Potency and Quality of Reconstituted Botulinum Neurotoxin Type A According to Storage Temperatures.

BACKGROUND: In clinical practice, one of the most important issues regarding the use of botulinum neurotoxin A (BoNT-A) is the proper storage conditions and the change in potency and quality over time after reconstitution. OBJECTIVE: This study aimed to investigate the change in potency and quality of reconstituted prabotulinumtoxin A (PraBoNT-A) over time when stored at different storage temperatures. MATERIALS AND METHODS: ICR/CD-1 mice and PraBoNT-A were used for the mouse intraperitoneal lethal dose 50% (LD50) test. A thorough quality evaluation of the product was performed. RESULTS: All of the reconstituted PraBoNT-A stored at different temperatures met the evaluation criteria for the suggested limits of estimated potency and for the quality assessment at every evaluated time point. When the stability of reconstituted PraBoNT-A was evaluated by regression analysis, the shelf life of reconstituted PraBoNT-A was found to be 99.24, 73.80, and 16.34 weeks in the case of PraBoNT-A stored at freezing, refrigeration, or room temperatures, respectively. CONCLUSION: Based on the results, the authors conclude that the efficacy and quality of the reconstituted PraBoNT-A product are not compromised at least for a certain period of time and that the shelf life of reconstituted PraBoNT-A is longest when stored at the freezing temperature.

Influence of Local Myocardial Infarction on Endothelial Function, Neointimal Progression, and Inflammation in Target and Non-Target Vascular Territories in a Porcine Model of Acute Myocardial Infarction.

BACKGROUND: Patients with acute myocardial infarction (AMI) have worse clinical outcomes than those with stable coronary artery disease despite revascularization. Non-culprit lesions of AMI also involve more adverse cardiovascular events. This study aimed to investigate the influence of AMI on endothelial function, neointimal progression, and inflammation in target and non-target vessels. METHODS: In castrated male pigs, AMI was induced by balloon occlusion and reperfusion into the left anterior descending artery (LAD). Everolimus-eluting stents (EES) were implanted in the LAD and left circumflex (LCX) artery 2 days after AMI induction. In the control group, EES were implanted in the LAD and LCX in a similar fashion without AMI induction. Endothelial function was assessed using acetylcholine infusion before enrollment, after the AMI or sham operation, and at 1 month follow-up. A histological examination was conducted 1 month after stenting. RESULTS: A total of 10 pigs implanted with 20 EES in the LAD and LCX were included. Significant paradoxical vasoconstriction was assessed after acetylcholine challenge in the AMI group compared with the control group. In the histologic analysis, the AMI group showed a larger neointimal area and larger area of stenosis than the control group after EES implantation. Peri-strut inflammation and fibrin formation were significant in the AMI group without differences in injury score. The non-target vessel of the AMI also showed similar findings to the target vessel compared with the control group. CONCLUSION: In the pig model, AMI events induced endothelial dysfunction, inflammation, and neointimal progression in the target and non-target vessels.

Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

BACKGROUND & AIMS: Prostaglandin E2 (PGE2) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE2 function. METHODS: DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE2, with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). RESULTS: Incubation of colon cancer cell lines with PGE2 led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice developed colitis after administration of DSS, but injection of PGE2 led to colon regeneration in these mice. However, YAP-knockout mice did not regenerate colon tissues and died soon after administration of DSS. 15-PGDH-knockout mice regenerated colon tissues more rapidly than control mice after withdrawal of DSS, and had faster recovery of body weight, colon length, and colitis histology scores. These effects were reversed by injection of indomethacin. SAV1-knockout or 15-PGDH-knockout mice did not develop spontaneous tumors after colitis induction, but SAV1/15-PGDH double-knockout mice developed polyps that eventually progressed to carcinoma in situ. Administration of indomethacin to these mice prevented spontaneous tumor formation. Levels of PGE2 correlated with those of YAP levels in human sporadic colorectal tumors and colitis-associated tumors. CONCLUSIONS: PGE2 signaling increases the expression and transcriptional activities of YAP1, leading to increased expression of cyclooxygenase 2 and EP4 to activate a positive signaling loop. This pathway promotes proliferation of colon cancer cell lines and colon tissue regeneration in mice with colitis. Constitutive activation of this pathway led to formation of polyps and colon tumors in mice.

Validation of Freezing-of-Gait Monitoring Using Smartphone.

BACKGROUND: Freezing of gait (FOG) is a commonly observed motor symptom for patients with Parkinson's disease (PD). The symptoms of FOG include reduced step lengths or motor blocks, even with an evident intention of walking. FOG should be monitored carefully because it not only lowers the patient's quality of life, but also significantly increases the risk of injury. INTRODUCTION: In previous studies, patients had to wear several sensors on the body and another computing device was needed to run the FOG detection algorithm. Moreover, the features used in the algorithm were based on low-level and hand-crafted features. In this study, we propose a FOG detection system based on a smartphone, which can be placed in the patient's daily wear, with a novel convolutional neural network (CNN). METHODS: The walking data of 32 PD patients were collected from the accelerometer and gyroscope embedded in the smartphone, located in the trouser pocket. The motion signals measured by the sensors were converted into the frequency domain and stacked into a 2D image for the CNN input. A specialized CNN model for FOG detection was determined through a validation process. RESULTS: We compared our performances with the results acquired by the previously reported settings. The proposed architecture discriminated the freezing events from the normal activities with an average sensitivity of 93.8% and a specificity of 90.1%. CONCLUSIONS: Using our methodology, the precise and continuous monitoring of freezing events with unconstrained sensing can assist patients in managing their chronic disease in daily life effectively.

Oxytocin produces thermal analgesia via vasopressin-1a receptor by modulating TRPV1 and potassium conductance in the dorsal root ganglion neurons.

Recent studies have provided several lines of evidence that peripheral administration of oxytocin induces analgesia in human and rodents. However, the exact underlying mechanism of analgesia still remains elusive. In the present study, we aimed to identify which receptor could mediate the analgesic effect of intraperitoneal injection of oxytocin and its cellular mechanisms in thermal pain behavior. We found that oxytocin-induced analgesia could be reversed by d(CH2)5[Tyr(Me)2,Dab5] AVP, a vasopressin-1a (V1a) receptor antagonist, but not by desGly-NH2-d(CH2)5[DTyr2, Thr4]OVT, an oxytocin receptor antagonist. Single cell RT-PCR analysis revealed that V1a receptor, compared to oxytocin, vasopressin-1b and vasopressin-2 receptors, was more profoundly expressed in dorsal root ganglion (DRG) neurons and the expression of V1a receptor was predominant in transient receptor potential vanilloid 1 (TRPV1)-expressing DRG neurons. Fura-2 based calcium imaging experiments showed that capsaicin-induced calcium transient was significantly inhibited by oxytocin and that such inhibition was reversed by V1a receptor antagonist. Additionally, whole cell patch clamp recording demonstrated that oxytocin significantly increased potassium conductance via V1a receptor in DRG neurons. Taken together, our findings suggest that analgesic effects produced by peripheral administration of oxytocin were attributable to the activation of V1a receptor, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons.

Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma.

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.

Automatic Classification of Tremor Severity in Parkinson's Disease Using a Wearable Device.

Although there is clinical demand for new technology that can accurately measure Parkinsonian tremors, automatic scoring of Parkinsonian tremors using machine-learning approaches has not yet been employed. This study aims to fill this gap by proposing machine-learning algorithms as a way to predict the Unified Parkinson's Disease Rating Scale (UPDRS), which are similar to how neurologists rate scores in actual clinical practice. In this study, the tremor signals of 85 patients with Parkinson's disease (PD) were measured using a wrist-watch-type wearable device consisting of an accelerometer and a gyroscope. The displacement and angle signals were calculated from the measured acceleration and angular velocity, and the acceleration, angular velocity, displacement, and angle signals were used for analysis. Nineteen features were extracted from each signal, and the pairwise correlation strategy was used to reduce the number of feature dimensions. With the selected features, a decision tree (DT), support vector machine (SVM), discriminant analysis (DA), random forest (RF), and k-nearest-neighbor (kNN) algorithm were explored for automatic scoring of the Parkinsonian tremor severity. The performance of the employed classifiers was analyzed using accuracy, recall, and precision, and compared to other findings in similar studies. Finally, the limitations and plans for further study are discussed.

The relative importance of performance factors in Korean archery.

This study explored the factors affecting archery performance by calculating their relative importance in Korean archery. This study used the Delphi technique and the analytic hierarchy process (AHP). After reviewing the literature and collecting data on performance factors in archery, the importance of factors affecting archery performance was calculated by holding meetings with experts (20 archery experts) and conducting confirmatory factor analysis (463 archers) and the AHP (36 archery experts). Performance factors were divided into mental, skill, and fitness categories. Fitness factors affecting performance included "drawing a bow without an arrow," "lower-body weight training," and "upper-body weight training." Skill factors affecting performance included "extending by maintaining left and right shoulder balance during aiming," "shooting skill over a regular clicker time," "maintaining pace and direction at release," and "drawing skill by maintaining left and right shoulder balance." Mental factors affecting performance were "confidence," "concentration," "emotion control," and "positive thinking." "Confidence" was identified as the most important factor among the 11 subfactors. The performance factors identified in this study and their relative importance in determining successful performance can be used in training for optimal archery performance worldwide.

Gallic Acid Inhibits Proliferation and Migration of Smooth Muscle Cells in a Pig In-Stent Restenosis Model.

In-stent restenosis (ISR) develops primarily due to neointimal hyperplasia. Gallic acid (GA) has anti-inflammatory, antioxidant, and cardioprotective effects. This study sought to investigate the effects of GA on neointimal hyperplasia and proliferation and migration of vascular smooth muscle cells (VSMCs) in a pig ISR model. In vitro proliferation and migration experiments were confirmed, after VSMCs were treated with platelet-derived growth factor (PDGF-BB) and GA (100 µM) using a 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay and a scratch wound assay for 24 hours and 48 hours. A bare metal stent (BMS) was implanted in the pig coronary artery to induce ISR with overdilation (1.1-1.2:1), and GA (10 mg/kg/day) was administered for 4 weeks. At the 4-week follow-up, optical coherence tomography (OCT) and histopathological analyses were performed. GA decreased the proliferation of VSMCs by PDGF-BB for 24 hours (89.24±24.56% vs. 170.04±19.98%, p<0.001) and 48 hours (124.87±7.35% vs. 187.64±4.83%, p<0.001). GA inhibited the migration of VSMCs induced by PDGF-BB for 24 hours (26.73±2.38% vs. 65.38±9.73%, p<0.001) and 48 hours (32.96±3.04% vs. 77.04±10.07%, p<0.001). Using OCT, % neointimal hyperplasia was shown to have significantly decreased in the GA group compared with control vehicle group (28.25±10.07% vs. 37.60±10.84%, p<0.001). GA effectively reduced neointimal hyperplasia by inhibiting the proliferation and migration of VSMCs in a pig ISR model. GA could be a potential treatment strategy for reducing ISR after stent implantation.

Semiautomated Algorithm for the Diagnosis of Multiple System Atrophy With Predominant Parkinsonism.

OBJECTIVE: Putaminal iron deposition is an important feature that helps differentiate multiple system atrophy with predominant parkinsonism (MSA-p) from Parkinson's disease (PD). Most previous studies used visual inspection or quantitative methods with manual manipulation to perform this differentiation. We investigated the value of a new semiautomated diagnostic algorithm using 3T-MR susceptibility-weighted imaging for MSA-p. METHODS: This study included 26 MSA-p, 68 PD, and 41 normal control (NC) subjects. The algorithm was developed in 2 steps: 1) determine the image containing the remarkable putaminal margin and 2) calculate the phase-shift values, which reflect the iron concentration. The next step was to identify the best differentiating conditions among several combinations. The highest phaseshift value of each subject was used to assess the most effective diagnostic set. RESULTS: The raw phase-shift values were present along the lateral margin of the putamen in each group. It demonstrates an anterior- to-posterior gradient that was identified most frequently in MSA-p. The average of anterior 5 phase shift values were used for normalization. The highest area under the receiver operating characteristic curve (0.874, 80.8% sensitivity, and 86.7% specificity) of MSA-p versus PD was obtained under the combination of 3 or 4 vertical pixels and one dominant side when the normalization methods were applied. In the subanalysis for the MSA-p patients with a longer disease duration, the performance of the algorithm improved. CONCLUSION: This algorithm detected the putaminal lateral margin well, provided insight into the iron distribution of the putaminal rim of MSA-p, and demonstrated good performance in differentiating MSA-p from PD.

FSP-1 expression in cancer cells is relevant to long-term oncological outcomes in nonmetastatic colorectal cancer.

Purpose: Recent studies have revealed that the expression of cancer-associated fibroblast (CAF) activation biomarkers in cancer cells is associated with clinical outcomes in patients with certain types of malignant tumors. However, whether the expression of CAF activation biomarkers affects the prognosis of colorectal cancer (CRC) has not been fully elucidated. This study aimed to evaluate the association between the expression of CAF activation biomarkers in cancer cells with cancer invasion and long-term oncological outcomes in patients with CRC. Methods: Cancer specimens obtained from 135 patients with stage I-III CRC were examined using immunohistochemical staining to evaluate the expression of fibroblast specific protein-1 (FSP-1), fibroblast activation protein α (FAPα), α-smooth muscle actin (α-SMA), and vimentin in cancer cells. Results: FSP-1 expression in cancer cells was significantly associated with lymphatic invasion, perineural invasion, tumor (T) status, and lymph node (N) status. FAPα expression in cancer cells was significantly associated with lymphatic invasion. On univariate and multivariate analyses, FSP-1 and α-SMA expression in cancer cells were associated with a short 10-year overall survival (OS) and high 10-year systemic recurrence (SR), respectively. Tumor budding was associated with a short 10-year OS. However, FAPα and vimentin did not contribute to the prognosis in this study. Conclusion: In this study, we found that FSP-1 expression in cancer cells was related to cancer invasion. Additionally, FSP-1 and α-SMA expression in cancer cells was associated with 10-year OS and SR, respectively. Therefore, these markers may be used as predictors of long-term oncological outcomes in patients with CRC.

Reduced restenosis and enhanced re-endothelialization of functional biodegradable vascular scaffolds by everolimus and magnesium hydroxide.

BACKGROUND: Coronary artery disease is a cardiovascular disease with a high mortality and mortality rate in modern society. Vascular stent insertion to restore blood flow is essential to treat this disease. A fully biodegradable vascular scaffold (BVS) is a vascular poly (L-lactic acid) (PLLA) stent that is receiving growing interest as this is biodegradable in the body and does not require secondary removal surgery. However, acidic byproducts composed of PLLA produced during the biodegradation of the BVS can induce an inflammatory response. Magnesium hydroxide, a basic inorganic particle, neutralizes the acidic byproducts of PLLA.  METHODS: In this study, we investigated using a BVS coated with everolimus and surface-modified magnesium hydroxide that suppresses smooth muscle cell proliferation and protects endothelial cells, respectively. The various characteristics of the functional stent were evaluated using in vitro and in vivo analyses.  RESULTS: The BVS was successfully prepared with evenly coated everolimus and surface-modified magnesium hydroxide. A neutral pH value was maintained by magnesium hydroxide during degradation, and everolimus was released for one month. The coated BVS effectively inhibited protein adsorption and platelet adhesion, demonstrating excellent blood compatibility. In vitro analysis showed that BVS protects endothelial cells with magnesium hydroxide and selectively inhibits smooth muscle cell proliferation via everolimus treatment. The functional BVS was inserted into porcine coronary arteries for 28 days, and the results demonstrated that the restenosis and inflammation greatly decreased and re-endothelialization was enhanced as compared to others. CONCLUSIONS: This study provides new insights into the design of drug-incorporated BVS stent for coronary artery disease.

Cushing syndrome in pregnancy, diagnosed after delivery.

Cushing syndrome (CS) is rare in pregnancy, and few cases have been reported to date. Women with untreated CS rarely become pregnant because of the ovulatory dysfunction induced by hypercortisolism. It is difficult to diagnose CS in pregnancy because of its very low incidence, the overlap between the clinical signs of hypercortisolism and the physiological changes that occur during pregnancy and the changes in hypothalamus-pituitary-adrenal axis activity that occur during pregnancy and limit the value of standard diagnostic testing. However, CS in pregnancy is associated with poor maternal and fetal outcomes; therefore, its early diagnosis and treatment are important. Here, we report two patients with CS that was not diagnosed during pregnancy, in whom maternal and fetal morbidity developed because of hypercortisolism.

Antinociceptive effect of intrathecal P7C3 via GABA in a rat model of inflammatory pain.

The recently identified molecule P7C3 has been highlighted in the field of pain research. We examined the effect of intrathecal P7C3 in tissue injury pain evoked by formalin injection and determined the role of the GABA system in the activity of P7C3 at the spinal level. Male Sprague-Dawley rats with intrathecal catheters implanted for experimental drug delivery were studied. The effects of intrathecal P7C3 and nicotinamide phosphoribosyltransferase (NAMPT) administered 10 min before the formalin injection were examined. Animals were pretreated with bicuculline, a GABA-A receptor antagonist; saclofen, a GABA-B receptor antagonist; L-allylglycine, a glutamic acid decarboxylase (GAD) blocker; and CHS 828, an NAMPT inhibitor; to observe involvement in the effects of P7C3. The effects of P7C3 alone and the mixture of P7C3 with GABA receptor antagonists on KCl-induced calcium transients were examined in rat dorsal root ganglion (DRG) neurons. The expression of GAD and the concentration of GABA in the spinal cord were evaluated. Intrathecal P7C3 and NAMPT produced an antinociceptive effect in the formalin test. Intrathecal bicuculline, saclofen, L-allylglycine, and CHS 828 reversed the antinociception of P7C3 in both phases. P7C3 decreased the KCl-induced calcium transients in DRG neurons. Both bicuculline and saclofen reversed the blocking effect of P7C3. The levels of GAD expression and GABA concentration decreased after formalin injection and were increased by P7C3. These results suggest that P7C3 increases GAD activity and then increases the GABA concentration in the spinal cord, which in turn may act on GABA receptors causing the antinociceptive effect against pain evoked by formalin injection.

A model of atherosclerosis using nicotine with balloon overdilation in a porcine.

Pigs are important experimental animals for cardiovascular research. Few porcine coronary atherosclerosis models have been developed; however, their induction requires more than six months. We developed a porcine coronary artery atherosclerosis model using nicotine injection with a balloon overdilation. A coronary balloon was placed in the porcine coronary artery and overdilated to induce a mechanical injury. Nicotine was administrated via intramuscular injection every day, and changes in the coronary artery were observed after four weeks. Coronary angiography revealed nicotine injection with a balloon overdilation group showed narrowing of the coronary artery at the injury site. The combination of balloon and nicotine significantly increased the intimal hyperplasia in optical coherence tomography analysis. Proliferated tunica media were noted in the nicotine injection with balloon overdilation groups and lack of collagen was observed in the tunica media at eight weeks. Quantitative analysis showed increased smooth muscle actin alpha (SMA), cluster of differentiation 68 (CD68), and Krüppel-like factor 4 (KLF4) in the nicotine injection with balloon overdilation groups. Immunohistochemistry results showed CD68-positive cells displayed SMA- and KLF4-positive reactivity in the border zone of the intimal hyperplasia. Our results show that nicotine injection with balloon overdilation can induce atherosclerotic lesions within one month, which can serve as an alternative pig animal model for the development of coronary stents.

Effect of Novel Polymer-Free Nitrogen-Doped Titanium Dioxide Film-Coated Coronary Stent Loaded With Mycophenolic Acid.

Background: Titanium is commonly used in blood-exposed medical devices because it has superior blood compatibility. Mycophenolic acid inhibits the proliferation of vascular smooth muscle cells. This study examined the effect of a non-polymer TiO2 thin film-coated stent with mycophenolic acid in a porcine coronary overstretch restenosis model. Methods: Thirty coronary arteries in 15 pigs were randomized into three groups in which the coronary arteries were treated with a TiO2 film-coated stent with mycophenolic acid (NTM, n = 10), everolimus-eluting stent with biodegradable polymer (EES, n = 10), or TiO2 film-coated stent (NT, n = 10). A histopathologic analysis was performed 28 days after the stenting. Results: There were no significant intergroup differences in injury score, internal elastic lamina area, or inflammation score. Percent area stenosis was significantly smaller in the NTM and EES groups than in the NT group (36.1 ± 13.63% vs. 31.6 ± 7.74% vs. 45.5 ± 18.96%, respectively, p = 0.0003). Fibrin score was greater in the EES group than in the NTM and NT groups [2.0 (range, 2.0-2.0) vs. 1.0 (range, 1.0-1.75) vs. 1.0 (range, 1.0-1.0), respectively, p < 0.0001]. The in-stent occlusion rate measured by micro-computed tomography demonstrated similar percent area stenosis rates on histology analysis (36.1 ± 15.10% in NTM vs. 31.6 ± 8.89% in EES vs. 45.5 ± 17.26% in NT, p < 0.05). Conclusion: The NTM more effectively reduced neointima proliferation than the NT. Moreover, the inhibitory effect of NTM on smooth muscle cell proliferation was not inferior to that of the polymer-based EES with lower fibrin deposition in this porcine coronary restenosis model.

Coronary Circulatory Indexes in Non-Infarct-Related Vascular Territories in a Porcine Acute Myocardial Infarction Model.

OBJECTIVES: The aim of this study was to evaluate temporal changes in coronary hemodynamic and physiological indexes in the non-infarct-related artery (IRA), which might be affected by adjacent infarcted myocardium, using an experimental animal model of acute myocardial infarction. BACKGROUND: There has been debate on the reliability of fractional flow reserve and resting pressure-derived indexes, including instantaneous wave-free ratio, in the non-IRA in patients with acute ST-segment elevation myocardial infarction. METHODS: In Yorkshire swine, acute myocardial infarction was simulated with selective balloon occlusion at the left circumflex coronary artery as the IRA for 30 min. Non-IRA stenosis was created using bare-metal stent implantation in the left anterior descending coronary artery 4 weeks before the experiments. Serial changes in systemic hemodynamic status, coronary pressure, and Doppler-derived coronary flow velocity were measured in a nonoccluded left anterior descending coronary artery as the non-IRA from baseline, balloon occlusion of the left circumflex coronary artery, and 15 min after reperfusion of the left circumflex coronary artery. RESULTS: Among the 6 experimental subjects, the median diameter stenosis of the non-IRA was 33.9% (interquartile range: 21.7% to 46.1%). During balloon occlusion of the IRA, there were transient significant changes in both resting and hyperemic aortic pressure, distal coronary pressure, averaged peak velocity, transstenotic pressure gradient, and microvascular resistance of the non-IRA (p < 0.020 for all). After reperfusion of the IRA, the resting averaged peak velocity (p = 0.002) and resting transstenotic pressure gradient (p = 0.004) were significantly increased and resting microvascular resistance (p = 0.004) was significantly decreased compared with their values in the baseline phase. However, the hyperemic averaged peak velocity (p = 0.479), hyperemic transstenotic pressure gradient (p = 0.778), and hyperemic microvascular resistance (p = 0.816) were not significantly different compared with those in the baseline phase. After reperfusion, fractional flow reserve in the non-IRA was not significantly different (0.94 ± 0.01 vs. 0.93 ± 0.01; p = 0.353), while coronary flow reserve (1.93 ± 0.07 vs. 1.36 ± 0.07; p = 0.025) and instantaneous wave-free ratio (0.97 ± 0.01 vs. 0.93 ± 0.01; p = 0.001) were significantly lower than baseline values. CONCLUSIONS: In a porcine model of acute myocardial infarction, occlusion of the IRA induced significant changes in systemic hemodynamic status and coronary circulatory indexes of the non-IRA. However, after reperfusion of the IRA, fractional flow reserve did not change significantly, whereas coronary flow reserve and instantaneous wave-free ratio showed significant changes compared with baseline values.

Effect of Renal Denervation on Suppression of PVC and QT Prolongation in a Porcine Model of Acute Myocardial Infarction.

BACKGROUND AND OBJECTIVES: Antiarrhythmic effect of renal denervation (RDN) after acute myocardial infarction (AMI) remains unclear. The goal of this study was to evaluate the effect of RDN on ventricular arrhythmia (VA) after AMI in a porcine model. METHODS: Twenty pigs were randomly divided into 2 groups based on RDN (RDN, n=10; Sham, n=10). After implanting a loop recorder, AMI was induced by occlusion of the middle left anterior descending coronary artery. Catheter-based RDN was performed for each renal artery immediately after creating AMI. Sham procedure used the same method, but a radiofrequency current was not delivered. Electrocardiography was monitored for 1 hour to observe VA. One week later, the animals were euthanized and the loop recorder data were analyzed. RESULTS: Ventricular fibrillation event rate and the interval from AMI creation to first VA in acute phase were not different between the 2 groups. However, the incidence of premature ventricular complex (PVC) was lower in the RDN than in the Sham. Additionally, RDN inhibited prolongation of the corrected QT (QTc) interval after AMI. The frequency of non-sustained or sustained ventricular tachycardia, arrhythmic death was lower in the RDN group in the early period. CONCLUSIONS: RDN reduced the incidence of PVC, inhibited prolongation of the QTc interval, and reduced VA in the early period following an AMI. These results suggest that RDN might be a therapeutic option in patients with electrical instability after AMI.

Effects of Fimasartan/Amlodipine Fixed-Dose Combination on Left Ventricular Systolic Function and Infarct Size in Rat Myocardial Infarction Model.

The aim of this study was to evaluate the effects of fimasartan/amlodipine fixed-dosed combination (F/A) on left ventricle (LV) systolic function and infarct size in the rat myocardial infarction (MI) model. We induced MI in 20 rats by ligation of the left anterior descending coronary artery and they were divided into two groups [MI group (n=10) vs. MI+F/A 10 mg/kg group (n=10)]. F/A was administered for 28 days between day-7 and day-35 in the MI+F/A group and echocardiography was performed at day-7 and at day-35 after the induction of MI. Picrosirius red staining was performed to confirm the fibrotic tissue and infarct size was measured using image analysis program for Image J. At the 35-day follow-up, the LV ejection fraction (EF) was significantly higher (38.10±3.92% vs. 29.86±4.56%, p<0.001) and delta (day-35 minus day-7) EF was significantly higher (0.14±2.66% vs. -8.53±2.66%. p<0.001) in the MI+F/A group than the MI group. Systolic blood pressure was significantly lower in the MI+F/A group than the MI group (103.23±13.35 mmHg vs. 123.43±14.82 mmHg, p<0.01). The MI+F/A group had a smaller infarct size (26.84±5.31% vs. 36.79±3.10%, p<0.01) than the MI group at the 35-day follow-up. Oral administration of F/A 10 mg/kg could improve LV systolic function and reduce infarct size in a rat MI model.