Publications by authors named "Congxin Huang"

168 Publications

A narrative review of non-coding RNAs in atrial fibrillation: potential therapeutic targets and molecular mechanisms.

Ann Transl Med 2021 Sep;9(18):1486

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

Objective: This review summarizes the advances in the study of ncRNAs and atrial remodeling mechanisms to explore potential therapeutic targets and strategies for AF.

Background: Atrial fibrillation (AF) is one of the most common arrhythmias, and its morbidity and mortality rates are gradually increasing. Non-coding ribonucleic acid RNAs (ncRNAs) are transcribed from the genome and do not have the ability to be translated into proteins. A growing body of evidence has shown ncRNAs are extensively involved in the pathophysiological processes underlying AF. However, the precise molecular mechanisms of these associations have not been fully elucidated. Atrial remodeling plays a key role in the occurrence and development of AF, and includes electrical remodeling, structural remodeling, and autonomic nerve remodeling. Research has shown that ncRNA expression is altered in the plasma and tissues of AF patients that mediate cardiac excitation and arrhythmia, and is closely related to atrial remodeling.

Methods: Literatures about ncRNAs and atrial fibrillation were extensively reviewed to discuss and analyze.

Conclusions: The biology of ncRNAs represents a relatively new field of research and is still in an emerging stage. Recent studies have laid a foundation for understanding the molecular mechanisms of AF, future studies aimed at identifying how ncRNAs act on atrial fibrillation to provide potentially promising therapeutic targets for the treatment of atrial fibrillation.
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http://dx.doi.org/10.21037/atm-21-4483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506732PMC
September 2021

Beware of the hazards: limitations of the proportional hazards assumption-Authors' reply.

Europace 2021 Sep 4. Epub 2021 Sep 4.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan university, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China.

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http://dx.doi.org/10.1093/europace/euab138DOI Listing
September 2021

Improvement in hard outcomes following catheter ablation for atrial fibrillation: the debate is far from over-Authors' reply.

Europace 2021 Sep 3. Epub 2021 Sep 3.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan university, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China.

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http://dx.doi.org/10.1093/europace/euab224DOI Listing
September 2021

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

J Appl Physiol (1985) 2021 09 8;131(3):966-976. Epub 2021 Jul 8.

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

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 patients with cancer. However, cardiac outcomes of cancer patients with COVID-19 have not been closely examined. We retrospectively assessed 1,244 patients with COVID-19 from February 1 to August 31, 2020 (140 cancer and 1,104 noncancer patients). Demographic and clinical data were obtained and compared between cancer and noncancer 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. For cancer group, 56% were in severe and critical status with more diabetes and immune deficiency, whereas the proportion was 10% for noncancer group. Patients with cancer had increased levels of leukocyte, neutrophil count, and blood urea nitrogen (BUN) (all < 0.01), whereas lymphocyte count was significantly lower ( < 0.001). The most common solid tumor types were gastrointestinal cancer (26%), lung cancer (21%), and breast and reproductive cancer (both 19%). There is a rising for cardiac biomarkers, including pro-B-type natriuretic peptide (Pro-BNP), sensitive troponin I (cTnI), myoglobin (MYO), creatine kinase-MB (CK-MB), as well as D-Dimer in COVID-19 cancer population, especially in deceased subjects with cancer. The 30-day in-hospital mortality in cancer group was dramatically raised than that in noncancer group (12.9% vs. 4.0%, < 0.01). In multivariable Cox regression models, fever, disease severity status, and underlying diseases were risk factors for mortality. 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. Our study indicates that the 30-day mortality is higher in COVID-19 patients with cancer; more COVID-19 patients with cancer are in severe and critical status; age, respiratory rate, neutrophil count, AST, BUN, MYO, Pro-BNP, disease severity status, underlying diseases, and fever are risk factors for in-hospital mortality among COVID-19 cancer cases; COVID-19 patients with cancer display severely impaired myocardium, damaged heart function, and imbalanced homeostasis of coagulation; what is more, those with both cancer and CVD have more significantly increased Pro-BNP and D-Dimer level.
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http://dx.doi.org/10.1152/japplphysiol.00325.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422422PMC
September 2021

Resiniferatoxin reduces cardiac sympathetic nerve activation to exert a cardioprotective effect during myocardial infarction.

Int J Clin Exp Pathol 2021 15;14(4):408-416. Epub 2021 Apr 15.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology Wuhan 430000, People's Republic of China.

Background And Objective: Myocardial infarction (MI) is a common critical disease of the cardiovascular system. The process of MI is often accompanied by the excessive activation of cardiac sympathetic nerves, which leads to arrhythmia. Resiniferatoxin (RTX) is a transient receptor potential vanilloid 1 (TRPV1), involved in the cardiac sympathetic afferent reflex. However, whether RTX can reduce the occurrence of arrhythmia and exert a cardioprotective effect by inhibiting the sympathetic reflex during MI is still unknown.

Methods: The left anterior descending artery of cardiac was clamped to construct a model of MI. RTX (50 μg/ml) was used by epicardial application in MI rats. Ventricular electrophysiologic properties were continuously monitored by a body surface ECG. Yrosine hydroxylase (TH) and growth associated protein 43 (GAP43) were detected by Immunofluorescence staining. Connexin43 and transforming growth factor beta receptor 1 (TGF-β1) were detected by western blot. Norepinephrine (NE) and BNP levels in blood and tissue were determined by ELISA. Cardiac function was assessed by echocardiography.

Results: The ERP, APD90, QRS, QT and the Tend-Tpeak intervals in MI rats were all prolonged, but decreased after RTX treatment ( = 3, <0.05). In contrast, the RR interval was shortened in the MI group, but prolonged in the MI+RTX group ( = 3, <0.05). RTX treatment significantly reduced ventricular arrhythmias after MI. TH- and GAP43-positive nerve densities and TGF-β1, and cx-43 protein expression were up-regulated in the MI group compared to the sham group, and they were decreased in the MI+RTX group compared to the MI group ( = 3, <0.05). RTX can decrease serum and tissue NE and BNP levels ( = 3, <0.05). RTX pretreatment significantly decreased heart rate, HW/BW ratio and LVIDS, and increased LVEF andLVFS values ( = 3, <0.05).

Conclusion: RTX improved cardiac dysfunction, ventricular electrophysiologic properties, and sympathetic nerve remodeling in rats with MI by inhibiting the excessive cardiac sympathetic drive.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085824PMC
April 2021

Long-term observation of catheter ablation vs. pharmacotherapy in the management of persistent and long-standing persistent atrial fibrillation (CAPA study).

Europace 2021 05;23(5):731-739

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan university, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China.

Aims: The roles of radiofrequency catheter ablation (RFCA) and pharmacotherapy in treating persistent and long-standing persistent atrial fibrillation (AF) have not been sufficiently investigated. We conducted a multicentre, randomized, controlled trial to compare the effects of RFCA and pharmacotherapy on the prognosis of these patients.

Methods And Results: A total of 648 patients with persistent and long-standing persistent AF were enrolled from 30 centres and randomized to either the ablation group (n = 327) or the pharmacotherapy group (n = 321). After 54.2 ± 10.6 months of follow-up, the primary endpoints occurred significantly more rarely in the ablation group than in the pharmacotherapy group (10.4% vs. 17.4%; hazard ratio 0.59, 95% confidence interval 0.48-0.75; P < 0.001). The incidence of stroke/transient ischaemic attack (TIA) was significantly lower in the ablation group (4.2% vs. 7.2%, P < 0.001). Likewise, the incidence of new-onset congestive heart failure (CHF) was lower in the ablation group (2.8% vs. 7.2%, P < 0.001). More patients had sinus rhythm in the ablation group than in the pharmacotherapy group (60.6% vs. 20.9%, P < 0.001), but fewer patients were on antiarrhythmic drugs (24.4% vs. 41.6%, P < 0.001) and warfarin (60.8% vs. 83.9%, P = 0.001). Both the 6-min walk distance and the quality of life (QoL) were improved in the ablation group at the end of follow-up.

Conclusion: In patients with persistent and long-standing persistent AF, RFCA-based treatment was superior to pharmacotherapy in decreasing stroke/TIA and new-onset CHF and improving QoL.
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http://dx.doi.org/10.1093/europace/euaa356DOI Listing
May 2021

Incidence, risk factors, and clinical impact of peridevice leak following left atrial appendage closure with the LAmbre device-Data from a prospective multicenter clinical study.

J Cardiovasc Electrophysiol 2021 02 7;32(2):354-359. Epub 2020 Dec 7.

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

Background: In the present study, we sought to explore the incidence, risk factors, and clinical impact of peridevice leaks (PDLs), following LAmbre-assisted left atrial appendage closure (LAAC).

Methods: We performed transesophageal echocardiography (TEE) on patients participating in the LAmbre multicenter study, at Day 1 postimplantation, then at 3 and 12 months to assess PDL, device-related thrombus, left atrial appendage (LAA) thrombus, and left atrial thrombus. Clinical events were recorded during follow-up.

Result: A total of 152 patients with atrial fibrillation successfully completed LAAC. At 3 months follow-up, 123 patients underwent TEE, with 21 (17%) of them presenting PDL. Among the 121 patients who underwent TEE at 12 months follow-up, 19 (15.7%) presented PDL. Patients with PDL exhibited larger LAA orifice diameters and larger device sizes compared to those in the no leak group. In addition, we found no significant differences in thromboembolic events between patients in the PDL and no leak groups.

Conclusion: LAmbre-assisted LAA closure resulted in a relatively low PDL occurrence, and its rate decreased over time. In addition, PDL was more prominent in patients with larger LAA orifice diameter and larger device size. However, the condition was not associated with an increased risk for thromboembolic events.
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http://dx.doi.org/10.1111/jce.14824DOI Listing
February 2021

Optical capture and defibrillation in rats with monocrotaline-induced myocardial fibrosis 1 year after a single intravenous injection of adeno-associated virus channelrhodopsin-2.

Heart Rhythm 2021 01 8;18(1):109-117. Epub 2020 Aug 8.

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; Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China. Electronic address:

Background: Optogenetics uses light to regulate cardiac rhythms and terminate malignant arrhythmias.

Objective: The purpose of this study was to investigate the long-term validity of optical capture properties based on virus-transfected channelrhodopsin-2 (ChR2) and evaluate the effects of optogenetic-based defibrillation in an in vivo rat model of myocardial fibrosis enhanced by monocrotaline (MCT).

Methods: Fifteen infant rats received jugular vein injection of adeno-associated virus (AAV). After 8 weeks, 5 rats were randomly selected to verify the effectiveness ChR2 transfection. The remaining rats were administered MCT at 11 months. Four weeks after MCT, the availability of 473-nm blue light to capture heart rhythm in these rats was verified again. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were induced by burst stimulation on the basis of enhanced myocardial fibrosis, and the termination effects of the optical manipulation were tested.

Results: Eight weeks after AAV injection, there was ChR2 expression throughout the ventricular myocardium as reflected by both fluorescence imaging and optical pacing. Four weeks after MCT, significant myocardial fibrosis was achieved. Light could still trigger the corresponding ectopic heart rhythm, and the pulse width and illumination area could affect the light capture rate. VT/VF was induced successfully in 1-year-observation rats, and the rate of termination of VT/VF under light was much higher than that of spontaneous termination.

Conclusion: Viral ChR2 transfection can play a long-term role in the rat heart, and light can successfully regulate heart rhythm and defibrillate after cardiac fibrosis.
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http://dx.doi.org/10.1016/j.hrthm.2020.08.002DOI Listing
January 2021

Overexpression of TBX3 in human induced pluripotent stem cells (hiPSCs) increases their differentiation into cardiac pacemaker-like cells.

Biomed Pharmacother 2020 Oct 6;130:110612. Epub 2020 Aug 6.

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:

Backgroud: The TBX3(T-box 3)transcription factor is considered as an essential factor in sinoatrial node formation. While the effect of TBX3 in the differentiation of sinoatrial node cells from embryonic stem cells(ESCs) has been recognized, its role in human induced pluripotent stem cell derived cardiomyocytes(hiPSCMs) has not been addressed. Therefore, the purpose of the present study was to investigate whether overexpression of TBX3 in hiPSCs could increase their differentiation into pacemaker-like cells.

Methods: The hiPSCs were transfected with TBX3 gene during differentiation into cardiomyocytes(CMs). The hiPSCMs were analyzed using immunofluorescence, RT-qPCR, flow cytometry, whole-cell patch clamp recording to identify the differentiation effect exerted by TBX3. We discovered that hiPSCs transfected with TBX3 showed more proportions of NKX2.5-cTNT + sinoatrial node cells and faster contracting rates.

Results: The results showed increment in transcription factor TBX18, SHOX2; hyperpolarization-activated cyclic nucleotide (HCN) channel: HCN1, HCN2, HCN4, connexin 45(CX45), Na + Ca2+ exchanger(NCX) in TBX3 transfected hiPSCMs. Sinoatrial node cell specific If current and action potential were also confirmed by patch clamp in TBX3 transfected hiPSCMs and the pacemaker-like cells were able to pace hiPSCMs ex vivo.

Conclusion: In conclusion, the present study demonstrated that overexpression of TBX3 could increase the differentiation of hiPSCs into pacemaker-like cells. Our study provide new strategy to construct a biological pacemaker, however, further study is still needed to identify the efficacy and safety of using the pacemaker-like cells to produce biological pacemaker in vivo.
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http://dx.doi.org/10.1016/j.biopha.2020.110612DOI Listing
October 2020

β-adrenergic activation may promote myosin light chain kinase degradation through calpain in pressure overload-induced cardiac hypertrophy: β-adrenergic activation results in MLCK degradation.

Biomed Pharmacother 2020 Sep 4;129:110438. Epub 2020 Jul 4.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China; Department of Cardiology, Ezhou Hospital, Renmin Hospital of Wuhan University, Ezhou, 436000, China. Electronic address:

Background: β-adrenergic activation is able to exacerbate cardiac hypertrophy. Myosin light chain kinase (MLCK) and its phosphorylated substrate, phospho-myosin light chain 2 (p-MLC2), play vital roles in regulating cardiac hypertrophy. However, it is not yet clear whether there is a relationship between β-adrenergic activation and MLCK in the progression of cardiac hypertrophy. Therefore, we explored this relationship and the underlying mechanisms in this work.

Methods: Cardiac hypertrophy and cardiomyocyte hypertrophy were induced by pressure overload and isoproterenol (ISO) stimulation, respectively. Echocardiography, histological analysis, immunofluorescence and qRT-PCR were used to confirm the successful establishment of the models. A β-blocker (metoprolol) and a calpain inhibitor (calpeptin) were administered to inhibit β-adrenergic activity in rats and calpain in cardiomyocytes, respectively. The protein expression levels of MLCK, myosin light chain 2 (MLC2), p-MLC2, myosin phosphatase 2 (MYPT2), calmodulin (CaM) and calpain were measured using western blotting. A cleavage assay was performed to assess the degradation of recombinant human MLCK by recombinant human calpain.

Results: The β-blocker alleviated cardiac hypertrophy and dysfunction, increased MLCK and MLC2 phosphorylation and decreased calpain expression in pressure overload-induced cardiac hypertrophy. Additionally, the calpain inhibitor calpeptin attenuated cardiomyocyte hypertrophy, upregulated MLCK and p-MLC2 and reduced MLCK degradation in ISO-induced cardiomyocyte hypertrophy. Recombinant human calpain degraded recombinant human MLCK in vitro in concentration- and time-dependent manners, and this degradation was inhibited by the calpain inhibitor calpeptin.

Conclusion: Our study suggested that β-adrenergic activation may promote the degradation of MLCK through calpain in pressure overload-induced cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.biopha.2020.110438DOI Listing
September 2020

Edaravone attenuates myocyte apoptosis through the JAK2/STAT3 pathway in acute myocardial infarction.

Free Radic Res 2020 May 16;54(5):351-359. Epub 2020 Jun 16.

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

Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the JAK2/STAT3 signaling pathway. AMI in rats was established by left anterior descending coronary artery ligation. Two hours after AMI model established rats were treated with edaravone, edaravone plus AG490, physiological saline, respectively. We detected antioxidant effects by reduced glutathione (GSH), glutathione S-transferase (GST), and Glutathione Peroxidase (GSHPx) Activity. The expressions of t-JAK2, p-JAK2, t-STAT3, p-STAT3 and cleaved caspase-3 were examined by western blot. The mRNA levels for Bcl-2, Bax, Fas, and FasL were measured by RT-PCR and apoptosis was assessed by TUNEL. Edaravone significantly improved hemodynamics after AMI ( < 0.05) and reduced the total infarct volumes ( < 0.05). Compared with Sham rats, the mRNA of Bax, Fas, and FasL increased in different degrees in the AMI group, however, the mRNA of Bcl-2 and the ratio of Bcl-2/Bax decreased, especially the myocardial apoptosis index significantly increased in AMI hearts (all  < 0.05). After treatment with edaravone, the mRNA levels of Bcl-2 and the ratio of Bcl-2/Bax significantly upregulated whereas Bax, Fas, FasL apparently decreased, and the protein expressions of p-JAK2 and p-STAT3 dramatically increased ( < 0.05). In addition, cotreatment with JAK2 inhibitor AG490 abolished the effects of edaravone. We conclude that edaravone attenuated myocardial apoptosis induced by AMI JAK2/STAT3 signaling pathway.
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http://dx.doi.org/10.1080/10715762.2020.1772469DOI Listing
May 2020

Effect of Ginkgo biloba extract on pacemaker channels encoded by HCN gene.

Herz 2021 Jun 20;46(3):255-261. Epub 2020 May 20.

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

Background: In the present study, the electropharmacological activity of traditional Chinese medicine, Ginkgo biloba extract (GBE), on human hyperpolarization-activated nucleotide-gated (HCN) channels and the underlying "funny" currents was investigated.

Methods: Standard two-electrode voltage-clamp recordings were employed to examine the properties of cloned HCN subunit currents expressed in Xenopus oocytes under controlled conditions and GBE administration.

Results: We found that GBE irreversibly inhibited the HCN2 and HCN4 channel currents in a concentration-dependent fashion and that the HCN4 current was more sensitive to GBE compared with HCN2. In addition, GBE inhibition of the current amplitudes of HCN2 and HCN4 currents was accompanied by a decrease in the activation and deactivation kinetics.

Conclusion: The results of this study contribute toward illustrating the antiarrhythmic mechanism of GBE, which might be useful for the treatment of arrhythmia.
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http://dx.doi.org/10.1007/s00059-020-04933-zDOI Listing
June 2021

SK4 calcium-activated potassium channels activated by sympathetic nerves enhances atrial fibrillation vulnerability in a canine model of acute stroke.

Heliyon 2020 May 7;6(5):e03928. Epub 2020 May 7.

Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan City, 430060, PR China.

Background: New-onset atrial fibrillation (AF) is common in patients with acute stroke (AS). Studies have shown that intermediate-conductance calcium-activated potassium channel channels (SK4) play an important role in cardiomyocyte automaticity. The aim of this study was to investigate the effects of SK4 on AF vulnerability in dogs with AS.

Experimental: Eighteen dogs were randomly divided into a control group, AS group and left stellate ganglion ablation (LSGA) group. In the control group, dogs received craniotomy without right middle cerebral artery occlusion (MCAO). AS dogs were established using a cerebral ischemic model with right MCAO. LSGA dogs underwent MCAO, and LSGA was performed.

Results: Three days later, the dispersion of the effective refractory period (dERP) and AF vulnerability in the AS group were significantly increased compared with those in the control group and LSGA group. However, no significant difference in dERP and AF vulnerability was found between the control group and the LSGA group. The SK4 inhibitor (TRAM-34) completely inhibited the inducibility of AF in AS dogs. SK4 expression and levels of noradrenaline (NE), β1-AR, p38 and c-Fos in the atrium were higher in the AS dogs than in the control group or LSGA group. However, no significant difference in SK4 expression or levels of NE, β1-AR, p38 and c-Fos in the left atrium was observed between the control group and LSGA group.

Conclusion: SK4 plays a key role in AF vulnerability in a canine model with AS. The effects of LSGA on AF vulnerability were associated with the p38 signaling pathways.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215192PMC
May 2020

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019.

Eur Heart J 2020 06;41(22):2070-2079

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.

Aims: To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19).

Methods And Results: We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years. Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors. Risk factors of death and myocardial injury were analysed using multivariable regression models. A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs. 9.7%; P < 0.001) than survivors. The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001]. The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively. In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury.

Conclusion: The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.
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http://dx.doi.org/10.1093/eurheartj/ehaa408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239100PMC
June 2020

MicroRNA‑24 attenuates diabetic vascular remodeling by suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway.

Int J Mol Med 2020 May 9;45(5):1534-1542. Epub 2020 Mar 9.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

Vascular remodeling plays an important role in the pathogenesis of diabetic cardiovascular complications. Previous published research has indicated that microRNA‑24 (miR‑24) is involved in diabetic vascular remodeling, but the underlying molecular mechanisms have yet to be fully elucidated. The aim of the present study was to investigate whether adenovirus‑mediated miR‑24 overexpression can suppress the NOD‑like receptor family pyrin domain‑containing 3 (NLRP3)‑related inflammatory signaling pathway and attenuate diabetic vascular remodeling. The carotid arteries of diabetic rats were harvested and prepared for analysis. Reverse transcription‑quantitative PCR and western blotting assays were used to detect the expressions of related mRNAs and proteins. Morphological examinations, including hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, were also performed. The results of the present study demonstrated that miR‑24 upregulation suppressed neointimal hyperplasia and accelerated reendothelialization in the injured arteries, lowered the expression of NLRP3, apoptosis‑associated speck‑like protein, caspase‑1, proliferating cell nuclear antigen, CD45, interleukin (IL)‑1β, IL‑18 and tumor necrosis factor‑α, and increased the expression of CD31, smooth muscle (SM) α‑actin and SM‑myosin heavy chain. These data indicated that miR‑24 overexpression can attenuate vascular remodeling in a diabetic rat model through suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway.
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http://dx.doi.org/10.3892/ijmm.2020.4533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138286PMC
May 2020

C1q/Tumor Necrosis Factor-Related Protein-9 Attenuates Diabetic Nephropathy and Kidney Fibrosis in db/db Mice.

DNA Cell Biol 2020 Jun 13;39(6):938-948. Epub 2020 Apr 13.

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

Diabetic nephropathy (DN) is characterized by excessive accumulation of extracellular matrix leading to early thickening of glomerular and tubular basement membrane. C1q/tumor necrosis factor (TNF)-related protein-9 (CTRP9) was recently identified as an adiponectin paralog of superior prominence. CTRP9 is an anti-inflammatory, antioxidant, vasodilation and atheroprotective adipose cytokine that share a similar metabolic regulatory function as adiponectin. Additionally, CTRP9 inhibits apoptosis of endothelial cells, decreases blood glucose level, and increases insulin sensitivity. However, the renoprotective effects of CTRP9 and the underlying molecular mechanisms in DN have not been explored. This study examined the effects of CTRP9 on DN in diabetic db/db mice through adenovirus-mediated overexpression. From the results, CTRP9 ameliorated renal dysfunction and injury at the structural and functional level in diabetic db/db mice. Additionally, CTRP9 inhibited glomerular and tubular glycogen accumulation, fibrosis, relieved hyperglycemia-mediated oxidative stress, and apoptosis. This is the first study to report on therapeutic effects of CTRP9 on DN, presenting a potentially effective clinical treatment method for DN patients.
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http://dx.doi.org/10.1089/dna.2019.5302DOI Listing
June 2020

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation-remodeled hearts.

JCI Insight 2020 04 7;5(8). Epub 2020 Apr 7.

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.

Atrial fibrillation (AF) alters atrial cardiomyocyte (ACM) Ca2+ handling, promoting ectopic beat formation. We examined the effects of AF-associated remodeling on Ca2+-related action potential dynamics and consequences for AF susceptibility. AF was maintained electrically in dogs by right atrial (RA) tachypacing. ACMs isolated from AF dogs showed increased Ca2+ release refractoriness, spontaneous Ca2+ spark frequency, and cycle length (CL) threshold for Ca2+ and action potential duration (APD) alternans versus controls. AF increased the in situ CL threshold for Ca2+/APD alternans and spatial dispersion in Ca2+ release recovery kinetics, leading to spatially discordant alternans associated with reentrant rotor formation and susceptibility to AF induction/maintenance. The clinically available agent dantrolene reduced Ca2+ leak and CL threshold for Ca2+/APD alternans in ACMs and AF dog right atrium, while suppressing AF susceptibility; caffeine increased Ca2+ leak and CL threshold for Ca2+/APD alternans in control dog ACMs and RA tissues. In vivo, the atrial repolarization alternans CL threshold was increased in AF versus control, as was AF vulnerability. Intravenous dantrolene restored repolarization alternans threshold and reduced AF vulnerability. Immunoblots showed reduced expression of total and phosphorylated ryanodine receptors and calsequestrin in AF and unchanged phospholamban/SERCA expression. Thus, along with promoting spontaneous ectopy, AF-induced Ca2+ handling abnormalities favor AF by enhancing vulnerability to repolarization alternans, promoting initiation and maintenance of reentrant activity; dantrolene provides a lead molecule to target this mechanism.
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http://dx.doi.org/10.1172/jci.insight.133754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205430PMC
April 2020

Role of intermediate-conductance calcium-activated potassium channels in atrial fibrillation in canines with rapid atrial pacing.

J Interv Card Electrophysiol 2021 Mar 4;60(2):247-253. Epub 2020 Apr 4.

Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, People's Republic of China.

Purpose: The aim of the present study was to explore the role of intermediate-conductance Ca-activated K (SK4) in atrial fibrillation (AF) inducibility in canines with rapid atrial pacing.

Methods: Eighteen dogs were divided into the control group, the pacing group and the stellate ganglion ablation (SGA) + pacing group. In the pacing group, dogs were subjected to rapid atrial pacing, and the atrial effective refractory period (AERP) and AF inducibility were measured. After cessation of 7-h pacing, SK4 inhibitor (TRAM-34) was administered. After SGA, the SGA + pacing group received the same procedure of pacing and electrophysiological measurement as the pacing group. The expression of SK4 was measured in the left atrium (LA) and the right atrium (RA) in the three groups.

Results: The duration of the AERP decreased, while the number of AF episodes, the duration of induced AF, and the amplitude of stellate ganglion neural activity all increased after rapid atrial pacing. TRAM-34 completely inhibited AF induction in the pacing group. There was no significant difference in AERP shortening or AF vulnerability between the SGA + pacing group and the control group. The expression of SK4 in the LA and RA was higher in the pacing group than in the control and SGA + pacing groups. However, there was no significant difference in the expression of SK4 in the LA or the RA between the SGA + pacing group and the control group.

Conclusion: The higher expression of SK4 plays an important role in AF induction and the increased expression of SK4 in the atrium is related to SG activity during rapid atrial pacing.
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http://dx.doi.org/10.1007/s10840-020-00736-8DOI Listing
March 2021

Optogenetic approaches for termination of ventricular tachyarrhythmias after myocardial infarction in rats in vivo.

J Biophotonics 2020 07 20;13(7):e202000003. Epub 2020 Apr 20.

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

Cardiac optogenetics facilitates the painless manipulation of the heart with optical energy and was recently shown to terminate ventricular tachycardia (VT) in explanted mice heart. This study aimed to evaluate the optogenetic-based termination of induced VT under ischemia in an open-chest rat model and to develop an optimal, optical-manipulation procedure. VT was induced by burst stimulation after ligation of the left anterior descending coronary artery, and the termination effects of the optical manipulation, including electrical anti-tachycardia pacing (ATP) and spontaneous recovery, were tested. Among different multisegment optical modes, four repeated illuminations of 1000 ms in duration with 1-second interval at a 20-times intensity threshold on the right ventricle achieved the highest termination rate of 86.14% ± 4.145%, higher than that achieved by ATP and spontaneous termination. We demonstrated that optogenetic-based cardioversion is feasible and effective in vivo, with the underlying mechanism involving the light-triggered, ChR2-induced depolarization of the illuminated myocardium, in turn generating an excitation that disrupts the preexisting reentrant wave front.
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http://dx.doi.org/10.1002/jbio.202000003DOI Listing
July 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

Conversion of human cardiac progenitor cells using reprogramming factors into heterogeneous cardiac pacemaker-like cells.

J Mol Cell Cardiol 2020 04 21;141:53. Epub 2020 Mar 21.

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

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http://dx.doi.org/10.1016/j.yjmcc.2020.01.014DOI Listing
April 2020

Near-infrared light driven tissue-penetrating cardiac optogenetics via upconversion nanoparticles in vivo.

Biomed Opt Express 2020 Mar 18;11(3):1401-1416. Epub 2020 Feb 18.

Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.

This study determines whether near-infrared (NIR) light can drive tissue-penetrating cardiac optical control with upconversion luminescent materials. Adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) was injected intravenously to rats to achieve ChR2 expression in the heart. The upconversion nanoparticles (UCNP) NaYF4:Yb/Tm or upconversion microparticles (UCMP) NaYF4 to upconvert blue light were selected to fabricate freestanding polydimethylsiloxane films. These were attached on the ventricle and covered with muscle tissue. Additionally, a 980-nm NIR laser was programmed and illuminated on the film or the tissue. The NIR laser successfully captured ectopic paced rhythm in the heart, which displays similar manipulation characteristics to those triggered by blue light. Our results highlight the feasibility of tissue-penetration cardiac optogenetics by NIR and demonstrate the potential to use external optical manipulation for non-invasive or weakly invasive applications in cardiovascular diseases.
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http://dx.doi.org/10.1364/BOE.381480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075614PMC
March 2020

and Reprogram Human-Induced Pluripotent Stem Cells-Derived Cardiomyocytes into Pacemaker-Like Cells.

DNA Cell Biol 2020 Feb 9;39(2):289-298. Epub 2020 Jan 9.

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

reprograms cardiac myocytes into cells that possess sinoatrial node phenotype, but no specific funny current (If) was detected. We explore whether overexpression of alone or combined with can reprogram human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) into pacemaker-like cells. HiPSC-CMs were transfected with and/or in this study. Expression analysis showed that overexpression of induces a reduced reduction expression profile of working cardiomyocytes into that of pacemaker cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and electrophysiological analyses showed a reduced expression of connexins subunits (CX40, CX43), the sodium current (, INa), the inward rectified potassium channels (, IK1), and an increased expression of connexins subunits (CX30.2, CX45). No If was detected. The reduction of IK1 resulted in a more depolarized maximum diastolic potential together with an expression of If (generated by ), which they work in synergy to generate spontaneous diastolic depolarization that was the most typical characteristic of pacemaker cells. In conclusion, overexpression of and could reprogram hiPSC-CMs into pacemaker-like cells. The ability to enable diastolic depolarization formation provides a new strategy for the construction of a biological pacemaker.
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http://dx.doi.org/10.1089/dna.2019.5135DOI Listing
February 2020

C-type natriuretic peptide suppresses ventricular arrhythmias in rats with acute myocardial ischemia.

Peptides 2020 04 20;126:170238. Epub 2019 Dec 20.

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

This study aimed to investigate the effects of C-type natriuretic peptide (CNP) on ventricular arrhythmias in rats with acute myocardial ischemia (AMI). Forty male Sprague-Dawley rats were randomly divided into sham group (n = 10), AMI group (n = 15) and AMI + CNP group (n = 15). AMI model was induced by ligating the left anterior descending branch of the coronary artery, and CNP was pumped through the femoral vein starting 30 min before ischemia and continuing until 1 h after AMI. The occurrence of ventricular arrhythmias after ischemia and heart rate variability (HRV) were recorded and analyzed. The plasma norepinephrine level was detected at 15 min after AMI. Ventricular electrophysiological parameters including ventricular effective refractory period (ERP), ERP dispersion, ventricular action potential duration (APD) alternans and ventricular fibrillation threshold (VFT) were measured one hour after AMI. Then, the expressions of cyclic guanosine monophosphate in myocardial tissue and left stellate ganglion were examined. Compared to sham group, AMI significantly shortened the ERP, augmented ERP dispersion, elevated APD alternans cycle length, reduced VFT, and increased the incidence of ventricular arrhythmias. Moreover, AMI increased the sympathetic component of HRV, raised plasma norepinephrine levels, and decreased the cyclic guanosine monophosphate levels in myocardium and left stellate ganglion. All those changes were attenuated by CNP treatment. These findings suggest that CNP protected against ventricular arrhythmias in rats with AMI, potentially by inhibiting ischemia-induced cardiac sympathetic hyperactivity and cardiac electrophysiology instability.
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http://dx.doi.org/10.1016/j.peptides.2019.170238DOI Listing
April 2020

Adipose‑derived stem cells overexpressing SK4 calcium‑activated potassium channel generate biological pacemakers.

Int J Mol Med 2019 Dec 16;44(6):2103-2112. Epub 2019 Oct 16.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

Recent studies have suggested that calcium‑activated potassium channel (KCa) agonists increase the proportion of mouse embryonic stem cell‑derived cardiomyocytes and promote the differentiation of pacemaker cells. In the present study, it was hypothesized that adipose‑derived stem cells (ADSCs) can differentiate into pacemaker‑like cells via overexpression of the SK4 gene. ADSCs were transduced with a recombinant adenovirus vector carrying the mouse SK4 gene, whereas the control group was transduced with GFP vector. ADSCs transduced with SK4 vector were implanted into the rat left ventricular free wall. Complete atrioventricular block (AVB) was established in isolated perfused rat hearts after 2 weeks. SK4 was successfully and stably expressed in ADSCs following transduction. The mRNA levels of the pluripotent markers Oct‑4 and Sox‑2 declined and that of the transcription factor Shox2 was upregulated following SK4 transduction. The expression of α‑actinin and hyperpolarization‑activated cyclic nucleotide‑gated potassium channel 4 (HCN4) increased in the SK4 group. The hyperpolarizing activated pacemaker current If (8/20 cells) was detected in ADSCs transduced with SK4, but not in the GFP group. Furthermore, SK4 transduction induced the expression of p‑ERK1/2 and p‑p38 MAPK. In the ex vivo experiments, the heart rate of the SK4 group following AVB establishment was significantly higher compared with that in the GFP group. Immunofluorescence revealed that the transduced ADSCs were successfully implanted and expressed HCN4 in the SK4 group. In conclusion, SK4 induced ADSCs to differentiate into cardiomyocyte‑like and pacemaker‑like cells via activation of the extracellular signal‑regulated kinase 1/2 and p38 mitogen‑activated protein kinase pathways. Therefore, ADSCs transduced with SK4 may be used to generate biological pacemakers in ex vivo rat hearts.
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http://dx.doi.org/10.3892/ijmm.2019.4374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844603PMC
December 2019

Transcription Factor Reprograms Vascular Smooth Muscle Cells of Ascending Aorta to Pacemaker-Like Cells.

DNA Cell Biol 2019 Dec 18;38(12):1470-1479. Epub 2019 Oct 18.

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

Vascular smooth muscle cells (VSMCs) of ascending aorta and sinus node both originated from the second heart field. The study explored whether ascending aortic smooth muscle cells could be reprogrammed into pacemaker-like cells with human . In the study, VSMCs were infected with , and then cocultured with neonatal rat ventricular cardiomyocytes (NRVMs) . By overexpressing , the transfected VSMCs expressed high levels of hyperpolarization-activated cyclic nucleotide-gated channel 4 (), insulin gene enhancer binding protein 1, and human dwarf homeobox gene SHOX2, cardiac troponin I, and low level of connexin 43. In addition, funny current (I) was recorded by patch clamp appeared the time and voltage dependence in TBX18 group, which the amplitude of I density was from 5.164 ± 0.662 pA/pF to -0.765 ± 0.358 pA/pF ( = 14). Furthermore, -transfected VSMCs coupled with NRVMs showed typical action potential of pacemaker-like cells and the beating rate was faster (178.00 ± 7.55 bpm,  < 0.05) compared with other groups. In conclusion, our study indicated that transcription factor could reprogram VSMCs into pacemaker-like cells .
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http://dx.doi.org/10.1089/dna.2019.4940DOI Listing
December 2019

CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats.

J Am Heart Assoc 2019 11 18;8(21):e013133. Epub 2019 Oct 18.

Department of Cardiology Renmin Hospital of Wuhan University Hubei China.

Background Inflammation and fibrosis play an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). CTRP9 (C1q/tumor necrosis factor-related protein-9) as a secreted glycoprotein can reverse left ventricle remodeling post-MI, but its effects on MI-induced atrial inflammation, fibrosis, and associated AF are unknown. Methods and Results MI model rats received adenoviral supplementation of CTRP9 (Ad-CTRP9) by jugular-vein injection. Cardiac function, inflammatory, and fibrotic indexes and related signaling pathways, electrophysiological properties, and AF inducibility of atria in vivo and ex vivo were detected in 3 or 7 days after MI. shCTRP9 (short hairpin CTRP9) and shRNA were injected into rat and performed similar detection at day 5 or 10. Adverse atrial inflammation and fibrosis, cardiac dysfunction were induced in both MI and Ad-GFP (adenovirus-encoding green fluorescent protein)+MI rats. Systemic CTRP9 treatment improved cardiac dysfunction post-MI. CTRP9 markedly ameliorated macrophage infiltration and attenuated the inflammatory responses by downregulating interleukin-1β and interleukin-6, and upregulating interleukin-10, in 3 days post-MI; depressed left atrial fibrosis by decreasing the expressions of collagen types I and III, α-SMA, and transforming growth factor β1 in 7 days post-MI possibly through depressing the Toll-like receptor 4/nuclear factor-κB and Smad2/3 signaling pathways. Electrophysiologic recordings showed that increased AF inducibility and duration, and prolongation of interatrial conduction time induced by MI were attenuated by CTRP9; moreover, CTRP9 was negatively correlated with interleukin-1β and AF duration. Downregulation of CTRP9 aggravated atrial inflammation, fibrosis, susceptibility of AF and prolonged interatrial conduction time, without affecting cardiac function. Conclusions CTRP9 is effective at attenuating atrial inflammation and fibrosis, possibly via its inhibitory effects on the Toll-like receptor 4/nuclear factor-κB and Smad2/3 signaling pathways, and may be an original upstream therapy for AF in early phase of MI.
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http://dx.doi.org/10.1161/JAHA.119.013133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898814PMC
November 2019

A brain-stellate ganglion-atrium network regulates atrial fibrillation vulnerability through macrophages in acute stroke.

Life Sci 2019 Nov 9;237:116949. Epub 2019 Oct 9.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan City, Hubei Province, China. Electronic address:

Aims: New-onset atrial fibrillation (AF) is frequently observed following acute stroke. The aim of this study was to investigate the effects of the brain-stellate ganglion-atrium network on AF vulnerability in a canine model with acute middle cerebral artery occlusion (MCAO).

Materials And Methods: Twenty-six dogs were randomly divided into the sham-operated group (n = 6), acute stroke (AS) group (n = 7), stellate ganglion ablation (SGA) group (n = 6) and clodronate liposome (CL) group (n = 7). In the sham-operated group, dogs received craniotomy without MCAO. Cerebral ischemic model was established in AS dogs by right MCAO. Right MCAO along with SGA and CL injection into the atrium was performed in SGA and CL dogs, respectively. After 3 days, atrial electrophysiology, neural activity, and the phenotype and function of macrophages in the atrium were studied in all the dogs.

Key Findings: Higher AF inducibility (24.4 ± 4.4% versus 4.4 ± 2.2%, P < 0.05) and AF duration (15.7 ± 3.8 s versus 2.6 ± 1.1 s, P < 0.05) were observed in the AS group compared with the sham-operated group, and were associated with increased left stellate ganglion activity, higher macrophage infiltration and higher levels of inflammatory cytokines in the atrium. SGA or CL injection sharply suppressed AF inducibility (5.5 ± 2.7% versus 24.4 ± 4.4%; 5.3 ± 3.2% versus 24.4 ± 4.4%, both P < 0.05) and AF duration (2.9 ± 1.2 s versus 15.7 ± 3.8 s; 3.6 ± 1.0 s versus 15.7 ± 3.8 s, both P < 0.05) in canines with acute stroke.

Significance: A brain-stellate ganglion-atrium network may increase AF vulnerability through macrophage activation after acute stroke.
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http://dx.doi.org/10.1016/j.lfs.2019.116949DOI Listing
November 2019

Selective chemical ablation of transient receptor potential vanilloid 1 expressing neurons in the left stellate ganglion protects against ischemia-induced ventricular arrhythmias in dogs.

Biomed Pharmacother 2019 Dec 7;120:109500. Epub 2019 Oct 7.

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

Objectives: Findings from prior investigations show that left stellate ganglion (LSG) inhibitory approaches protect the heart from ventricular arrhythmias (VAs) caused by acute myocardial infarction (AMI), which still remain many side effects. Targeted transient receptor potential vanilloid 1/tyrosine hydroxylase (TRPV-1/TH) expressing sympathetic neurons ablation is a novel neuro-ablative strategy. The aim of this investigation was to explore if targeted molecular neuro-ablative strategy by resiniferatoxin (RTX) stellate microinjection could protect against ischemia-induced VAs.

Methods: Twenty-four anesthetized beagles were assigned to a control group (n = 12) and RTX group (n = 12) in a random manner. Targeted molecular neuro-ablative was produced by RTX stellate microinjection and DMSO was microinjected into LSG in the same way as control. Plasma norepinephrine (NE) level, heart rate variability (HRV), Tpeak-Tend interval (Tp-Te), LSG neural activity and function, ventricular effective refractory period (ERP), beat-to-beat variability of repolarization (BVR) and ventricular action potential duration (APD) were measured at baseline and 60 min after RTX or DMSO microinjection. AMI model was established by the ligation of left anterior descending coronary artery and 60-minute electrocardiography was continuously recorded for VAs analysis. Subsequently, HRV, Tp-Te, plasma NE level from jugular vein and coronary sinus, LSG neural activity and function, ventricular ERP, ventricular APD, BVR, action potential duration alternans (APDA) cycle length and ventricular fibrillation threshold (VFT) were evaluated after AMI. Finally, tissue collection of LSG was performed for examining the TRPV-1, nerve growth factor (NGF) protein and c-fos protein.

Results: TRPV-1 was highly expressed in the TH-expressing neurons and RTX injection significantly ablated TRPV-1/TH-positive neurons in LSG. Compared with baseline, RTX stellate microinjection significantly reduced plasma NE level, the sympathetic component of HRV, LSG neural activity and LSG function, shortened Tp-Te, prolonged ventricular ERP and APD, but there were no remarkable differences existed for control group. AMI resulted in the significant raise in plasma NE level from jugular vein and coronary sinus, the sympathetic component of HRV, LSG neural activity and LSG function, the marked prolongation in Tp-Te and BVR, the significant decrease in ERP and APD from ischemia area, and the increase in APDA cycle length in the ischemic region of the control group, which were remarkably attenuated in the RTX group. RTX pretreatment markedly rose the VFT in the RTX group. Furthermore, the AMI-triggered VAs was significantly prevented by RTX injection in the RTX group. RTX microinjection down-regulated significantly TRPV-1, NGF and c-fos expression in the LSG compared with the control group.

Conclusion: Targeted ablation of TRPV-1/TH positive sympathetic neurons induced by RTX stellate microinjection could suppress ischemia-induced cardiac autonomic imbalances and cardiac electrophysiology instability to protect against AMI-induced VAs.
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http://dx.doi.org/10.1016/j.biopha.2019.109500DOI Listing
December 2019

Trends of Cardiovascular Implantable Electronic Device Infection in 3 Decades: A Population-Based Study.

JACC Clin Electrophysiol 2019 09 28;5(9):1071-1080. Epub 2019 Aug 28.

Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota. Electronic address:

Objectives: This study assessed trends in the incidence of cardiovascular implantable electronic device (CIED) infection in the last 3 decades using a population-based records linkage study.

Background: Infection remains an important issue associated with increased implantation rate and dwell time of CIEDs.

Methods: We identified a cohort of all adults with CIEDs who resided in Olmsted County, Minnesota, from 1988 to 2015, using the medical linkage system of the Rochester Epidemiology Project. Standardized criteria were used to identify all CIED infection cases. The cumulative rate of CIED infection was estimated using the Kaplan-Meier method, and the trends of CIED infection incidence were calculated with person-years of follow-up after device implantation.

Results: The cumulative probabilities of overall CIED infection were 6.2% (95% confidence interval [CI]: 4.0% to 8.4%) at 15 years and 11.7% (95% CI: 6.8% to 17.3%) at 25 years of follow-up. The incidence of CIED infection every 7 years from 1988 to 2015 was 1.3, 5.7, 4.1, and 4.7 per 1,000-person years, respectively. The 15-year cumulative probabilities of CIED infection after the initial, second, and third procedures were 2.6% (95% CI: 1.4% to 3.8%), 2.7% (95% CI: 1.2% to 4.2%), and 24.1% (95% CI: 3.8% to 44.4%), respectively. Generator changes (hazard ratio [HR]: 3.91; 95% CI: 1.47 to 10.37; p = 0.006) and upgrades (HR: 3.08; 95% CI: 1.24 to 7.62; p = 0.02) were significantly associated with infection.

Conclusions: The incidence of CIED infection had a trend of increasing in the past 2 decades. Contemporary implantable cardioverter-defibrillator and cardiac resynchronization therapies and repeated manipulation of device pockets introduced a greater risk of CIED infection.
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http://dx.doi.org/10.1016/j.jacep.2019.06.016DOI Listing
September 2019
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