Performance of a Novel CT-Derived Fractional Flow Reserve Measurement to Detect Hemodynamically Significant Coronary Stenosis.

BACKGROUND: Fractional flow reserve (FFR) based on computed tomography (CT) has been shown to better identify ischemia-causing coronary stenosis. However, this current technology requires high computational power, which inhibits its widespread implementation in clinical practice. This prospective, multicenter study aimed at validating the diagnostic performance of a novel simple CT based fractional flow reserve (CT-FFR) calculation method in patients with coronary artery disease. METHODS: Patients who underwent coronary CT angiography (CCTA) within 90 days and invasive coronary angiography (ICA) were prospectively enrolled. A hemodynamically significant lesion was defined as an FFR ≤ 0.80, and the area under the receiver operating characteristic curve (AUC) was the primary measure. After the planned analysis for the initial algorithm A, we performed another set of exploratory analyses for an improved algorithm B. RESULTS: Of 184 patients who agreed to participate in the study, 151 were finally analyzed. Hemodynamically significant lesions were observed in 79 patients (52.3%). The AUC was 0.71 (95% confidence interval [CI], 0.63-0.80) for CCTA, 0.65 (95% CI, 0.56-0.74) for CT-FFR algorithm A (P = 0.866), and 0.78 (95% CI, 0.70-0.86) for algorithm B (P = 0.112). Diagnostic accuracy was 0.63 (0.55-0.71) for CCTA alone, 0.66 (0.58-0.74) for algorithm A, and 0.76 (0.68-0.82) for algorithm B. CONCLUSION: This study suggests the feasibility of automated CT-FFR, which can be performed on-site within several hours. However, the diagnostic performance of the current algorithm does not meet the a priori criteria for superiority. Future research is required to improve the accuracy.

Fluid Shear Stress Regulates the Landscape of microRNAs in Endothelial Cell-Derived Small Extracellular Vesicles and Modulates the Function of Endothelial Cells.

Blood fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology. The small extracellular vesicles (sEVs) such as exosomes are potent mediators of intercellular communication, and their contents reflect cellular stress. Here, we explored the miRNA profiles in endothelial cells (EC)-derived sEVs (EC-sEVs) under atheroprotective laminar shear stress (LSS) and atheroprone low-oscillatory shear stress (OSS) and conducted a network analysis to identify the main biological processes modulated by sEVs' miRNAs. The EC-sEVs were collected from culture media of human umbilical vein endothelial cells exposed to atheroprotective LSS (20 dyne/cm2) and atheroprone OSS (±5 dyne/cm2). We explored the miRNA profiles in FSS-induced EC-sEVs (LSS-sEVs and OSS-sEVs) and conducted a network analysis to identify the main biological processes modulated by sEVs' miRNAs. In vivo studies were performed in a mouse model of partial carotid ligation. The sEVs' miRNAs-targeted genes were enriched for endothelial activation such as angiogenesis, cell migration, and vascular inflammation. OSS-sEVs promoted tube formation, cell migration, monocyte adhesion, and apoptosis, and upregulated the expression of proteins that stimulate these biological processes. FSS-induced EC-sEVs had the same effects on endothelial mechanotransduction signaling as direct stimulation by FSS. In vivo studies showed that LSS-sEVs reduced the expression of pro-inflammatory genes, whereas OSS-sEVs had the opposite effect. Understanding the landscape of EC-exosomal miRNAs regulated by differential FSS patterns, this research establishes their biological functions on a system level and provides a platform for modulating the overall phenotypic effects of sEVs.

Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Protect Cardiomyocytes from Doxorubicin-Induced Cardiomyopathy by Upregulating Survivin Expression via the miR-199a-3p-Akt-Sp1/p53 Signaling Pathway.

Cardiotoxicity is associated with the long-term clinical application of doxorubicin (DOX) in cancer patients. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) including exosomes have been suggested for the treatment of various diseases, including ischemic diseases. However, the effects and functional mechanism of MSC-sEVs in DOX-induced cardiomyopathy have not been clarified. Here, MSC-sEVs were isolated from murine embryonic mesenchymal progenitor cell (C3H/10T1/2) culture media, using ultrafiltration. H9c2 cardiac myoblast cells were pretreated with MSC-sEVs and then exposed to DOX. For in vivo studies, male C57BL/6 mice were administered MSC-sEVs intravenously, prior to a single dose of DOX (15 mg/kg, intraperitoneal). The mice were sacrificed 14 days after DOX treatment. The results showed that MSC-sEVs protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX showed downregulation of both phosphorylated Akt and survivin, whereas the treatment of MSC-sEVs recovered expression, indicating their anti-apoptotic effects. Three microRNAs (miRNAs) (miR 199a-3p, miR 424-5p, and miR 21-5p) in MSC-sEVs regulated the Akt-Sp1/p53 signaling pathway in cardiomyocytes. Among them, miR 199a-3p was involved in regulating survivin expression, which correlated with the anti-apoptotic effects of MSC-sEVs. In in vivo studies, the echocardiographic results showed that the group treated with MSC-sEVs recovered from DOX-induced cardiomyopathy, showing improvement of both the left ventricle fraction and ejection fraction. MSC-sEVs treatment also increased both survivin and B-cell lymphoma 2 expression in heart tissue compared to the DOX group. Our results demonstrate that MSC-sEVs have protective effects against DOX-induced cardiomyopathy by upregulating survivin expression, which is mediated by the regulation of Akt activation by miRNAs in MSC-sEVs. Thus, MSC-sEVs may be a novel therapy for the prevention of DOX-induced cardiomyopathy.

Blood flow characteristics of diabetic patients with complications detected by optical measurement.

BACKGROUND: Diabetes mellitus (DM) is one of the most common diseases worldwide. Uncontrolled and prolonged hyperglycemia can cause diabetic complications, which reduce the quality of life of patients. Diabetic complications are common in DM patients. Because it is impossible to completely recover from diabetic complications, it is important for early detection. In this study, we suggest a novel method of determining blood flow characteristics based on fluorescence image analysis with indocyanine green and report that diabetic complications have unique blood flow characteristics. METHODS: We analyzed time-series fluorescence images obtained from controls, DM patients, and DM patients with complications. The images were segmented into the digits and the dorsum of the feet and hands, and each part has been considered as arterial and capillary flow. We compared the blood flow parameters in each region among the three groups. RESULTS: The DM patients with complications showed similar blood flow parameters to the controls, except the area under the curve and the maximum intensity, which indicate the blood flow volume. These parameters were significantly decreased in DM patients with complications. Although some blood flow parameters in the feet of DM patients with complications were close to normal blood flow, the vascular response of the macrovessels and microvessels to stimulation of the hands was significantly reduced, which indicates less reactivity in DM patients with complications. CONCLUSIONS: Our results suggest that DM patients, and DM patients with complications, have unique peripheral blood flow characteristics.

Clinical implication of an impaired fasting glucose and prehypertension related to new onset atrial fibrillation in a healthy Asian population without underlying disease: a nationwide cohort study in Korea.

AIMS: For healthy populations without comorbidities, whether prehypertension and impaired fasting glucose (IFG) are associated with new onset atrial fibrillation (AF) is not well known. METHODS AND RESULTS: We included 366 507 subjects (age ≥20 years) not diagnosed with non-valvular AF from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2003 to 2008. In total, 139 306 subjects diagnosed with AF-related comorbidities were excluded, and a 227 102 healthy population was followed up until 2013. The body mass index (BMI), blood pressure (BP), and fasting blood glucose (BG) level were acquired during National health check-ups. Subjects with IFG [hazard ratio (HR) 1.16, P = 0.017] had a higher AF risk and the diastolic BP (HR 1.11, P = 0.045) was a stronger indicator for an AF incidence than the systolic BP. After dividing the subjects into two mutually exclusive groups, AF incidence was increased dramatically by the combination effect of both prehypertension and an IFG in BMI <25 kg/m2 group, but, in BMI ≧25 kg/m2 group, did not show this tendency. An IFG related to AF risk was more prominent in the BMI <25 kg/m2 population (HR 1.18, P = 0.025) than those with a BMI ≥25 kg/m2, and subjects with both an IFG and prehypertension had a greater AF risk (HR 1.27, P = 0.016) than those without. CONCLUSION: Even in a healthy Asian populations without comorbidities, prehypertension and IFG were important risk factors of AF. Specifically, when prehypertension, including systolic and diastolic BPs, was finally combined with the IFG, the risk of new onset AF was increased especially in the BMI <25 kg/m2 group.

Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.

BACKGROUND: Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown. METHODS AND RESULTS: Immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H2O2 in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-ß- and vascular endothelial growth factor receptor-mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization. CONCLUSIONS: This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting.

A prospective randomized controlled trial to determine the safety and efficacy of extracorporeal shock waves therapy for primary prevention of subclinical cardiotoxicity in breast cancer patients without a cardiovascular risk treated with doxorubicin.

Background: Doxorubicin is a highly effective anti-cancer drug that causes left ventricular (LV) dysfunction and induces late-onset cardiomyopathy. However, an effective and clinically applicable preventive treatment is yet to be discovered. Objective: Cardiac-Extracorporeal shockwave therapy (C-ESWT) has been suggested to treat inflammatory and ischemic diseases and protect cardiomyocytes from doxorubicin-induced cardiomyopathy. This study aims to assess the safety and efficacy of C-ESWT in the prevention of subclinical cardiotoxicity. Methods: We enrolled 64 breast cancer patients. C-ESWT group 33 patients were treated with our C-ESWT (200 shots/spot at 0.09 mJ/mm2 for 20 spots, 3 times every six weeks). The efficacy endpoints were the difference in left ventricular global longitudinal strain (LVGLS) change by 2D speckle tracking echocardiography and chemotherapy-related cardiac dysfunction (CTRCD). Echocardiography was performed on the baseline line and every 4 cycles of chemotherapy, followed by a follow-up 3,6 months after chemotherapy to compare the incidence of cardiomyopathy of subclinical LV dysfunction due to chemotherapy between the two groups. Results: Participants averaged 50 ± 9 years in age, 100% female. In the results of follow-up 6 months after the end of chemotherapy, there was a significant difference in delta LVGLS between the C-ESWT group and the control group (LVGLS; -1.1 ± 10.9% vs. -11.5 ± 11.6% p-value; <0.001). A total of 23% (15 patients) of patients developed CTRCD (Control group; 13 vs. C-ESWT group; (2). C-ESWT was performed safely without any serious adverse events. Conclusion: In this prospective study, C-ESWT established efficacy in preventing subclinical cardiotoxicity, especially in breast cancer patients using doxorubicin chemotherapy, and the safety of C-ESWT. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05584163).

Scalable production of siRNA-encapsulated extracellular vesicles for the inhibition of KRAS-mutant cancer using acoustic shock waves.

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.

Blood flow patterns switch VEGFR2 activity through differential S-nitrosylation and S-oxidation.

Vascular endothelial growth factor receptor-2 (VEGFR2) plays a key role in maintaining vascular endothelial homeostasis. Here, we show that blood flows determine activation and inactivation of VEGFR2 through selective cysteine modifications. VEGFR2 activation is regulated by reversible oxidation at Cys1206 residue. H2O2-mediated VEGFR2 oxidation is induced by oscillatory flow in vascular endothelial cells through the induction of NADPH oxidase-4 expression. In contrast, laminar flow induces the expression of endothelial nitric oxide synthase and results in the S-nitrosylation of VEGFR2 at Cys1206, which counteracts the oxidative inactivation. The shear stress model study reveals that disturbed blood flow operated by partial ligation in the carotid arteries induces endothelial damage and intimal hyperplasia in control mice but not in knock-in mice harboring the oxidation-resistant mutant (C1206S) of VEGFR2. Thus, our findings reveal that flow-dependent redox regulation of the VEGFR2 kinase is critical for the structural and functional integrity of the arterial endothelium.

Comparison of efficacy and safety between third-dose triple and third-dose dual antihypertensive combination therapies in patients with hypertension.

We compared the efficacy and safety of third-standard-dose triple and third-standard-dose dual antihypertensive combination therapies in patients with mild to moderate hypertension. This was a phase II multicenter, randomized, double-blind, parallel-group trial. After a 4-week placebo run-in period, 245 participants were randomized to the third-dose triple combination (ALC group; amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg) or third-dose dual combination (AL group; amlodipine 1.67 mg + losartan potassium 16.67 mg, LC group; losartan potassium 16.67 mg + chlorthalidone 4.17 mg, AC group; amlodipine 1.67 mg + chlorthalidone 4.17 mg) therapy groups and followed up for 8 weeks. The mean systolic blood pressure (BP) reduction was -18.3 ± 13.2, -13.0 ± 13.3, -16.3 ± 12.4, and -13.8 ± 13.2 mmHg in the ALC, AL, LC, and AC groups, respectively. The ALC group showed significant systolic BP reduction compared to the AL and AC groups at weeks 4 (P = .010 and P = .018, respectively) and 8 (P = .017 and P = .036, respectively). At week 4, the proportion of systolic BP responders was significantly higher in the ALC group (42.6%) than in the AL (22.0%), LC (23.3%), and AC (27.1%) groups (P = .013, P = .021, and P = .045, respectively). At week 8, the proportion of systolic and diastolic BP responders was significantly higher in the ALC group (59.7%) than in the AL (39.3%) and AC (42.4%) groups (P = .022 and P = .049, respectively) at week 8. Third-standard-dose triple antihypertensive combination therapy demonstrated early effective BP control compared to third-standard-dose dual combination therapies, without increasing adverse drug reactions in patients with mild-to-moderate hypertension.

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

Discovery of novel mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow.

Recently, we showed that disturbed flow caused by a partial ligation of mouse carotid artery rapidly induces atherosclerosis. Here, we identified mechanosensitive genes in vivo through a genome-wide microarray study using mouse endothelial RNAs isolated from the flow-disturbed left and the undisturbed right common carotid artery. We found 62 and 523 genes that changed significantly by 12 hours and 48 hours after ligation, respectively. The results were validated by quantitative polymerase chain reaction for 44 of 46 tested genes. This array study discovered numerous novel mechanosensitive genes, including Lmo4, klk10, and dhh, while confirming well-known ones, such as Klf2, eNOS, and BMP4. Four genes were further validated for protein, including LMO4, which showed higher expression in mouse aortic arch and in human coronary endothelium in an asymmetric pattern. Comparison of in vivo, ex vivo, and in vitro endothelial gene expression profiles indicates that numerous in vivo mechanosensitive genes appear to be lost or dysregulated during culture. Gene ontology analyses show that disturbed flow regulates genes involved in cell proliferation and morphology by 12 hours, followed by inflammatory and immune responses by 48 hours. Determining the functional importance of these novel mechanosensitive genes may provide important insights into understanding vascular biology and atherosclerosis.

GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide.

RATIONALE: GTP cyclohydrolase I (GTPCH-1) is the rate-limiting enzyme involved in de novo biosynthesis of tetrahydrobiopterin (BH(4)), an essential cofactor for NO synthases and aromatic amino acid hydroxylases. GTPCH-1 undergoes negative feedback regulation by its end-product BH(4) via interaction with the GTP cyclohydrolase feedback regulatory protein (GFRP). Such a negative feedback mechanism should maintain cellular BH(4) levels within a very narrow range; however, we recently identified a phosphorylation site (S81) on human GTPCH-1 that markedly increases BH(4) production in response to laminar shear. OBJECTIVE: We sought to define how S81 phosphorylation alters GTPCH-1 enzyme activity and how this is modulated by GFRP. METHODS AND RESULTS: Using prokaryotically expressed proteins, we found that the GTPCH-1 phospho-mimetic mutant (S81D) has increased enzyme activity, reduced binding to GFRP and resistance to inhibition by GFRP compared to wild-type GTPCH-1. Using small interfering RNA or overexpressing plasmids, GFRP was shown to modulate phosphorylation of GTPCH-1, BH(4) levels, and NO production in human endothelial cells. Laminar, but not oscillatory shear stress, caused dissociation of GTPCH-1 and GFRP, promoting GTPCH-1 phosphorylation. We also found that both GTPCH-1 phosphorylation and GFRP downregulation prevents endothelial NO synthase uncoupling in response to oscillatory shear. Finally oscillatory shear was associated with impaired GTPCH-1 phosphorylation and reduced BH(4) levels in vivo. CONCLUSIONS: These studies provide a new mechanism for regulation of endothelial GTPCH-1 by its phosphorylation and interplay with GFRP. This mechanism allows for escape from GFRP negative feedback and permits large amounts of BH(4) to be produced in response to laminar shear stress.

Potential application of biomimetic exosomes in cardiovascular disease: focused on ischemic heart disease.

Cardiovascular disease, especially ischemic heart disease, is a major cause of mortality worldwide. Cardiac repair is one of the most promising strategies to address advanced cardiovascular diseases. Despite moderate improvement in heart function via stem cell therapy, there is no evidence of significant improvement in mortality and morbidity beyond standard therapy. The most salutary effect of stem cell therapy are attributed to the paracrine effects and the stem cell-derived exosomes are known as a major contributor. Hence, exosomes are emerging as a promising therapeutic agent and potent biomarkers of cardiovascular disease. Furthermore, they play a role as cellular cargo and facilitate intercellular communication. However, the clinical use of exosomes is hindered by the absence of a standard operating procedures for exosome isolation and characterization, problems related to yield, and heterogeneity. In addition, the successful clinical application of exosomes requires strategies to optimize cargo, improve targeted delivery, and reduce the elimination of exosomes. In this review, we discuss the basic concept of exosomes and stem cell-derived exosomes in cardiovascular disease, and introduce current efforts to overcome the limitations and maximize the benefit of exosomes including engineered biomimetic exosomes. [BMB Reports 2022; 55(1): 30-38].

Size Effect of a Piezoelectric Material as a Separator Coating Layer for Suppressing Dendritic Li Growth in Li Metal Batteries.

Li metal has been intensively investigated as a next-generation rechargeable battery anode. However, its practical application as the anode material is hindered by the deposition of dendritic Li. To suppress dendritic Li growth, introducing a modified separator is considered an effective strategy since it promotes a uniform Li ion flux and strengthens thermal and mechanical stability. Herein, we present a strategy for the surface modification of separator, which involves coating the separator with a piezoelectric material (PM). The PM-coated separator shows higher thermal resistance than the pristine separator, and its modified surface properties enable the homogeneous regulation of the Li-ion flux when the separator is punctured by Li dendrite. Furthermore, PM was synthesized in different solvents via solvothermal method to explore the size effect. This strategy would be helpful to overcome the intrinsic Li metal anode problems.

A randomized, double-blind, multicenter, phase III study on the efficacy and safety of a combination treatment involving fimasartan, amlodipine, rosuvastatin in patients with essential hypertension and dyslipidemia who fail to respond adequately to fimasartan monotherapy.

BACKGROUND: To assess the efficacy and safety of a combination therapy involving fimasartan, amlodipine, and rosuvastatin in patients with essential hypertension and dyslipidemia who fail to respond to fimasartan monotherapy. METHODS: This phase III, randomized, double-blind, multicenter study was conducted in adults aged 19-70 years. Patients who voluntarily consented were screened for eligibility to enroll in the study. Patients who failed to respond to 4 weeks of fimasartan monotherapy were randomized with a 1:1:1 ratio to the fimasartan 60 mg/amlodipine 10 mg + rosuvastatin 20 mg (FMS/ALD + RSV) as study group, fimasartan 60 mg/amlodipine 10 mg (FMS/ALD) as control 1 group, and fimasartan 60 mg + rosuvastatin 20 mg (FMS + RSV) as control 2 group. The primary efficacy endpoints were the change in the sitting systolic blood pressure and the rate of change in the low-density lipoprotein cholesterol (LDL-C) level from baseline to 8 weeks. The adverse events, adverse drug reactions, physical examination findings, laboratory test results, electrocardiograms, and vital signs were evaluated to assess safety in the study. RESULTS: Of 138 randomized patients, 131 were conducted efficacy analysis, and 125 completed the study. For the change in LDL-C and sitting SBP (SiSBP) as primary efficacy assessments, the change in LDL-C at week 8 was significantly reduce in the FMS/ALD + RSV group than in the control 1 group (P < 0.001). The change in SiSBP at week 8 were greater reduce in the FMS/ALD + RSV group than in the FMS + RSV group (both P < 0.001). For the safety evaluation, there were no differences among the treatment groups in the incidence of adverse drug reactions. CONCLUSIONS: The fimasartan/amlodipine + rosuvastatin combination therapy can effectively and safely lower blood pressure and improve lipid levels in patients with essential hypertension and dyslipidemia who fail to respond adequately to fimasartan monotherapy. TRIAL REGISTRATION: NCT03156842, Registered 17 May 2017.

Efficacy and Safety of SID142 in Patients With Peripheral Arterial Disease: A Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group, Phase III Clinical Trial.

PURPOSE: Renexin® is a combination pill of cilostazol and Ginkgo biloba leaf extract that is used for the improvement of ischemic symptoms associated with peripheral arterial disease (PAD). SID142 is a controlled-release tablet of cilostazol (200 mg) and G biloba leaf extract (160 mg) that was developed to address the limitation of BID administration with Renexin. This study aimed to verify that SID142 was not inferior to Renexin in the treatment of patients with PAD. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III clinical trial. Study subjects were randomized to receive SID142 once daily or Renexin twice a day for 12 weeks. The primary end point was a change in the patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. If the lower limit of the two-sided 95% CI was greater than -10, the study drug was declared noninferior to the reference drug. Secondary efficacy end points included cold sensation, ankle-brachial index, ankle systolic pressure, maximum walking distance, pain-free walking distance, and investigator's global assessment. Study group results were compared 4, 8, and 12 weeks after treatment. Adverse events were assessed as a safety end point. FINDINGS: In total, 344 subjects from 19 medical centers were screened, and a total of 170 subjects were randomly assigned to either the SID142 (n = 86) or the Renexin (n = 84) group. Analysis of the change in lower extremity pain at 12 weeks compared with baseline revealed that SID142 was not inferior to Renexin (21.44 [19.23] vs 22.30 [17.75]; 95% CI, -7.70 to 5.97; P = 0.5942). No significant differences were found between groups in any secondary efficacy end point. However, the incidence of adverse reactions was significantly lower in the SID142 group (22.35% vs 39.29%; P = 0.0171). IMPLICATIONS: SID142 once daily was not inferior to Renexin twice a day for efficacy in patients with PAD. SID142 had a favorable safety profile. CLINICALTRIALS: gov identifier: NCT03318276.

Dynamic fluorescence imaging of indocyanine green for reliable and sensitive diagnosis of peripheral vascular insufficiency.

Quantitative measurement of functional tissue perfusion is essential for early diagnosis and proper treatment of peripheral arterial occlusive disease (PAOD). We have previously demonstrated that dynamic imaging of near-infrared fluorophore indocyanine green (ICG) can be a noninvasive and sensitive tool to measure tissue perfusion. In the present study, we investigated the clinical efficacy of ICG perfusion imaging method for the diagnosis of PAOD. Total nineteen PAOD patients and age-matched controls (n=10) were evaluated for lower extremity tissue perfusion using ICG perfusion imaging. The perfusion rates of the lower extremities with severe PAOD (n=25 legs, 16.6±8.3%/min) were significantly lower than those of normal controls (38.1±17.3%/min, p<0.001). In cases of mild PAOD, the perfusion rates (n=11 legs, 18.3±10.3%/min) were also significantly lower compared to the control; while the conventional ankle-brachial index (ABI) test failed to detect mild functional impairment. These results collectively indicate that ICG perfusion imaging can be a very effective tool for diagnosis of PAOD with a superior efficacy in comparison to conventional ABI test.

Unsorted human adipose tissue-derived stem cells promote angiogenesis and myogenesis in murine ischemic hindlimb model.

We examined the protective effect of unsorted human adipose tissue-derived stem cells (hADSCs) with a short-term culture in endothelial differentiation medium on tissue repair after ischemic injury. hADSCs were isolated from human subcutaneous adipose tissue and cultured in vitro in endothelial differentiation medium for 2wks before transplantation. Cultured hADSCs showed a typical mesenchymal stromal cell-like phenotype, positive for endothelial-specific markers including VE-cadherin, Flt-1, eNOS, and vWF but not CD31. Two hours after ligation of the femoral artery and vein, mice were injected with the unselected hADSCs locally near the surgery site and tested for tissue perfusion and repair. Tissue perfusion rates of the ischemic limbs were significantly higher in the group treated with hADSCs compared with those of the control mice as early as post-operative day 3 (median 195.3%/min; interquartile range, 82.0-321.1 vs. median 47.1%/min; interquartile range, 18.0-58.7; p=0.001 by Friedman two-way analysis). Subsequently, the mice treated with hADSC showed better prognosis at 4wks after surgery, and the histological analysis revealed increased vascular density and reduced muscle atrophy in the hADSC-transplanted limbs. Moreover, hADSC-treated muscle contained differentiated myocytes positive for human NF-κB and myogenin antigen. These results collectively indicate that unsorted hADSCs after a 2-wk-in vitro culture have a therapeutic potential in ischemic tissue injury via inducing both angiogenesis and myogenesis.

Validation of the diagnostic performance of 'HeartMedi V.1.0', a novel CT-derived fractional flow reserve measurement, for patients with coronary artery disease: a study protocol.

INTRODUCTION: Coronary CT angiography (CCTA) is widely used for non-invasive coronary artery evaluation, but it is limited in identifying the nature of functional characteristics that cause ischaemia. Recent computational fluid dynamic (CFD) techniques applied to CCTA images permit non-invasive computation of fractional flow reserve (FFR), a measure of lesion-specific ischaemia. However, this technology has limitations, such as long computational time and the need for expensive equipment, which hinder widespread use. METHODS AND ANALYSIS: This study is a prospective, multicentre, comparative and confirmatory trial designed to evaluate the diagnostic performance of HeartMedi V.1.0, a novel CT-derived FFR measurement for the detection of haemodynamically significant coronary artery stenoses identified by CCTA, based on invasive FFR as a reference standard. The invasive FFR values ≤0.80 will be considered haemodynamically significant. The study will enrol 184 patients who underwent CCTA, invasive coronary angiography and invasive FFR. Computational FFR (c-FFR) will be analysed by CFD techniques using a lumped parameter model based on vessel length method. Blinded core laboratory interpretation will be performed for CCTA, invasive coronary angiography, invasive FFR and c-FFR. The primary objective of the study is to compare the area under the receiver-operator characteristic curve between c-FFR and CCTA to non-invasively detect the presence of haemodynamically significant coronary stenosis. The secondary endpoints include diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value and correlation of c-FFR with invasive FFR. ETHICS AND DISSEMINATION: The study has ethic approval from the ethics committee of Seoul National University Bundang Hospital (E-1709/420-001) and informed consent will be obtained for all enrolled patients. The result will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: KCT0002725; Pre-results.