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Purpose: This study aimed to compare and analyze the effectiveness of unilateral biportal endoscopic (UBE) decompressive laminectomy plus fusion and microscope-assisted open decompressive laminectomy plus fusion. Methods: A total of 143 patients with lumbar spinal stenosis were enrolled in this study between March 2020 and February 2021 with a minimum 2 years follow-up visit to our hospital. Sixty-five patients underwent the unilateral biportal endoscopic technique and were assigned to the UBE group, and the remaining 78 patients with microscope assistant were assigned to the Microscope group. The baseline characteristics, clinical outcomes, and radiological data were retrospectively collected and analyzed, as well as Clinical outcomes, radiological data and complications. Results: There were no significant differences between the two groups in terms of baseline characteristics (P > 0.05). The UBE group was demonstrated to be significantly superior in CRP, drainage, blood loss, treatment cost and Hospital stay than the Microscope group (P 0.05). Conclusion: In view of the satisfactory clinical outcomes of patients and notable decompression at the stenosed segment, UBE is a feasible, minimally invasive technique for single level lumbar canal stenosis.

Abstract Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/β-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.

Abstract Background Advanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD. Methods Human aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr −/− ) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group. Results AGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities. Conclusions AGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD. Graphic Abstract

BackgroundOsteoporosis vertebral compression fractures (OVCF) are common with the aging process. This study aimed to compare the effects of unilateral transverse process extrapedicular (UEPKP) and bilateral transpedicular percutaneous kyphoplasty (BTPKP) for patients with thoracolumbar OVCF.MethodsData from 136 patients with OVCF treated with single-level PKP in our hospital between May 2019 and April 2021 were studied. Patients were grouped based on surgical procedure: there were 62 patients in the UEPKP group and 74 in the BTPKP group. All clinical and radiological data were collected from medical records. Clinical outcomes, including visual analog scale (VAS), Oswestry Disability Index (ODI), and Japanese Orthopaedic Association (JOA) scores of the lumbar spine, were evaluated preoperatively, postoperatively, and at the follow-up visit. The radiological evaluations (anterior vertebral height rate and local kyphosis angle) and complications were also collected.ResultsAll patients had successfully improved after surgery. In the UEPKP group, patients showed a significantly shorter operating time and lower fluoroscopy frequency than patients in the BTPKP group (p

Abstract Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD+ levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes. Methods In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD+ levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis. Results AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD+ levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed. Conclusion Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD+, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.

With the escalating incidence of heart failure, accurate diagnosis is paramount for tailored therapeutic interventions. The tricuspid valve, particularly tricuspid regurgitation, once relegated as the “forgotten valve”, has gained prominence due to increasing evidence implicating severe tricuspid valve disease in the prognosis of diverse cardiovascular conditions. This review delineates recent significant advancements in imaging modalities, transcatheter interventions, and epidemiological and pathophysiological insights regarding tricuspid regurgitation complicating heart failure. A comprehensive understanding of these innovative concepts and technologies can significantly improve patient outcomes.

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD. Methods We obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms. Results Here, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 → 6)-β-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions. Conclusion PTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs. Graphical Abstract Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.

Abstract Aims The commonly used treatments of adult degeneration scoliosis (ADS) were posterior long segment screw fixation with osteotomies. Recently, lateral lumbar intervertebral fusion combined two-stage posterior screw fixation (LLIF + PSF) as a new strategy without osteotomy. Herein, this study aimed to compare the clinical and radiological outcomes among LLIF + PSF and pedicle subtraction osteotomy (PSO), posterior column osteotomies (PCO). Methods Totals of 139 ADS patients underwent operation with 2 years longer follow-up visit between January 2013 and January 2018 in Ningbo No.6 Hospital were enrolled into this study. 58 patients were included in PSO group, 45 in PCO group and 36 in LLIF + PSF group, The clinical and radiological data were reviewed from medical records. Baseline characteristic, perioperative radiological data (sagittal vertical axis (SVA), coronal balance (CB), Cobb angle of Mian curve (MC), Lumbar lordosis (LL), pelvic tilt (PT) and pelvic incidence-lumbar lordosis mismatch (PI-LL)), clinical outcomes (VAS of back and leg, Oswestry disability index (ODI) and Scoliosis Research Society 22-question Questionnaire (SRS-22)) and complications were evaluated and compared. Result There were no significantly difference in baseline characteristics, preoperative radiological parameters and clinical outcomes among three groups. LLIF + PSF group was significantly shorter in operation time than other two groups (P

Abstract Objective Recent studies have found that polycyclic aromatic hydrocarbons (PAHs) exposure may increase the risk of cardiovascular disease. The present study aimed to explore the association between PAHs exposure and severe abdominal aortic calcification (AAC) in adults. Methods Data were collected from the 2013–2014 National Health and Nutrition Examination Survey. PAHs exposure was analyzed from urinary mono hydroxylated metabolites of PAHs. Logistic regression models and subgroup analysis were performed to explore the association of PAHs exposure with severe AAC prevalence. Results A total of 1,005 eligible individuals were recruited into the study. After adjusting for confounding factors, those with the highest quartiles of 1-hydroxynaphthalene (1-NAP: OR 2.19, 95% CI 1.03–4.68, P for trend

Abstract Aims Heart failure (HF) remains a major public health problem with increasing prevalence in China. This study evaluated the clinical performance and quality measures for HF management to identify gaps in the standardization of care for patients hospitalized for HF in China. Methods and results Following the results of China‐HF stage I (2012–2015), the second stage of the China‐HF was launched in 2017. Among 113 hospitals with ≥100 cases, the China‐HF Stage II assessed the quality of care measures for HF and compared results with previous data in China and the US‐based Get with The Guidelines‐Heart Failure (GWTG‐HF) registries. In total, 34 938 patients hospitalized with HF were enrolled from January 2017 to October 2020. Echocardiographic left ventricular function and natriuretic peptide test were performed in 93.7% and 93.0% of the cases, respectively. Adherence to standardized guidelines in China‐HF stage II was higher than that in the China‐HF stage I, but generally lower than GWTG‐HF registry with 78.2% of eligible patients was prescribed oral diuretics, 78.7% renin‐angiotensin‐system inhibitors, and 82.2% beta‐blockers. Implantable cardioverter‐defibrillators and cardiac resynchronization devices were implanted in 3.9% and 14.6%, respectively. In contrast, the proportion of eligible patients discharged with spironolactone (87.8%) was higher than GWTG‐HF. The median length of hospitalization was 9 (6, 12) days, and 938 (2.8%) patients died or withdrew from treatment during hospitalization. Conclusions Despite significant improvements in the use of guideline‐recommended testing and therapy, there remain major gaps in quality of care for patients hospitalized for HF in China that are generally larger than gaps observed in the United States.

Abstract Aims This study sought to investigate the association between blood pressure (BP) trajectories from early to middle adulthood and echocardiographic indices of structure and function in middle age. Methods and results This prospective cohort study included 4717 black and white adults aged 18–30 years at baseline (1985–86) who were followed over 30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Trajectories of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) from the Year 0 examination to Year 30 examination were identified using latent mixture modelling. Echocardiographic indices of myocardial structure, systolic function, and diastolic function were assessed at the Year 30 examination. Five distinct SBP trajectory groups were identified: low‐stable [1110 participants (23.5%)], moderate‐stable [2188 (46.4%)], high‐stable [850 (18.0%)], moderate‐increasing [416 (8.8%)], and high‐increasing [153 (3.2%)]. After adjustment for clinical variables, a significant decreasing trend was observed from the high‐increasing and moderate‐increasing groups through to the low‐stable group for left ventricular (LV) mass index [mean (SE): high‐increasing, 112.3 (3.4); moderate‐increasing, 99.3 (2.6); high‐stable, 88.9 (2.5); moderate‐stable, 86.1 (2.3); low‐stable, 82.1 (2.4), P trend

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Valvular fibrocalcification is a characteristic pathological change. In diseased valves, monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities. However, the impact of activated monocytes on valular fibrocalcification remains unclear. We tested the hypothesis that pro-inflammatory mediators from activated monocytes elevate AVIC fibrogenic and osteogenic activities. Methods and results Picro-sirius red staining and Alizarin red staining revealed collagen and calcium depositions in cultured human AVICs exposed to conditioned media derived from Pam3CSK4-stimulated monocytes (Pam3 CM). Pam3 CM up-regulated alkaline phosphatase (ALP), an osteogenic biomarker, and extracellular matrix proteins collagen I and matrix metalloproteinase-2 (MMP-2). ELISA analysis identified high levels of RANTES and TNF-α in Pam3 CM. Neutralizing RANTES in the Pam3 CM reduced its effect on collagen I and MMP-2 production in AVICs while neutralizing TNF-α attenuated the effect on AVIC ALP production. In addition, Pam3 CM induced NF-κB and JNK activation. While JNK mediated the effect of Pam3 CM on collagen I and MMP-2 production, NF-κB was critical for the effect of Pam3 CM on ALP production in AVICs. Conclusions This study demonstrates that activated monocytes elevate the fibrogenic and osteogenic activities in human AVICs through a paracrine mechanism. TNF-α and RANTES mediate the pro-fibrogenic effect of activated monocytes on AVICs through activation of JNK, and TNF-α also activates NF-κB to elevate AVIC osteogenic activity. The results suggest that infiltrated monocytes elevate AVIC fibrocalcific activity to promote CAVD progression.

ObjectiveHeart failure with mildly reduced ejection fraction (HFmrEF) has been recently recognized as a unique phenotype of heart failure (HF) in current practical guideline. However, risk stratification models for mortality and HF re-hospitalization are still lacking. This study aimed to develop and validate a novel machine learning (ML)-derived model to predict the risk of mortality and re-hospitalization for HFmrEF patients.MethodsWe assessed the risks of mortality and HF re-hospitalization in HFmrEF (45–49%) patients enrolled in the TOPCAT trial. Eight ML-based models were constructed, including 72 candidate variables. The Harrell concordance index (C-index) and DeLong test were used to assess discrimination and the improvement in discrimination between models, respectively. Calibration of the HF risk prediction model was plotted to obtain bias-corrected estimates of predicted versus observed values.ResultsLeast absolute shrinkage and selection operator (LASSO) Cox regression was the best-performing model for 1- and 6-year mortality, with a highest C-indices at 0.83 (95% CI: 0.68–0.94) over a maximum of 6 years of follow-up and 0.77 (95% CI: 0.64–0.89) for the 1-year follow-up. The random forest (RF) showed the best discrimination for HF re-hospitalization, scoring 0.80 (95% CI: 0.66–0.94) and 0.85 (95% CI: 0.71–0.99) at the 6- and 1-year follow-ups, respectively. For risk assessment analysis, Kansas City Cardiomyopathy Questionnaire (KCCQ) subscale scores were the most important predictor of readmission outcome in the HFmrEF patients.ConclusionML-based models outperformed traditional models at predicting mortality and re-hospitalization in patients with HFmrEF. The results of the risk assessment showed that KCCQ score should be paid increasing attention to in the management of HFmrEF patients.

ObjectiveThis study aimed to assess the association between triglyceride-glucose (TyG) index/homeostasis model assessment-insulin resistance (HOMA-IR) within young adults and congestive heart failure (CHF), and to explore whether TyG index can replace HOMA-IR as a surrogate marker for IR in predicting the risk of CHF.MethodsA total of 4,992 participants between the ages of 18 and 30 years were enrolled from the Coronary Artery Risk Development in Young Adults (CARDIA) investigation [from 1985 to 1986 (year 0)]. A Cox proportional hazard regression analysis was conducted for assessing correlations between baseline TyG index/HOMA-IR and CHF events, together with the receiver operating characteristic (ROC) curve employed for scrutinizing TyG index/HOMA-IR and the risk of CHF.ResultsDuring the 31-year follow-up period, 64 (1.3%) of the 4,992 participants developed CHF. In multivariable Cox proportional hazards models, adjusted for confounding factors for CHF, an increased risk of CHF was associated with a per-unit increase in the TyG index [hazard ratio (HR) 2.8; 95% confidence interval (CI), 1.7–4.7] and HOMA-IR (HR 1.2; 95% CI, 1.1–1.3). A Kaplan–Meier curve analysis showed that participants in the TyG index and HOMA-IR index Q4 group had a higher risk of CHF than those in the Q1 group. The area under curve (AUC) for the TyG index and HOMA-IR consisted of 0.67 (95% CI, 0.6–0.742) and 0.675 (95% CI, 0.604–0.746), respectively. There were no significant differences between the TyG index and HOMA-IR for AUC (p = 0.986).ConclusionThe higher TyG index and HOMA-IR are independent risk factors for CHF. The TyG index can replace HOMA-IR in young adulthood as a surrogate marker for IR to predict the risk of CHF.

Both mitochondrial quality control and energy metabolism are critical in maintaining the physiological function of cardiomyocytes. When damaged mitochondria fail to be repaired, cardiomyocytes initiate a process referred to as mitophagy to clear defective mitochondria, and studies have shown that PTEN-induced putative kinase 1 (PINK1) plays an important role in this process. In addition, previous studies indicated that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that promotes mitochondrial energy metabolism, and mitofusin 2 (Mfn2) promotes mitochondrial fusion, which is beneficial for cardiomyocytes. Thus, an integration strategy involving mitochondrial biogenesis and mitophagy might contribute to improved cardiomyocyte function. We studied the function of PINK1 in mitophagy in isoproterenol (Iso)-induced cardiomyocyte injury and transverse aortic constriction (TAC)-induced myocardial hypertrophy. Adenovirus vectors were used to induce PINK1/Mfn2 protein overexpression. Cardiomyocytes treated with isoproterenol (Iso) expressed high levels of PINK1 and low levels of Mfn2, and the changes were time dependent. PINK1 overexpression promoted mitophagy, attenuated the Iso-induced reduction in MMP, and reduced ROS production and the apoptotic rate. Cardiac-specific overexpression of PINK1 improved cardiac function, attenuated pressure overload-induced cardiac hypertrophy and fibrosis, and facilitated myocardial mitophagy in TAC mice. Moreover, metformin treatment and PINK1/Mfn2 overexpression reduced mitochondrial dysfunction by inhibiting ROS generation leading to an increase in both ATP production and mitochondrial membrane potential in Iso-induced cardiomyocyte injury. Our findings indicate that a combination strategy may help ameliorate myocardial injury by improving mitochondrial quality.

ObjectiveTo explore the association between dietary fiber and heart failure (HF).MethodsData were collected from the 2009–2018 National Health and Nutrition Examination Survey. Dietary fiber intake data were obtained from two 24-h dietary recall interviews. Logistic regression and restricted cubic spline models were used to explore the association of dietary intakes of total, cereal, fruit, and vegetable fiber with HF prevalence.ResultsA total of 21869 adults were included in this study. After adjusting for multiple confounding factors, the odds ratios (OR) and 95% confidence intervals (CI) for HF was 0.49 (0.28 to 0.87, P for trend = 0.016) for the highest tertile versus lowest tertile of total fiber intake. Similar results were observed for cereal but not fruit and vegetable fiber intake. Dose-response analysis indicated that dietary intake of total and cereal fiber were inversely associated with HF in a linear manner.ConclusionIntakes of total and cereal fiber were inversely associated with HF in adults.

Abstract Aims The aim of this study was to investigate the impact of digoxin use on the outcomes of patients with heart failure with reduced ejection fraction (HFrEF) and its possible interaction with atrial fibrillation or use of currently guideline‐recommended treatments in the real world in China. Methods and results Patients hospitalized with HFrEF from 45 hospitals participating in the China National Heart Failure Registration Study (CN‐HF) were enrolled to assess the all‐cause mortality, HF mortality, all‐cause re‐hospitalization, and HF re‐hospitalization associated with digoxin use. Eight hundred eighty‐two eligible HFrEF patients in the CN‐HF registry were included: 372 patients with digoxin and 510 patients without digoxin. Among them, 794 (90.0%) patients were followed up for the endpoint events, with a median follow‐up of 28.6 months. Kaplan–Meier survival analysis showed that the all‐cause mortality (P < 0.001) and all‐cause re‐hospitalization (P = 0.020) were significantly higher in digoxin group than non‐digoxin group, while HF mortality (P = 0.232) and HF re‐hospitalization (P = 0.098) were similar between the two groups. The adjusted Cox proportional‐hazards regression analysis demonstrated that digoxin use remained as an independent risk factor for increased all‐cause mortality [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.27–2.44; P = 0.001] and all‐cause re‐hospitalization (HR 1.27; 95% CI 1.03–1.57; P = 0.029) in HFrEF patients and the predictive value of digoxin for all‐cause mortality irrespective of rhythm or in combination with other guideline‐recommended therapies. Conclusions Digoxin use is independently associated with increased risk of all‐cause mortality and all‐cause re‐hospitalization in HFrEF patients.

ObjectiveTo evaluate the association between serum galectin-3 and all-cause death (ACD) and cardiovascular death (CVD) in patients with chronic heart failure (CHF).MethodsThe PubMed and Embase databases and Clinical Trials Registry (www.clinicaltrials.gov) were searched for studies with data on serum galectin-3 and ACD and CVD in CHF patients. The hazard ratios (HRs) of ACD and CVD were calculated and presented with 95% CIs. HRs were pooled using fixed effects or random effects models when appropriate. Sensitivity analysis, meta-regression and subgroup analysis were applied to find the origin of heterogeneity. Visual inspection of Begg's funnel plot and Egger's test were performed to assess the possibility publication bias.ResultsPooled data included the results from 6,440 patients from 12 studies in the meta-analysis. Higher serum galectin-3 was associated with a higher risk of ACD (HR, 1.38; 95% CI, 1.14–1.67) and CVD (HR, 1.13; 95% CI, 1.02–1.25) in CHF patients. In the subgroup analyses, higher serum galectin-3 was associated with an increased risk of ACD in all subgroups. The pooled HR of the shorter follow-up group (1.78; 95% CI, 1.50–2.11) was significantly higher than the pooled HR of the longer follow-up group (1.15; 95% CI, 1.05–1.25). Sensitivity analysis of eliminating one study in each turn indicated that Koukoui et al.'s study had the largest influence on the risk of all-cause death. All-cause death publication bias was not detected (Pr>|z| = 0.35 for Begg's test and P>|t| = 0.15 for Egger's test).ConclusionsSerum galectin-3 has prognostic value of both all-cause death and cardiovascular death in CHF. Serum galectin-3 could be useful for risk classification in patients with CHF.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=193399.

Heme, the protoporphyrin IX iron complex is widely present in the human body and it is involved in oxygen storage, electron transfer, and enzymatic reactions. However, free heme can be toxic as it catalyzes the production of reactive oxygen species, oxidizes lipids and proteins, and causes DNA damage, thereby inducing a pro-inflammatory environment. The generation, metabolism, and degradation of heme in the human body are regulated by precise mechanisms to ensure that heme remains non-toxic. However, in several types of cardiovascular diseases, impaired metabolism and exposure to heme may occur in pathological processes, including neovascularization, internal hemorrhage, ischemia, and reperfusion. Based on years of research, in this review, we aimed to summarize the underlying mechanisms by which heme contributes to the development of cardiovascular diseases through oxidative stress, relative pathway gene expression regulation and phenotypic changes in cells. Excess heme plays a detrimental role in atherosclerosis, heart failure, myocardial ischemia-reperfusion injury, degenerative aortic valve stenosis, cardiac iron overload. Recent researches revealed that in some cases heme involved in cardiac damage though ferroptosis. Thus, heme concentrations beyond normal levels are dangerous. Further research on the role of heme in cardiovascular diseases is needed.

Objective: A meta-analysis was performed to compare the efficacy and safety of antithrombotic therapy with non-vitamin K antagonist oral anticoagulants (NOACs) versus standard care in patients after successful transcatheter aortic valve replacement (TAVR). Methods: A systematic search of PubMed, Cochrane Central Register of Controlled Trials, and EMBASE databases and ClinicalTrials.gov website (through 21 October 2020) was performed. Risk ratios (RRs) with 95% confidence intervals (CIs) for all outcomes were calculated using random-effects models. Results: Twelve studies (two studies were randomized controlled trials) comprising 6943 patients were included (5299 had indications for oral anticoagulation (OAC) and 1644 had none). No significant differences were found between NOACs and the standard care in the incidences of all stroke, a composite endpoint, and major/life-threatening bleeding. NOACs were associated with lower all-cause mortality than vitamin K antagonists (VKAs) in post-TAVR patients with indications for OAC after more than 1 year of follow-up [RR = 0.64; 95% CI, (0.42, 0.96); p = 0.03], whereas NOACs exhibited poor outcomes than antiplatelet therapy (APT) in patients without indications for OAC [RR = 1.66; 95% CI, (1.12, 2.45); p = 0.01]. In the prevention of valve thrombosis, NOACs and VKAs were not significantly different in patients with indications for OAC [RR = 0.66; 95% CI, (0.24, 1.84); p = 0.43], whereas NOACs were better than APT in patients without indications for OAC [RR = 0.19; 95% CI, (0.04, 0.83); p = 0.03]. Conclusions: In patients with indications for OAC, post-TAVR antithrombotic therapy with NOACs was more favorable due to its lower all-cause mortality after more than 1 year of follow-up. In those without indications for OAC, NOACs presented poorer outcomes due to its higher all-cause mortality.

Purpose: To compare the effect between C2 spinous muscle complex graft and iliac bone graft in C2-3 pedicle screw fixation for instable Hangman fracture. Using axial spinous muscle complex instead of iliac bone for instable Hangman fracture can decrease neck pain, bone donor site complication, and operation time.Method: The outcomes of C2-3 pedicle screw fixation with C2 spinous muscle complex were compared with iliac bone graft in 18 and 21 patients with instable Hangman fracture. The mean age was 49.1 ± 15.8 years in the complex group and 55.3 ± 12.2 years in the Iliac group, and the mean time to surgery of the patients was 3.3 ± 0.6 days in the complex group and 3.6 ± 0.9 days in the iliac group. Outcome measures including operation time, blood loss, visual analog scale (VAS) for pain, Japanese orthopedic association score (JOA), American spine injure association classification (ASIA), and bone fusion time were collected from medical records. In addition, the postoperative complications were also recorded.Results: There were significant differences in operation time and interoperative blood loss between the two groups (P < 0.01). Also a significant difference was found in VAS score and JOA score between the two groups (P = 0.0012 and P < 0.001, respectively) at 1-month follow-up, whereas, no significant difference was found at other visit time. In the final visit, all patients showed good bone fusion, and two patients shows incision edema and exudation in the iliac group.Conclusion: C2-3 pedicle screw fixation with C2 spinous muscle complex graft maybe a feasible and safe procedure for instable Hangman fracture.

Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

The new guidelines classify heart failure (HF) into three subgroups based on the ejection fraction (EF): HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF), and HF with preserved EF (HFpEF). The new guidelines regarding the declaration of HFmrEF as a unique phenotype have achieved the goal of stimulating research on the basic characteristics, pathophysiology, and treatment of HF patients with a left ventricular EF of 40–49%. Patients with HFmrEF have more often been described as an intermediate population between HFrEF and HFpEF patients; however, with regard to etiology and clinical indicators, they are more similar to the HFrEF population. Concerning clinical prognosis, they are closer to HFpEF because both populations have a good prognosis and quality of life. Meanwhile, growing evidence indicates that HFmrEF and HFpEF show heterogeneity in presentation and pathophysiology, and the emergence of this heterogeneity often plays a crucial role in the prognosis and treatment of the disease. To date, the exact mechanisms and effective treatment strategies of HFmrEF and HFpEF are still poorly understood, but some of the current evidence, from observational studies and post-hoc analyses of randomized controlled trials, have shown that patients with HFmrEF may benefit more from HFrEF treatment strategies, such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sacubitril/valsartan. This review summarizes available data from current clinical practice and mechanistic studies in terms of epidemiology, etiology, clinical indicators, mechanisms, and treatments to discuss the potential association between HFmrEF and HFpEF patients.

Background: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary supplementation has been proposed as a novel treatment modality for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to exert protective effects in multiple diseases. However, the role of hesperetin in CAVD remains unclear. Methods: Human aortic valve interstitial cells (VICs) were isolated from aortic valve leaflets. A mouse model of aortic valve stenosis was constructed by direct wire injury (DWI). Immunoblotting, immunofluorescence staining, and flow cytometry were used to investigate the roles of sirtuin 7 (Sirt7) and nuclear factor erythroid 2-related factor 2 (Nrf2) in hesperetin-mediated protective effects in VICs. Results: Hesperetin supplementation protected the mice from wire-injury-induced aortic valve stenosis; in vitro, hesperetin inhibited the lipopolysaccharide (LPS)-induced activation of NF-κB inflammatory cytokine secretion and osteogenic factors expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in the antioxidant levels in VICs. These benefits of hesperetin may have been obtained by activating Nrf2–ARE signaling, which corrected the dysfunctional mitochondria. Furthermore, we found that hesperetin could directly bind to Sirt7 and that the silencing of Sirt7 decreased the effects of hesperetin in VICs and potently abolished the ability of hesperetin to increase Nrf2 transcriptional activation. Conclusions: Our work demonstrates that hesperetin plays protective roles in the aortic valve through the Sirt7–Nrf2–ARE axis; thus, hesperetin might be a potential dietary supplement that could prevent the development of CAVD.

Background: Despite that nutritional deficiency existed in congestive heart failure (CHF), there is a large amount of CHF patients suffering from obesity. This study aimed to identify the differences for increased BMI or obesity in CHF patients.Methods: This cross-sectional study included adults from the National Health and Nutrition Examination Survey 2007–2016. Differences were compared between CHF participants vs. non-CHF participants, and BMI ≥ 30 kg/m2 vs. BMI < 30 kg/m2 CHF participants.Results: CHF participants were with higher BMI, lower energy and macronutrient intake, lower physical activity level and longer rest time, and lower hematocrit and hemoglobin level (all P < 0.05) than non-CHF participants. The prevalence of BMI ≥ 30 kg/m2 in participants with CHF was 53.48%. There was no significant difference observed in energy and macronutrient intake between CHF participants with BMI ≥ 30 kg/m2 or

Background and purpose — Artificial intelligence has rapidly become a powerful method in image analysis with the use of convolutional neural networks (CNNs). We assessed the ability of a CNN, with a fast object detection algorithm previously identifying the regions of interest, to detect distal radius fractures (DRFs) on anterior–posterior (AP) wrist radiographs. Patients and methods — 2,340 AP wrist radiographs from 2,340 patients were enrolled in this study. We trained the CNN to analyze wrist radiographs in the dataset. Feasibility of the object detection algorithm was evaluated by intersection of the union (IOU). The diagnostic performance of the network was measured by area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, specificity, and Youden Index; the results were compared with those of medical professional groups. Results — The object detection model achieved a high average IOU, and none of the IOUs had a value less than 0.5. The AUC of the CNN for this test was 0.96. The network had better performance in distinguishing images with DRFs from normal images compared with a group of radiologists in terms of the accuracy, sensitivity, specificity, and Youden Index. The network presented a similar diagnostic performance to that of the orthopedists in terms of these variables. Interpretation — The network exhibited a diagnostic ability similar to that of the orthopedists and a performance superior to that of the radiologists in distinguishing AP wrist radiographs with DRFs from normal images under limited conditions. Further studies are required to determine the feasibility of applying our method as an auxiliary in clinical practice under extended conditions.

Abstract Background Effects of β-blockers on outcomes in patients with chronic heart failure (CHF) and atrial fibrillation (AF) is still in controversy. Methods Searching was conducted by using keywords “atrial fibrillation”, and “heart failure” in PubMed, MEDLINE and Embase databases before November 30, 2017. Prospective studies [i.e. randomized control trials (RCTs), post-hoc analysis of RCTs, prospective cohort studies and registry studies] that studied the effect of β-blockers and all-cause mortality in patients with CHF and AF were included. The analysis was stratified by study design. Results We identified 12 studies, including 6 post-hoc analysis of RCTs and 6 observational studies (including prospective registry studies and prospective cohort studies), which enrolled 38,133 patients with CHF and AF. Overall, β-blockers treatment was associated with significant decrease in all-cause mortality [Risk Ratio (RR) =0.73; 95% Confidence Interval (CI) 0.65–0.82, P

Objectives: To determine whether hypertension (HTN) affects cardiac structure and function in different types of hypertrophic cardiomyopathy (HCM). Design: Patients with obstructive HCM (n = 40), septal HCM (n = 88), and apical HCM (n = 42) were separated into hypertensive and non-hypertensive subgroups, and echocardiographic parameters at baseline and at follow-up were compared between the subgroups. Results: At follow-up, hypertensive obstructive HCM patients showed a decrease in end-diastolic volume (from 93.87 ± 26.08 mL to 79.06 ± 20.07 mL; p= 0.045) and in left ventricular end-diastolic diameter (from 45.00 ± 5.32 mm to 41.83 ± 4.58 mm; p =0.042). Non-hypertensive obstructive HCM patients showed a decrease in maximum aortic velocity (from 2.01 ± 0.53 m/s to 1.28 ± 0.25 m/s; p= 0.011) and in aortic maximum pressure gradient (from 17.22 ± 9.57 mm Hg to 6.79 ± 2.44 mm Hg; p= 0.03). Hypertensive apical HCM patients showed an increase in end-diastolic volume (from 95.28 ± 16.54 mL to 119.74 ± 25.19 mL; p= 0.016) and in left ventricular end-diastolic diameter (from 45.28 ± 3.36 mm to 50.20 ± 4.56 mm; p= 0.007). Conclusions: HTN can affect left ventricular capacity in obstructive HCM and apical HCM, causing a decrease in ventricular capacity in the former and increase in the latter; it has no significant effect on the size of the left ventricular cavity in septal HCM. HTN can lead to a poor therapeutic effect on aortic flow rate and pressure gradient in obstructive HCM patients.

Abstract Background 2-oxoglutarate (2OG), an intermediate metabolite in the tricarboxylic acid cycle, has been found to associate with chronic heart failure (HF), but its effect on short-term adverse outcomes in patients with acute HF (AHF) is uncertain. Methods This prospective cohort study included 411 consecutive hospitalized patients with AHF. During hospitalization, fasting plasma samples were collected within the first 24 h of admission. Plasma 2OG levels were measured by hydrophilic interaction liquid chromatography-liquid chromatography tandem mass spectrometry (HILIC-LC/MS/MS). All participants were followed up for six months. Multiple logistic regression was used to determine the odds ratio (OR) and 95% confidence interval (CI) for primary outcomes. Results The AHF cohort consisted of HF with preserved ejection fraction (EF) (64.7%), mid-range EF (16.1%), and reduced EF (19.2%), the mean age was 65 (±13) years, and 65.2% were male. Participants were divided into two groups based on median 2OG levels (μg/ml): low group (

Heart failure with mid-range ejection fraction (HFmrEF) was first proposed by Lam and Solomon in 2014, and was listed as a new subtype of heart failure (HF) in 2016 European Society of Cardiology guidelines. Since then, HFmrEF has attracted an increasing amount of attention, and the number of related studies on this topic has grown rapidly. The diagnostic criteria on the basis of left ventricular ejection fraction (LVEF) are straightforward; however, LVEF is not a static parameter, and it changes dynamically during the course of HF. Thus, HFmrEF may not be an independent disease with a uniform pathophysiological process, but rather a collection of patients with different characteristics. HFmrEF is often associated with various cardiovascular and non-cardiovascular diseases. Thus, the pathophysiological mechanisms of HFmrEF are particularly complex, and its clinical phenotypes are diverse. The complexity and heterogeneity of HFmrEF may be one reason for inconsistent results between clinical studies. In fact, whether HFmrEF is a distinctive subtype or a transitional stage between HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) is controversial. In this review, we discuss the clinical characteristics, treatment and prognosis of patients with HFmrEF, as well as the differences among HFmrEF, HFrEF, and HFpEF.

Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.

Atrial fibrillation (AF) is prevalent in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Depending on the timing of AF detection, it is usually categorized as pre-existing AF or new-onset AF. Antiplatelet therapy, rather than a vitamin K antagonist, may be considered as the primary treatment for patients without an indication for oral anticoagulants who undergo TAVR. However, the optimal postprocedural antithrombotic regimen for patients with AF undergoing TAVR remains unknown. In this review, we briefly introduce the management strategies of antithrombotic therapy and list the evidence from related studies to elucidate the optimal antithrombotic management for patients with AF undergoing TAVR.

Macrophage-orchestrated chronic inflammation plays an important role in cardiovascular disease, including accelerating the development of calcific aortic valve disease (CAVD). M1 and M2 macrophage polarization imbalances can alter intensity of inflammatory responses. Recombinant human interleukin 37 (IL-37) could be involved in regulating immune cell function to attenuate inflammation. This study aimed to identify IL-37 specifically modulates M1 polarization and investigate the underlying mechanism. Compared with normal valves, there are more M1 macrophages accumulation and less IL-37 expression in calcific aortic valves, which may indicate a negative relationship between IL-37 and M1 polarization. THP-1 cells could differentiate into resting macrophages with phorbol-12-myristate-13-acetate (PMA) and then polarize into M1 macrophages following treatment with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). In vitro, recombinant human IL-37 attenuated the expression of inducible nitric oxide synthase (iNOS), CD11c, IL-6 and monocyte chemoattractant protein 1 (MCP-1) in M1 but augmented the expression of CD206 and IL-10 in M2. The suppression of M1 polarization was associated with the inhibition of the activation of the nuclear factor kappa B (NF-κB) and Notch1 signaling pathways. These results demonstrated that IL-37 inhibits the macrophages polarizing into M1 type via the inhibition of the Notch1 and nuclear factor kappa B pathways. In summary, IL-37 could be a potential therapeutic candidate for progressive CAVD by modulating M1 polarization and its orchestrated inflammation.

Ferulic acid, a main ingredient of Ligusticum, exhibits anti-oxidant and anti-inflammation effects in heart diseases. Some studies indicate that gut microbiome is associated with the generation of ferulic acid. Whether the beneficial effect of ferulic is raised by the alteration of gut microbiota is still unknown. This study examined the effect of sodium ferulate on gut microbiome and cardiac function in TAC mice. Cell Counting Kit-8 (CCK8) assay verified that ferulic acid has low toxicity in vitro and that ferulic acid inhibited the up-regulation of β-MHC and ANP induced by Angiotensin II. In addition, daily supplement of 50 mg/kg sodium ferulate improved the ejection fraction and changed the gut microbiota composition of TAC mice. Relative abundance of Lactobacillus and Parabacteroides are increased in TAC mice gavaged with sodium ferulate. In addition, Lactobacillus is negatively correlated with HW/BW and LW/BW ratio. These results suggest that the beneficial effect of ferulic in TAC mice is probably through the regulation of gut microbiota.

Background: Although a large number of studies on heart failure with reduced ejection fraction (HFrEF) have found that anemia and renal dysfunction (RD) independently predicted poor outcomes, there are still few reports on patients with heart failure with preserved ejection fraction (HFpEF). Methods: Clinical data of HFpEF patients registered in the China National Heart Failure Registration Study (CN-HF) were evaluated and the clinical features of patients with or without anemia/RD were compared to explore the impact of anemia and RD on all-cause mortality and all-cause re-hospitalization. Results: 1604 patients with HFpEF were enrolled, the prevalence of anemia was 51.0%. Although anemia was associated with increased risk of all-cause mortality and all-cause re-hospitalization in univariate COX regression (p

Abstract Background The use of bone graft for the radial head fractures has been previously described and occasionally used by other authors.This is the first paper, to my knowledge, dealing with the relevant issue about the importance that the use of an autologous bone graft can have on the radial head fractures. Methods From July 2010 to July 2014, 20 consecutive patients who underwent open reduction and internal fixation for a closed Mason type II radial head fracture were retrospectively reviewed. Patients with Mason type I, III, simple type II, and comminuted type II fractures treated without bone grafting were excluded. A clinical examination and radiographic evaluation were performed. The overall functional result was evaluated using the Mayo Elbow Performance Score (MEPS). The Broberg and Morrey classification was used to evaluate traumatic arthritis. Results The average follow-up duration was 31 months (range, 24–50 months). Bone union of the radial head fracture was achieved in all patients at an average of 13.5 weeks (range, 12–17 weeks). Postoperative radiographs showed no cases of postsurgical ligamentous instability, necrosis of the radial head, or internal fixation failure. The mean range of motion of the affected elbow was 128° ± 8.4° in flexion, 14.5° ± 11.1° in extension, 68.7° ± 14.1° in pronation, and 65.2° ± 18.2° in supination. The mean MEPS was 92 ± 7.9 points (range, 80–100); the outcome was excellent (90–100 points) in 13 patients and good (75–89 points) in 7 patients. The MEPS tended to be higher in patients with an isolated fracture (p = 0.016). Based on the Broberg and Morrey classification for radiographic assessment of post-traumatic arthritis, 15 elbows had no evidence of degenerative changes (grade 0), and 5 elbows had grade 1 changes. Conclusion Although radial head fractures may not be amenable to internal fixation, our findings suggest that open reduction and internal fixation with an autogenous bone graft from the lateral epicondyle of the humerus provides satisfactory elbow function in patients with comminuted Mason type II radial head fractures.

Abstract Background Hemoconcentration has been proposed as surrogate for changes in volume status among patients hospitalized with acute heart failure (AHF) and is associated with a favorable outcome. However, there is a dearth of research assessing the clinical outcomes of hospitalized patients with hemoconcentration, hemodilution and unchanged volume status. Methods We enrolled 510 consecutive patients hospitalized for AHF from April 2011 to July 2015. Hematocrit (HCT) levels were measured at admission and either at discharge or on approximately the seventh day of admission. Patients were stratified by delta HCT tertitles into hemodilution (ΔHCT ≤ − 1.6%), no change (NC, −1.6% 1.5%) groups. The endpoint was all-cause death, with a median follow-up duration of 18.9 months. Results Hemoconcentration was associated with lower left ventricle ejection fraction, as compared with NC and hemodilution groups, while renal function at entry, New York Heart Association class IV, and in-hospital worsening renal function (WRF) were not significantly different across the three groups. After multivariable adjustment, hemoconcentration had a lower risk of mortality as compared with hemodilution [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.24–0.63, P

Apigenin is a non-mutagenic flavone that displays both cytostatic and cytoprotective activity. Here, we report results from a preliminary study which explored the mechanism by which apigenin protects myocardium against damage due to acute myocardial infarction (AMI). An AMI model was induced by occluding the left anterior descending (LAD) coronary artery in rats. We then examined the effect of apigenin administration on the function and structure of the AMI-injured heart. Apigenin improved the function and structure of AMI-injured cardiomyocytes, and inhibited TGF-β1 and Smad 2 expression. Although Smad 7 showed a complicated expression pattern, the activity of that indicator was not only induced by AMI induction, but also further augmented by apigenin. Our data conclusively show that apigenin exerts its protective effect by inhibiting TGF-β1, and subsequently modulating the activity of downstream Smads.

Abstract Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to proinflammatory stimulation, which plays an important role in valvular fibrosis and calcification. Thus, suppression of AVIC proinflammatory response may have therapeutic utility for the prevention of CAVD progression. Interleukin (IL)-37, an antiinflammatory cytokine, reduces tissue inflammation. This study aimed to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor-inducing interferon-β differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-κB activation induced by TLR2 or TLR4 through a mechanism dependent of IL-18 receptor α-chain. Activation of TLR2, TLR3 or TLR4 upregulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This antiinflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.

Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1α is an alternative splicing variant of PGC-1α that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1α into the nucleus and activate PGC-1α target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1α and NT-PGC-1α were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of β-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1α or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1α and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1α. After NT-PGC-1α was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-α, Tfam, ERR-γ, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1α transportation.

BackgroundMitochondrial dynamics play a critical role in mitochondrial function. The mitofusin 2 (MFN2) gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion to maintain and operate the mitochondrial network. Moreover, MFN2 is essential for mitophagy. In Ang II-induced cardiac remodeling, the combined effects of MFN2-mediated mitochondrial fusion and mitophagy are unclear. This study was designed to explore a novel strategy for preventing cardiomyocyte injury via modulation of mitochondrial dynamics.MethodsWe studied the function of MFN2 in mitochondrial fusion and mitophagy in Ang II-stimulated cardiomyocyte injury. Cardiomyocyte injury experiments, including reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and apoptosis rate of cardiomyocytes were performed. The mitochondrial morphology in cardiomyocytes was examined via transmission electron microscopy (TEM) and confocal microscopy. Autophagic levels in response to Ang II were examined by immunoblotting of autophagy-related proteins. Moreover, PINK1/MFN2/Parkin pathway-related proteins were examined.ResultsWith stimulation by Ang II, MFN2 expression was progressively reduced. MFN2 deficiency impaired mitochondrial quality, resulting in exacerbated mitochondrial damage induced by Ang II. The Ang II-induced increases in ROS production and apoptosis rate were alleviated by MFN2 overexpression. Moreover, MFN2 alleviated the Ang II-induced reduction in MMP. MFN2 promoted mitochondrial fusion, and MFN2 promoted Parkin translocation and phosphorylation, leading to mitochondrial autophagy. The effects of MFN2 overexpression were reversed by autophagy inhibitors.ConclusionMitofusin 2 promotes Parkin translocation and phosphorylation, leading to mitophagy to clear damaged mitochondria. However, the beneficial effects of MFN2 were reversed by autophagy inhibitors. Additionally, MFN2 participates in mitochondrial fusion to maintain mitochondrial quality. Thus, MFN2 participated in mitophagy and mitochondrial fusion against Ang II-induced cardiomyocyte injury.

Near-infrared (NIR) region has been considered as a diagnostic window since it avoids sample autofluorescence and light scattering. Upconversion nanoparticles (UCNPs) convert NIR light into high energy excitation light, making them a suitable excitation source for nanoprobes with deep penetration depth and high signal-to-noise ratio. The current work reported a rhodamine-derived probe for the detection of Hg(II). Corresponding absorption and emission responses for Hg(II) and detailed recognizing mechanism were discussed. An absorption titration experiment was performed. It was found that Hg(II) directly bonded with probe with chemical stoichiometry of 1:1, its association constant was calculated as 2.59 × 105 M−1. Such a high value indicated a direct coordination affinity between Hg(II) and this rhodamine-derived probe. Most metal cations exerted no increasing effect on the probe emission or absorption, exhibiting good sensing selectivity of probe towards Hg(II). Upconversion nanoparticles (UCNPs) were firstly encapsulated with silica (SiO2) and then bonded with the probe via a covalent bond. Given a near-infrared (NIR) laser excitation with wavelength of 980 nm, this probe, (E)-2-((3′,6′-bis(diethylamino)-2′,7′-dimethyl-3-oxospiro[isoindoline-1,9′-xanthen]-2-yl)imino)acetaldehyde (denoted as RHO), captured the energy of UCNPs via a FRET (fluorescence resonance energy transfer) path, resulting in the emission quenching of UCNPs. This composite system showed linear sensing behavior towards Hg(II) with high selectivity, which was similar to the case of pure probe. No probe emission, however, was observed from the composite system, which was different from the case of most literature reports. The self-quenching between probe molecules was claimed responsible for the probe emission, which was confirmed by experiment result and analysis. To the best of our knowledge, this is the first demonstration of covalently integrating SiO2-coated UCNPs with a rhodamine-derived probe for Hg(II) sensing.

Physical exercise is commonly regarded as protective against cardiovascular disease (CVD). Recent studies have reported that exercise alters the gut microbiota and that modification of the gut microbiota can influence cardiac function. Here, we focused on the relationships among exercise, the gut microbiota and cardiac function after myocardial infarction (MI). Four-week-old C57BL/6J mice were exercised on a treadmill for 4 weeks before undergoing left coronary artery ligation. Cardiac function was assessed using echocardiography. Gut microbiomes were evaluated post-exercise and post-MI using 16S rRNA gene sequencing on an Illumina HiSeq platform. Exercise training inhibited declines in cardiac output and stroke volume in post-MI mice. In addition, physical exercise and MI led to alterations in gut microbial composition. Exercise training increased the relative abundance of Butyricimonas and Akkermansia. Additionally, key operational taxonomic units were identified, including 24 lineages (mainly from Bacteroidetes, Barnesiella, Helicobacter, Parabacteroides, Porphyromonadaceae, Ruminococcaceae, and Ureaplasma) that were closely related to exercise and cardiac function. These results suggested that exercise training improved cardiac function to some extent in addition to altering the gut microbiota; therefore, they could provide new insights into the use of exercise training for the treatment of CVD.

The gene ankyrin repeat domain 1 (Ankrd1) is an enigmatic gene and may exert pleiotropic function dependent on its expression level, subcellular localization and even types of pathological stress, but it remains unclear how these factors influence the fate of cardiomyocytes. Here we attempted to investigate the role of CARP on cardiomyocyte hypertrophy. In neonatal rat ventricular cardiomyocytes (NRVCs), angiotensin II (Ang II) increased the expression of both calpain 1 and CARP, and also induced cytosolic translocation of CARP, which was abrogated by a calpain inhibitor. In the presence of Ang-II in NRVCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced myocyte hypertrophy, the upregulation of atrial natriuretic peptide and β-myosin heavy chain genes and calcineurin proteins as well as nuclear translocation of nuclear factor of activated T cells. Cyclosporin A attenuated Ad-Ankrd1-enhanced cardiomyocyte hypertrophy. Intra-myocardial injection of Ad-Ankrd1 in mice with transverse aortic constriction (TAC) markedly increased the cytosolic CARP level, the heart weight/body weight ratio, while short hairpin RNA targeting Ankrd1 inhibited TAC-induced hypertrophy. The expression of calcineurin was also significantly increased in Ad-Ankrd1-infected TAC mice. Olmesartan (an Ang II receptor antagonist) prevented the upregulation of CARP in both Ang II-stimulated NRVCs and hearts with pressure overload. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac remodeling through the enhancement of cytosolic translocation of CARP and upregulation of calcineurin.

Aortic valve calcification causes the progression of calcific aortic valve disease (CAVD). Stimulation of aortic valve interstitial cells (AVICs) with lipopolysaccharide (LPS) up-regulates the expression of osteogenic mediators, and NF-κB plays a central role in mediating AVIC osteogenic responses to Toll-like receptor 4 (TLR4) stimulation. Diseased aortic valves exhibit greater levels of oxidized low-density lipoprotein (oxLDL). This study tested the hypothesis that oxLDL augments the osteogenic responses in human AVICs through modulation of NF-κB and Notch1 activation. AVICs isolated from normal human aortic valves were treated with LPS (0.1 µg/ml), oxLDL (20 µg/ml) or LPS plus oxLDL for 48 h. OxLDL alone increased cellular bone morphogenetic protein-2 (BMP-2) levels while it had no effect on alkaline phosphatase (ALP) levels. Cells exposed to LPS plus oxLDL produced higher levels of BMP-2 and ALP than cells exposed to LPS alone. Further, LPS plus oxLDL induced greater NF-κB activation, and inhibition of NF-κB markedly reduced the expression of BMP-2 and ALP in cells treated with LPS plus oxLDL. OxLDL also induced Notch1 activation and resulted in augmented Notch1 activation when it was combined with LPS. Inhibition of Notch1 cleavage attenuated NF-κB activation induced by LPS plus oxLDL, and inhibition of NF-κB suppressed the expression of BMP-2 and ALP induced by the synergistic effect of Jagged1 and LPS. These findings demonstrate that oxLDL up-regulates BMP-2 expression in human AVICs and synergizes with LPS to elicit augmented AVIC osteogenic responses. OxLDL exerts its effect through modulation of the Notch1-NF-κB signaling cascade. Thus, oxLDL may play a role in the mechanism underlying CAVD progression.

OBJECTIVE: Elevated myocardial energy expenditure (MEE) is related with reduced left ventricular ejection fraction, and has also been documented as an independent predictor of cardiovascular mortality. However, the serum small-molecule metabolite profiles and pathophysiological mechanisms of elevated MEE in heart failure (HF) are still lacking. Herein, we used 1H-NMR-based metabolomics analysis to screen for potential biomarkers of MEE in HF. METHODS: A total of 61 subjects were enrolled, including 46 patients with heart failure and 15 age-matched controls. Venous serum samples were collected from subjects after an 8-hour fast. An INOVA 600 MHz nuclear magnetic resonance spectrometer with Carr-Purcell-Melboom-Gill (CPMG) pulse sequence was employed for the metabolomics analysis and MEE was calculated using colored Doppler echocardiography. Metabolomics data were processed using orthogonal signal correction and regression analysis was performed using the partial least squares method. RESULTS: The mean MEE levels of HF patients and controls were 139.61±58.18 cal/min and 61.09±23.54 cal/min, respectively. Serum metabolomics varied with MEE changed, and 3-hydroxybutyrate, acetone and succinate were significantly elevated with the increasing MEE. Importantly, these three metabolites were independent of administration of angiotensin converting enzyme inhibitor, β-receptor blockers, diuretics and statins (P>0.05). CONCLUSIONS: These results suggested that in patients with heart failure, MEE elevation was associated with significant changes in serum metabolomics profiles, especially the concentration of 3-hydroxybutyrate, acetone and succinate. These compounds could be used as potential serum biomarkers to study myocardial energy mechanism in HF patients.