Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.

Management of Venous Thromboembolisms: Part II. The Consensus for Pulmonary Embolism and Updates.

Pulmonary embolism (PE) is a potential life-threatening condition and risk-adapted diagnostic and therapeutic management conveys a favorable outcome. For patients at high risk for early complications and mortality, prompt exclusion or confirmation of PE by imaging is the key step to initiate and facilitate reperfusion treatment. Among patients with hemodynamic instability, systemic thrombolysis improves survival, whereas surgical embolectomy or percutaneous intervention are alternatives in experienced hands in scenarios where systemic thrombolysis is not the best preferred thromboreduction measure. For patients with suspected PE who are not at high risk for early complications and mortality, the organized approach using a structured evaluation system to assess the pretest probability, the age-adjusted D-dimer cut-offs, the appropriate selection of imaging tools, and proper interpretation of imaging results is important when deciding the allocation of treatment strategies. Patients with PE requires anticoagulation treatment. In patients with cancer and thrombosis, low-molecular-weight heparin (LMWH) used to be the standard regimen. Recently, three factor Xa inhibitors collectively show that non-vitamin K oral anticoagulants (NOACs) are as effective as LMWH in four randomized clinical trials. Therefore, NOACs are suitable and preferred in most conditions. Finally, chronic thromboembolic pulmonary hypertension is the most disabling long-term complication of PE. Because of its low incidence, the extra caution should be given when managing patients with PE.

Arterial Stiffness Index and Coronary Artery Plaques in Patients with Subclinical Coronary Atherosclerosis.

BACKGROUND: Arterial stiffness is a physiologic quantitative value used to measure arterial compliance. It is predictive of coronary atherosclerosis in patients with intermediate to high cardiovascular risk. However, a correlation between arterial stiffness and subclinical coronary atherosclerosis has yet to be established. Therefore, the purpose of this study was to evaluate arterial stiffness using an arterial stiffness index (ASI) and investigate its association with coronary artery plaque in patients with subclinical coronary atherosclerosis. METHODS: Our study enrolled 156 consecutive subjects who underwent health screening using a 64-slice cardiac computed tomography angiography (CCTA). Their arterial stiffness index was assessed noninvasively by CardioVision(®) MS-2000. The atheroma on the coronary vessel walls was analyzed. RESULTS: Of the 156 patients, 53 displayed at least one > 50% stenotic lesion over the coronary arteries in CCTA images. The patients with at least one > 50% coronary stenotic plaque were older and had higher systolic blood pressure and ASI values than patients without > 50% coronary stenotic plaque. After dividing the study population into 2 groups by those patients over and under 50 years of age, the ASI positively correlated with the presentation of at least one > 50% coronary stenotic plaque in patients aged ≥ 50 years (odds ratio = 1.02, 95% confidence interval: 1.00-1.04, p = 0.03). CONCLUSIONS: The ASI could play a role in risk stratification systems for coronary artery disease in patients with subclinical coronary atherosclerosis, and is a useful clinical marker for the correlation of early coronary plaque. KEY WORDS: Arterial stiffness; Arterial stiffness index; Atherosclerosis; Coronary artery plaque.

Exercise capacity-hemodynamics mismatch in elderly patients with pulmonary hypertension: A nationwide multicenter study from Taiwan Society of Cardiology Pulmonary Hypertension Registry (TAIPANS).

Background: Demographics of pulmonary hypertension (PH) has changed a lot over the past forty years. Several recent registries noted an increase in mean age of PH but only a few of them investigated the characteristics of elderly patients. Thus, we aimed to analyze the characteristics of PH in such a population in this study. Methods: This multicenter study enrolled patients diagnosed with PH in group 1, 3, 4, and 5 consecutively from January 1, 2019 to December 31, 2020. A total of 490 patients was included, and patients were divided into three groups by age (≤45 years, 45-65 years, and >65 years). Results: The mean age of PH patients diagnosed with PH was 55.3 ± 16.3 years of age. There was higher proportion of elderly patients classified as group 3 PH (≤45: 1.3, 45-65: 4.5, >65: 8.1 %; p = 0.0206) and group 4 PH (≤45: 8.4, 45-65: 14.5, >65: 31.6 %; p < 0.0001) than young patients. Elderly patients had shorter 6-min walking distance (6 MWD) (≤45 vs. >65, mean difference, 77.8 m [95% confidence interval (CI), 2.1-153.6 m]), lower mean pulmonary arterial pressure (mPAP) (≤45 vs. >65, mean difference, 10.8 mmHg [95% CI, 6.37-15.2 mmHg]), and higher pulmonary arterial wedge pressure (PAWP) (≤45 vs. 45-65, mean difference, -2.1 mmHg [95% CI, -3.9 to -0.3 mmHg]) compared to young patients. Elderly patients had a poorer exercise capacity despite lower mPAP level compared to young population, but they received combination therapy less frequently compared to young patients (triple therapy in group 1 PH, ≤45: 16.7, 45-65: 11.3, >65: 3.8 %; p = 0.0005). Age older than 65 years was an independent predictor of high mortality for PH patients. Conclusions: Elderly PH patients possess unique hemodynamic profiles and epidemiologic patterns. They had higher PAWP, lower mPAP, and received combination therapy less frequently. Moreover, ageing is a predictor of high mortality for PH patients. Exercise capacity-hemodynamics mismatch and inadequate treatment are noteworthy in the approach of elderly population with PH.

Combined Framingham Risk Score and Coronary Artery Calcium Score Predict Subclinical Coronary Plaque Assessed by Coronary Computed Tomography Angiogram in Asymptomatic Taiwanese Population.

BACKGROUND: We sought to determine the predictive value of the combined traditional Framingham risk score (FRS) and coronary artery calcium score (CACS) for subclinical coronary plaque detected by computed tomography coronary angiogram (CTCA) in asymptomatic subjects. METHOD: We evaluated 167 asymptomatic Taiwanese subjects (mean age, 57 ± 11.2 years), who underwent CTCA as part of a health evaluation. We examined the associations between FRS, CACS, serum biomarkers, and coronary plaque assessed by CTCA. RESULTS: Out of 167 subjects in the study, 95 had coronary artery atheroma. Of those possible predictors for coronary atherosclerosis, both FRS and CACS were independent predictors for the presence of coronary plaque [relative risk (RR): 1.29, 95% confidence interval (CI): 1.07-1.54, p = 0.006 and RR: 1.42, 95% CI: 1.16-1.75, p = 0.001, respectively]. Receiver operating characteristics curve analysis revealed that CACS and FRS were indicators of the presence of coronary plaque. The area under the curve for FRS and CACS was 0.729 and 0.889, respectively (p < 0.001). Furthermore, the area under the curve for combination of FRS and CACS was 0.936 (95% CI: 0.887-0.969, p < 0.001), and this combination provided a better diagnostic advantage than either FRS or CACS alone (p < 0.001 and p = 0.012 by C-statistic, respectively). CONCLUSIONS: In asymptomatic Taiwanese subjects with low to intermediate cardiovascular risk, both FRS and CACS were independently related to subclinical atherosclerosis. A combined FRS and CACS evaluation improved the efficacy of prediction for atherosclerotic plaque burden. KEY WORDS: Atherosclerosis; Computed coronary tomography angiogram; Coronary artery calcium score; Framingham risk score; Subclinical coronary plaque.

Machine Learning-Based Prediction of Atrial Fibrillation Risk Using Electronic Medical Records in Older Aged Patients.

Atrial fibrillation (AF) is an independent risk factor that increases the risk of stroke 5-fold. The purpose of our study was to develop a 1-year new-onset AF predictive model by machine learning based on 3-year medical information without electrocardiograms in our database to identify AF risk in older aged patients. We developed the predictive model according to the Taipei Medical University clinical research database electronic medical records, including diagnostic codes, medications, and laboratory data. Decision tree, support vector machine, logistic regression, and random forest algorithms were chosen for the analysis. A total of 2,138 participants (1,028 women [48.1%]; mean [standard deviation] age 78.8 [6.8] years) with AF and 8,552 random controls (after the matching process) without AF (4,112 women [48.1%]; mean [standard deviation] age 78.8 [6.8] years) were included in the model. The 1-year new-onset AF risk prediction model based on the random forest algorithm using medication and diagnostic information, along with specific laboratory data, attained an area under the receiver operating characteristic of 0.74, whereas the specificity was 98.7%. Machine learning-based model focusing on the older aged patients could offer acceptable discrimination in differentiating the risk of incident AF in the next year. In conclusion, a targeted screening approach using multidimensional informatics in the electronic medical records could result in a clinical choice with efficacy for prediction of the incident AF risk in older aged patients.

Inhibition of AMPK-associated autophagy enhances caffeic acid phenethyl ester-induced cell death in C6 glioma cells.

An increasing number of studies show that AMP-activated protein kinase (AMPK) activation can inhibit apoptosis. To clarify the antitumor mechanism of caffeic acid phenethyl ester (CAPE) and achieve increased therapeutic efficiency, we investigated the potential roles of AMPK and autophagy in CAPE treatment against C6 glioma cells. The roles of AMPK and autophagy inhibition in CAPE's cytotoxic action were investigated. Phosphorylation of AMPK and mitogen-activated protein kinases (MAPKs) were observed in tumor cells following CAPE treatment. A combination of CAPE and the AMPK inhibitor, compound C, resulted in augmented cell death. Similar effects of compound C were observed in response to changes in the mitochondrial membrane potential ( ΔΨ(m)). Small interfering RNA-mediated AMPK downregulation increased CAPE-induced cell death. The results suggest that AMPK activation plays a role in diminishing apoptosis. CAPE treatment induced an increase in LC3 conversion as represented by the LC3-II/LC3-I ratio. Enlarged lysosomes and autophagosomes were present according to electron microscopy. The autophagy inhibitor, 3-MA, caused increased CAPE cytotoxicity, which suggests that autophagy induction protected glioma cells from CAPE. The combination of CAPE with autophagy and AMPK inhibitors markedly enhanced the cytotoxicity toward C6 glioma cells. Accordingly, CAPE-triggered activation of AMPK and the autophagic response protected tumor cells from apoptotic death. This provides new insights for combined therapy to enhance the therapeutic potential of cancer treatments.

Association of multiple preventive therapies postdischarge and long-term health outcomes after acute myocardial infarction.

BACKGROUND: Statins, beta-blockers, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers have been advocated by guidelines as secondary prevention medications to improve the long-term outcomes of post-acute myocardial infarction (AMI) patients. However, adequate drug adherence has always been challenging, and different treatment regimens may lead to divergent outcomes that remain unclear under current myocardial infarction (MI) care standards. This study investigated the association between use of different preventive regimens post-AMI and patients' long-term outcomes. METHODS: This cohort study used data files from the Taiwan National Health Insurance Research Database. A total of 77 520 people who were hospitalized with AMI between 2002 and 2015 were assessed. On the basis of medication possession ratio (MPR) to individual medications, eight treatment groups were examined in this study. Receiving therapy was defined as MPR ≥40%. We investigated the association between different treatment groups and all-cause mortality in 24 months. RESULTS: Overall, 51 322 patients with ST-elevation MI and 26 198 with non-ST-elevation MI were included in the study. Patients received all three preventive medications show the lowest mortality in 24 months follow-up periods among all treatment groups. Patients who did not usage of any of these three preventive medications had the highest mortality in 24 months (adjusted hazard ratio, 1.78; 95% CI, 1.64-1.93). This mortality rate had the same pattern across the three cohort generations (2002-2005, 2006-2010, and 2011-2015). CONCLUSION: In this large population-based real-world study, usage of three preventive therapies post-MI was associated with the lowest rate of all-cause mortality.

Effectiveness and safety of rivaroxaban versus warfarin in Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation: A real-world nationwide cohort study.

BACKGROUND: The optimal anticoagulant for end-stage renal disease patients for stroke prophylaxis is unknown. The efficacy and safety of warfarin in this population are debatable. In addition, real-world evidence of direct oral anticoagulants in patients with end-stage renal disease is limited. The aim of this study was to evaluate the clinical outcomes of rivaroxaban compared with warfarin in Taiwanese patients with end-stage renal disease with nonvalvular atrial fibrillation in a real-world setting. METHODS AND RESULTS: This was a retrospective population-based cohort study conducted using Taiwan's National Health Insurance Research Database. Patients with nonvalvular atrial fibrillation and end-stage renal disease who started on rivaroxaban or warfarin between February 2013 and September 2017 were eligible to participate in the study. The inverse probability of treatment weighting approach was used to balance baseline characteristics. Bleeding and thromboembolic outcomes were compared using competing risk analyses. The study population consisted of 3358 patients (173 and 3185 patients on rivaroxaban and warfarin, respectively). In the rivaroxaban group, 50.8%, 38.7%, and 10.4% of the patients received 10, 15, and 20 mg of the drug, respectively. The cumulative incidence of major bleeding was similar between the two groups; however, the gastrointestinal bleeding rate was lower in the rivaroxaban group (adjusted subdistribution hazard ratio [SHR]: 0.56, 95% confidence interval [CI]: 0.34-0.91) than in the warfarin group. Furthermore, the composite risk of ischemic stroke or systemic embolism was significantly lower in the rivaroxaban group (adjusted SHR: 0.36, 95% CI: 0.17-0.79). Similar findings were observed for patients who received 10 mg of rivaroxaban. CONCLUSIONS: In Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation, rivaroxaban may be associated with a similar risk of major bleeding but a lower risk of thromboembolism compared with warfarin. The potential benefit of 10 mg of rivaroxaban in this population requires further investigation.

The association between renin angiotensin aldosterone system blockers and future osteoporotic fractures in a hypertensive population - A population-based cohort study in Taiwan.

Some cohort studies showed the possibility of renin-angiotensin-aldosterone system (RAAS) blockade in preventing future osteoporotic fractures. The study aimed to evaluate the association between angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and future osteoporotic fracture in a hypertensive population. We queried the Taiwan Longitudinal Health Insurance Database between 2001 and 2012. We used propensity score matching and the total cohort was made up of 57,470 participants (28,735 matched-pairs using or not using RAAS blockers). The mean follow-up period was 6 years. The number of incident fractures was 3757. Hazard ratios (HRs) [95% confidence interval (CI)] of ACEIs and ARBs use with incident fractures were calculated. The incidence of future osteoporotic fracture was significantly lower in the ACEI and ARB user groups but not in the group using an ACEI plus ARB concomitantly, when compared with RAAS blocker nonusers. Comparing ACEI users with RAAS blocker non-users and ARB users with RAAS blocker non-users, the HRs for composite fractures were 0.70 (0.62-0.79) and 0.58 (0.51-0.65), respectively. Sensitivity analysis confirmed a lower incidence of future osteoporotic fracture in patients taking an ACEI for >55 cumulative defined daily doses (cDDDs) and those who received an ARB for >90 cDDDs. These results suggested a lower incidence of future osteoporotic fracture in a hypertensive population who were using an ACEI or ARB compared with RAAS blocker nonusers but not in the group taking an ACEI and ARB concomitantly.

Comparison of the TIMI, GRACE, PAMI and CADILLAC risk scores for prediction of long-term cardiovascular outcomes in Taiwanese diabetic patients with ST-segment elevation myocardial infarction: From the registry of the Taiwan Society of Cardiology.

Acute coronary syndrome (ACS) patients with diabetes have significantly worse cardiovascular outcomes than those without diabetes. This study aimed to compare the performance of The Thrombolysis In Myocardial Infarction (TIMI), Global Registry of Acute Coronary Events (GRACE), Primary Angioplasty in Myocardial Infarction (PAMI), and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) risk scores in predicting long-term cardiovascular outcomes in diabetic patients with ST-segment elevation myocardial infarction (STEMI). From the Acute Coronary Syndrome-Diabetes Mellitus Registry of the Taiwan Society of Cardiology, patients with STEMI were included. The TIMI, GRACE, PAMI, and CADILLAC risk scores were calculated. The discriminative potential of risk scores was analyzed using the area under the receiver-operating characteristics curve (AUC). In the 455 patients included, all four risk score systems demonstrated predictive accuracy for 6-, 12- and 24-month mortality with AUC values of 0.67-0.82. The CADILLAC score had the best discriminative accuracy, with an AUC of 0.8207 (p<0.0001), 0.8210 (p<0.0001), and 0.8192 (p<0.0001) for 6-, 12-, and 24-month mortality, respectively. It also had the best predictive value for bleeding and acute renal failure, with an AUC of 0.7919 (p<0.05) and 0.9764 (p<0.0001), respectively. Patients with CADILLAC risk scores >8 had poorer 2-year survival than those with lower scores (log-rank p<0.0001). In conclusion, the CADILLAC risk score is more effective than other risk scores in predicting 6-month, 1-year, and 2-year all-cause mortality in diabetic patients with STEMI. It also had the best predictive value for in-hospital bleeding and acute renal failure.

Effectiveness and Safety of Standard- and Low-Dose Rivaroxaban in Asians With Atrial Fibrillation.

BACKGROUND: Low-dose rivaroxaban (10 mg/day) has been widely used in Asia for patients with atrial fibrillation (AF), although there is a lack of evidence regarding its effectiveness. In Asians, it is unclear whether low-dose rivaroxaban is equally effective as that of the standard dose or is associated with less bleeding risk. OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of standard-dose (15 or 20 mg/day) and low-dose (10 mg/day) rivaroxaban in Asians with AF. METHODS: Using data files from the National Health Insurance Research Database between May 1, 2014, and September 30, 2015, a retrospective population-based cohort study was conducted in patients diagnosed with AF or atrial flutter and treated with low- or standard-dose rivaroxaban. Patients were followed up until the first occurrence of the study outcome or the end of the observation period (December 31, 2015). RESULTS: Among 6,558 eligible patients, a total of 2,373 and 4,185 patients took low- and standard-dose rivaroxaban, respectively. Compared to standard-dose rivaroxaban, low-dose rivaroxaban was associated with a significantly higher risk of myocardial infarction (subdistribution hazard ratio: 2.26; 95% confidence interval: 1.13 to 4.52), with similar risk of ischemic stroke, systemic embolism, major bleeding, and nonmajor clinically relevant bleeding. CONCLUSIONS: Compared to standard-dose rivaroxaban, low-dose rivaroxaban in Asian patients with AF was associated with similar risks of thromboembolism and bleeding except myocardial infarction.

Higher post-acute myocardial infarction plasma haptoglobin level is associated with poor long-term overall survival.

AIM: To evaluate the association of post-acute myocardial infarction (AMI) plasma haptoglobin (Hp) levels with long-term overall survival in AMI patients. METHODS AND RESULTS: Patients who were diagnosed of AMI were recruited and their Hp phenotypes and plasma levels were determined. According to previously reported cutoff point for Hp level (288.4ng/ml), patients were classified as higher Hp group (>288.4ng/ml) and lower Hp group (≤288.4ng/ml). The primary outcome was overall survival. This study recruited and followed a total of 117 patients for a median of 11.0 (3.2-17.6) years. Higher Hp group had 46 patients (39.3%) and lower Hp group had 71 patients (60.7%). Twelve patients had Hp 1-1 (10.3%), 50 with Hp 2-1 (42.7%), and 55 with Hp 2-2 (47.0%). The lower Hp group had significantly better overall survival (174.1 [51.6-212.5] vs. 106.5 [22.2-209.1], P=0.037). There was no significant difference in overall survival between the three phenotype groups (P=0.477). Multivariate regression analysis revealed that increased age (adjusted HR=1.06, 95% CI: 1.03-1.10, P<0.001) and higher Hp level (adjusted HR=1.65, 95%=1.02-2.67, P=0.040) were significantly associated with poor overall survival. CONCLUSION: Higher post-AMI plasma Hp level was independently associated with poor overall survival in AMI patients. No significant difference in overall survival was noted between three Hp phenotype groups. Acute phase Hp level might reflect the severity of oxidative stress during inflammation process.

Association between renin-angiotensin-aldosterone system blockade and future osteoporotic fracture risk in hypertensive population: A population-based cohort study in Taiwan.

Tissue renin-angiotensin-aldosterone system (RAAS) activation in sites of osteoporosis had been demonstrated in animal studies; however, the possibility of RAAS blockade to prevent future osteoporotic fracture had rarely been verified in clinical studies. We Used the Taiwan Longitudinal Health insurance database 2000 to 2008, the cohort study comprised patients age over 40 with a recorded new diagnosis of hypertension between January 1, 2000 to December 31, 2008, in addition, patients who had diagnosis of osteoporosis before the date of cohort enter were excluded. After the definite diagnosis of hypertension, each patient was followed until osteoporotic fracture happened or the end of 2008. The occurrence of osteoporotic fracture was evaluated in patients who either were or without taking RAAS blockade agents. Cox proportional hazard regressions were used to evaluate the osteoporotic fracture incidence after adjusting for known confounding factors. In total, 57,132 hypertensive patients comprised the study cohort. Our study results showed that the incidence of osteoporosis fracture in the whole cohort was significantly higher in the RAAS blockade non-user group than the user group. This phenomenon was observed in both sex and all age categories. Sensitivity analysis further showed the concordant lower osteoporosis fracture risk in patients with various RAAS blockers usage durations; the risk of osteoporosis fracture was the lowest in those drug use >365 days when compared with the non-user cohort. In conclusion, our study result demonstrated the lower future osteoporotic fracture risk in hypertensive subjects who received long term RAAS blocker treatment.

Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor ß (TGF-ß), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved neovascularization in hindlimb ischemia mice; this effect may have been mediated by increased CXCR4 expression in EPCs.

MK-0626, a dipeptidyl peptidase-4 inhibitor, improves neovascularization by increasing both the number of circulating endothelial progenitor cells and endothelial nitric oxide synthetase expression.

Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances in therapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeutic potential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administered daily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo-vasculogenesis and the number of circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelial nitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon- like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to an ischemia-induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in the ischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesis and phosphorylation of eNOS were also increased in ischemic thigh muscle after MK-0626 treatment. In contrast, similar effects of MK-0626 were not observed in B6.129P2-Nos3(tm1Unc)/J mice (an eNOS knockout mouse). Additionally, MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increased in response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The results highlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mouse model.

Subacute bacterial endocarditis presenting as left upper quadrant abdominal pain.

Infective endocarditis is a microbial infection of the endocardial surface of the heart. Its symptoms and signs are varied, and include fever, heart murmur, peripheral embolism, and heart failure. The diagnosis of subacute bacterial endocarditis (SBE) is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, and unexplained weight loss. These patients may have had an invasive procedure, such as dental work, or abused intravenous drugs prior to the diagnosis of SBE. Although uncommon, the patients may present with nonspecific symptoms caused by peripheral embolic events. Herein, we report a 25-year-old male diagnosed with SBE, who presented with the unusual symptom of sudden onset of left upper quadrant abdominal pain for 2 days. His clinical history is also discussed.

An endoluminal aortic prosthesis infection presenting as pneumoaorta and aortoduodenal fistula.

Herein, we present a case of pneumoaorta and aortoduodenal fistula (ADF) caused by an endoluminal aortic prosthesis infection. An 82-year-old man underwent endovascular aneurysm repair with a stent graft to exclude a 5.1-cm abdominal aortic aneurysm. Three months after the index procedure, the patient was taken to the emergency department at a medical university hospital. He presented with a 2-d history of bloody diarrhea. An endoluminal aortic stent graft infection was diagnosed, and an ADF was identified. The patient died of septic shock despite emergency surgery and intensive care. When encountered, stent graft infections require appropriate antibiotics and graft explantation. The diagnosis of an ADF is important, and surgery remains the most effective management if septic shock presents despite conservative treatment.