Publications by authors named "Jinjun Liang"

34 Publications

Clinical characteristics, risk factors and cardiac manifestations of cancer patients with COVID-19.

J Appl Physiol (1985) 2021 Jul 8. Epub 2021 Jul 8.

Department of Cardiology and Cardiovascular Research Institute, grid.412632.0Renmin Hospital of Wuhan University, China.

Background: Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been associated with cardiovascular features, which may be deteriorated in cancer patients. However, cardiac outcomes of cancer patients with COVID-19 have not been closely examined.

Methods: We retrospectively assessed 1244 patients with COVID-19 from February 1 to August 31 (140 cancer and 1104 non-cancer patients). Demographic and clinical data were obtained and compared between cancer and non-cancer groups. Including the cardiac biomarkers, we also analyzed laboratory findings between these two groups. Risk factors for in hospital mortality were identified by multivariable COX regression models.

Results: For cancer group, 56% were in severe and critical status with more diabetes and immune deficiency, while the proportion was 10% for non-cancer group. Cancer patients had increased levels of leukocyte, neutrophil count and BUN (all p<0.01), while lymphocyte count was significantly lower (p<0.001). The most common solid tumor types were gastrointestinal cancer (26%), lung cancer (21%), breast and reproductive cancer (both 19%). There is a rising for cardiac biomarkers, including Pro-BNP, cTnI, MYO, CK-MB, as well as D-Dimer in COVID-19 cancer population, especially in deceased cancer subjects. The 30-day in hospital mortality in cancer group was dramatically raised than that in non-cancer group (12.9% vs. 4.0%, p<0.01). In multivariable COX regression models, fever, disease severity status, underlying diseases were risk factors for mortality.

Conclusion: COVID-19 patients with cancer relate to deteriorating conditions and poor cardiac outcomes accompanied by a high in-hospital mortality, which warrants more aggressive treatment.
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http://dx.doi.org/10.1152/japplphysiol.00325.2021DOI Listing
July 2021

Decreased Low-Density Lipoprotein Cholesterol Level Indicates Poor Prognosis of Severe and Critical COVID-19 Patients: A Retrospective, Single-Center Study.

Front Med (Lausanne) 2021 26;8:585851. Epub 2021 May 26.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Coronavirus disease 2019 (COVID-19) has become a global public health crisis. Reduced low-density lipoprotein cholesterol (LDL-C) levels were observed in COVID-19 patients. The present study aimed to explore the relationship between LDL-C levels and the prognosis of severe and critical COVID-19 patients. A total of 211 severe and critical COVID-19 patients were enrolled and divided into four groups according to the LDL-C levels, including 53 patients in Group A (LDL-C ≥ 2.71 mmol/L), 53 patients in Group B (2.28 ≤ LDL-C < 2.71 mmol/L), 53 patients in Group C (1.83 ≤ LDL-C < 2.28 mmol/L) and 52 patients in Group D (LDL-C < 1.83 mmol/L). LDL-C levels were lower in critically ill patients than in severe patients. The main symptoms before admission, characteristics on admission and comorbidities of enrolled patients did not differ among the four groups. Compared with patients with high LDL-C levels, patients with low LDL-C levels were more likely to have immune and inflammation dysfunction, renal dysfunction, liver dysfunction and cardiac dysfunction on admission. The proportions of patients with shock and acute cardiac injury, of those admitted to intensive care unit (ICU) and of those treated with mechanical ventilation were inversely related to LDL-C level. The mortality of COVID-19 patients increased with LDL-C reduction. Serum LDL-C levels of COVID-19 patients was negatively correlated with CRP level, but positively correlated with lymphocyte count, as shown by Pearson correlation analysis. Proportional hazard models showed that low LDL-C levels were associated with increased risk of hospitalization death, cardiac injury and admission to the ICU. Taken together, these results suggest that decreased LDL-C levels indicate poor prognosis of severe and critical COVID-19 patients.
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http://dx.doi.org/10.3389/fmed.2021.585851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187559PMC
May 2021

Pinocembrin ameliorates arrhythmias in rats with chronic ischaemic heart failure.

Ann Med 2021 12;53(1):830-840

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Objective: Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism.

Methods: Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure.

Results: Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (C43).

Conclusion: We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.
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http://dx.doi.org/10.1080/07853890.2021.1927168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172224PMC
December 2021

Corrigendum: Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression.

Front Pharmacol 2021 4;12:647320. Epub 2021 May 4.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

[This corrects the article DOI: 10.3389/fphar.2020.547966.].
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http://dx.doi.org/10.3389/fphar.2021.647320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129570PMC
May 2021

MADS-Box Protein Complex VvAG2, VvSEP3 and VvAGL11 Regulates the Formation of Ovules in L. cv. 'Xiangfei'.

Genes (Basel) 2021 Apr 26;12(5). Epub 2021 Apr 26.

College of Horticulture, China Agricultural University, Beijing 100193, China.

The phenomenon of multi-carpel and multi-ovule exists in the grapevine cultivar 'Xiangfei', but the mechanism of ovule formation is seldom reported. In this study, we observed the ovule formation process by using 'Xiangfei' grapes. The role of the () gene in ovule formation was identified, and we explored the relationship between VvAG2, VvSEP3(VvMADS4) and VvAGL11(VvMADS5) proteins. The results showed that the ovule primordium appeared when the inflorescence length of 'Xiangfei' grapes were 4-5 cm long; the relative expression levels of , and genes were higher during ovule formation, and the expression levels of gene was the highest. Transgenic tomato () plants expressing produced higher numbers of ovules and carpels than the wild type. Moreover, yeast two-hybrid and yeast three-hybrid experiments demonstrated that VvSEP3 acts as a bridge and interacts with VvAG2 and VvAGL11 proteins, respectively. Meanwhile, a homodimer can be formed between VvSEP3 and VvSEP3, but there was no interaction between VvAG2 and VvAGL11. These findings suggest that the gene is involved in the formation of ovules, and VvAG2/VvSEP3 together with VvAGL11/VvSEP3 can form a tetrameric complex. In summary, our data showed that along with and jointly regulate the ovule formation of 'Xiangfei' grapes.
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http://dx.doi.org/10.3390/genes12050647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146481PMC
April 2021

4-CPA (4-Chlorophenoxyacetic Acid) Induces the Formation and Development of Defective "Fenghou" () Grape Seeds.

Biomolecules 2021 03 30;11(4). Epub 2021 Mar 30.

College of Horticulture, China Agricultural University, Beijing 100193, China.

For some horticultural plants, auxins can not only induce normal fruit setting but also form fake seeds in the induced fruits. This phenomenon is relatively rare, and, so far, the underlying mechanism remains unclear. In this study, "Fenghou" ( × ) grapes were artificially emasculated before flowering and then sprayed with 4-CPA (4-chlorophenoxyacetic acid) to analyze its effect on seed formation. The results show that 4-CPA can induce normal fruit setting in "Fenghou" grapes. Although more seeds were detected in the fruits of the 4-CPA-treated grapevine, most seeds were immature. There was no significant difference in the seed shape; namely, both fruit seeds of the grapevines with and without 4-CPA treatment contained a hard seed coat. However, the immature seeds lacked embryo and endosperm tissue and could not germinate successfully; these were considered defective seeds. Tissue structure observation of defective seeds revealed that a lot of tissue redifferentiation occurred at the top of the ovule, which increased the number of cell layers of the outer integument; some even differentiated into new ovule primordia. The qRT-PCR results demonstrated that 4-CPA application regulated the expression of the genes and , which are associated with integument development in "Fenghou" grape ovules. Together, this study evokes the regulatory role of 4-CPA in the division and continuous redifferentiation of integument cells, which eventually develop into defective seeds with thick seed coats in grapes.
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http://dx.doi.org/10.3390/biom11040515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067128PMC
March 2021

Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression.

Front Pharmacol 2020 24;11:547966. Epub 2020 Nov 24.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Depression is associated with the increased risk of mortality and morbidity and is an independent risk factor for many cardiovascular diseases. Depression may promote cardiac arrhythmias, but little is known about the mechanisms. Pinocembrin mitigated depressive-like behaviors and exhibited cardioprotective effects in several models; however, whether pinocembrin benefits ventricular arrhythmias in depression models has not been elucidated. Thus, this study was to evaluate the effects of pinocembrin on ventricular fibrillation susceptibility in rat models of depression. Male Sprague-Dawley rats were randomly assigned into control, control + pinocembrin, MDD (major depressive disorder), and MDP (MDD + pinocembrin) groups, respectively. Depressive-like behaviors, ventricular electrophysiological parameters, electrocardiogram parameters, heart rate variability, ventricular histology, serum norepinephrine, tumor necrosis factor-α, and interleukin-1β were detected. Protein levels in left ventricle were measured by Western blot assays. Compared with the MDD group, pinocembrin significantly mitigated depressive-like behaviors, prolonged ventricular effective refractory period, action potential duration, QT, and corrected QT (QTc) interval, improved heart rate variability, decreased Tpeak-Tend interval, ventricular fibrillation inducibility rate, ventricular fibrosis, ventricular positive nerve densities, and protein expression of tyrosine hydroxylase and growth associated protein-43, reduced serum norepinephrine, tumor necrosis factor-α, interleukin-1β concentrations, and the expression levels of p-IκBα and p-p65, and increased the protein expression of Cx43, Cav1.2, and Kv.4.2 in the MDP group. Pinocembrin attenuates ventricular electrical remodeling, autonomic remodeling, and ion-channel remodeling, lowers ventricular fibrosis, and suppresses depression-induced inflammatory responses, providing new insights in pinocembrin and ventricular arrhythmias in depressed patients.
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http://dx.doi.org/10.3389/fphar.2020.547966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775674PMC
November 2020

Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder.

Psychopharmacology (Berl) 2021 Feb 2;238(2):487-499. Epub 2020 Nov 2.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.

Rationale: It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias.

Objective: We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats.

Methods: MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique.

Results: Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (I) amplitudes. On the other hand, a trend of depolarization of I and hyperpolarization of I was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and I. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca by hyperpolarizing the steady-state activation of I. All these effects were blocked by BD1047.

Conclusion: Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and I to possibly exert antiarrhythmic effects.
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http://dx.doi.org/10.1007/s00213-020-05697-4DOI Listing
February 2021

Outcomes of Cardiac Resynchronization Therapy in Patients with Hypothyroidism and Heart Failure.

BMC Cardiovasc Disord 2020 09 23;20(1):424. Epub 2020 Sep 23.

Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.

Background: Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear.

Methods: The study included 1316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record.

Results: Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2 years). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P = 0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P = 0.004).

Conclusions: CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.
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http://dx.doi.org/10.1186/s12872-020-01693-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509921PMC
September 2020

The VvSUPERMAN-like Gene Is Differentially Expressed between Bicarpellate and Tricarpellate Florets of Vitis vinifera L. Cv. 'Xiangfei' and Its Heterologous Expression Reduces Carpel Number in Tomato.

Plant Cell Physiol 2020 Oct;61(10):1760-1774

College of Horticulture, China Agriculture University, Beijing 100094, China.

Multicarpellate fruits are larger and produce more seeds than mono- or bicarpellate fruits, enhancing the reproductive capacity of the plant. To identify the phenotypic and molecular differences among florets of different carpel types, we studied carpel formation and fusion in the grapevine (Vitis vinifera) cultivar 'Xiangfei', which produces a high proportion of multicarpellate fruit. We also determined the function of VvSUPERMAN-like (VvSUP-like) and explored its relationship with VvWUS (VvWUSCHEL) and VvAG1 (VvAGAMOUS), which is related to the formation of carpel primordia. We showed that carpel formation and fusion were largely consistent between bicarpellate and tricarpellate ovaries, which both involve congenital fusion; rather, the differences between these ovary types arose from variation in carpel primordia number and location. Transgenic tomato (Solanum lycopersicum) plants expressing VvSUP-like produced significantly fewer carpels and other floral organs than the wild type. Moreover, transcriptome sequencing results indicate that VvSUP-like was more highly expressed in bicarpellate than in tricarpellate 'Xiangfei' florets. Luciferase reporter assays indicated that VvSUP-like inhibits the expression of VvAG1 and VvWUS by directly binding to their promoters, and VvWUS promotes VvAG1 expression by directly binding to its promoter. VvSUP-like inhibits the feedback signaling between VvWUS and VvAG1. Together, these results suggest that VvSUP-like negatively regulates the number of carpels that develop by inhibiting VvAG1 and VvWUS expression.
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http://dx.doi.org/10.1093/pcp/pcaa103DOI Listing
October 2020

Chronic stimulation of the sigma-1 receptor ameliorates ventricular ionic and structural remodeling in a rodent model of depression.

Life Sci 2020 Sep 3;257:118047. Epub 2020 Jul 3.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China. Electronic address:

Aim: The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs).

Materials And Methods: To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining.

Key Findings: We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (I) and the restoration of reduced transient outward potassium current (I) resulting from CMUS induction. The S1R also decelerated I inactivation and accelerated I recovery by activating Ca/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R.

Significance: Activation of S1R could decrease the vulnerability to VAs by inhibiting I and restoring I, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.
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http://dx.doi.org/10.1016/j.lfs.2020.118047DOI Listing
September 2020

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China.

JAMA Cardiol 2020 07;5(7):802-810

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Importance: Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity and mortality worldwide since December 2019. However, information on cardiac injury in patients affected by COVID-19 is limited.

Objective: To explore the association between cardiac injury and mortality in patients with COVID-19.

Design, Setting, And Participants: This cohort study was conducted from January 20, 2020, to February 10, 2020, in a single center at Renmin Hospital of Wuhan University, Wuhan, China; the final date of follow-up was February 15, 2020. All consecutive inpatients with laboratory-confirmed COVID-19 were included in this study.

Main Outcomes And Measures: Clinical laboratory, radiological, and treatment data were collected and analyzed. Outcomes of patients with and without cardiac injury were compared. The association between cardiac injury and mortality was analyzed.

Results: A total of 416 hospitalized patients with COVID-19 were included in the final analysis; the median age was 64 years (range, 21-95 years), and 211 (50.7%) were female. Common symptoms included fever (334 patients [80.3%]), cough (144 [34.6%]), and shortness of breath (117 [28.1%]). A total of 82 patients (19.7%) had cardiac injury, and compared with patients without cardiac injury, these patients were older (median [range] age, 74 [34-95] vs 60 [21-90] years; P < .001); had more comorbidities (eg, hypertension in 49 of 82 [59.8%] vs 78 of 334 [23.4%]; P < .001); had higher leukocyte counts (median [interquartile range (IQR)], 9400 [6900-13 800] vs 5500 [4200-7400] cells/μL) and levels of C-reactive protein (median [IQR], 10.2 [6.4-17.0] vs 3.7 [1.0-7.3] mg/dL), procalcitonin (median [IQR], 0.27 [0.10-1.22] vs 0.06 [0.03-0.10] ng/mL), creatinine kinase-myocardial band (median [IQR], 3.2 [1.8-6.2] vs 0.9 [0.6-1.3] ng/mL), myohemoglobin (median [IQR], 128 [68-305] vs 39 [27-65] μg/L), high-sensitivity troponin I (median [IQR], 0.19 [0.08-1.12] vs <0.006 [<0.006-0.009] μg/L), N-terminal pro-B-type natriuretic peptide (median [IQR], 1689 [698-3327] vs 139 [51-335] pg/mL), aspartate aminotransferase (median [IQR], 40 [27-60] vs 29 [21-40] U/L), and creatinine (median [IQR], 1.15 [0.72-1.92] vs 0.64 [0.54-0.78] mg/dL); and had a higher proportion of multiple mottling and ground-glass opacity in radiographic findings (53 of 82 patients [64.6%] vs 15 of 334 patients [4.5%]). Greater proportions of patients with cardiac injury required noninvasive mechanical ventilation (38 of 82 [46.3%] vs 13 of 334 [3.9%]; P < .001) or invasive mechanical ventilation (18 of 82 [22.0%] vs 14 of 334 [4.2%]; P < .001) than those without cardiac injury. Complications were more common in patients with cardiac injury than those without cardiac injury and included acute respiratory distress syndrome (48 of 82 [58.5%] vs 49 of 334 [14.7%]; P < .001), acute kidney injury (7 of 82 [8.5%] vs 1 of 334 [0.3%]; P < .001), electrolyte disturbances (13 of 82 [15.9%] vs 17 of 334 [5.1%]; P = .003), hypoproteinemia (11 of 82 [13.4%] vs 16 of 334 [4.8%]; P = .01), and coagulation disorders (6 of 82 [7.3%] vs 6 of 334 [1.8%]; P = .02). Patients with cardiac injury had higher mortality than those without cardiac injury (42 of 82 [51.2%] vs 15 of 334 [4.5%]; P < .001). In a Cox regression model, patients with vs those without cardiac injury were at a higher risk of death, both during the time from symptom onset (hazard ratio, 4.26 [95% CI, 1.92-9.49]) and from admission to end point (hazard ratio, 3.41 [95% CI, 1.62-7.16]).

Conclusions And Relevance: Cardiac injury is a common condition among hospitalized patients with COVID-19 in Wuhan, China, and it is associated with higher risk of in-hospital mortality.
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http://dx.doi.org/10.1001/jamacardio.2020.0950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097841PMC
July 2020

The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism.

Front Physiol 2019 14;10:1346. Epub 2019 Nov 14.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Aim: Sigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress.

Methods And Results: Sprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats' hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-α, IL-6, and TGF-β), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group ( < 0.01 for all groups).

Conclusion: These findings show the effects of the σ1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation.
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http://dx.doi.org/10.3389/fphys.2019.01346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870537PMC
November 2019

Pinocembrin attenuates autonomic dysfunction and atrial fibrillation susceptibility via inhibition of the NF-κB/TNF-α pathway in a rat model of myocardial infarction.

Int Immunopharmacol 2019 Dec 5;77:105926. Epub 2019 Nov 5.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China. Electronic address:

Previous studies indicate that myocardial infarction (MI) may contribute to atrial fibrillation (AF). Emerging evidence has shown that pinocembrin protects myocardial ischemic injury (I/R)-induced cardiac fibrosis and arrhythmias in animals via its anti-inflammatory or antioxidant activities. However, the effects of pinocembrin on MI-induced atrial arrhythmias remain unknown. Thus, this study aimed to investigate the effects of pinocembrin on autonomic dysfunction and AF susceptibility in MI rats and the possible mechanism. In a standard experimental MI model, Sprague-Dawley rats received permanent ligation of the left anterior descending (LAD) coronary artery and were treated with pinocembrin or saline for 6 days. Our results demonstrated that pinocembrin treatment significantly decreased sympathetic activity, augmented parasympathetic activity, improved heart rate variability (HRV), prolonged the atrial effective refractory period (ERP) and action potential duration (APD), shortened activation latency (AL), lowered the indicibility rate of AF, attenuated atrial fibrosis, and decreased concentrations of norepinephrine (NE), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the serum and the left atrial (LA). Furthermore, pinocembrin treatment significantly increased the expression levels of Cx43 and Cav1.2 and suppressed the phosphorylation of inhibitor-κBα (IκBα) and the activation of nuclear factor-kappa B (NF-κB)subunit p65. In conclusion, the findings indicate that pinocembrin treatment decreases autonomic remodeling, lowers atrial fibrosis, ameliorates atrial electrical remodeling, and suppresses MI-induced inflammatory responses, which suggests a potential novel strategy for atrial arrhythmias.
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http://dx.doi.org/10.1016/j.intimp.2019.105926DOI Listing
December 2019

Different effects of norepinephrine and nerve growth factor on atrial fibrillation vulnerability.

J Cardiol 2019 Nov 15;74(5):460-465. Epub 2019 May 15.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China. Electronic address:

Background: The sympathetic nerve plays an important role in atrial fibrillation (AF) vulnerability. Norepinephrine (NE) has a relationship with AF and nerve growth factor (NGF) injection can induce sympathetic innervation. However, the mechanisms of NE and NGF on AF vulnerability remain unclear.

Methods: Four groups of rabbits were studied: the control group, the NGF group, the NE group, and the NGF+valsartan+metoprolol group. After receiving drugs for 15 days, induced AF was observed, and left atrium (LA) tissues were obtained. Immunocytochemical staining of cardiac nerves and ionic remodeling were performed using anti-growth-associated protein 43 (GAP43), anti-tyrosine hydroxylase (TH) antibodies, and patch clamp.

Results: The incidence of AF was significantly higher (p<0.01) in the NGF group and the NE group than in the control group and the NGF+valsartan+metoprolol group. The nerve densities for TH and GAP43-positive at the LA were significantly higher (p<0.01) after NGF, but the nerve densities decreased after NE. I was increased while instant outward K+ channel current (Ito) was decreased in the LA of rabbits after treatment with NGF and NE. Metoprolol and valsartan can reverse the I and Ito remodeling and the vulnerability to AF. However, these drugs did not inhibit the effect of NGF on sympathetic sprouting.

Conclusions: The effects of NE and NGF on AF vulnerability have a relationship with the ionic remodeling, while the sympathetic hyperinnervation did not have a strong association with the induction of AF.
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http://dx.doi.org/10.1016/j.jjcc.2019.04.009DOI Listing
November 2019

Cardiac resynchronization therapy improves myocardial conduction.

Pacing Clin Electrophysiol 2019 02 27;42(2):238-246. Epub 2018 Dec 27.

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.

Background: Cardiac resynchronization therapy (CRT) reverses left ventricular remodeling and improves left ventricular systolic function. However, little is known about whether CRT improves ventricular conduction.

Objective: To determine the relationship between CRT response and QRS narrowing.

Methods: The study included consecutive patients who underwent CRT with defibrillator (CRT-D) implantation between January 2002 and December 2012 and had subsequent generator replacement (GR). At the time of GR, super-responder was defined as those who had left ventricular ejection fraction (LVEF) of 50% or more; patients who had an LVEF of 36-49% with an increase of more than 5% were considered responders, and the others were nonresponders. All patients were assessed 6 months after CRT-D implantation and at the time of GR.

Results: Of 114 study patients, 58 (50.9%) were nonresponders, 29 (25.4%) responders, and 27 (23.7%) super-responders. QRS narrowing at 6 months was significant in super-responders (175.4 ± 21.4 to 159.7 ± 20.7 ms, P = 0.001) and responders (169.0 ± 21.3 to 157.7 ± 17.6 ms, P = 0.008). At time of GR, only super-responders had further QRS narrowing (159.7 ± 20.7 to 146.3 ± 19.2 ms, P < 0.001). QRS duration change after 6 months was independently associated with super-response (hazard ratio: 1.20 for every 5 ms QRS duration narrowing; 95% confidence interval, 1.06-1.38; P = 0.005), and QRS narrowing of 10 ms or more was associated with lower risk of all-cause mortality after GR.

Conclusion: Continuous QRS narrowing after CRT, as an electrical marker, is associated with a super-response to CRT. Further QRS narrowing 6 months after CRT implantation was associated with lower risk of mortality after GR.
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http://dx.doi.org/10.1111/pace.13581DOI Listing
February 2019

Chronic stimulation of the sigma-1 receptor ameliorates autonomic nerve dysfunction and atrial fibrillation susceptibility in a rat model of depression.

Am J Physiol Heart Circ Physiol 2018 12 14;315(6):H1521-H1531. Epub 2018 Sep 14.

Department of Cardiology, Renmin Hospital of Wuhan University , Wuhan , China.

The present study aimed to assess the effect of sigma-1 receptor (S1R) stimulation on autonomic nerve dysfunction and susceptibility to atrial fibrillation (AF) in a rat depression model. Male rats were randomly divided into one of the following four treatment groups: saline [control (CTL)]; saline + intragastric administration of SA4503, an agonist of S1R (CTS); chronic unpredictable mild stress (CUMS) to produce depression (MDD); and CUMS + intragastric administration of SA4503 (MDS). Depression-like behaviors, such as reduced sucrose preference, decreased body weight gain, and increased immobility time during forced swimming, improved in the MDS group after 4 wk of SA4503 treatment. Compared with rats in the CTL group, rats in the MDD group showed significantly augmented sympathetic activity, reduced parasympathetic activity, decreased heart rate variability, and lowered S1R expression in the atrium and hippocampus (all P < 0.01). However, rats in the MDS group showed mitigated aforementioned alterations and improved electrical remodeling compared with rats in the MDD group (all P < 0.01). Furthermore, rats in the MDS group showed shortened activation latencies, increased effective refractory periods, and lowered frequency of AF incidence duration and fibrosis compared with rats in the MDD group (all P < 0.01). The results indicate that S1R stimulation reduces sympathetic activity and susceptibility to AF by improving depressive behaviors, modulating cardiac autonomic nerve balance, lightening nerve remodeling, and upregulating S1R and ion channel protein expression. NEW & NOTEWORTHY Chronic stimulation of the sigma-1 receptor (S1R) ameliorates depression-induced autonomic nerve dysfunction by modulating the imbalance between overactivated sympathetic activity and decreased vagal activity. Chronic S1R stimulation alleviates atrial electrical remodeling, fibrosis, and susceptibility to atrial fibrillation (AF). The S1R agonist may target the underlying mechanisms related to AF occurrence. The results indicate that the S1R could be a potential clinical target for atrial arrhythmia, especially when it is combined with major depressive disorders.
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http://dx.doi.org/10.1152/ajpheart.00607.2017DOI Listing
December 2018

Outcomes of cardiac resynchronization therapy using left ventricular quadripolar leads.

Pacing Clin Electrophysiol 2018 May 25. Epub 2018 May 25.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Quadripolar left ventricular (LV) leads provide a more optimal pacing configuration for cardiac resynchronization therapy (CRT) than conventional bipolar leads. The objective of this study is to determine the clinical outcomes of CRT using quadripolar leads.

Methods: This study included 516 CRT patients who received bipolar LV leads (n = 278) or quadripolar LV leads (n = 238) from January 2013 to June 2016. Data were retrospectively collected from a prospective CRT database and electronic health records. CRT response to CRT was defined as >5% improvement in the LV ejection fraction (LVEF) from baseline. Baseline characteristics and outcomes were compared between groups.

Results: New York Heart Association Functional Classification and LVEF significantly improved in the quadripolar and bipolar groups after CRT. There was no difference in the all-cause mortality rate. The implant success rate was significantly higher in the quadripolar group (100% vs 97.8%; P = 0.02). Quadripolar lead placement was an independent predictor of CRT response at 12 months (hazard ratio, 0.76; 95% confidence interval, 0.58-0.98; P = 0.04). The rate of LV lead-related complications requiring invasive lead revision or abandonment was significantly higher in the bipolar group (11.2% vs 4.6%; P = 0.007).

Conclusions: Quadripolar leads achieve similar CRT outcomes as bipolar LV leads but with a higher implant success rate and fewer procedure-related complications.
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http://dx.doi.org/10.1111/pace.13388DOI Listing
May 2018

Spatiotemporal Risk of Bacillary Dysentery and Sensitivity to Meteorological Factors in Hunan Province, China.

Int J Environ Res Public Health 2017 12 29;15(1). Epub 2017 Dec 29.

Hunan Provincial Center for Disease Control and Prevention, Changsha 410005, China.

Bacillary dysentery remains a public health concern in the world. Hunan Province is one of the provinces having the highest risk of bacillary dysentery in China, however, the spatial-temporal distribution, variation of bacillary dysentery and sensitivity to meteorological factors in there are unclear. In this paper, a Bayesian space-time hierarchical model (BSTHM) was used to detect space-time variation, and effects of meteorological factors between 2010 and 2015. The risk of bacillary dysentery showed apparent spatial-temporal heterogeneity. The highest risk occurred in the summer season. Economically undeveloped mountainous areas in the west and south of the province had the highest incidence rates. Twenty three (18.9%) and 20 (16.4%) counties were identified as hot and cold spots, respectively. Among the hotspots, 11 counties (47.8%) exhibited a rapidly decreasing trend, suggesting they may become low-risk areas in the future. Of the cold spot counties, six (30%) showed a slowly decreasing trend, and may have a higher risk in the future. Among meteorological factors, air temperature, relative humidity, and wind speed all played a significant role in the spatial-temporal distribution of bacillary dysentery risk. These findings can contribute to the implementation of an early warning system for controlling and preventing bacillary dysentery.
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http://dx.doi.org/10.3390/ijerph15010047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800146PMC
December 2017

[Analysis of spatiotemporal patterns and influential factors for mushroom poisoning in Hunan Province in 2015].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2017 Sep;42(9):1080-1085

Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China.

Objective: To understand the spatial distribution of mushroom poisoning in Hunan Province and its influential factors, and to provide the evidence for control of the mushroom poisoning.
 Methods: The surveillance data for mushroom poisoning cases from 122 counties in Hunan Province in 2015 were collected. Based on geographical information system database, spatial autocorrelation analysis and spatial regression analysis (via OpenGeoDa) was conducted.
 Results: The incidence of mushroom poisoning in Hunan Province in 2015 was 2.94/100 000. Global Moran's I values was 0.315 (P<0.05). Local spatial autocorrelation analysis indicated that Ningxiang, Xiangtan, Shaoyang, Lingling, Jiahe, and Linwu districts et al were "positive hotspot" regions. Guzhang, Hecheng, Dingcheng, Yueyang districts et al were "negative hotspot" regions. Spatial regression analysis revealed that the reported incidence of mushroom poisoning was positively correlated with the annual average temperate (Z=2.145, P=0.032), the number of health care institutions per capita (Z=2.352, P=0.019), and the number of students enrollment in secondary schools (Z=4.309, P<0.001). It was negatively associated with the number of school staff and workers of secondary schools (Z=-2.626, P=0.009).
 Conclusion: The spatial distribution of mushroom poisoning cases in Hunan Province in 2015 is highly clustered. Mushroom poisoning cases are more prevalent in the middle and southern regions and less prevalent in the northern areas of the province. The annual average temperate and the number of students enrollment in secondary schools demonstrate a certain positive influence on the distribution of mushroom poisoning in Hunan.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2017.09.014DOI Listing
September 2017

Predictors and outcomes of cardiac resynchronization therapy extended to the second generator.

Heart Rhythm 2017 12 14;14(12):1793-1800. Epub 2017 Sep 14.

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: A proportion of patients who receive cardiac resynchronization therapy with defibrillator (CRT-D) live to receive a second generator. Controversy exists on whether an implantable cardioverter-defibrillator (ICD) should be offered to patients who have normalized or near-normalized left ventricular ejection fraction (LVEF) at the time of generator replacement (GR).

Objective: The purpose of this study was to evaluate incidence of appropriate ICD therapy after CRT-D GR.

Methods: This series involved 1026 consecutive patients who underwent CRT-D implant between January 1, 2002 and December 31, 2012. Echocardiography was assessed before the initial device implant and before GR. ICDs were monitored at our device clinic in person or remotely, or both.

Results: Of the cohort, 227 patients (22.1%) underwent CRT-D GR at our institution. Approximately 48% of the patients who received new CRT-D generators were no longer meeting the guidelines indication for ICD use at the time of GR. These patients received subsequent appropriate ICD therapies at a significantly lower rate than those with LVEF <35% (12% vs 35%; P < .001). Of these patients, 47 (20.7%) had LVEF improvement to ≥50% at the time of GR. ICD therapy for ventricular arrhythmia in the ischemic group was 18.2%, while no patient in the nonischemic group received ICD therapy from the second generator after GR.

Conclusion: Improvement in LVEF after CRT-D GR is associated with significantly reduced incidence of appropriate ICD therapy. Ventricular arrhythmia is less likely to develop with normalized LVEF in nonischemic cardiomyopathy.
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http://dx.doi.org/10.1016/j.hrthm.2017.09.002DOI Listing
December 2017

The activation of -methyl-d-aspartate receptors downregulates transient outward potassium and L-type calcium currents in rat models of depression.

Am J Physiol Cell Physiol 2017 Aug 31;313(2):C187-C196. Epub 2017 May 31.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China;

Major depression is an important clinical factor in ventricular arrhythmia. Patients diagnosed with major depression overexpress -methyl-d-aspartate receptors (NMDARs). Previous studies found that chronic NMDAR activation increases susceptibility to ventricular arrhythmias. We aimed to explore the mechanisms by which NMDAR activation may increase susceptibility to ventricular arrhythmias. Male rats were randomly assigned to either normal environments as control (CTL) group or 4 wk of chronic mild stress (CMS) to produce a major depression disorder (MDD) model group. After 4 wk of CMS, depression-like behaviors were measured in both groups. Varying doses (1-100 μM) of NMDA and 10 μM NMDA antagonist (MK-801) were perfused through ventricular myocytes isolated from MDD rats to measure the L-type calcium current () and transient outward potassium current (). Structural remodeling was assessed using serial histopathology including Masson's trichrome dye. Electrophysiological characteristics were evaluated using Langendorff perfusion. Depression-like behaviors were observed in MDD rats. MDD rats showed longer action potential durations at 90% repolarization and higher susceptibility to ventricular arrhythmias than CTL rats. MDD rats showed lower and current densities than CTL rats. Additionally, NMDA reduced both currents in a concentration-dependent manner, whereas there was no significant impact on the currents when perfused with MK-801. MDD rats exhibited significantly more fibrosis areas in heart tissue and reduced expression of Kv4.2, Kv4.3, and Cav1.2. We observed that acute NMDAR activation led to downregulation of potassium and L-type calcium currents in a rat model of depression, which may be the mechanism underlying ventricular arrhythmia promotion by depression.
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http://dx.doi.org/10.1152/ajpcell.00092.2017DOI Listing
August 2017

Is hybrid subcutaneous implantable cardioverter-defibrillator and leadless pacemaker the future of device therapy?

Int J Cardiol 2017 05;235:201

Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2017.02.132DOI Listing
May 2017

Depression and Risk of Sudden Cardiac Death and Arrhythmias: A Meta-Analysis.

Psychosom Med 2017 Feb/Mar;79(2):153-161

From the Department of Cardiology (Yang, Shi, Liu, Liang, Hu), Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China (Yang, Shi, Liu, Liang, Hu); Masonic Medical Research Laboratory (Hu), Utica, New York.

Objective: Depression is an independent risk factor for cardiac events and mortality in individuals with or without cardiovascular disease (CVD), although the underlying mechanisms involved in sudden cardiac death (SCD) and arrhythmias remain unclear. This meta-analysis aimed to assess the relationship between depression and risk of SCD and arrhythmias.

Methods: We systematically searched MEDLINE, Elsevier, and PsycINFO databases for articles (January 1990 to June 2015) describing the correlation of depression ("depressive symptoms," "depression," or "depressive disorder") with SCD or arrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF], or atrial fibrillation [AF]). Data were meta-analyzed with random-effects models.

Results: A total of 17 studies met the inclusion criteria: 4 of SCD (n = 83,659), 8 of VT/VF (n = 4,048), and 5 of AF (n = 31,247). The total sample consisted of 8,533 individuals with and 110,421 individuals without previous CVD. Depression was associated with increased risk of SCD (hazard risk [HR], 1.62; 95% confidence interval [CI], 1.37-1.92; p < .001), VT/VF (HR, 1.47; 95% CI, 1.23-1.76; p < .001) and AF recurrence (HR, 1.88; 95% CI, 1.54-2.30; p < .001). There was no significant association, however, between depression and risk of new-onset AF (HR, 0.96; 95% CI, 0.87-1.04; p = .311).

Conclusions: Depression (clinical depression and depressive symptoms) is associated with increased risk of SCD, VT/VF, and AF recurrence. These findings suggest that arrhythmias play an important role in the association between depression and increased mortality in individuals with or without CVD. Systematic evaluation and treatment of depression may contribute to the prevention of lethal cardiac events in the general population and in high-risk individuals with CVD.
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http://dx.doi.org/10.1097/PSY.0000000000000382DOI Listing
July 2017

Five Complete Chloroplast Genome Sequences from Diospyros: Genome Organization and Comparative Analysis.

PLoS One 2016 21;11(7):e0159566. Epub 2016 Jul 21.

Key Laboratory of Cultivation and Protection for Non-Wood Forest Trees, Ministry of Education, Central South University of Forestry and Technology, Changsha, Hunan, China.

Diospyros is the largest genus in Ebenaceae, comprising more than 500 species with remarkable economic value, especially Diospyros kaki Thunb., which has traditionally been an important food resource in China, Korea, and Japan. Complete chloroplast (cp) genomes from D. kaki, D. lotus L., D. oleifera Cheng., D. glaucifolia Metc., and Diospyros 'Jinzaoshi' were sequenced using Illumina sequencing technology. This is the first cp genome reported in Ebenaceae. The cp genome sequences of Diospyros ranged from 157,300 to 157,784 bp in length, presenting a typical quadripartite structure with two inverted repeats each separated by one large and one small single-copy region. For each cp genome, 134 genes were annotated, including 80 protein-coding, 31 tRNA, and 4 rRNA unique genes. In all, 179 repeats and 283 single sequence repeats were identified. Four hypervariable regions, namely, intergenic region of trnQ_rps16, trnV_ndhC, and psbD_trnT, and intron of ndhA, were identified in the Diospyros genomes. Phylogenetic analyses based on the whole cp genome, protein-coding, and intergenic and intron sequences indicated that D. oleifera is closely related to D. kaki and could be used as a model plant for future research on D. kaki; to our knowledge, this is proposed for the first time. Further, these analyses together with two large deletions (301 and 140 bp) in the cp genome of D. 'Jinzaoshi', support its placement as a new species in Diospyros. Both maximum parsimony and likelihood analyses for 19 taxa indicated the basal position of Ericales in asterids and suggested that Ebenaceae is monophyletic in Ericales.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956199PMC
July 2017

Activation of N-methyl-d-aspartate receptors reduces heart rate variability and facilitates atrial fibrillation in rats.

Europace 2017 Jul;19(7):1237-1243

Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, China.

Aims: The goal of this study was to assess the effects of N-methyl-d-aspartate (NMDA) receptors activation on heart rate variability (HRV) and susceptibility to atrial fibrillation (AF).

Methods And Results: Rats were randomized for treatment with saline, NMDA (agonist of NMDA receptors), or NMDA plus MK-801 (antagonist of NMDA receptors) for 2 weeks. Heart rate variability was evaluated by using implantable electrocardiogram telemeters. Atrial fibrillation susceptibility was assessed with programmed stimulation in isolated hearts. Compared with the controls, the NMDA-treated rats displayed a decrease in the standard deviation of normal RR intervals, the standard deviation of the average RR intervals, the mean of the 5-min standard deviations of RR intervals, the root mean square of successive differences, and high frequency (HF); and an increase in low frequency (LF) and LF/HF (all P< 0.01). Additionally, the NMDA-treated rats showed prolonged activation latency and reduced effective refractory period (all P< 0.01). Importantly, AF was induced in all NMDA-treated rats. While atrial fibrosis developed, connexin40 downgraded and metalloproteinase 9 upgraded in the NMDA-treated rats (all P< 0.01). Most of the above alterations were mitigated by co-administering with MK-801.

Conclusion: These results indicate that NMDA receptors activation reduces HRV and enhances AF inducibility, with cardiac autonomic imbalance, atrial fibrosis, and degradation of gap junction protein identified as potential mechanistic contributors.
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http://dx.doi.org/10.1093/europace/euw086DOI Listing
July 2017

Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study.

Neurology 2016 Mar 10;86(10):920-30. Epub 2016 Feb 10.

From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).

Objective: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563).

Methods: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg.

Results: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48).

Conclusions: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide.

Classification Of Evidence: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.
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http://dx.doi.org/10.1212/WNL.0000000000002441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782117PMC
March 2016

Genetic variants of potassium voltage-gated channel genes (KCNQ1, KCNH2, and KCNE1) affected the risk of atrial fibrillation in elderly patients.

Genet Test Mol Biomarkers 2015 Jul 11;19(7):359-65. Epub 2015 Jun 11.

3 Department of Cardiology, Renmin Hospital of Wuhan University , Wuhan, China .

Background: Atrial fibrillation (AF) is a common type of cardiac arrhythmia and is a major healthcare burden. Around 20% of patients show no obvious clinical manifestations; this can lead to a delay of AF diagnosis and prevention. Genetic mutations are one of the important risk factors for AF. This study aimed to assess the associations between polymorphisms on KCNE1, KCNQ1, and KCNH2 with the risk of AF in a Chinese population.

Materials And Methods: A case-control study comprised of 438 AF patients and 450 controls. The tag single-nucleotide polymorphisms (SNPs) were retrieved in the International HapMap database and Haploview software was used to capture all the polymorphisms on KCNE1, KCNQ1, and KCNH2. DNA was extracted from blood and polymerase chain reaction-based assays were used to genotype polymorphisms of the KCNE1, KCNQ1, and KCNH2 genes. Chi-square test and student t-tests were used to evaluate the differences in the clinical characteristics between AF cases and controls. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association between genetic variants of KCNQ1, KCNH2, KCNE1, and AF risk.

Results: Among the nine tag SNPs, three were significantly associated with the risk of AF: the rs1805127*G allele on KCNE1, and the rs2283228*C and rs1057128*A alleles on KCNQ1. In contrast, rs1805120*T variant was correlated with lower risk of AF. However, the other five genetic variants (rs2237892, rs2237895, rs2237897, rs2070357, and rs2070356) showed no significant association with AF risk (all p>0.05).

Conclusions: Our study suggested that the rs1805127*G allele of KCNE1, and the rs2283228*C and rs1057128*A alleles on KCNQ1 are risk factors for AF, while the rs1805120*T allele on KCNH2 may serve as a protective factor for AF.
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http://dx.doi.org/10.1089/gtmb.2014.0307DOI Listing
July 2015

Effect and mechanism of fluoxetine on electrophysiology in vivo in a rat model of postmyocardial infarction depression.

Drug Des Devel Ther 2015 10;9:763-72. Epub 2015 Feb 10.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China ; Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China.

Background: Major depression is diagnosed in 18% of patients following myocardial infarction (MI), and the antidepressant fluoxetine is shown to effectively decrease depressive symptoms and improve coronary heart disease prognosis. We observed the effect of fluoxetine on cardiac electrophysiology in vivo in a rat model of post-MI depression and the potential mechanism.

Methods And Results: Eighty adult male Sprague Dawley rats (200-250 g) were randomly assigned to five groups: normal control (control group), MI (MI group), depression (depression group), post-MI depression (model group), and post-MI depression treated with intragastric administration of 10 mg/kg fluoxetine (fluoxetine group). MI was induced by left anterior descending coronary artery ligation. Depression was developed by 4-week chronic mild stress (CMS). Behavior measurement was done before and during the experiment. Electrophysiology study in vivo and Western blot analysis were carried on after 4 weeks of CMS. After 4 weeks of CMS, depression-like behaviors were observed in the MI, depression, and model groups, and chronic fluoxetine administration could significantly improve those behaviors (P<0.05 vs model group). Fluoxetine significantly increased the ventricular fibrillation threshold compared with the model group (20.20±9.32 V vs 14.67±1.85 V, P<0.05). Expression of Kv4.2 was significantly reduced by 29%±12%, 24%±6%, and 41%±15%, respectively, in the MI group, CMS group, and model group, which could be improved by fluoxetine (30%±9%). But fluoxetine showed no improvement on the MI-induced loss of Cx43.

Conclusion: The susceptibility to ventricular arrhythmias was increased in depression and post-MI depression rats, and fluoxetine may reduce the incidence of ventricular arrhythmia in post-MI depression rats and thus improve the prognosis. This may be related in part to the upregulation of Kv4.2 by fluoxetine.
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http://dx.doi.org/10.2147/DDDT.S75863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330040PMC
May 2016

Depression increases sympathetic activity and exacerbates myocardial remodeling after myocardial infarction: evidence from an animal experiment.

PLoS One 2014 18;9(7):e101734. Epub 2014 Jul 18.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.

Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101734PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103791PMC
March 2015
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