Simultaneous ST-elevation in lead augmented vector right (aVR) and III in non-ST-elevation acute coronary syndromes.

Background: The value of ST-elevation in lead augmented vector right (aVR) remains controversial in clinical practice. This study aimed to investigate the association of simultaneous ST-elevation in lead aVR and III with angiographic findings and clinical outcomes in patients with non-ST-elevation acute coronary syndromes (NSTEACS). Methods: In this observational study, patients who had been diagnosed with NSTEACS and presented with ST-elevation in lead aVR and without ST-elevation in any other two contiguous leads were enrolled from January 2018 to June 2019. Demographic, baseline clinical, angiographic and interventional characteristics as well as clinical outcomes were collected and recorded on standardized case report forms. Results: A total of 157 patients meeting the criteria were finally enrolled in this study and classified into two groups according to the presence of ST-elevation in lead III. Patients in the two groups were similar in average age and previous history of hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, stroke, and peripheral vascular diseases (all P>0.05). Patients with ST-elevation in lead III tended to present with myocardial hypertrophy in the echocardiography (P=0.02). The cases with ST-elevation in lead III showed higher high sensitivity troponin T (hs-TnT; P=0.08) and creatinine kinase MB isoenzyme (CK-MB; P<0.01) whereas those without ST-elevation in lead III showed higher N-terminal pro brain natriuretic peptide (NT-proBNP; P=0.02). Of note, patients with ST-elevation in lead III presented with more ST-depression in multiple leads [especially in lead I, augmented vector left (aVL), V3-V6] as well as higher degree of ST-depression (all P<0.05) and were more likely to develop multi-vessel and left main trunk (LM) lesions (P=0.04), with 20% of the cases having a LM lesion and 60% having triple vessel lesions. Patients with ST-elevation in lead III were at increased risk of 3-year major adverse cardiovascular events (MACEs), despite no significant statistical difference between the two groups (hazard ratio =1.29; P=0.26). Conclusions: The NSTEACS cases with simultaneous ST-elevation in lead III and aVR tended to present with more multiple leads with ST-depression, higher degree of ST-depression, and more LM or multi-vessel lesions, suggesting a broader range of severe myocardial ischemia. The concurrent presentation of ST-elevation in lead III and aVR may play a vital role in the diagnosis, risk-stratification, and prediction of poor prognosis during the management of NSTEACS patients.

Enhanced hydrolysis of waste activated sludge and recovery of volatile fatty acids: Performance and mechanistic analysis of synergistic treatment with sodium citrate and calcium oxide.

Anaerobic fermentation has emerged as a promising method of transforming waste activated sludge into high-value products (e.g., volatile fatty acids (VFAs)). This work developed sodium citrate (SC)-calcium oxide (CaO) pretreatment to accelerate the production of VFAs by enhancing sludge solubilization and disintegration of extracellular polymeric substances. The results showed that co-pretreatment with 0.25 g/g TSS of SC and 0.05 g/g TSS of CaO effectively boosted VFAs accumulation (5823.3 mg COD/L), which was 12.2 times higher than the Control group. SC-CaO pretreatment enhanced hydrolysis and acidogenesis by providing ample organic substrates, thereby promoting the growth of hydrolytic and acidogenic bacteria. Additionally, the fermentation broth resulting from co-pretreatment exhibited lower phosphorus concentration and higher biodegradability. Economic analysis confirmed that the combined pretreatment is cost-effective. This work provides a viable strategy for enhancing high-value product recovery from sludge.

Enhancing the efficacy of synthesising PHA from nitrogen-limited activated sludge using magnetic field.

Polyhydroxyalkanes (PHA) is a biodegradable biopolyester. In this study, we introduced the biological effects of magnetic field into a sequencing batch reactor (SBR) for PHA production to evaluate the effect of different strength of magnetic field on the efficacy of PHA synthesis by activated sludge and used the magnetic field to enhance the PHA synthesis capacity of nitrogen-limited activated sludge and to optimise the percentage of the content of the two monomers in PHA. The results showed that the magnetic field of appropriate strength was favourable to increase the production of PHA and to increase the percentage of PHV. In addition, microbial community analysis showed that there was an obvious succession of key functional bacteria under different strength of magnetic field. The highest PHA accumulation was achieved after the magnetic field of 16 mT, which reached 57.65% of the dry weight of sludge. In addition, the PHV monomers were more sensitive to the response of the magnetic field, and the magnetic field of 8mT and 16mT positively promoted the synthesis of PHV. It is worth noting that too high a magnetic field would have an inhibitory effect on the synthesis of PHA.

Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.

PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury. METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC). RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy. CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.

Causal associations between thyroid cancer and IgA nephropathy: a Mendelian randomization study.

BACKGROUND: The incidence of kidney disease caused by thyroid cancer is rising worldwide. Observational studies cannot recognize whether thyroid cancer is independently associated with kidney disease. We performed the Mendelian randomization (MR) approach to genetically investigate the causality of thyroid cancer on immunoglobulin A nephropathy (IgAN). METHODS AND RESULTS: We explored the causal effect of thyroid cancer on IgAN by MR analysis. Fifty-two genetic loci and single nucleotide polymorphisms were related to thyroid cancer. The primary approach in this MR analysis was the inverse variance weighted (IVW) method, and MR‒Egger was the secondary method. Weighted mode and penalized weighted median were used to analyze the sensitivity. In this study, the random-effect IVW models showed the causal impact of genetically predicted thyroid cancer across the IgAN risk (OR, 1.191; 95% CI, 1.131-1.253, P < 0.001). Similar results were also obtained in the weighted mode method (OR, 1.048; 95% CI, 0.980-1.120, P = 0.179) and penalized weighted median (OR, 1.185; 95% CI, 1.110-1.264, P < 0.001). However, the MR‒Egger method revealed that thyroid cancer decreased the risk of IgAN, but this difference was not significant (OR, 0.948; 95% CI, 0.855-1.051, P = 0.316). The leave-one-out sensitivity analysis did not reveal the driving influence of any individual SNP on the association between thyroid cancer and IgAN. CONCLUSION: The IVW model indicated a significant causality of thyroid cancer with IgAN. However, MR‒Egger had a point estimation in the opposite direction. According to the MR principle, the evidence of this study did not support a stable significant causal association between thyroid cancer and IgAN. The results still need to be confirmed by future studies.

Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.

BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI. METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury. RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury. CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition.

ABSTRACT: Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.

Prognostic role of preoperative inflammatory markers in postoperative patients with colorectal cancer.

Background: Inflammatory response markers are prognostic factors for several cancers, but their role in postoperative colorectal cancer (CRC) is unclear. The purpose was to evaluate the role of preoperative Neutrophil-to-Lymphocyte ratio (NLR), Platelet-to-Lymphocyte-ratio (PLR), and Lymphocyte-to-Monocyte ratio (LMR) in the prognosis of postoperative CRC patients. Methods: We retrospectively reviewed 448 CRC patients who had undergone surgical resection from December 2015 to December 2017 in our hospital. The plasma NLR, PLR, LMR, CEA, and CA19-9 were collected within 2 weeks before the operation. We recorded the clinical characteristics and survival data by reviewing medical records and phone calls. We analyzed preoperative inflammatory markers and clinical features using Pearson chi-squared tests or Fisher's tests. Uni- and multivariate Cox regression analyses were performed, and overall survival (OS) was estimated with the Kaplan-Meier method. Results: High NLR and PLR were associated with worse overall survival in postoperative CRC (HR = 2.140, 95%CI = (1.488-3.078), P < 0.001; HR =1.820, 95%CI = (1.271-2.605), P = 0.001). High LMR was associated with improved overall survival in postoperative CRC (HR = 0.341, 95%CI = (0.188-0.618), P < 0.001). In the multivariate regression analysis, the increase of NLR resulted in an increase in the risk of death (HR = 1.678, 95%CI = (1.114-2.527), P = 0.013), and for the LMR, a reduction of the risk of death (HR = 0.480, 95%CI = (0.256 - 0.902), P = 0.023). Moreover, TNM stage, CA-199, CEA, nerve or vascular invasion (NVI) and adjuvant chemotherapy after surgery also were associated with worse overall survival in postoperative CRC. Conclusion: Current evidence indicates that preoperative inflammatory markers NLR, LMR, and PLR are associated with overall survival in postoperative patients with colorectal cancer. NLR is an independent risk factor, and LMR is an independent protective factor in CRC patients after surgery.

GAS-STING signaling plays an essential pathogenetic role in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: The severe unfavorable effects of doxorubicin on the heart restrict its clinical usage. Numerous investigations document that cyclic GMP-AMP synthase (cGAS) activator of interferon genes (STING) cascade influences inflammation along with the immune response in a variety of diseases. The pathophysiological function of the cGAS-STING cascade in Doxorubicin-induced cardiomyopathy (DIC) is, nevertheless, unknown. METHODS: In vivo, cardiotoxicity was triggered by a single dose of intra-peritoneal inoculation of doxorubicin (15 mg/kg) in wild-type C57BL/6J mice and STING knockdown animals. Adeno-associated virus 9 (AAV9) was utilized to silence STING. qPCR along with Western blotting were adopted to assess alterations in the cGAS/STING cascade. To assess cardiac function, we employed echocardiography coupled with histology, as well as molecular phenotyping. In vitro, HL-1 cardiomyocytes were introduced as test models. RESULTS: In wild type mice, doxorubicin stimulation significantly activated the cGAS/STING pathway. STING silencing increased rate of survival along with heart function in mice, as well as diminished myocardial inflammatory cytokines along with apoptosis. These observations were also confirmed by utilizing siRNA of STING in vitro studies. CONCLUSION: This research premise established that STING inhibition could alleviate Dox-triggered cardiotoxicity in mice. As a result, preventing DIC by repressing STING in cardiomyocytes might be a possible treatment approach.

Left Bundle Branch Area Pacing versus Biventricular Pacing for Cardiac Resynchronization Therapy on Morbidity and Mortality.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). We aimed to compare the morbidity and mortality associated with LBBAP versus BVP in patients undergoing CRT implantation. METHODS: Consecutive patients who received CRT from two high-volume implantation centers were retrospectively recruited. The primary endpoint was a composite of all-cause death and heart failure hospitalization, and the secondary endpoint was all-cause death. RESULTS: A total of 491 patients receiving CRT (154 via LBBAP and 337 via BVP) were included, with a median follow-up of 31 months. The primary endpoint was reached by 21 (13.6%) patients in the LBBAP group, as compared with 74 (22.0%) patients in the BVP group [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.43-1.14, P = 0.15]. There were 10 (6.5%) deaths in the LBBAP group, as compared with 31 (9.2%) in the BVP group (HR 0.91, 95% CI 0.44-1.86, P = 0.79). No significant difference was observed in the risk of either the primary or secondary endpoint between LBBAP and BVP after multivariate Cox regression (HR 0.74, 95% CI 0.45-1.23, P = 0.24, and HR 0.77, 95% CI 0.36-1.67, P = 0.51, respectively) or propensity score matching (HR 0.72, 95% CI 0.41-1.29, P = 0.28, and HR 0.69, 95% CI 0.29-1.65, P = 0.40, respectively). CONCLUSION: LBBAP was associated with a comparable effect on morbidity and mortality relative to BVP in patients with indications for CRT.

Translocation of gasdermin D induced mitochondrial injury and mitophagy mediated quality control in lipopolysaccharide related cardiomyocyte injury.

BACKGROUNDS: Inflammation underlies the mechanism of different kinds of heart disease. Cytoplasmic membrane localized N-terminal fragment of gasdermin-D (GSDMD-N) could induce inflammatory injury to cardiomyocyte. However, effects and dynamic changes of GSDMD during the process of lipopolysaccharide (LPS) related inflammatory stress induced cardiomyocyte injury are barely elucidated to date. In this study, LPS related cardiomyocyte injury was investigated based on potential interaction of GSDMD-N induced mitochondrial injury and mitophagy mediated mitochondria quality control. METHODS: HL-1 cardiomyocytes were treated with LPS and Nigericin to induce inflammatory stress. The dual-fluorescence-labelled GSDMD expressed HL-1 cardiomyocytes were constructed to study the translocation of GSDMD. The mitochondrial membrane potential (MMP) was measured by JC-1 staining. Mitophagy and autophagic flux were recorded by transmission electron microscopy and fluorescent image. RESULTS: GSDMD-N showed a time-dependent pattern of translocation from mitochondria to cytoplasmic membrane under LPS and Nigericin induced inflammatory stress in HL-1 cardiomyocytes. GSDMD-N preferred to localize to mitochondria to permeablize its membrane and dissipate the MMP. This effect couldn't be reversed by cyclosporine-A (mPTP inhibitor), indicating GSDMD-N pores as alternative mechanism underlying MMP regulation, in addition to mitochondrial permeability transition pore (mPTP). Moreover, the combination between GSDMD-N and autophagy related Microtubule Associated Protein 1 Light Chain 3 Beta (LC3B) was verified by co-immunoprecipitation. Besides, mitophagy alleviating GSDMD-N induced mitochondrial injury was proved by pre-treatment of autophagy antagonist or agonist in GSDMD-knock out or GSDMD-overexpression cells. A time-dependent pattern of GSDMD translocation and mitochondrial GSDMD targeted mitophagy were verified. CONCLUSION: Herein, our study confirmed a crosstalk between GSDMD-N induced mitochondrial injury and mitophagy mediated mitochondria quality control during LPS related inflammation induced cardiomyocyte injury, which potentially facilitating the development of therapeutic target to myocardial inflammatory disease. Our findings support pharmaceutical intervention on enhancing autophagy or inhibiting GSDMD as potential target for inflammatory heart disease treatment.

Role of the Gut Microbiota in Glucose Metabolism During Heart Failure.

Background: Blood glucose disorders are prevalent in heart failure, while the influence of the gut microbiota on this process remains unclear. Here, we used heart failure model mice and fecal microbiota transplantation (FMT) mice to evaluate the effect of the gut microbiota on the regulation of blood glucose during heart failure. Methods: Thoracic aortic constriction (TAC) surgery was performed in a heart failure model, while an antibiotic cocktail was used to eliminate the microbiota to establish a germ-free (GF) model. Blood glucose, insulin, and glucagon levels were measured, and an intraperitoneal glucose tolerance test (IPGTT) was performed. 16S rRNA sequencing and metabolomics were used to evaluate the changes in gut microbiota structure and metabolism induced by TAC. Another group of FMT mice was established to observe the effect of the gut microbiota on host metabolism. Results: After microbiota clearance, the glucagon concentration, the homeostasis model assessment for insulin resistance (HOMA-IR), and the area under the curve (AUC) of the IPGTT were decreased significantly in the TAC germ-free (TAC-GF) group in the third month as compared to the other groups. 16S rRNA sequencing indicated that TAC surgery affected the gut microbiota structure, and fecal metabolomics suggested that noradrenaline and adrenaline levels were higher in the TAC group than in the sham group. The FMT mice transplanted with the feces of the TAC (FMT-TAC) mice displayed a higher AUC of IPGTT, accompanied by a higher glucagon level, insulin level, and HOMA-IR than those of the mice in the other groups. The serum metabolomics of the FMT-TAC group showed that noradrenaline levels were significantly higher than those of the FMT-sham group. Conclusion: The gut microbiota and its metabolism were altered during heart failure, which increased blood glucose and glucagon in the host.

Risk factors of pacing dependence and cardiac dysfunction in patients with permanent pacemaker implantation.

AIMS: Right ventricular pacing (RVP) dependence could impair left ventricular ejection fraction (LVEF). This study aimed to illuminate the relationship between RVP proportion and LVEF, as well as disclosing independent predictors of RVP dependence. METHODS AND RESULTS: Patients indicated for permanent pacemaker implantation were included (2016-2020). The ventricular pacing lead was placed in right ventricular apex or septum. Pacing mode programming followed universal standard. Electrocardiographic, echocardiographic, and serological parameters were collected. RVP dependence was defined according to its influence on LVEF. This study was of case-control design. Included patients were matched by potentially confounding factors through propensity score matching. A total of 1183 patients were included, and the mean duration of follow-up was 24 months. Percentage of RVP < 80% hardly influenced LVEF; however, LVEF tended to decrease with higher RVP proportion. High degree/complete atrioventricular block (AVB) [odds ratio (OR) = 5.71, 95% confidence interval (CI): 3.66-8.85], atrial fibrillation (AF) (OR = 2.04, 95% CI: 1.47-2.82), percutaneous coronary intervention (PCI) (OR = 2.89, 95% CI: 1.24-6.76), maximum heart rate (HRmax ) < 110 b.p.m. (OR = 2.74, 95% CI: 1.58-4.76), QRS duration > 120 ms (OR = 2.46, 95% CI: 1.42-4.27), QTc interval > 470 ms (OR = 2.01, 95% CI: 1.33-3.05), and pulmonary artery systolic pressure (PASP) > 40 mmHg (OR = 1.93, 95% CI: 1.46-2.56) were proved to predict RVP dependence. CONCLUSIONS: High RVP percentage (>80%) indicating RVP dependence significantly correlates with poor prognosis of cardiac function. High degree/complete AVB, AF, ischaemic aetiology, PCI history, HRmax  < 110 b.p.m., QRS duration > 120 ms, QTc interval > 470 ms, and PASP > 40 mmHg were verified as independent risk factors of RVP dependence.

Calcitriol ameliorates damage in high-salt diet-induced hypertension: Evidence of communication with the gut-kidney axis.

Several studies have established a link between high-salt diet, inflammation, and hypertension. Vitamin D supplementation has shown anti-inflammatory effects in many diseases; gut microbiota is also associated with a wide variety of cardiovascular diseases, but potential role of vitamin D and gut microbiota in high-salt diet-induced hypertension remains unclear. Therefore, we used rats with hypertension induced by a high-salt diet as the research object and analyzed the transcriptome of their tissues (kidney and colon) and gut microbiome to conduct an overall analysis of the gut-kidney axis. We aimed to confirm the effects of high salt and calcitriol on the gut-kidney immune system and the composition of the intestinal flora. We demonstrate that consumption of a high-salt diet results in hypertension and inflammation in the colon and kidney and alteration of gut microbiota composition and function. High-salt diet-induced hypertension was found to be associated with seven microbial taxa and mainly associated with reduced production of the protective short-chain fatty acid butyrate. Calcitriol can reduce colon and kidney inflammation, and there are gene expression changes consistent with restored intestinal barrier function. The protective effect of calcitriol may be mediated indirectly by immunological properties. Additionally, the molecular pathways of the gut microbiota-mediated blood pressure regulation may be related to circadian rhythm signals, which needs to be further investigated. An innovative association analysis of the microbiota may be a key strategy to understanding the association between gene patterns and host.