Single-center experience with self-expanding transcatheter aortic valve system for symptomatic high-risk patients with severe aortic regurgitation: One-year outcomes.

AIMS: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for the treatment of aortic regurgitation (AR). METHODS: From September 2019 to February 2022, 62 patients who underwent transfemoral TAVI procedure for pure, symptomatic severe AR with the VitaFlow system were enrolled in the current study. The outcomes were assessed according to the Valve Academic Research Consortium 3 criteria. Procedural results and clinical outcomes for 1 year were analyzed. RESULTS: The mean age was 71.56 ± 7.34 years and 58.1% were male. The mean Society of Thoracic Surgeons score was 5.44 ± 3.22%. The device success rate was 79.0%. Only one patient was converted to open surgery. The in-hospital mortality rate was 1.6%. The 1-year all-cause mortality rate was 6.5%. The new permanent pacemaker implantation rate was 29.0% in-hospital and 30.7% at 1-year follow-up. The second valve implantation rate was 14.5%. No patient developed more than moderate paravalvular leakage during follow-up. The mean ejection fraction improved from 54.05 ± 10.83% at baseline to 59.32 ± 8.70% (p < 0.001 compared with baseline) at 12 months. Left ventricular end-diastolic diameter decreased from 61.62 ± 5.58 mm at baseline to 55.20 ± 4.51 mm (p < 0.001 compared with the baseline) at 12 months. CONCLUSIONS: Transfemoral TAVI procedure shows efficacy in treating patients with severe pure native AR. The safety is improved with the development of the VitaFlow system.

Intravascular Ultrasound vs Angiography-Guided Drug-Coated Balloon Angioplasty: The ULTIMATE â ¢ Trial.

BACKGROUND: Drug-coated balloon (DCB) angioplasty seems a safe and effective option for specific de novo coronary lesions. However, the beneficial effect of intravascular ultrasound (IVUS)-guided DCB angioplasty in de novo lesions remains uncertain. OBJECTIVES: This study aimed to assess the benefits of IVUS guidance over angiography guidance during DCB angioplasty in de novo coronary lesions. METHODS: A total of 260 patients with high bleeding risk who had a de novo coronary lesion (reference vessel diameter 2.0-4.0 mm, and lesion length ≤15 mm) were randomly assigned to either an IVUS-guided or an angioplasty-guided DCB angioplasty group. The primary endpoint was in-segment late lumen loss (LLL) at 7 months after procedure. The secondary endpoint was target vessel failure at 6 months. RESULTS: A total of 2 patients in the angiography-guided group and 7 patients in the IVUS-guided group underwent bailout stent implantation (P = 0.172). The primary endpoint of 7-month LLL was 0.03 ± 0.52 mm with angiography guidance vs -0.10 ± 0.34 mm with IVUS guidance (mean difference 0.14 mm; 95% CI: 0.02-0.26; P = 0.025). IVUS guidance was also associated with a larger 7-month minimal lumen diameter (2.06 ± 0.62 mm vs 1.75 ± 0.63 mm; P < 0.001) and a smaller diameter stenosis (28.15% ± 13.88% vs 35.83% ± 17.69%; P = 0.001) compared with angiography guidance. Five target vessel failures occurred at 6 months, with 4 (3.1%) in the angiography-guided group and 1 (0.8%) in the IVUS-guided group (P = 0.370). CONCLUSIONS: This study demonstrated that IVUS-guided DCB angioplasty is associated with a lower LLL in patients with a de novo coronary lesion compared with angiography guidance. (Intravascular Ultrasound Versus Angiography Guided Drug-Coated Balloon [ULTIMATE-III]; NCT04255043).

[Interactive scalp acupuncture for hemiplegic upper extremity motor dysfunction in patients with ischemic stroke: a randomized controlled trial].

OBJECTIVE: To compare the curative effect between interactive scalp acupuncture and traditional scalp acupuncture on hemiplegic upper extremity motor dysfunction in the patients with ischemic stroke. METHODS: Seventy cases of hemiplegic upper extremity motor dysfunction of ischemic stroke were randomly divided into an interactive scalp acupuncture group (35 cases, 1 case breaked off) and a traditional scalp acupuncture group (35 cases, 1 case dropped off). The patients of the two groups received the secondary prevention medication and routine rehabilitation therapy. Besides, in the interactive scalp acupuncture group, the upper extremity occupational therapy was operated during the needle retaining of scalp acupuncture; and in the traditional scalp acupuncture group, the upper extremity occupational therapy was delivered after the completion of scalp acupuncture. The same points were selected in the two groups such as Fuxiang head area, Fuxiang upper-limb-shoulder point, Fuxiang upper-limb-elbow point and Fuxiang upper-limb-wrist point. The needles were inserted perpendicularly by flying-needle technique and manipulated by triple technique of gentle twisting, heavy pressure and vibrating. The needles were retained for 30 min. Based on the degree of the upper extremity motor impairment, the regimen of the upper extremity occupational therapy was formulated individually and one treatment took 30 min. In the two groups, the therapies were delivered once daily, 5 times a week, lasting 4 weeks. Before and after treatment, the scores of Fugl-Meyer assessment of upper extremity (FMA-UE), Wolf motor function test (WMFT), the modified Barthel index (MBI) and the modified Ashworth scale (MAS) grade in the two groups were observed before and after treatment. RESULTS: After treatment, the scores of FMA-UE, WMFT and MBI were higher than those before treatment (P<0.01), and MAS grade was improved (P<0.05) in the two groups. The scores of FMA-UE, WMFT and MBI in the interactive scalp acupuncture group were higher than those in the traditional scalp acupuncture group (P<0.01, P<0.05), and there was no statistical significance in the difference of MAS grade between the two groups (P>0.05). CONCLUSION: The interactive scalp acupuncture can effectively improve the motor function of the hemiplegic upper extremities and the activities of daily living in the patients with ischemic stroke and its efficacy is better than traditional scalp acupuncture. But these two types of scalp acupuncture obtain the similar effect on spasticity.

A Novel Electrochemical Sensor Modified with a Computer-Simulative Magnetic Ion-Imprinted Membrane for Identification of Uranyl Ion.

In this paper, a novel ion-imprinted electrochemical sensor modified with magnetic nanomaterial Fe3O4@SiO2 was established for the high sensitivity and selectivity determination of UO22+ in the environment. Density functional theory (DFT) was employed to investigate the interaction between templates and binding ligands to screen out suitable functional binding ligand for the reasonable design of the ion imprinted sensors. The MIIP/MCPE (magnetic ion imprinted membrane/magnetic carbon paste electrode) modified with Fe3O4@SiO2 exhibited a strong response current and high sensitivity toward uranyl ion comparison with the bare carbon paste electrodes. Meanwhile, the MCPE was fabricated simultaneously under the action of strong magnetic adsorption, and the ion imprinted membrane can be adsorbed stably on the electrode surface, handling the problem that the imprinted membrane was easy to fall off during the process of experimental determination and elution. Based on the uranyl ion imprinting network, differential pulse voltammetry (DPV) was adopted for the detection technology to realize the electrochemical reduction of uranyl ions, which improved the selectivity of the sensor. Thereafter, uranyl ions were detected in the linear concentration range of 1.0 × 10-9 mol L-1 to 2.0 × 10-7 mol L-1, with the detection and quantification limit of 1.08 × 10-9 and 3.23 × 10-10 mol L-1, respectively. In addition, the sensor was successfully demonstrated for the determination of uranyl ions in uranium tailings soil samples and water samples with a recovery of 95% to 104%.

Single-Cell RNA Sequencing of the Rat Carotid Arteries Uncovers Potential Cellular Targets of Neointimal Hyperplasia.

Aims: In-stent restenosis (ISR) remains an Achilles heel of drug-eluting stents despite technical advances in devices and procedural techniques. Neointimal hyperplasia (NIH) is the most important pathophysiological process of ISR. The present study mapped normal arteries and stenotic arteries to uncover potential cellular targets of neointimal hyperplasia. Methods and Results: By comparing the left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both the control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. An abnormal cell type expressing both VSMC and fibroblast markers at the same time was termed a transitional cell via pseudotime analysis. Due to the high proportion of VSMCs, we divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. Moreover, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker. Finally, we proposed several novel target genes by disease susceptibility gene analysis, such as Cyp7a1 and Cdk4, which should be validated in future studies. Conclusion: Maps of the heterogeneous cellular landscape in the carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. This study highlights the crucial role of VSMC phenotype switching in the progression of neointimal hyperplasia and provides clues regarding the underlying mechanism of NIH.

A review on traditional uses, phytochemistry, pharmacology, toxicology and the analytical methods of the genus Nardostachys.

ETHNOPHARMACOLOGICAL RELEVANCE: The plants of the genus Nardostachys (Caprifoliaceae) have been used for a long history in different cultural systems of medicine, including Chinese, Ayurvedic, Korean folk medicine and Islamic, for treatments of disorders in nervous, digestive, cardiovascular and integumentary systems. AIM OF THE REVIEW: This review aims to provide comprehensive information on Nardostachys plants including botany update, traditional uses, data mining of uses in traditional Chinese medicine (TCM) and current Chinese medicinal patents, chemical constituents, pharmacological effects, toxicity and analytical method studies. MATERIALS AND METHODS: Studies of the genus Nardostachys were collected via Google Scholar and Baidu Scholar, ScienceDirect, SciFinder, Wiley Online Library, ACS Publications, NLM/NCBI, Web of Science, CNKI, WANFANG DATA, EMBASE, Huabeing database and Traditional Chinese Medicine Resource Network and libraries. Some local books, PhD or MS's dissertations were also included. The literatures cited in this review covered the period from 1962 to March 2021. The Plant List and Kew Herbarium Catalogue databases were used to authenticate the scientific name. RESULTS: Botany description of Nardostachys genus is updated. Analysis of the literatures indicates that Nardostachys species are valuable herbs with therapeutic potentials for various disorders. Data mining on ancient TCM prescriptions and current Chinese medicinal patents containing Nardostachys revealed its common compatibility with other herbs in China. Phytochemical studies identified terpenoids and phenolic compounds as the main constituents in the genus Nardostachys and sesquiterpenoids as the major bioactive components. Experimental studies demonstrated that crude extracts, major fractions and the main constituents from Nardostachys species mainly exhibited pharmacological activities on nervous, digestive, cardiovascular and skin systems. Further, in vivo and in vitro toxicological studies demonstrated that Nardostachys plants showed either no or low toxicities, except at high doses. Finally, methods of qualitative and quantitative analyses on chemical constituents of genus Nardostachys were summarized, including TLC/HPTLC, GC and HPLC/UPLC methods, combined with common detectors including PDA, DAD and MS. CONCLUSIONS: This review summarizes the progress on phytochemistry, pharmacology, toxicology and analytical methods of the genus Nardostachys. Studies demonstrate traditional uses of the genus Nardostachys, and reveal novel bioactive effects for clinical uses. These achievements expand our knowledge on the genus Nardostachys and its clinical value.

Therapeutic Exosomes in Prognosis and Developments of Coronary Artery Disease.

Exosomes, with an diameter of 30~150 nm, could be released from almost all types of cells, which contain diverse effective constituent, such as RNAs, proteins, lipids, and so on. In recent years, exosomes have been verified to play an important role in mechanism, diagnosis, treatment, and prognosis of cardiovascular disease, especially coronary artery disease (CAD). Moreover, it has also been shown that exosomes derived from different cell types have various biological functions based on the cell stimulation and microenvironment. However, therapeutic exosomes are currently far away from clinical translation, despite it is full of hope. In this review, we summarize an update of the recent studies and systematic knowledge of therapeutic exosomes in atherosclerosis, myocardial infarction, and in-stent restenosis, which might provide a novel insight into the treatment of CAD and promote the potential clinical application of therapeutic exosomes.

Plasma Small Extracellular Vesicle-Carried miRNA-501-5p Promotes Vascular Smooth Muscle Cell Phenotypic Modulation-Mediated In-Stent Restenosis.

Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation. sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation. Plasma sEV in ISR patients are elevated markedly and decrease the expression of VSMC contractile markers α-SMA and calponin and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then, we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis (R 2 = 0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α-SMA and calponin and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p. Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3.

Primary Cilia and Atherosclerosis.

In artery tree, endothelial function correlates with the distribution of shear stress, a dragging force generated by flowing blood. In laminar shear stress areas, endothelial cells (ECs) are available to prevent atherosclerosis, however, ECs in disturbed shear stress sites are featured with proinflammation and atherogenesis. Basic studies in the shear stress field that focused on the mechanosensors of ECs have attracted the interest of researchers. Among all the known mechanosensors, the primary cilium is distinctive because it is enriched in disturbed shear stress regions and sparse in laminar shear stress areas. The primary cilium, a rod liked micro-organelle, can transmit extracellular mechanical and chemical stimuli into intracellular space. In the cardiovascular system, primary cilia are enriched in disturbed shear stress regions, where blood flow is slow and oscillatory, such as the atrium, downstream of the aortic valve, branches, bifurcations, and inner curves of the artery. However, in the atrioventricular canal and straight vessels, blood flow is laminar, and primary cilia can barely be detected. Primary cilia in the heart cavity prevent ECs from mesenchymal transition and calcification by suppressing transforming growth factor (TGF) signaling. Besides, primary cilia in the vascular endothelium protected ECs against disturbed shear stress-induced cellular damage by triggering Ca2+ influx as well as nitric oxide (NO) release. Moreover, primary cilia inhibit the process of atherosclerosis. In the current review, we discussed ciliogenesis, ciliary structure, as well as ciliary distribution, function and the coordinate signal transduction with shear stress in the cardiovascular system.

Antidepressant activities and regulative effects on serotonin transporter of Nardostachys jatamansi DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Nardostachys jatamansi (D.Don) DC. (family Caprifoliaceae, NJ) is well-documented and commonly used in the systems of traditional medicine in China, Tibet, Nepal, Bhutan, India and Japan for curing digestive and neuropsychiatric disorders with a long history of medication. However, the possible action mechanisms of antidepressant effects of NJ remain unraveled. AIM OF THE STUDY: The aim of this study was to systematically investigate chemical substances of NJ and their effects on serotonin transporter (SERT) in antidepressant activity. MATERIALS AND METHODS: Antidepressant effects of total methanol extract of NJ were evaluated by tail suspension test (TST) and open field test (OFT). Then the total extract was analyzed by ultra-high-performance liquid chromatography (UHPLC) method, and its effect on SERT activity was evaluated by high content assay (HCA) to determine half maximal effective concentration (EC50). This total extract was subfractioned into twenty subfractions by preparative high-performance liquid chromatography (p-HPLC) method, and 'subfraction-SERT activity' relationship curve was fitted with medians of the retention time of those subfractions and their SERT activity values. Then, the fraction NJFr.01 enriched with SERT enhancers was optimized, prepared and analyzed by UHPLC method. Antidepressant effects of the fraction NJFr.01 were evaluated by TST and OFT. Further, major constituents of the total extract and fraction NJFr.01 were isolated by p-HPLC and identified by extensive nuclear magnetic resonance (NMR) analyses and comparisons with those reported data, and their SERT activities were also evaluated. Finally, antagonistic effects of chlorogenic acid and desoxo-narchinol A against fluoxetine on SERT were evaluated. RESULTS: Results of TST and OFT demonstrated antidepressant effects of toatal extract of NJ. The EC50 of total extract on SERT enhancement was 31.63 µg/mL. The fitted 'subfraction-SERT activity' relationship curve revealed that fraction NJFr.01 was enriched with SERT enhancing constituents. Both total extract and fraction NJFr.01 significantly enhanced SERT activity, while the rest fraction NJFr.02 didn't show any SERT activity. Then, antidepressant effects of fraction NJFr.01 were demonstrated by TST and OFT. Further, phytochemistry investigation and UHPLC analyses confirmed the identification of fourteen constituents in the total extract of NJ, including 7-oxonardinoperoxide (1), desoxo-narchinol A (2), kanshone B (3), narchinol B (4), nardosinonediol (5), kanshone A (6), 1-hydroxylaristolone (7), debilon (8), nardosinone (9), kanshone H (10), 1,8,9,10-tetradehydroaristolan-2-one (11), (-)-aristolone (12), 1(10)-aristolene-2-one (13) and jatamol A (14), and seven constituents in the fraction NJFr.01, including chlorogenic acid (15), 8α-dihydrogeniposide (16), 7-deoxy-8-epi-loganic acid (17), adoxosidic acid (18), 8-epi-loganic acid (19), 8α-6,7-dihydroapodantheroside acetate (20) and 6″-acetylpatrinalloside (21). Their structures were established by NMR analyses and comparisons with those reported data. HCA results of these constituents demonstrated the major components of fraction NJFr.01 enhanced SERT activity. Antagonistic results showed that chlorogenic acid and desoxo-narchinol A reversed inhibition effect of fluoxetine on SERT activity. CONCLUSION: This study first systematically expatiated the roles of SERT activity in antidepressant effects of NJ, including total methanol extract and the water-soluble fraction NJFr.01 enriched with SERT enhancing constituents. This is the first report of natural SERT enhancing extract and fractions with antidepressant potential in NJ.

Knockout of AKAP150 improves impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3ß signalling contributed to decreased BK-ß1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-ß1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-ß1 expression, and treatment with AKAP150 siRNA suppressed GSK3ß expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

ALDH2 rs671 polymorphism and the risk of heart failure with preserved ejection fraction (HFpEF) in patients with cardiovascular diseases.

Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is an established genetic risk of hypertension, diabetes, and coronary heart diseases in Asian population. Previous experimental data showed ALDH2 regulated inflammation, a potential mechanism of heart failure with preserved ejection fraction (HFpEF). However, clinically, the association between ALDH2 polymorphism and incidence of HFpEF remains unknown. In this prospective cross-sectional study, ALDH2 genotyping was performed in 613 consecutive patients enrolled with cardiovascular diseases (CVDs), including hypertension, coronary heart diseases, and/or diabetes mellitus, with normal left ventricular ejection fraction (LVEF). HFpEF was diagnosed according to symptoms and/or signs of dyspnea, fatigue or ankle swelling, N-terminal pro-B-Type natriuretic peptide (NT pro-BNP ≥ 280 pg/mL), LVEF ≥ 50%, and at least one additional criterion: left atrial enlargement (left atrial diameter > 40 mm), diastolic dysfunction (E/E' ≥ 13 or E'/A' < 1) or concurrently with atrial fibrillation. Finally, of 613 patients with CVD, 379 patients (61.8%) were assigned to the wild-type ALDH2*1/*1 group and 234 patients (38.2%) to the mutation-type ALDH2*2 group according to genotyping results. Sixty-nine patients (11.3%) were diagnosed with HFpEF. In ALDH2*2 group, the occurrence of HFpEF was higher (15.4% vs. 8.7%, p = 0.011) than that in ALDH2*1/*1 group. Leukocyte count, the indicator of systemic inflammation, was significantly higher (6.9 ± 2.4 × 109/L vs. 6.5 ± 1.9 × 109/L, p = 0.010) in ALDH2*2 group compared to ALDH2*1/*1 group. In conclusion, ALDH2*2 variant is associated with the risk of HFpEF in patients with CVD. Increased systemic inflammation probably involved in this disease process.

Exosomes in Coronary Artery Disease.

Exosomes, the nanosized vesicles released from various cell types, contain many bioactive molecules, such as proteins, lipids, and nucleic acids, which can participate in intercellular communication in a paracrine manner or an endocrine manner, in order to maintain the homeostasis and respond to stress adaptively. Currently, exosomes have already been utilized as diagnostic biomarkers and therapeutic tools in cancer clinical trials. There has also been great progress in cell and animal exosomes studies of coronary artery disease (CAD). Emerging evidence suggests that exosomes released from endothelial cells, smooth muscle cells, adipose cells, platelets, cardiomyocytes, and stem cells have been reported to play crucial roles in the development and progression of CAD. Moreover, it has been showed that exosomes released from different cell types exhibit diverse biological functions, either detrimental or protective, depending on the cell state and the microenvironment. However, the systematic knowledge of exosomes in CAD at the patient level has not been well established, which are far away from clinical application. This review summarizes the basic information about exosomes and provides an update of the recent findings on exosome-mediated intercellular communication in the development and progression of CAD, which could be helpful for understanding the pathophysiology of CAD and promoting the further potential clinical translation.

Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott.

ETHNOPHARMACOLOGICAL RELEVANCE: Acrorus tatarinowii Schott has been widely used in the treatments of neuropsychiatric and digestive disorders in clinical practices of traditional Chinese medicine for thousands of years. Both clinical and preclinical studies demonstrated antidepressant effects of A. tatarinowii. However, the possible action mechanisms of antidepressant effects of A. tatarinowii remain unraveled. AIM OF THE STUDY: The present study aimed to investigate the roles of serotonin transporter (SERT) in antidepressant effects of A. tatarinowii. MATERIALS AND METHODS: Antidepressant effects of water extract of A. tatarinowii were evaluated by forced swimming test (FST), tail suspension test (TST) and locomotor activity test. The water extract was analyzed by ultra high performance liquid chromatography (UPLC) method. Two major fractions of A. tatarinowii, petroleum ether extract and water extract after petroleum ether processed, were prepared and analyzed by UPLC method. Further, volatile oil extracted by ether extraction, solid phase micro-extraction (SPME) and hydro-distillation were compared and analyzed by gas chromatography-mass spectrometer (GC-MS) method. Finally, major constituents of water extract of A. tatarinowii were isolated by preparative high performance liquid chromatography (HPLC) and identified by extensive spectroscopic analyses. Effects of all of the above mentioned samples on SERT activity were tested by a high content assay (HCA). RESULTS: Results of FST, TST and locomotor activity confirmed that water extract of A. tatarinowii significantly decreased mice immobility time but did not change mice locomotor activity. UPLC analysis results revealed that the water extract contained trace amount of ß-asarone (0.0004206%) and α-asarone (0.0001918%). HCA results demonstrated that the water extract significantly enhanced SERT activity at 100 µg/mL. Further, GC-MS and UPLC analyses revealed that petroleum ether extract contained high content of ß-asarone (45.63%) and α-asarone (12.50%). GC-MS analysis results demonstrated that the volatile oil extracted by ether extraction, SPME and hydro-distillation contained similar major components. HCA results verified that the petroleum ether extract significantly enhanced SERT activity at 1.56 µg/mL. Moreover, UPLC analysis of water extract after petroleum ether processed did not show any characteristic peaks. HCA results demonstrated that this extract significantly inhibited SERT activity at 50-100 µg/mL. Finally, phytochemistry investigation on the water extract of A. tatarinowii afforded seven constituents including veratric acid (9), anisic acid (7), 3,4,5-trimethoxybenzoic acid (3), trans-isoferulic acid (2), 2,4,5-trimethoxybenzoic acid (11), 4-hydroxybenzoic acid (6) and syringic acid (13). Their structures were established on the basis of nuclear magnetic resonance (NMR) and mass spectrometer (MS) data and comparative UPLC analyses. HCA results demonstrated the major components of the water extract of A. tatarinowii demonstrated SERT enhancement/inhibition activities. CONCLUSIONS: This study first systematically demonstrated the roles of SERT activity in antidepressant effects of A. tatarinowii, including water extract, major fractions and main constituents. These results revealed that A. tatarinowii could regulate SERT activities in bidirectional ways.

Intravascular ultrasound guidance reduces cardiac death and coronary revascularization in patients undergoing drug-eluting stent implantation: results from a meta-analysis of 9 randomized trials and 4724 patients.

Intravascular ultrasound (IVUS) guidance is not routinely performed in real-word clinical practice partly because the benefit of IVUS guidance is not well established. This updated meta-analysis aims to compare IVUS-guided and angiography-guided drug-eluting stent (DES) implantation, simultaneously stressing the value of an optimal IVUS-defined procedure. Medline, Scopus, Google Scholar, and Cochrane Controlled Trials Registry were searched for the randomized trials comparing IVUS-guided and angiography-guided DES implantation. Nine eligible randomized trials including 4,724 patients were identified. At a mean follow-up of 16.7 months, IVUS guidance was associated with a significant lower risk of major adverse cardiovascular events (MACE) [5.4% vs. 9.0%; relative risks (RR): 0.61, 95% confident interval (CI) 0.49-0.74, p < 0.001], cardiac death (0.6% vs. 1.2%; RR: 0.49, 95% CI 0.26-0.92, p = 0.03), target vessel revascularization (3.5% vs .6.1%; RR: 0.58, 95% CI 0.42-0.80, p = 0.001), target lesion revascularization (3.1% vs. 5.2%; RR: 0.59, 95% CI 0.44-0.80, p = 0.001), and definite/probable stent thrombosis (0.5% vs .1.1%; RR: 0.45, 95% CI 0.23-0.87, p = 0.02) compared with angiography guidance. No significant differences in all cause death and myocardial infarction were noted between the two groups. Subgroup analysis showed that patients who met the optimal criteria had a lower rate of MACE than those with IVUS-defined suboptimal procedure (RR: 0.33, 95% CI 0.06-0.60, p = 0.02). The present meta-analysis with the largest sample size to date demonstrates that IVUS-guided DES implantation significantly reduces cardiac death, coronary revascularization and stent thrombosis, particularly for patients with IVUS-defined optimal procedures compared with angiography guidance.

Relationship between high platelet reactivity on clopidogrel and long-term clinical outcomes after drug-eluting stents implantation (PAINT-DES): a prospective, propensity score-matched cohort study.

BACKGROUND: The relationship between platelet reactivity and long-term clinical outcomes remains controversial. The present prospective study was designed to explore the association between high platelet reactivity (HPR) on clopidogrel and long-term clinical outcomes following implantation of drug eluting stents (DES). METHODS: A total of 1769 consecutive patients assessed by Aggrestar (PL-11) were enrolled at our center from February 2011 to December 2017. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), defined as definite or probable stent thrombosis, spontaneous myocardial infarction, all cause death, clinically driven target vessel revascularization (TVR), or ischemic stroke. Bleeding served as the safety endpoint. Propensity score matching (PSM) analysis was performed to adjust for baseline differences in the overall cohort. RESULTS: Finally, 409 patients (23.1%) were identified with HPR on clopidogrel. At a median follow-up of 4.1 years (interquartile range, 1.8 years), the occurrence of MACCE was significantly higher in HPR on clopidogrel group than normal platelet reactivity (NPR) on clopidogrel group (15.6% vs. 5.4%, p < 0.001). After PSM, 395 paired patients were matched, and the difference in MACCE between HPR (15.7%) versus NPR (9.4%) on clopidogrel groups remained significant (P < 0.001), mainly driven by increased all cause death (5.3% vs. 1.8%, p < 0.001), and clinically driven TVR (8.1% vs. 6.3%, p = 0.019) in the HPR group. The risk of bleeding between two groups was similar. CONCLUSIONS: This prospective study confirms the relationship between HPR on clopidogrel and long-term adverse cardiovascular events after coronary stenting.

Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH. METHODS: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD). RESULTS: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001) vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: -6.99, -0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo. CONCLUSION: All targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy. However, all these drugs seem to show less favorable effects on survival in the short-term follow-up, suggesting further clinical trials are required.

Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1.

The aim of this study was to determine whether long non-coding RNA PVT1 can participate in the regulation of cardiac hypertrophy. A C57BL/6 mouse cardiac hypertrophic model was established using transverse aortic constriction (TAC). The animals subjected to sham operation were used as controls. Transcripts of PVT1 were analyzed in hearts of model and sham control groups after TAC for 4 weeks using quantitative real-time PCR (qRT-PCR). Additionally, to investigate whether PVT1 was involved in cardiac hypertrophy, 1 µM angiotensin II (Ang II) was used to induce hypertrophy and PVT1 siRNA was performed in the cultured neonatal mouse cardiac cardiomyocytes. Cell size was measured by cell surface area and total protein content analyses in response to Ang II treatment. Moreover, some hypertrophic markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and beta-myosin heavy chain (ß-MHC) were also quantified using qRT-PCR. As a result, PVT1 was up-regulated by 2.5-fold (P<0.05) in hypertrophic hearts after TAC for 4 weeks as compared to sham group. In addition, siRNA of endogenous PVT1 in cardiomyocytes significantly reduced (P<0.05) Ang II-induced increase of cell size in terms of cell surface area (by 5.6-fold) and total protein content (by 23.0%). PVT1 siRNA also obviously attenuated Ang II-induced ANP and ß-MHC expression by 40.9% and 41.5%, respectively (P<0.05), but had no effect on BNP mRNA expression. Our results demonstrated that PVT1 was essential for the maintenance of cell size of cardiomyocytes and might play a role in the regulation of cardiac hypertrophy.

Antithrombotic Regimens for Patients Taking Oral Anticoagulation After Coronary Intervention: A Meta-analysis of 16 Clinical Trials and 9,185 Patients.

The optimal antithrombotic regimen remains controversial in patients taking oral anticoagulation (OAC) undergoing coronary stenting. This study sought to compare efficacy and safety outcomes of triple therapy (OAC, aspirin, and clopidogrel) vs dual therapy (clopidogrel with aspirin or OAC) in these patients. We hypothesize OAC plus clopidogrel could be the optimal regimen for patients with indications for OAC receiving stent implantation. Medline, the Cochrane Library, and other Internet sources were searched for clinical trials comparing the efficacy and safety of triple vs dual therapy for patients taking OAC after coronary stenting. Sixteen eligible trials including 9185 patients were identified. The risks of major adverse cardiac events (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 0.82-1.39, P = 0.65), all-cause mortality (OR: 0.98, 95% CI: 0.76-1.27, P = 0.89), myocardial infarction (OR: 1.01, 95% CI: 0.77-1.31, P = 0.97), and stent thrombosis (OR: 0.91, 95% CI: 0.49-1.69, P = 0.75) were similar between triple and dual therapy. Compared with dual therapy, triple therapy was associated with a reduced risk of ischemic stroke (OR: 0.57, 95% CI: 0.35-0.94, P = 0.03) but with higher major bleeding (OR: 1.52, 95% CI: 1.11-2.10, P = 0.01) and minor bleeding (OR: 1.59, 95% CI: 1.05-2.42, P = 0.03). Subgroup analysis indicated there were similar ischemic stroke and major bleeding outcomes between triple therapy and therapy with OAC plus clopidogrel. Treatment with OAC and clopidogrel was associated with similar efficacy and safety outcomes compared with triple therapy. Triple therapy could be replaced by OAC plus clopidogrel without any concern about additional risk of thrombotic events.

Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline.

OBJECTIVES: This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms. BACKGROUND: SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear. METHODS: Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution. RESULTS: PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction. CONCLUSIONS: PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.