Clinical effect of vein of Marshall ethanol infusion on mitral isthmus ablation.

Purpose: This study aimed to investigate the effect of Marshall ethanol infusion (VOM-Et) in the vein on mitral isthmus (MI) ablation. Methods: Patients with persistent atrial fibrillation (AF) were grouped into vein of VOM-Et combined with radiofrequency (RF) ablation (VOM-Et-RF) and RF groups. The primary outcome was MI block immediate block rate after surgery. Stratified analysis was also performed for factors affecting the outcome measures. Results: A total of 118 consecutive patients underwent AF ablation at Taizhou Hospital of Zhejiang Province from January 2018 to December 2021. Successful bidirectional perimitral block was achieved in 96% of patients in VOM-Et-RF (69 of 72) and in 76% of patients in the RF group (35 of 46) (P < 0.01). In the subgroup analysis, male sex, elder than 60 years, Left atrial diameter <55 mm, and AF duration <3 years were associated with the benefits of VOM-Et in AF Patients. Conclusion: The vein of Marshall ethanol infusion for catheter ablation can improve the MI block rate. Male sex, elder age, smaller Left atrial diameter and shorter AF duration may have significant benefits for VOM-Et.

Individual Trajectories of Health Status During the First Year of Discharge From Hospitalization for Heart Failure and Their Associations With Death in the Following Years.

Background Improving health status is one of the major goals in the management of heart failure (HF). However, little is known about the long-term individual trajectories of health status in patients with acute HF after discharge. Methods and Results We enrolled 2328 patients hospitalized for HF from 51 hospitals prospectively and measured their health status via the Kansas City Cardiomyopathy Questionnaire-12 at admission and 1, 6, and 12 months after discharge, respectively. The median age of the patients included was 66 years, and 63.3% were men. Six patterns of Kansas City Cardiomyopathy Questionnaire-12 trajectories were identified by a latent class trajectory model: persistently good (34.0%), rapidly improving (35.5%), slowly improving (10.4%), moderately regressing (7.4%), severely regressing (7.5%), and persistently poor (5.3%). Advanced age, decompensated chronic HF, HF with mildly reduced ejection fraction, HF with preserved ejection fraction, depression symptoms, cognitive impairment, and each additional HF rehospitalization within 1 year of discharge were associated with unfavorable health status (moderately regressing, severely regressing, and persistently poor) (P<0.05). Compared with the pattern of persistently good, slowly improving (hazard ratio [HR], 1.50 [95% CI, 1.06-2.12]), moderately regressing (HR, 1.92 [1.43-2.58]), severely regressing (HR, 2.26 [1.54-3.31]), and persistently poor (HR, 2.34 [1.55-3.53]) were associated with increased risks of all-cause death. Conclusions One-fifth of 1-year survivors after hospitalization for HF experienced unfavorable health status trajectories and had a substantially increased risk of death during the following years. Our findings help inform the understanding of disease progression from a patient perception perspective and its relationship with long-term survival. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT02878811.

SIRT3 attenuates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome via autophagy.

Doxorubicin (DOX) is a highly effective and extensively used chemotherapeutic drug but is limited by its cardiotoxicity. In our previous study, we showed that DOX-induced cardiotoxicity (DIC) triggers autophagy and pyroptosis. Sirtuin 3(SIRT3) is an NAD + -dependent deacetylase of the mitochondria that regulates autophagy. However, it is unknown if the protective effects of SIRT3 on DOX-induced cardiotoxicity involve the inhibition of NLRP3 inflammasome activation. In this study, we constructed in vivo and in vitro DIC models to investigate the effects and potential mechanisms of SIRT3 on DIC. We found that the overexpression of SIRT3 remarkably attenuated DIC through inhibition of the NLRP3 inflammasome. Moreover, we found that the overexpression of SIRT3 restored the dynamic balance of autophagosome/autolysosomes by targeting the mTOR/ULK1 signaling pathway. Application of the mTOR agonist MHY1485 further demonstrated that SIRT3 inhibited NLRP3 inflammasome activation by regulating autophagy. Collectively, the results suggest that SIRT3 effectively attenuates the cardiotoxicity of DOX and provides a theoretical foundation for further exploration of DIC.

LCZ696 protects against doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation.

Doxorubicin (DOX) is an effective and widely used anticancer drug but has limited clinical applicability because of its cardiotoxicity. Ferroptosis plays a key role in DOX-induced cardiac damage and cardiomyocyte cell death. The inhibition of ferroptosis reverses DOX-induced cardiotoxicity (DIC). LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, protects against DIC. However, the mechanism of action of LCZ696, especially its effect on ferroptosis, is incompletely understood. This study investigates the cardioprotective effects of LCZ696 on DIC in vivo and in vitro.Cardiotoxicity was induced in Wistar rats by tail intravenous injection of 2.5 mg/kg DOX once a week for six weeks. Rats and H9c2 cells were treated with or without LCZ696 to determine the cardioprotective role and underlying mechanisms of LCZ696 against DIC. To assess the role of SIRT3 and correlated pathways in ferroptosis, SIRT3 knockout was performed using lentiviral vectors, and AKT was inhibited with LY294002. LCZ696 significantly attenuated DIC by decreasing the concentrations of lipid reactive oxygen species and malondialdehyde and increasing the levels of glutathione peroxidase-4 and reduced glutathione in cells and heart tissues. Moreover, LCZ696 remodeled myocardial structures and improved heart ventricular function in DOX-treated rats. LCZ696 treatment increased SIRT3 expression and deacetylated its target gene SOD2, and these changes were mediated by AKT activation. SIRT3 knockdown and AKT inhibition induced lipid peroxidation and reduced the protective effect of LCZ696 in H9c2 cells. Collectively,LCZ696 prevents DIC by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation. Thus, LZC696 is a potential therapeutic strategy for DIC.

rhBMP­7 suppresses TGF­ß1­induced endothelial to mesenchymal transition in circulating endothelial cells by regulating Smad5.

Endothelial to mesenchymal transition (EndMT) has been confirmed to participate in several cardiovascular diseases. In addition, EndMT of circulating endothelial cells (CECs) contributes to the pathology of musculoskeletal injury. However, little is known about the molecular mechanism of CECs undergoing EndMT. In the present study, human CECs were isolated and identified using anti­CD146­coupled magnetic beads. CECs were exposed to transforming growth factor (TGF)­ß1 or TGF­ß1 + recombinant human bone morphogenetic protein 7 (rhBMP­7) or TGF­ß1 + rhBMP­7 + Smad5 antagonist Jun activation domain­binding protein 1. Vascular endothelial (VE)­cadherin and vimentin expression were detected by immunofluorescence staining in TGF­ß1­treated CECs. The expression levels of von Willebrand factor (vWF), E­selectin, VE­cadherin, vimentin, fibronectin, α smooth muscle actin (α­SMA) and Smad2/3 were detected by reverse transcription­quantitative PCR or western blot analysis. It was identified that rhBMP­7 attenuated TGF­ß1­induced endothelial cell injury. TGF­ß1 could induce the EndMT process in CECs, as confirmed by the co­expression of VE­cadherin and vimentin. TGF­ß1 significantly reduced the expression of VE­cadherin, and induced the expression of vimentin, fibronectin and α­SMA. rhBMP­7 reversed the effects of TGF­ß1 on the expression of these genes. Additionally, Smad5 antagonist reversed the effects of rhBMP­7 on TGF­ß1­induced EndMT, and upregulated rhBMP­7­inhibited Smad2/3 expression. In conclusion, TGF­ß1 could induce EndMT in CECs and rhBMP­7 may suppress this process by regulating Smad5.

Ultra-high pre-membrane lung oxygen saturation in a patient on veno-arterial extracorporeal membrane oxygenation.

A 55-year-old man who suffered from acute myocardial infarction complicated with cardiogenic shock was administered veno-arterial extracorporeal membrane oxygenation. Ultra-high pre-membrane lung oxygen saturation of 93% was observed. Transthoracic echocardiography revealed the presence of patent foramen ovale. The four-chamber view showed that the tip of the cannula was located in the patent foramen ovale, which resulted in a left-to-right shunt. Without adjusting the position of the drainage cannula, the patient was weaned from extracorporeal membrane oxygenation at 136 hours after initiation and survived to hospital discharge.

Discovery of potential plasma protein biomarkers for acute myocardial infarction via proteomics.

BACKGROUND: Acute myocardial infarction (AMI) is an acute disease with high mortality and seriously threatens human health. The identification of new effective biological markers for AMI is a prerequisite for treatment. Most proteomic studies have focused on atherosclerotic plaques, vascular cells, monocytes and platelets in the blood; however, the concentration of these factors in plasma is low, making it difficult to measure the complexity of plasma components. Moreover, some studies have examined the plasma protein of patients with acute coronary syndrome with histochemistry; however, the results are not consistent. Therefore, it is necessary to further investigate the differential proteins in the plasma of patients with AMI via proteomics to identify new biomarkers of AMI. METHODS: In this study, immunodepletion of high-abundance plasma proteins followed by an isobaric tagging for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was used to analyze plasma samples from 5 control individuals and 10 AMI patients. RESULTS: Four hundred sixty-eight proteins were identified from two samples, and 33 proteins were differentially expressed in AMI patients compared to the controls. Among the 33 proteins, 12 proteins showed a ≥1.5-fold change between AMI and control samples. These proteins included fatty acid binding protein 3 (FABP3, ratio =6.36), creatine kinase-MB (CK-MB ratio =4.89), adenylate kinase1 (AK1 ratio =4.16), pro-platelet basic protein (PPBP ratio =3.29), creatine kinase (CK ratio =2.88), platelet factor 4 (PF4 ratio =2.62), peptidyl prolyl isomerase Cyclophilin A (PPIA ratio =2.05), Cofilin-1 (CFL1 ratio =1.81), coronin1A (CORO1A ratio =1.71), protein kinase M (PKM ratio =1.63), ribonuclease inhibitor (RNH1, ratio =1.67), and triose phosphate isomerase (TPI1 ratio =1.56). By contrast, there was a decrease of 19 proteins, such as adiponectin (ADIPOQ ratio =0.70), insulin-like growth factor binding protein6 (IGFBP6 ratio =0.70), Dickkopf-related protein 3 (DKK3 ratio =0.70) and complement 4B (C4B ratio =0.68). The most over-represented term was regulation of cell proliferation in the cellular component category of Gene Ontology (GO). The top 3 biological process terms were regulation of cell proliferation, response to wounding and wound healing. These proteins included immune proteins, blood coagulation proteins, lipid metabolism proteins, cytoskeleton proteins, energy metabolism proteins, gene regulation proteins, myocutaneous proteins, and myocardial remodeling proteins and were highly connected with each other, which indicates that the functional network of these processes contribute to the pathophysiology of AMI. CONCLUSIONS: In conclusion, the present quantitative proteomic study identified novel AMI biomarker candidates and might provide fundamental information for the development of an AMI biomarker.

Clinical significance of leukotriene b4 and extracellular matrix metalloproteinase inducer in acute coronary syndrome.

PURPOSE: Leukotriene B4 (LTB4) and extracellular matrix metalloproteinase (EMMPRIN) have been suggested as modulators of atherosclerotic plaque instability. This study sought to evaluate the potential diagnostic implication of LTB4 and EMMPRIN in patients with acute coronary syndrome (ACS). METHODS: Patients (n=153) who underwent coronary angiography, including 105 patients diagnosed with ACS, were divided into four groups: stable angina pectoris (SAP, n=19), unstable angina pectoris (UAP, n=39), acute myocardial infarction (AMI, n=66) and control (with normal coronary angiography, n=29). EMMPRIN expression in peripheral blood mononuclear cells was determined by flow cytometry and serum LTB4 levels were measured by ELISA. To examine whether LTB4 can regulate the expression of EMMPRIN and matrix metalloproteinases (MMPs) in macrophages, differentiated THP-1 macrophages were stimulated with different concentrations of LTB4 (10-10-10-7mmol/L). Expression of EMMPRIN was evaluated by Western blotting. MMP-9 mRNA expression and enzymatic activity were determined by RT-PCR and SDS-PAGE gelatin zymography. RESULT: Serum LTB4 concentration was significantly higher in AMI and UAP groups, compared with control and SAP groups (p < 0.01). Subgroups analysis showed that LTB4 was significantly higher in the AMI < 24h group, compared with the AMI > 24h group. Expression of EMMPRIN on circulating monocytes was significantly higher in patients with UAP and AMI (> 24h), compared with control, SAP and AMI (< 24h) groups (p < 0.05). In vitro study showed LTB4 up-regulated the expression of EMMPRIN, as well as the expression and activity of MMP-9, in cultured THP-1-derived macrophages (p < 0.05). CONCLUSION: LTB4 and EMMPRIN are associated with the pathogenesis of ACS and may be potential biomarkers for patients with ACS.

Ameliorated stress related proteins are associated with improved cardiac function by sarcoplasmic reticulum calcium ATPase gene transfer in heart failure.

BACKGROUND: Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. METHODS: A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated virus 1 (rAAV1) mediated gene transfection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein (control) gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular (LV) sample was determined using two-dimensional (2-D) gel electrophoresis and MALDI-TOF-MS. The serum levels of the systemic inflammatory and neuro-hormonal factors were assayed using radioimmunoassay kits. RESULTS: The cardiac function improved after SERCA- 2a gene transfer due to the significantly increased SERCA2a protein level. Beagles treated with SERCA2a had significantly decreased serum levels of the inflammatory markers (interleukin-6 and tumor necrosis factor-α) and neuro-hormonal factors (brain natriuretic peptide, endothelin-1 and angiotensin II) compared with HF animals. The myocardial proteomic analysis showed that haptoglobin heavy chain, heat shock protein (alpha-crystallin-related, B6) were down-regulated, and galectin-1 was up-regulated in SERCA2a group compared with HF group, companied by up-regulated contractile proteins and NADH dehydrogenase. CONCLUSIONS: These findings demonstrate that regional intramyocardial injections of rAAV1-SERCA2a vectors may improve global LV function, correlating with reverse activation of the systemic inflammatory, excessive neuroendocrine factors and the stress-associated myocardial proteins, suggesting that the beneficial effects of SERCA2a gene transfer may involve the attenuation of stress-associated reaction.

[Expression of extracellular matrix metalloproteinase inducer in the unstable plaque of patients with acute coronary syndrome].

OBJECTIVE: To observe the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the unstable plaque of patients with acute coronary syndrome (ACS), and the impact of leukotriene B4 (LTB4) on the EMMPRIN expression in macrophages. METHODS: The EMMPRIN expression was detected by immunohistochemistry in 11 unstable plaques from patients with ACS. Protein expression of EMMPRIN was evaluated by Western blot on macrophages differentiated from THP-1 which were stimulated with LTB4 in the absence or presence of LTB4 antagonist U75302. There are 8 study groups: 1-THP-1, 2-8-the macrophages derived from THP-1, 2-6-macrophages were stimulated by LTB4 (0, 10(-10), 10(-9), 10(-8) and 10(-7) mol/L) for 24 h, 7-8-the macrophages were pretreated by 10(-6) mol/L or 10(-7) mol/L U75302 2 h before the LTB4 (10(-7) mol/L) stimulation. RESULTS: Abundant EMMPRIN expression was detected in macrophages and smooth muscle cells of unstable plaques from ACS patients. As to the THP-1 derived macrophages, EMMPRIN expression was significantly upregulated in a concentration-dependent manner in LTB4 stimulated groups, which was significantly higher in group 3-6 than in the THP-1 group (group 1) and macrophages group (group 2) (all P < 0.05) and pretreatment with U75302 significantly reduced the LTB4 induced upregulation of EMMPRIN in a dose-dependent manner (P < 0.05). CONCLUSION: EMMPRIN expression is enhanced in macrophages and smooth muscle cells on unstable coronary artery plaques from ACS patients. LTB4 could stimulate EMMPRIN expression on THP-1 derived macrophages suggesting that LTB4 and EMMPRIN might be both involved in the formation and progression of unstable plaques, future studies are warranted to explore if LTB4 and EMMPRIN antagonists are effective or not for treating patients with ACS.

Improvement in cardiac function after sarcoplasmic reticulum Ca2+-ATPase gene transfer in a beagle heart failure model.

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral (rAAV) gene transfer of Sarco-endoplasmic reticulum calcium ATPase (SERCA2a) can be effective in treating rats with chronic heart failure (CHF). The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model. METHODS: HF was induced in beagles by rapid right ventricular pacing (230 beats/min) for 30 days. A reduced rate ventricular pacing (180 beats/min) was continued for another 30 days. The beagles were assigned to four groups: (a) control group (n = 4); (b) HF group (n = 4); (c) enhanced green fluorescent protein group (n = 4); and (d) SERCA2a group (n = 4). rAAV1-EGFP (1 x 10(12) microg) and rAAV1-SERCA2a (1 x 10(12) microg) were delivered intramyocardially. SERCA2a expression was assessed by Western blotting and immunohistochemistry. RESULTS: Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group (P < 0.05). Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure (+dp/dt(max)), and the maximal rate of decline of left ventricular pressure (-dp/dt(max)) (P < 0.05). Left ventricular end-diastole pressure significantly decreased (P < 0.05). The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group (P < 0.05). CONCLUSIONS: Intramyocardial injection of rAAV1-SERCA2a can improve the cardiac function in beagles induced with HF. We expect further studies on SERCA2a's long-term safety, efficacy, dosage and the optimization before using it in humans with HF.

[Overexpression of sarcoplasmic reticulum calcium ATPase induced hemodynamic and proteomic changes in a dog model of heart failure].

OBJECTIVE: Overexpression of SERCA2a could improve cardiac function in human and experimental heart failure (HF) models. We observed the proteomics changes post SERCA2a overexpression in a pacing induced HF model in dogs. METHODS: Beagles were divided into four groups: control group, HF group (230 beats/min for 4 weeks), HF + EGFP group (myocardial injection of 1 x 10(12) v.g recombinant adeno-associated virus carrying enhanced green fluorescent protein gene, rAAV2/1-EGFP) and HF + SERCA2a group (myocardial injection of 1 x 10(12) v.g recombinant adeno-associated virus carrying SERCA2a gene, rAAV2/1-SERCA2a). Thirty days after gene transduction, left ventricular systolic and diastolic functions were measured by echocardiography and invasive hemodynamics in all animals. By use of 2-dimensional gel electrophoresis (2-DE), -500 distinct protein spots were detected in myocardium of all animals. Protein spots observed to be altered between failing and SERCA2a overexpressed hearts were subjected to tryptic peptide mass fingerprinting for identification by MALDI-TOF mass spectrometry in combination with LC/MS/MS analysis. RESULTS: At 30 day after gene transfer, HF signs were significantly reduced, cardiac function [LVSP: (214.72 +/- 31.74) mm Hg (1 mm Hg = 0.133 kPa) vs. (139.32 +/- 36.79) mm Hg, +dp/dt(max): (6779.43 +/- 217.58) mm Hg/s vs. (2746.85 +/- 931.23) mm Hg/s and -dp/dt(max): (-4341.42 +/- 322.02) mm Hg/s vs. (-2531.14 +/- 616.15) mm Hg/s, LVEDP: (21.86 +/- 6.95) mm Hg vs. (59.78 +/- 6.92) mm Hg] significantly improved in HF + SERCA2a dogs than those in HF + EGFP group(all P < 0.05) and parameters were comparable between HF + SERCA2a and control groups. We identified alterations in the expression level of more than 10 proteins in myocardium. These protein changes were observed mainly in two subcellular compartments: the cardiac contractile apparatus and metabolism/energetics. CONCLUSION: These results showed that overexpression of SERCA2a could improve cardiac function accompanied with numerous alterations in protein expressions involved in calcium handling, myofibrils, and energy production in this dog model of chronic heart failure.