Follistatin-like protein 1 attenuates doxorubicin-induced cardiomyopathy by inhibiting MsrB2-mediated mitophagy.

Doxorubicin (DOX) is a potent chemotherapeutic drug; however, its clinical use is limited due to its cardiotoxicity. Mitochondrial dysfunction plays a vital role in the pathogenesis of DOX-induced cardiomyopathy. Follistatin-like protein 1 (FSTL1) is a potent cardiokine that protects the heart from diverse cardiac diseases, such as myocardial infarction, cardiac ischemia/reperfusion injury, and heart failure. However, its role in DOX-induced cardiomyopathy is unclear. Therefore, the present study investigated whether administering recombinant FSTL1 could mitigate DOX-induced cardiomyopathy and clarified the underlying molecular mechanisms. FSTL1 treatment attenuated DOX-induced cardiac dysfunction, cardiac fibrosis, and cellular apoptosis by inhibiting excess mitochondrial matrix protein methionine sulfoxide reductase B2 (MsrB2)-mediated mitophagy. Furthermore, FSTL1 administration reduced the expression of apoptotic proteins, including MsrB2, Bax, caspase 3, mitochondrial Parkin, and LC3-II, increased myocardial ATP content, and decreased cardiac malondialdehyde levels, thus protecting mitochondrial function against DOX-induced cardiac injury. Furthermore, FSTL1 treatment protected the contractile properties of adult cardiomyocytes against DOX-induced injury in vitro. Furthermore, carbonyl cyanide m-chlorophenylhydrazone, a mitophagy inducer, impaired the protective effects of FSTL1 in DOX-treated H9c2 cardiomyocytes. In conclusion, these results show that FSTL1 is a novel therapeutic agent against DOX-induced cardiotoxicity that improves mitochondrial function and decreases mitophagy.

Transcatheter Aortic Valve Replacement and Coronary Protection Guided by Deep Learning and 3-Dimensional Printing.

OBJECTIVE: In this case report, the auxiliary role of deep learning and 3-dimensional printing technology in the perioperative period was discussed to guide transcatheter aortic valve replacement and coronary stent implantation simultaneously. CASE PRESENTATION: A 68-year-old man had shortness of breath and chest tightness, accompanied by paroxysmal nocturnal dyspnea, 2 weeks before presenting at our hospital. Echocardiography results obtained in the outpatient department showed severe aortic stenosis combined with regurgitation and pleural effusion. The patient was first treated with closed thoracic drainage. After 800 mL of pleural effusion was collected, the patient's symptoms were relieved and he was admitted to the hospital. Preoperative transthoracic echocardiography showed severe bicuspid aortic valve stenosis combined with calcification and aortic regurgitation (mean pressure gradient, 42 mmHg). Preoperative computed tomography results showed a type I bicuspid aortic valve with severe eccentric calcification. The leaflet could be seen from the left coronary artery plane, which indicated an extremely high possibility of coronary obstruction. After preoperative imaging assessment, deep learning and 3-dimensional printing technology were used for evaluation and simulation. Guided transcatheter aortic valve replacement and a coronary stent implant were completed successfully. Postoperative digital subtraction angiography showed that the bioprosthesis and the chimney coronary stent were in ideal positions. Transesophageal echocardiography showed normal morphology without paravalvular regurgitation. CONCLUSION: The perioperative guidance of deep learning and 3-dimensional printing are of great help for surgical strategy formulation in patients with severe bicuspid aortic valve stenosis with calcification and high-risk coronary obstruction.

Feasibility of 3-dimensional printed models in simulated training and teaching of transcatheter aortic valve replacement.

In the study of TAVR, 3-dimensional (3D) printed aortic root models and pulsatile simulators were used for simulation training and teaching before procedures. The study was carried out in the following three parts: (1) experts were selected and equally divided into the 3D-printed simulation group and the non-3D-printed simulation group to conduct four times of TAVR, respectively; (2) another 10 experts and 10 young proceduralists were selected to accomplish three times of TAVR simulations; (3) overall, all the doctors were organized to complete a specific questionnaire, to evaluate the training and teaching effect of 3D printed simulations. For the 3D-printed simulation group, six proceduralists had a less crossing-valve time (8.3 ± 2.1 min vs 11.8 ± 2.7 min, P < 0.001) and total operation time (102.7 ± 15.3 min vs 137.7 ± 15.4 min, P < 0.001). In addition, the results showed that the median crossing-valve time and the total time required were significantly reduced in both the expert group and the young proceduralist group (all P<0.001). The results of the questionnaire showed that 3D-printed simulation training could enhance the understanding of anatomical structure and improve technical skills. Overall, cardiovascular 3D printing may play an important role in assisting TAVR, which can shorten the operation time and reduce potential complications.

Transcatheter tricuspid valve replacement for functional tricuspid regurgitation after left-sided valve surgery: A single-center experience.

BACKGROUND: Functional tricuspid regurgitation (FTR) following left-sided valve surgery (LSVS) is of clinical significance due to its high recurrence and mortality rates. Transcatheter therapy presents a potential solution to address this issue. AIMS: The study aimed to assess the safety and efficacy of transcatheter tricuspid valve replacement using the Lux-Valve system in a single center for patients with FTR after LSVS. METHODS: From June 2020 to April 2023, 20 patients with symptomatic severe FTR after LSVS were referred to our center. A multidisciplinary cardiac team evaluated these patients for suitability for transcatheter tricuspid valve replacement with Lux-Valve systems. Primary efficacy and safety endpoints were immediate postoperative tricuspid regurgitation severity ≤ moderate and major adverse events during follow-up. RESULTS: Twenty patients (average age 65.7 ± 7.4 years; 65.0% women) successfully underwent Lux-Valve system implantation after LSVS. All patients achieved ≤ moderate tricuspid regurgitation immediately after the procedure. Only one patient (5.0%) experienced a procedure-related major adverse event, leading to in-hospital mortality due to pulmonary infection. At the 6-month follow-up, 17 patients (89.5%) improved to New York Heart Association functional class I to II (p < 0.001). The overall Kansas City Cardiomyopathy Questionnaire score significantly improved (35.9 ± 6.7 points to 58.9 ± 5.8 points, p < 0.001). CONCLUSION: The Lux-Valve system was found to be safe and effective for treating FTR after LSVS. It resulted in positive early outcomes, including a significant reduction in FTR, improved functional status, and enhanced quality of life, especially in high-risk patients.

Irisin improves diabetic cardiomyopathy-induced cardiac remodeling by regulating GSDMD-mediated pyroptosis through MITOL/STING signaling.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM). However, the mechanisms underlying DCM-induced cardiac injury remain unclear. Recently, the role of cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling and pyroptosis in DCM has been investigated. Based on our previous results, this study was designed to examine the impact of irisin, mitochondrial ubiquitin ligase (MITOL/MARCH5), and cGAS/STING signaling in DCM-induced cardiac dysfunction and the effect of gasdermin D (GSDMD)-dependent pyroptosis. High-fat diet-induced mice and H9c2 cells were used for cardiac geometry and function or pyroptosis-related biomarker assessment at the end of the experiments. Here, we show that DCM impairs cardiac function by increasing cardiac fibrosis and GSDMD-dependent pyroptosis, including the activation of MITOL and cGAS/STING signaling. Our results confirmed that the protective role of irisin and MITOL was partially offset by the activation of cGAS/STING signaling. We also demonstrated that GSDMD-dependent pyroptosis plays a pivotal role in the pathological process of DCM pathogenesis. Our results indicate that irisin treatment protects against DCM injury, mitochondrial homeostasis, and pyroptosis through MITOL upregulation.

Cardioprotective effects of asiaticoside against diabetic cardiomyopathy: Activation of the AMPK/Nrf2 pathway.

Diabetic cardiomyopathy (DCM) is a chronic microvascular complication of diabetes that is generally defined as ventricular dysfunction occurring in patients with diabetes and unrelated to known causes. Several mechanisms have been proposed to contribute to the occurrence and persistence of DCM, in which oxidative stress and autophagy play a non-negligible role. Diabetic cardiomyopathy is involved in a variety of physiological and pathological processes. The 5' adenosine monophosphate-activated protein kinase/nuclear factor-erythroid 2-related factor 2 (AMPK/Nrf2) are expressed in the heart, and studies have shown that asiaticoside (ASI) and activated AMPK/Nrf2 have a protective effect on the myocardium. However, the roles of ASI and AMPK/Nrf2 in DCM are unknown. The intraperitoneal injection of streptozotocin (STZ) and high-fat feed were used to establish the DCM models in 100 C57/BL mice. Asiaticoside and inhibitors of AMPK/Nrf2 were used for intervention. Cardiac function, oxidative stress, and autophagy were measured in mice. DCM mice displayed increased levels of oxidative stress while autophagy levels declined. In addition, AMPK/Nrf2 was activated in DCM mice with ASI intervention. Further, we discovered that AMPK/Nrf2 inhibition blocked the protective effect of ASI by compound C and treatment with ML-385. The present study demonstrates that ASI exerts a protective effect against DCM via the potential activation of the AMPK/Nrf2 pathway. Asiaticoside is a potential therapeutic target for DCM.

Targeting the up-regulated CNOT3 reverses therapeutic resistance and metastatic progression of EGFR-mutant non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality worldwide. CNOT3, a subunit of the CCR4-NOT complex, has recently been suggested to be overexpressed in lung cancer and involved in tumor malignancy. However, its precise role and the underlying mechanisms still need to be fully revealed. In the present study, we found in lung cancer cells the expression of CNOT3 could be regulated by EGFR signaling pathway and c-Jun, a transcription factor downstream of EGFR, transcriptionally regulated its expression. Interestingly, CNOT3 could inversely regulate the expression of c-Jun via modulating its translation. Thus, a feedback loop existed between c-Jun and CNOT3. CNOT3 reduction post EGFR blockade facilitated the drug-induced cell death, and simultaneously inhibited cell proliferation via impacting TSC1/mTOR axis. Whereas, further up-regulation of the CNOT3 expression was observed in gefitinib-resistant cells, which dampened gefitinib sensitivity. Mechanically, the elevation of CNOT3 was induced by the bypass activation of HER2/c-Jun signaling. Depleting CNOT3 in vitro and in vivo sensitized the drug-resistant cells to gefitinib treatment and inhibited metastatic progression. These results give novel insights into the role of CNOT3 in lung cancer malignancy and provide a theoretical basis for the development of therapeutic strategies to solve acquired resistance to EGFR-TKIs.

Transcatheter mitral valve replacement to treat severe calcified rheumatic native mitral stenosis: role of three-dimensional printing-a case report.

Background: Rheumatic heart disease is a major disease that seriously affects human health and survival worldwide. Rheumatic mitral stenosis often has relatively complex pathological changes, and its progression leads to various manifestations of mitral valve dysfunction and adverse clinical events. Case summary: We present a 60-year-old patient who developed chest tightness, shortness of breath, and bilateral lower limb oedema in 2018 (New York Heart Association functional class III). Systolic and diastolic murmurs could be heard in the mitral auscultation area. In December 2021, the patient was admitted to the hospital with stroke. Thereafter, transthoracic echocardiography and computed tomography were performed, and the progress of rheumatic mitral stenosis was recorded. Due to the patient's high surgical risk, a patient-specific three-dimensional printed model was used to observe anatomical structures and simulate main procedures, and the surgeons finally chose to perform transcatheter mitral valve replacement. The balloon-expandable bioprothesis was released from the right femoral artery to treat the rheumatic mitral stenosis. The patient remained asymptomatic at the 6-month follow-up. Discussion: For patients with rheumatic mitral stenosis with high surgical risk, it is feasible to conduct transcatheter mitral valve replacement under the guidance of three-dimensional printing.

Transapical Mitral Valve-in-Ring Replacement Using the Innovative System under 3-Dimensional Printing Guidance.

BACKGROUND: Transcatheter mitral valve-in-ring replacement (TMViR) is an emerging alternative for patients with recurrent mitral regurgitation (MR) after a prior failed annuloplasty ring. However, intraoperative common issues and complications remain to be addressed. CASE SUMMARY: We describe the case of a 67-year-old male patient who underwent surgical mitral concomitant tricuspid annuloplasty repair 7 years ago who developed recurrent severe MR (New York Heart Association functional class IV). To avoid a high-risk surgical reoperation, we chose to perform a TMViR using an innovative dedicated device-the Mi-thos system-via a transapical approach. A patient-specific, 3-dimensional printed model was used to guide the procedure to avoid potential challenges. The procedure was performed successfully, and the patient exhibited symptomatic improvement. CONCLUSIONS: This case report highlights the first use of the innovative Mi-thos system in a TMViR procedure. The findings demonstrate the feasibility and safety of utilizing the Mi-thos system, guided by 3-dimensional printing technology, for patients who have experienced recurrent mitral regurgitation MR following a failed annuloplasty ring.

Treatment of severe tricuspid regurgitation induced by permanent pacemaker lead: Transcatheter tricuspid valve replacement with the guidance of 3-dimensional printing.

Background: Lead-induced tricuspid regurgitation is one of the complications after permanent pacemaker implantation (PPI) and refers to tricuspid regurgitation (TR) caused by the lead in the right ventricle (RV). Objectives: To study the clinical characteristics of severe TR after PPI and the effect of transcatheter tricuspid valve replacement (TTVR) with the guidance of 3-dimensional (3D) printing. Methods: This study was a single-center, descriptive study. Six patients with severe TR after PPI were enrolled in Xijing Hospital from January 2020 to May 2020. Before TTVR, the 3D printed tricuspid valve (TV) model was used for evaluation in the bench test. LuX-Valve was implanted under the guidance of TEE and x-ray fluoroscopy, and all patients underwent transatrial access. Six patients' data were collected at baseline, before discharge, and 6 months, 1 year and 2 years after TTVR. Results: The LuX-Valve was successfully implanted in 6 patients, TR was significantly reduced to ≤2+, and no deaths or cardiopulmonary bypass occurred during procedures. Three cases were caused by TV expansion: Patient #4 had TR caused by lead adhesion to TV, Patient #2 had TR caused by lead winding, and Patient #6 had TR caused by lead impingement on TV. During the 2-year follow-up, TTE revealed that 5 patients had no/trace regurgitation, and one patient (Patient #5) had mild regurgitation. All 6 patients (100.0%) reached primary endpoints. Conclusion: TTVR guided by 3D printing is safe and effective in the treatment of severe TR associated with permanent pacemaker lead, providing prospects and possibilities for the precise treatment of TV-related diseases.Clinical Trial Registration: ClinicalTrials.gov Protocol Registration System (NCT02917980).

Safety, efficacy, and clinical outcomes of transcatheter tricuspid valve replacement: One-year follow-up.

Objective: The aim was to evaluate the safety and efficacy of TTVR in patients with severe TR at the 1-year follow-up. Materials and methods: This project was a single-center, observational study. From September 2020 to May 2021, 15 patients with severe or extremely severe TR at high risk of traditional surgery were enrolled. All patients had preoperative imaging assessments to evaluate the tricuspid valve and the anatomy of the right heart. All patients were planned to treated with the LuX-Valve (Ningbo Jenscare Biotechnology, Ningbo, China). The LuX-Valve was implanted under the intraoperative guidance of TEE and X-ray fluoroscopy. Data were collected at baseline, before discharge, and at 30 days, 6 months, and 1 year postoperatively. Results: The LuX-Valves were successfully implanted in all 15 patients. TR was significantly reduced to ≤ 2 +. One patient died on postoperative day 12 of a pulmonary infection that was considered unrelated to the procedures or the devices. The remaining 14 patients (100.0%) reached the primary end point. One patient (7.1%) was rehospitalized during 1-year follow-up because of device thrombosis. The number of patients who survived at 1 year with New York Heart Association (NYHA) functional class II was higher than that before TTVR (11/14 vs. 0/15, P = 9.11 × 10-4). Patients with peripheral edema and ascites decreased from 100.0 to 46.7% at baseline to 28.6% and 14.3% at 1 year (P = 1.57 × 10-3 and 2.53 × 10-2). Conclusion: TTVR is associated with RV remodeling, increased cardiac output, and improvement in NYHA functional class. Using the LuX-Valve for TTVR to treat patients with severe TR is a feasible and relatively safe method with reliable clinical results. Further studies are needed to determine long-term outcomes.

Transcatheter aortic valve replacement in patients with quadricuspid aortic valve in a single center.

Background: Quadricuspid aortic valve (QAV) is a rare congenital malformation that can present with aortic regurgitation or aortic stenosis (AS)), requiring surgical treatment. Transcatheter aortic valve replacement (TAVR) is an alternative treatment for older patients and its prognosis for QAV therapy remains challenging. We sought to examine our early experience with TAVR in patients with QAV. Materials and methods: Prospectively collected data were retrospectively reviewed in patients with QAV undergoing TAVR in our institution. Results: Five patients with QAV and AR or AS were treated with TAVR between January 2016 and January 2022. The mean age was 73.8 years (range 69-82 years), and the median Society of Thoracic Surgeons score was 7.51% (range 2.668-18.138%). Two patients had type B and three had either type A, D, or F according to the Hurwitz and Roberts classification for QAV. Four patients with pure aortic regurgitation underwent transapical TAVR using the J-Valve system, and the patient with severe AS underwent transfemoral TAVR using the Venus-A system. Procedural success was achieved in all five patients. Trivial paravalvular leak was only detected in one case after the procedure, and one patient received a permanent pacemaker due to high-degree atrioventricular block three days later. The median follow-up period was 18 (12-56) months. After discharge, no deaths occurred during the 1 year follow-up. All patients improved by ≥1 New York Heart Association functional class at 30 days; four patients were in functional class ≤II later in the follow-up period. All patients' heart failure symptoms improved considerably. Conclusion: Our early experience with TAVR in QAV demonstrates these procedures to be feasible with acceptable early results. Further follow-up is necessary to determine the long-term outcomes of this modality. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT02917980].

Transcatheter Double Valve Replacement to Treat Aortic Stenosis and Severe Tricuspid Regurgitation with 3D Printing Guidance after Mechanical Mitral Valve Replacement.

BACKGROUND: Transcatheter treatments of tricuspid regurgitation (TR) have been emerging as alternatives for high-risk patients. In contrast to the immobilization of the common transcatheter tricuspid device, using a radial force-independent stent valve device at the native tricuspid annular site has several distinct advantages. CASE SUMMARY: A 76-year-old patient with renal insufficiency who underwent mechanical mitral valve replacement in 2001 and transcatheter aortic valve replacement in 2021 due to severe aortic stenosis presented with chest pain and shortness of breath. Echocardiography suggested that the flow velocities of the mitral mechanical valve and aortic prosthetic valve were both within the normal range, with no significant paravalvular regurgitation; the tricuspid valve exhibited massive regurgitation (VMAX 258 cm/s, PGMAX 27 mmHg). Due to the high surgical risk, we simulated the procedure with a three-dimensional (3D)-printed model and performed transcatheter tricuspid valve replacement using a LuX-Valve (Ningbo Jenscare Biotechnology Co., Ningbo, China). DISCUSSION: We describe transcatheter tricuspid valve replacement using the LuX-Valve and preprocedural guidance with 3D printing. Postprocedural TR was significantly reduced, indicating that 3D printing plays an important role in preprocedural guidance and that the LuX-Valve was safe and practicable for tricuspid valve replacement.

1-Deoxynojirimycin attenuates septic cardiomyopathy by regulating oxidative stress, apoptosis, and inflammation via the JAK2/STAT6 signaling pathway.

Cardiac dysfunction caused by sepsis is the predominant reason for death in patients with sepsis. However, the effective drugs for its prevention and the molecular mechanisms remain elusive. 1-Deoxynojirimycin (DNJ), a natural iminopyranose, exhibits various biological properties, such as hypoglycemic, antitumor, antiviral, and anti-inflammatory activities. However, whether DNJ can mediate biological activity resistance in sepsis-induced myocardial injury and the underlying mechanisms are unclear. Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling is an important pathway for the signal transduction of several key cytokines in the pathogenesis of sepsis, which can transcribe and modulate the host immune response. This study was conducted to confirm whether DNJ mediates oxidative stress, apoptosis, and inflammation in cardiomyocytes, thereby alleviating myocardial injury in sepsis via the JAK2/STAT6 signaling pathway. Septic cardiomyopathy was induced in mice using lipopolysaccharide (LPS), and they were then treated with DNJ. The results showed that DNJ markedly improved sepsis-induced cardiac dysfunction, attenuated reactive oxygen species generation, reduced cardiomyocyte apoptosis, and mitigated inflammation. Mechanistically, increased JAK2/STAT6 phosphorylation was observed in the mouse sepsis models, which decreased significantly after DNJ oral treatment. To further confirm whether DNJ mediates the JAK2/STAT6 pathway, the selective inhibitor fedratinib was used to block the JAK2 signaling pathway in vitro, which enhanced the protective effects of DNJ against the sepsis-induced cardiac damage. Collectively, these findings suggest that DNJ attenuates sepsis-induced myocardial injury by decreasing myocardial oxidative damage, apoptosis, and inflammation via the regulation of the JAK2/STAT6 signaling pathway.

Tetrahydrocurcumin improves lipopolysaccharide-induced myocardial dysfunction by inhibiting oxidative stress and inflammation via JNK/ERK signaling pathway regulation.

BACKGROUND: Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy. METHODS: After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was performed, and inflammatory markers were detected. RESULTS: Myocardial systolic function was severely compromised in parallel with the accumulation of reactive oxygen species and enhanced cardiomyocyte apoptosis in mice with sepsis. These adverse changes were markedly reversed in response to THC treatment in septic mice as well as in LPS-treated H9c2 cells. Mechanistically, THC inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-6, by upregulating mitogen-activated protein kinase phosphatase 1, to block the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK). Additionally, THC enhanced the levels of antioxidant proteins, including nuclear factor-erythroid 2-related factor 2, superoxide dismutase 2, and NAD(P)H quinone oxidoreductase 1, while decreasing gp91phox expression. Furthermore, upon THC treatment, Bcl-2 expression was significantly increased, along with a decline in Bax and cleaved caspase-3 expression, which reduced cardiomyocyte loss. CONCLUSION: Our findings indicate that THC exhibited protective potential against septic cardiomyopathy by reducing oxidative stress and inflammation through the regulation of JNK/ERK signaling. The findings of this study provide a basis for the further evaluation of THC as a therapeutic agent against septic cardiomyopathy.

Irisin attenuates sepsis-induced cardiac dysfunction by attenuating inflammation-induced pyroptosis through a mitochondrial ubiquitin ligase-dependent mechanism.

Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. However, the molecular mechanisms underlying septic cardiomyopathy remain elusive. Irisin is a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) that protects the heart from ischemia/reperfusion injury through upregulation of mitochondrial ubiquitin ligase (MITOL). Gasdermin D (GSDMD)-dependent pyroptosis plays a pivotal role in septic cardiomyopathy by regulating mitochondrial homeostasis. However, whether irisin can regulate MITOL to inhibit GSDMD-dependent pyroptosis in septic cardiomyopathy is yet to be investigated. Thus, this study was designed to explore the role of irisin in septic cardiomyopathy and its underlying molecular mechanisms. Our results demonstrate that irisin improves cardiac function against sepsis-induced cardiac dysfunction by reducing cardiac inflammation and myocardial pyroptosis. Using MITOL siRNA in vitro, the results revealed that the protective role of irisin against lipopolysaccharide (LPS)-induced cell injury was mediated by MITOL activation and the resulting inhibition of GSDMD-dependent pyroptosis. Moreover, irisin alleviated LPS-induced H9c2 cell injury by suppressing IL-1ß expression and reducing serum LDH and CK-MB concentrations in a MITOL/GSDMD-dependent manner. Collectively, our data suggest that irisin treatment ameliorates cardiac dysfunction in septic cardiomyopathy by activating MITOL and inhibiting GSDMD-dependent pyroptosis. These findings highlight the clinical relevance and therapeutic potential of irisin and MITOL for the management of sepsis-induced cardiac dysfunction.

Transcatheter Closure of a Paravalvular Leak Guided by Transesophageal Echocardiography and Three-Dimensional Printing.

Background: Closure of a percutaneous paravalvular leak (PVL) is a technically challenging procedure because of the specific anatomy postoperatively and the complex catheter techniques required. Transesophageal echocardiography (TEE) and three-dimensional (3D) printing might be helpful in identifying complex anatomical structures and the procedural design. Objectives: The purpose of this study was to review our experiences with transcatheter closure of PVL guided by TEE and 3D (TEE&3D) printing. Methods: A total of 166 patients with PVL after surgical valve replacement underwent transcatheter closure, from January 2015 through December 2020. Among these patients, 68 had preoperative guidance from TEE&3D printing. We reviewed the catheter techniques, perioperative characteristics, and prognosis. The median follow-up period was 36 (3-70) months. Results: Acute procedural success was achieved in 154/166 (92.8%) patients; of these, 64/68 (94.1%) had TEE&3D guidance and 90/98 (91.8%) had transthoracic echocardiography (TTE) guidance. No hospital deaths occurred. All patients having percutaneous procedures were given local anesthesia, while 13 patients having transapical procedures were given general anesthesia. Multiple approaches were used, including transfemoral, transapical, and transseptal via the arteriovenous loop. We also deployed multiple devices, including the Amplatzer Vascular Plug II (AVP II), the Amplatzer duct occluder II, the patent ductus arteriosus (PDA) occluder, and the Amplatzer muscular ventricular septal defect occluder. Those cases guided by TEE&3D printing had shorter procedural times compared with those guided by TTE [(61.2 ± 23.4) vs. (105.7 ± 53.9) min, p < 0.05]. The fluoroscopic time was also shorter for operations guided by TEE&3D printing compared with those guided by TTE alone [(18.5 ± 11.4) vs. (27.3 ± 5.6) min, p < 0.05]. The complications included recurrent hemolysis, residual regurgitation, acute renal insufficiency, and anemia. There was no significant difference in the incidence of complications between the 2 groups. Conclusion: Transesophageal echocardiography and 3D printing show advantages compared with standalone TTE in guiding the transcatheter closure of PVL with shorter procedural and fluoroscopic times. This minimally invasive treatment could provide reliable outcomes in selected patients. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02917980].

Effects of berbamine against myocardial ischemia/reperfusion injury: Activation of the 5' adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor pathway and changes in the mitochondrial state.

This study was designed to investigate whether berbamine (BA)-induced cardioprotective effects were related to 5' adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor (Nrf2) signaling and changes in the mitochondria in myocardial ischemia/reperfusion (I/R) injury. C57/BL6 mice were exposed to BA (10 mg/kg/d), with or without administration of the AMPK specific inhibitor compound C (5 mg/kg/d) or the Nrf2 specific inhibitor ML-385 (30 mg/kg/d), and then subjected to a myocardial I/R operation. As expected, BA significantly improved post-ischemic cardiac function, reduced infarct size and apoptotic cell death, decreased oxidative stress, and improved the mitochondrial state. Furthermore, BA markedly increased AMPK activation, Nrf2 nuclear translocation, and the levels of NAD(P)H quinone dehydrogenase and heme oxygenase-1. Nevertheless, these BA-induced changes were abrogated by compound C. In addition, ML-385 also canceled the cardioprotective effects of BA but had little effect on AMPK activation. Our results demonstrate that BA alleviates myocardial I/R injury and the mitochondrial state by inhibiting apoptosis and oxidative stress via the AMPK/Nrf2 signaling pathway.

GDF11 Alleviates Pathological Myocardial Remodeling in Diabetic Cardiomyopathy Through SIRT1-Dependent Regulation of Oxidative Stress and Apoptosis.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in diabetic cardiomyopathy (DCM) remain largely unknown. In this study, we sought to determine whether GDF11 could prevent DCM. After establishing a mouse model of diabetes by administering a high-fat diet and streptozotocin, intramyocardial injection of an adeno-associated virus was used to achieve myocardium-specific GDF11 overexpression. GDF11 remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression and activity were observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were eliminated by SIRT1 depletion. Our results demonstrate for the first time that GDF11 protects against DCM by regulating SIRT1 signaling pathway.