Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to function in a range of pathological conditions, such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodeling following AMI. Following AMI in mice, MDSCs frequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following the adoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-ß1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-ß1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly, blockade of IL-10 partially abolished the cardioprotective role of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

RNF13 protects against pathological cardiac hypertrophy through p62-NRF2 pathway.

Heart failure (HF) severely impairs human health because of its high incidence and mortality. Cardiac hypertrophy is the main cause of HF, while its underlying mechanism is not fully clear. As an E3 ubiquitin ligase, Ring finger protein 13 (RNF13) plays a crucial role in many disorders, such as liver immune, neurological disease and tumorigenesis, whereas the function of RNF13 in cardiac hypertrophy remains largely unknown. In the present study, we found that the protein expression of RNF13 is up-regulated in the transverse aortic constriction (TAC)-induced murine hypertrophic hearts and phenylephrine (PE)-induced cardiomyocyte hypertrophy. Functional investigations indicated that RNF13 global knockout mice accelerates the degree of TAC-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis and heart dysfunction. On the contrary, adeno-associated virus 9 (AAV9) mediated-RNF13 overexpression mice alleviated cardiac hypertrophy. Furthermore, we demonstrated that adenoviral RNF13 attenuates the PE-induced cardiomyocyte hypertrophy and down-regulates the expression of cardiac hypertrophic markers, while the opposite results were observed in the RNF13 knockdown group. The RNA-sequence of RNF13 knockout and wild type mice showed that RNF13 deficiency activates oxidative stress after TAC surgery. In terms of the mechanism, we found that RNF13 directly interacted with p62 and promoted the activation of downstream NRF2/HO-1 signaling. Finally, we proved that p62 knockdown can reverse the effect of RNF13 in cardiac hypertrophy. In conclusion, RNF13 protects against the cardiac hypertrophy via p62-NRF2 axis.

Stentless at ostium: a novel approach for treating ostial left anterior descending or left circumflex coronary artery lesions with drug-coated balloons.

BACKGROUND: Currently, there is no optimal treatment strategy for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. This study explored effectiveness and safety of drug-coated balloons (DCB) in individuals presenting with ostial LAD or LCx lesions. METHODS: A total of 137 patients with de novo ostial LAD or LCx lesions scheduled for DCB treatment were prospectively recruited into the study. After mandatory lesion preparation, DCB-only or hybrid strategy [DCB + drug-eluting stent (DES)] were performed on 120 patients (87.59%). The primary endpoint was the rate of 2-year target lesion revascularization (TLR). Rates of major adverse cardiovascular events (MACE), cardiac death, target vessel myocardial infarction (TVMI), and vessel thrombosis were explored as the secondary outcomes. Quantitative coronary angiography software was used to analyze coronary angiograms. RESULTS: Of the participants, 58 were treated with DCB-only and 62 with hybrid strategy. Relative to the DCB-only group, patients in the hybrid group had longer target lesions (15.47 ± 10.08 vs. 36.85 ± 9.46 mm, P<0.001) and higher Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) scores (23.47 ± 5.22 vs. 29.98 ± 3.18, P<0.001). During follow-up (731 ± 64 days), neither the primary endpoint (TLR) nor the secondary endpoints (including MACE, cardiac death, TVMI, and vessel thrombosis) differed statistically between the two groups (all P > 0.05). Treatment strategy (DCB-only or hybrid) was not a significant risk factor for TLR. Patients who underwent DCB-only exhibited less late lumen loss compared with the patients who underwent hybrid strategy (-0.26 ± 0.59 vs. 0.42 ± 0.47 mm, P<0.001) at 1-year angiographic follow-up. CONCLUSIONS: With regards to safety and efficacy, the strategy of DCB as a standalone therapy was similar in comparison with the hybrid strategy of DCB + DES for ostial LAD and ostial LCx lesions. This approach might be effective and technically easy in treating ostial LAD and LCx diseases.

Protective Effect of Ginsenoside Rb1 Nanoparticles Against Contrast-Induced Nephropathy by Inhibiting High Mobility Group Box 1 Gene/Toll-Like Receptor 4/NF-κB Signaling Pathway.

With the progress made in the widespread application of interventional radiology procedures, there has been an increasing number of patients who suffer from cardiovascular diseases and go through imaging and interventional treatment with iodine contrast medium (ICM) year by year. In turn, there has been an increasing amount of concern over acute kidney injury (AKI) brought about by ICM. As evidenced by numerous studies, the initiation of inflammatory response plays a critical role in the development of ICM-induced AKI. Correspondingly, the strategy of targeting renal inflammatory response and cytokine release could provide an effective solution to mitigating the ICM-induced AKI. Moreover, Ginsenoside Rb1 (GRb1) constitutes one of the major active components of ginseng and features a wide range of vital biological functions. Judging from the research findings, GRb1 could impose antioxidant and anti-inflammatory effects on cardiovascular diseases, in addition to lung, liver and kidney diseases. However, reports on whether GRb1 could impose a protective effect against contrast-induced nephropathy (CIN) are absent. In this study, we have examined the therapeutic effects imposed by GRb1 as well as the potential molecular mechanism by establishing an in vivo and in vitro model of CIN. In addition, we have set up a mouse model of CIN through sequential intravenous injection of indomethacin, N(ω)-nitro-Larginine methyl ester (L-NAME), and iopromide. To further enhance the bioavailability of GRb1, we have encapsulated GRb1 with polyethylene glycol (PEG)/poly lactic-co-glycolic acid (PLGA) nanocarriers to generate GRb1 nanoparticles (NPs) conducting the in vivo experiments. During the in vitro experiments, we have adopted GRb1 to treat NRK-52E cells or cells transfected with the high mobility group box 1 gene (HMGB1) overexpression plasmid. As shown by the in vivo experimental results, GRb1 NPs could evidently improve the renal dysfunction in CIN, diminish the extent of apoptosis of tubular epithelial cells, and reduce the expression of high mobility group box 1 (HMGB1) and cytokines (tumor necrosis factor (TNF-α), interleukin (IL) 6 and IL-1ß). In addition, GRb1 NPs are found to be capable of preventing the activation of Toll-like receptor 4 (TLR4)/NF-κB signaling pathway triggered by contrast medium. The in vitro experimental results have exactly confirmed the findings of the in vivo experiments. In the meantime, through the observation of the in vitro assays, overexpression of HMGB1 can partially counteract the beneficial effects imposed by GRb1. Judging from our research data, GRb1 could impose a protective effect against CIN by inhibiting inflammatory response via HMGB1/TLR4/NF-κB pathway, whereas HMGB1 constitutes a critical molecular target of GRb1.

Role of GALNT4 in protecting against cardiac hypertrophy through ASK1 signaling pathway.

Pathological myocardial hypertrophy is regulated by multiple pathways. However, its underlying pathogenesis has not been fully explored. The goal of this work was to elucidate the function of polypeptide N-acetylgalactosaminyltransferase 4 (GALNT4) in myocardial hypertrophy and its underlying mechanism of action. We illustrated that GALNT4 was upregulated in the models of hypertrophy. Two cardiac hypertrophy models were established through partial transection of the aorta in GALNT4-knockout (GALNT4-KO) mice and adeno-associated virus 9-GALNT4 (AAV9-GALNT4) mice. The GALNT4-KO mice demonstrated accelerated cardiac hypertrophy, dysfunction, and fibrosis, whereas the opposite phenotype was observed in AAV9-GALNT4 mice. Similarly, GALNT4 overexpression mitigated the degree of phenylephrine-induced cardiomyocyte hypertrophy in vitro whereas GALNT4 knockdown aggravated the hypertrophy. In terms of mechanism, GALNT4 deficiency increased the phosphorylation and activation of ASK1 and its downstream targets (JNK and p38), whereas GALNT4 overexpression inhibited activation of the ASK1 pathway. Furthermore, we demonstrated that GALNT4 can directly bind to ASK1 inhibiting its N-terminally mediated dimerization and the subsequent phosphorylation of ASK1. Finally, an ASK1 inhibitor (iASK1) was able to reverse the effects of GALNT4 in vitro. In summary, GALNT4 may serve as a new regulatory factor and therapeutic target by blocking the activation of the ASK1 signaling cascade.

Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy.

Follicular regulatory T cells (Tfr) have critical functions in inflammatory and autoimmune disorders. The main purpose of the current work was to assess Tfr cell frequency in patients with dilated cardiomyopathy (DCM). Flow cytometry showed that, compared with normal controls, DCM cases showed markedly reduced Tfr cell rates and Tfr/Tfh ratios, but significantly increased follicular helper T cell (Tfh) rates. Correlation analysis showed that the Tfr rate in DCM patients was positively correlated with left ventricular ejection fraction (LVEF), and negatively correlated with N-terminal brain natriuretic peptide (NT-proBNP) levels. Lower Foxp3 and higher Bcl-6, ICOS, and PD-1 mRNA expression levels were found in patients with DCM. In addition, plasma interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-21 levels were significantly increased in DCM cases. Moreover, IgG and IgG3 levels were also elevated in individuals with DCM. Correlation analysis showed that the Tfr rate in DCM patients was negatively correlated with IgG and IgG3, while the Tfh rate was positively correlated with IgG and IgG3. Changes in circulating Tfr levels may have a critical immunomodulatory function in DCM and may become a new therapeutic target for DCM.

The effect of left atrial remodeling after cryoballoon ablation and radiofrequency ablation for paroxysmal atrial fibrillation.

BACKGROUND: Cryoballoon ablation (CBA) and radiofrequency ablation (RFA) are the most common procedures used to treat refractory atrial fibrillation (AF) and are performed through pulmonary vein isolation (PVI). Studies have shown that CBA can approximately match the therapeutic effects of RFA against AF. However, few studies have investigated the difference between CBA and RFA of the effects on left atrial remodeling for paroxysmal AF. OBJECTIVE: Atrial remodeling is considered pivotal to the occurrence and development of AF, therefore we sought to assess the influence of atrial remodeling in patients with paroxysmal AF after CBA and RFA in this study. METHODS: In this nonrandomized retrospective observational study, we enrolled 328 consecutive patients who underwent CBA or RFA for refractory paroxysmal AF in May 2014 to May 2017 in our hospital. After propensity score matching, 96 patients were included in the CBA group, and 96 were included in the RFA group. Patients were asked to undergo a 12-lead electrocardiogram, a 24-h Holter monitor, and an echocardiogram and to provide their clinical history and symptoms at 6 months and 1, 2, and 3 years postprocedurally. Electrical remodeling of the left atrium was assessed by P wave dispersion (Pdis); structural remodeling was assessed by the left atrium diameter (LAD) and left atrial volume index (LAVI) during scheduled visits. RESULTS: As of January 2020, compared with baseline, at 1 year, 2 years, and 3 years after ablation, the average changes in Pdis (∆Pdis), LAD (∆LAD), and LAVI (∆LAVI) were significant in both the CBA and RFA groups. Six months after ablation, ∆Pdis, ∆LAD, and ∆LAVI were greater in the CBA group than in the RFA group. There was no significant difference between the two groups in AF/flutter recurrence, but the AF/flutter-free survival time of CBA group may be longer than RFA group after 2 years after ablation. A higher ∆Pdis, ∆LAD, or ∆LAVI at 1 year after ablation may increase AF/flutter-free survival. CONCLUSIONS: Although CBA and RFA are both effective in left atrial electrical and structural reverse-remodeling in paroxysmal AF, CBA may outperform RFA for both purposes 6 months after ablation. However, during long-term follow-up, there was no significant intergroup difference.

Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy

Follicular regulatory T cells (Tfr) have critical functions in inflammatory and autoimmune disorders. The main purpose of the current work was to assess Tfr cell frequency in patients with dilated cardiomyopathy (DCM). Flow cytometry showed that, compared with normal controls, DCM cases showed markedly reduced Tfr cell rates and Tfr/Tfh ratios, but significantly increased follicular helper T cell (Tfh) rates. Correlation analysis showed that the Tfr rate in DCM patients was positively correlated with left ventricular ejection fraction (LVEF), and negatively correlated with N-terminal brain natriuretic peptide (NT-proBNP) levels. Lower Foxp3 and higher Bcl-6, ICOS, and PD-1 mRNA expression levels were found in patients with DCM. In addition, plasma interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-21 levels were significantly increased in DCM cases. Moreover, IgG and IgG3 levels were also elevated in individuals with DCM. Correlation analysis showed that the Tfr rate in DCM patients was negatively correlated with IgG and IgG3, while the Tfh rate was positively correlated with IgG and IgG3. Changes in circulating Tfr levels may have a critical immunomodulatory function in DCM and may become a new therapeutic target for DCM.

Potential value of guard-wire technology in the interventional treatment for ostial coronary lesions.

BACKGROUND: To explore potential value of guard-wire technology during percutaneous coronary intervention (PCI) in patients with ostial coronary lesions. METHODS: Patients, who underwent PCI, were collected between October 2011 and March 2017. Of the 141 patients, 63 (44.7%) have ostial lesions, and 78 (55.3%) have distal bifurcation sites. They were divided into group A (n = 71) and group B (n = 70). Group A received PCI after guard-wire technology. Group B were given balloon dilation and stent after placing guide wire through target lesion vessel. X-ray exposure time, contrast agent dosage, total PCI duration, pressure incarceration times, cases of malignant arrhythmia and cases of failed PCI of all patients were analyzed, respectively. RESULTS: The general clinical characteristics includes patients age, sex ratio, the proportion of complications, smoking ratio and left ventricular ejection fraction of both groups was not significantly different. X-ray exposure time, contrast agent dosage, PCI total time, stent positioning time, pressure infestation frequency, arrhythmia frequency and complication number of group B were higher than those of group A. There is no case of malignant arrhythmia and case of failed PCI in group A, while there were five malignant arrhythmia and four failed PCI in group B. Contrast agent dosage and cases of failed PCI increased in group B compared with group A. CONCLUSION: The guard wire technology is safer and more feasible to patients with ostial coronary lesions who underwent PCI.

[Genotype and sequence analysis on G2 segments of hantavirus from HFRS patients in Hebei Province].

OBJECTIVE: To know the genotype and subtype of hantavirus (HV) which infected persons in Hebei province. METHODS: According to G2 coding region of 76-118 and R22 strains, specific type primers were designed to detect and identity the types of HV in HFRS patients' sera with RT-nested PCR. Nucleotides were assayed from partial products after purification and reclaim. Then, gene analysis was done with DNAStar package. RESULTS: 17 out of 69 positive serum specimens were successfully detected by RT-PCR and the detection rate was 24.64%, among which, or= 14 days were 0. 17 positive specimens were all belonged to SEO. The nucleotide homology of 9 typical specimens was 92.0%-100%. Between HeB7 and other 8 specimens was 92%-95%, and they belonged to different subtypes. When HeB7 compared with R22 strain, it was 97.7%. HeB7 and R22 belonged to S1 subtype. The 8 specimens except HeB7 was 95.7%-100% and they all belonged to S3 subtype. When compared with 76-118 strain, 9 specimens' nucleotide homology was only 70.3%-72.7%, belonged to different type. CONCLUSION: SEO was the major type of HV from HFRS patients in Hebei province, S3 was the major subtype and S1 was also existed. In a certain area, the HV which belonged to the same type was correspondingly conservative, and had the characteristic of regional stability.

[Mutation screening of RET proto-oncogene in Chinese sporadic patients with pheochromocytoma].

OBJECTIVE: To screen the mutations of RET proto-oncogene in sporadic patients with pheochromocytoma. METHODS: Forty-two cases of sporadic pheochromocytoma were tested for mutations of RET gene. Of these 42 DNA samples, 12 were extracted from peripheral blood cells and 30 from paraffin-embedded pheochromocytoma specimens. The PCR product of exon 10 and exon 11 was used to molecular analysis of the RET proto-oncogene. RESULTS: Among 42 patients, 2 were found to have RET gene mutations. One of mutations located at codon 634 (TGC>TAC) in exon 11 of RET proto-oncogene. Another one located at codon 632 (GAG>AAG). CONCLUSION: Some patients with apparently sporadic pheochromacytoma were carrier of mutations, a routine genetic analysis for mutations of RET gene is indicated for these patients.