL during ablation may not improve the clinical outcome of AF ablation in the patients with larger LA volume, nonparoxysmal AF, or post-PVI inducible AF.

Late fractionated potentials in catheter ablation for right ventricular outflow tract ventricular arrhythmias.

BACKGROUND: Endocardial late fractionated potentials during sinus rhythm mapping may reflect abnormal "subendocardial" substrates associated with right ventricular outflow tract (RVOT) ventricular arrhythmias (VAs). The aim of this study was to explore the clinical outcomes of catheter ablation guided by these late fractionated potentials for RVOT VAs in patients without structural heart disease. METHODS: From January 2016 to March 2018, 28 patients underwent catheter ablation for RVOT premature ventricular contractions (PVCs) or ventricular tachycardia (VT), guided by the EnSite NavX or Velocity V5.0 three-dimensional mapping system (Abbott, St. Paul, MN, USA). Among them, 10 patients (35.7%) were found to have endocardial late fractionated potentials during sinus rhythm mapping (Group 1). Group 2 was composed of 18 patients in whom no endocardial late fractionated potentials were seen. The burden of VAs, acute procedural success, and 3-month clinical outcomes were analyzed. RESULTS: The average duration of late fractionated potentials after the end of QRS during sinus rhythm mapping in group 1 was 45.00 ± 17.15 ms. Baseline demographics and morphology and burden of PVCs were similarly distributed between both groups. Group 1 had higher acute procedural success compared to group 2 (100% vs 66.7%; P = .039). Moreover, at 3-month follow-up, group 1 had lower total PVCs (49 (1-5986) versus 4316 (1-23231); P = .048), PVC burden (0% (0-5.9) vs 4.3% (0-18.9); P = .055), and higher clinical success (100% vs 55.6%; P = .025) compared to group 2. CONCLUSION: The identification and elimination of endocardial late fractionated potentials during sinus rhythm mapping could improve the acute success and short-term outcomes of ablation for RVOT VAs.

Evaluation of Bleeding Risk in Patients with Acute Myocardial Infarction Undergoing Transradial Percutaneous Coronary Intervention.

We investigated the accuracy of various bleeding risk scores to estimate the bleeding risk in patients with acute myocardial infarction (AMI) managed with percutaneous coronary intervention (PCI) access via the radial artery.We retrospectively enrolled 1,651 patients who were definitively diagnosed with ST-elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI). We assessed the predictive validities of 30-day bleeding events in various scoring systems using receiver operating characteristic curves.Overall, ACUITY-HORIZONS exhibited the highest area under the curve to predict 30-day bleeding, followed by ACTION and CRUSADE; HAS-BLED displayed the lowest score. With a cut-off of 17, ACUITY-HORIZONS demonstrated the best discrimination for the Thrombolysis in Myocardial Infarction (TIMI) 30-day serious bleeding rate. We observed significant differences among all-cause death, cardiovascular death, and major adverse cardiac events between the ACUITY-HORIZONS groups with a score of ≤ 17 and > 17. ACUITY-HORIZONS score > 17, initial systolic blood pressure (SBP) < 90 mmHg, and Killip III and IV upon admission positively predicted the 30-day bleeding risk, whereas myocardial infarction (MI) and TIMI major bleeding within 30 days, heart failure at admission, and initial SBP < 90 mmHg positively predicted the 30-day mortality.Comparatively, ACUITY-HORIZON is the most reliable system in predicting 30-day bleeding for patients with AMI via transradial PCI. In the transradial scenario, bleeding and MI within 30 days are substantially related to 30-day mortality.

The Role of Non-Selective ß-Blockers in Compensated Cirrhotic Patients without Major Complications.

Background and Objectives: Non-selective ß-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in cirrhotic patients with clinically significant portal hypertension (CSPH), but remained uncertain for compensated cirrhotic patients without major complications. We aimed to compare the clinical outcomes between propranolol users and non-users of a CC group without major complications. Material and Methods: We conducted this population-based cohort study by using the Taiwanese Longitudinal Health Insurance Database 2000. Propranolol users (classified as cumulative defined daily dose (cDDD)) and non-PPL users were matched with a 1:1 propensity score in both cohorts. Results: This study comprised 6896 propranolol users and 6896 non-propranolol users. There was no significant impact on the development of spontaneous bacterial peritonitis between the two groups (aHR: 1.24, 95% confidence interval (CI): 0.88~1.75; p = 0.2111). Male gender, aged condition, and non-liver related diseases (peripheral vascular disease, cerebrovascular disease, dementia, pulmonary disease, and renal disease) were the independent risk factors of mortality. PPL users had significantly lower incidence of HCC development than non-users (aHR: 0.81, p = 0.0580; aHR: 0.80, p = 0.1588; and aHR: 0.49, p < 0.0001 in the groups of 1-28, 29-90, and >90 cDDD, respectively). Conclusion: The current study suggested that high cumulative doses of propranolol could decrease the risk of hepatocellular carcinoma among compensated cirrhotic patients without major complications. Further large-scale prospective studies are still required to confirm the findings in this study. Results: It remained uncertain whether non-selective ß-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in compensatory cirrhotic patients without major complications. This study aimed to compare the clinical outcomes between propranolol users and non-users of the CC group without major complications.

Impact of Pharmacist Interventions on the Long-Term Clinical Outcomes in Patients with Myocardial Infarction.

BACKGROUND: Controlling modifiable risk factors (MRFs) in patients with cardiovascular diseases has been shown to be effective in reducing re-hospitalization rates. The aim of this study was to investigate the rates of controlled MRFs and clinical outcomes after pharmacist interventions in patients with myocardial infarction (MI) after hospital discharge. METHODS: This prospective randomized clinical study was conducted at one medical center in Taiwan, and enrolled patients with MI from January 1, 2012 to December 31, 2014. Patients received medication reconciliation and education from a pharmacist before hospital discharge. The intervention group (IG) received continuous consultations from the pharmacist after discharge, whereas the control group (CG) did not. Primary outcomes included achieving blood pressure < 140/70 mmHg, low-density lipoprotein-cholesterol (LDL-C) < 70 mg/dL, and hemoglobin A1c (HbA1c) < 7% targets. The secondary outcome was major adverse cardiac events (MACEs), defined as re-hospitalization due to MI, unstable angina and stroke. RESULTS: Two hundred and eight patients completed the study protocol (106 in the IG and 102 in the CG). The rate of achieving blood pressure goal was similar between the two groups. More patients in the IG achieved LDL-C and HbA1c goals than those in the CG at 1 year and 2 years post discharge. However, there was no significant difference in the cumulative incidence of MACEs between the two groups (5.7% vs. 9.8%) (p = 0.262). Diabetes was the only independent predictor of re-hospitalization due to a MACE. CONCLUSIONS: Pharmacist interventions led to a higher rate of optimal controlled MRFs but did not significantly reduce the MACE rate in the patients with MI.

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases.

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress.

BACKGROUND: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. METHODS: Forty-eight mice were divided into four groups (n = 12 per group): Group 1: Wild-type (WT) mice, Group 2: RasGRF1 deficiency (RasGRF1-/-) mice. Group 3: Streptozotocin (STZ)-induced diabetic WT mice, Group 4: STZ-induced diabetic RasGRF1-/- mice. Myocardial functions were assessed by cardiac echography. Heart tissues from all of the mice were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. RESULTS: Worse impaired diastolic function with elevation serum interleukin (IL)-6 was found in the diabetic group compared with the non-diabetic groups. Serum IL-6 levels were found to be elevated in the diabetic compared with the non-diabetic groups. However, the diabetic RasGRF1-/- mice exhibited lower serum IL-6 levels and better diastolic function than the diabetic WT mice. The diabetic RasGRF1-/- mice were associated with reduced cardiac inflammation, which was shown by lower invading inflammation cells, lower expression of matrix metalloproteinase 9, and less chemokines compared to the diabetic WT mice. Furthermore, less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was also found in the diabetic RasGRF1-/- mice compared with the diabetic WT mice. CONCLUSION: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress.

Upregulation of Interleukin-33 in obstructive renal injury.

Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases.

Bundled preparation of skin antisepsis decreases the risk of cardiac implantable electronic device-related infection.

AIMS: To evaluate the efficacy of bundled skin antiseptic preparation to prevent cardiac implantable electronic device (CIED) infections. METHODS AND RESULTS: From January 2010 to November 2013, 665 consecutive patients were divided into two groups according to the strategy of skin preparation. In Period 1 (January 2010 to June 2012), 395 patients received the standard skin antiseptic preparation. In Period 2 (July 2012 to November 2013), 270 patients received a triple-step skin antiseptic preparation, 'bundled skin antiseptic preparation', consisting of applying 75% alcohol over anterior chest on the night before the index day, povidone-iodine 10 min before operation, and the standard skin antiseptic preparation before incision. During follow-up, the occurrence of CIED infection was recorded. Multiple logistic regression analysis was used to determinate the risk factors of CIED infection. During a mean follow-up of 26.9 ± 16.2 months, 20 episodes of CIED infection developed in 19 patients (2.9%), and the incidence of minor and major infection episodes was 2.2% and 0.8%, respectively. Patients with the bundled skin antiseptic preparation had a significantly lower incidence of CIED infection, compared with patients with the standard preparation (0.7 vs. 4.3%, P = 0.007). In multivariate analysis, pocket haematoma (P = 0.020), atrial fibrillation (P = 0.033), and complex procedures (P = 0.047) were independent predictors for CIED infection. In contrast, the bundled skin antiseptic preparation was a significant predictor against CIED infection (P = 0.014). CONCLUSION: Pocket haematoma was the most important risk factor for CIED infection. The bundled skin antiseptic preparation strategy significantly reduced the risk of minor CIED infection.

Left ventricle remodeling predicts the recurrence of ventricular tachyarrhythmias in implantable cardioverter defibrillator recipients for secondary prevention.

BACKGROUND: Implantable cardioverter defibrillator (ICD) is an effective treatment for secondary prevention of ventricular tachycardia/ventricular fibrillation (VT/VF). Left ventricular (LV) remodeling may develop before ICD implant and over time. However, it remains unclear how LV remodeling affects subsequent risk for recurrence VT/VF in ICD recipients under optimal medical therapy. METHODS: From May of 2004 to June of 2015, 144 patients received ICD implantation for secondary prevention were enrolled in this study. All information interrogated from ICD devices during follow-up or ICD therapy history (anti-tachycardia pacing and shock therapy) were reviewed and validated the occurrences of VT/VF. RESULTS: At a mean follow-up of 1110.5 ± 860.6 days, 53 patients (36.8%) had recurrence of VT/VF episodes and 91 patients had no recurrence of VT/VF episode after ICD implant. Left ventricular end-diastolic volume (LVEDV) > 163.5 mL had significant predictive value for VT/VF recurrence (area under the curve: 0.602, p = 0.041). Moreover, the percentage of patients with LVEDV >163.5 mL was significantly higher in patients with recurrent VT/VF than patients without recurrent VT/VF (62.3 vs 40.0%, p = 0.010). Left ventricular ejection fraction ≤ 30% (p = 0.031), LVEDV > 163.5 mL (p = 0.012) and QRS width > 125 msec (p = 0.049) were significant predictors for VT/VF recurrence by univariate Cox regression analysis. However, only LVEDV > 163.5 mL (hazard ratio: 2.549, 95% confidence interval: 1.249 ~ 5.201, p = 0.010) and QRS width > 125 msec (hazard ratio: 2.173, 95% confidence interval: 1.030 ~ 4.586, p = 0.042) were independent predictors for recurrence of VT/VF after multivariable adjustment. CONCLUSION: LV remodeling and QRS width > 125 msec were independent predictors for VT/VF recurrence in secondary prevention ICD recipients under optimal medical therapy, independent of LV ejection fraction.

Administered circulating microparticles derived from lung cancer patients markedly improved angiogenesis, blood flow and ischemic recovery in rat critical limb ischemia.

BACKGROUND: We hypothesized that lung cancer patient's circulating microparticles (Lc-MPs) could promote angiogenesis, blood flow in ischemic zone and ischemic recovery in rat critical limb ischemia (CLI). METHODS: To investigate the impact of MP therapy on reversing the setting of CLI, adult-male Sprague-Dawley rats (n=50) equally randomized into sham control (SC) (group 1), SC-Lc-MPs (1.0 x 10(7) particles) (group 2), CLI (group 3), CLI-Hs-MPs (MPs from healthy-subject) (group 4), and CLI-Lc-MPs (group 5) were sacrificed by post-CLI day-14. RESULTS: In vitro study showed that Lc-MPs enhanced VEGFR2 expression, angiogenesis, nitric-oxide production, and endothelial cell proliferation (all p<0.005). By days 7 and 14, Laser Doppler showed significantly higher ischemic/normal blood-flow ratio in groups 1 and 2 compared with group 3, and was significantly higher in group 4 and further elevated in group 5 (p<0.0001). Numbers of small vessels and endothelial markers (CD31(+) and vWF(+) cells) and protein expressions (eNOS, CD31) exhibited a pattern identical to Lasre Doppler among the five groups (all p<0.001). Pro-angiogenic factors (VEGF, CXCR4, SDF-1α, HGF) at cellular and protein levels showed a significant step-wise increase from groups 1 and 2 to groups 3, 4, and 5 (all p<0.001). Protein expressions of fibrotic (Smad3, TGF-ß) and apoptotic (mitochondrial Bax, cleaved caspase 3, and PARP) biomarkers displayed an opposite pattern compared to that of Laser Doppler, whereas the protein expressions of anti-fibrotic (Smad1/5, BMP-2) and anti-apoptotic (Bcl-2) biomarkers showed an identical pattern compared with that of Laser Doppler among groups 1 to 3, and 5 (all p<0.001). CONCLUSION: Administration of Lc-MPs augmented angiogenesis and restored blood flow in a rat of CLI.

Systemic combined melatonin-mitochondria treatment improves acute respiratory distress syndrome in the rat.

Despite high in-hospital mortality associated with acute respiratory distress syndrome (ARDS), there is no effective therapeutic strategy. We tested the hypothesis that combined melatonin-mitochondria treatment ameliorates 100% oxygen-induced ARDS in rats. Adult male Sprague-Dawley rats (n = 40) were equally categorized into normal controls, ARDS, ARDS-melatonin, ARDS with intravenous liver-derived mitochondria (1500 µg per rat 6 hr after ARDS induction), and ARDS receiving combined melatonin-mitochondria. The results showed that 22 hr after ARDS induction, oxygen saturation (saO2 ) was lowest in the ARDS group and highest in normal controls, significantly lower in ARDS-melatonin and ARDS-mitochondria than in combined melatonin-mitochondria group, and significantly lower in ARDS-mitochondria than in ARDS-melatonin group. Conversely, right ventricular systolic blood pressure and lung weight showed an opposite pattern compared with saO2 among all groups (all P < 0.001). Histological integrity of alveolar sacs showed a pattern identical to saO2 , whereas lung crowding score exhibited an opposite pattern (all P < 0.001). Albumin level and inflammatory cells (MPO+, CD40+, CD11b/c+) from bronchoalveolar lavage fluid showed a pattern opposite to saO2 (all P < 0.001). Protein expression of indices of inflammation (MMP-9, TNF-α, NF-κB), oxidative stress (oxidized protein, NO-1, NOX-2, NOX-4), apoptosis (mitochondrial Bax, cleaved caspase-3, and PARP), fibrosis (Smad3, TGF-ß), mitochondrial damage (cytochrome C), and DNA damage (γ-H2AX+) exhibited an opposite pattern compared to saO2 in all groups, whereas protein (HO-1, NQO-1, GR, GPx) and cellular (HO-1+) expressions of antioxidants exhibited a progressively increased pattern from normal controls to ARDS combined melatonin-mitochondria group (all P < 0.001). In conclusion, combined melatonin-mitochondrial was superior to either treatment alone in attenuating ARDS in this rat model.

Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized, prospective, placebo-controlled clinical trial.

INTRODUCTION: Mortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO. METHODS: This was a prospective, randomized, placebo-controlled trial that was conducted between October 2008 and March 2010 in a tertiary referral center. IS stroke patients who were eligible for EPO therapy were enrolled into the study. RESULTS: The results showed that long-term recurrent stroke and mortality did not differ between group 1 (placebo-control; n = 71) and group 2 (EPO-treated; n = 71). Long-term Barthel index of <35 (defining a severe neurological deficit) was lower in group 2 than group 1 (P = 0.007). Multiple-stepwise logistic-regression analysis showed that EPO therapy was significantly and independently predictive of freedom from a Barthel index of <35 (P = 0.029). Long-term major adverse neurological event (MANE; defined as: death, recurrent stroke, or long-term Barthel index < 35) was lower in group 2 than group 1 (P = 0.04). Log-Rank test showed that MANE-free rate was higher in group 2 than group 1 (P = 0.031). Multiple-stepwise Cox-regression analysis showed that EPO therapy and higher Barthel Index at day 90 were independently predictive of freedom from long-term MANE (all P <0.04). CONCLUSION: EPO therapy significantly improved long-term neurological outcomes in patients after IS. TRIAL REGISTRATION: ISRCTN71371114 . Registered 10 October 2008.

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors.

AIM: Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats. METHODS: Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies. RESULTS: Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin. CONCLUSION: Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

Early Administration of Intracoronary Nitroprusside Compared with Thrombus Aspiration in Myocardial Perfusion for Acute Myocardial Infarction: A 3-Year Clinical Follow-Up Study.

BACKGROUND: Intracoronary nitroprusside and thrombus aspiration have been demonstrated to improve myocardial perfusion during percutaneous coronary interventions (PCI) for ST-segment elevation acute myocardial infarction (STEMI) However, no long-term clinical studies have been performed comparing these approaches. METHODS: A single medical center retrospective study was conducted to evaluate the effects of intracoronary nitroprusside administration before slow/no-reflow phenomena versus thrombus aspiration during primary PCI. Forty-three consecutive patients with STEMI were enrolled in the intracoronary nitroprusside treatment group. One hundred twenty-four consecutive STEMI patients who received thrombus aspiration were enrolled; ninety-seven consecutive STEMI patients who did not receive either thrombus aspiration or intracoronary nitroprusside treatment were enrolled and served as control subjects. Patients with cardiogenic shock, who had received platelet glycoprotein IIb/IIIa inhibitor, or intra-aortic balloon pump insertion were excluded. Thrombolysis in Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count and TIMI myocardial perfusion grade (TMPG) were assessed prior to and following PCI by two independent cardiologists blinded to the procedures. The rate of major adverse cardiac events (MACE) at 30 days, 1 year, and 3 years after study enrollment as a composite of recurrent myocardial infarction, target-vessel revascularization, and cardiac death were recorded. RESULTS: The control group had a significantly lower pre-PCI TIMI flow (≤ 1; 49.5% vs. 69.8% vs. 77.4%; p = < 0.001) compared with the nitroprusside and thrombus aspiration groups. The thrombus aspiration group had a significantly higher pre-PCI thrombus score (> 4; 98.4% vs. 88.4% vs. 74.3%; p = < 0.001) and post-PCI TMPG (3; 39.5% vs. 16.3% vs. 20.6%; p = 0.001) compared with the nitroprusside and control groups. No significant differences were noted in the post-PCI thrombus score, 30-day, 1-year and 3-year MACE rate, and Kaplan-Meier curve among 3 groups of patients. CONCLUSIONS: Although thrombus aspiration provided improved TMPG compared with early administration of intracoronary nitroprusside and neither of both during primary PCI, it did not have a significant impact on 30-day, 1-year and 3-year MACE rate. KEY WORDS: Acute myocardial infarction; Intracoronary nitroprusside; Thrombus aspiration.

Minimizing door-to-balloon time is not the most critical factor in improving clinical outcome of ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

OBJECTIVES: We tested the hypothesis that, as compared with conventional door-to-balloon, shortened door-to-balloon time would further improve 30-day outcome in ST-elevation myocardial infarction patients undergoing primary stenting. DESIGN: Retrospective cohort study SETTING: Academic tertiary care hospital with approximately 2600 beds PATIENTS: Between January 2008 and December 2009, 266 ST-elevation myocardial infarction patients underwent primary stenting with conventional Door-to-baloon were consecutively enrolled as group 1, while 293 ST-elevation myocardial infarction patients underwent primary stenting with shortened door-to-balloon between January 2010 and December 2011 were consecutively enrolled as group 2. INTERVENTION: Shorten door-to-balloon time. MEASUREMENTS AND MAIN RESULTS: The results showed that time from chest pain onset to door did not differ between two groups (p > 0.1), whereas door-to-balloon time was significantly reduced in group 2 compared with that in group 1 (p < 0.0001). The prevalences of successful reperfusion, acute and subacute stent thrombosis, 30-day death or combined endpoint (defined as congestive heart failure ≥ New York Heart Association functional class 3 or 30-d death), and left ventricular function did not differ between two groups (all p > 0.05), whereas the peak creatine phosphokinase level was significantly reduced in group 2 (< 0.05). Further analysis showed that shortening the chest pain-to-reperfusion time to less than 240 minutes was the most important factor in improving left ventricular function (p < 0.001) and 30-day combined endpoint. Multivariate analysis showed that congestive heart failure greater than or equal to New York Heart Association functional class 3, poor left ventricular function, and age (all p < 0.001) along with unsuccessful reperfusion (p = 0.25) were independently predictive of 30-day mortality. CONCLUSION: Shortening the duration between chest pain onset and reperfusion to less than 4.0 hours was critical in reducing myocardial necrosis and improving heart function and 30-day mortality.