Development and validation of a nomogram for major adverse cardiovascular events after chronic total occlusion percutaneous coronary intervention for ischemic heart failure.

BACKGROUND: Chronic total occlusion percutaneous coronary intervention (CTO-PCI) is an available means of revascularization in patients with ischemic heart failure (IHF). However, the prognosis of IHF patients undergoing CTO-PCI remains unclear due to the lack of reliable clinical predictive tools. AIM: This study aimed to establish a nomogram for major adverse cardiovascular events (MACE) after CTO-PCI in IHF patients. METHODS: Sixty-seven potential predictive variables for MACE in 560 IHF patients undergoing CTO-PCI were screened using least absolute shrinkage and selection operator regression. A nomogram was constructed based on multivariable Cox regression to visualize the risk of MACE, and then evaluation was carried out using the concordance index (C-index), time-independent receiver operating characteristic (timeROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: During a median follow-up of 32.0 months, there were 208 MACE occurrences. Seven variables were selected for nomogram construction: age, left ventricular ejection fraction, left ventricular end-diastolic diameter, N-terminal precursor B-type diuretic peptide, bending, and use of intravascular ultrasound and beta-blockers. The C-index was 0.715 (0.680-0.750) and the internal validation result was 0.715 (0.676-0.748). The timeROC area under the curve at 6 months, 1 year, and 2 years was 0.750 (0.653-0.846), 0.747 (0.690-0.804), and 0.753 (0.708-0.798), respectively. The calibration curves and DCA showed the nomogram had acceptable calibration and clinical applicability. CONCLUSIONS: We developed a simple and efficient nomogram for MACE after CTO-PCI in IHF patients, which helps in early risk stratification and postoperative management optimization.

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Different Doses of Empagliflozin in Patients with Heart Failure with Reduced Ejection Fraction.

It was unclear whether there are discrepancies among the efficacy and safety of different doses of empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to compare the efficacy and safety of 25 mg and 10 mg of empagliflozin in HFrEF patients.In this 3-month, single-center, open-label, randomized, positive-controlled, parallel-group study, 100 patients with HFrEF were divided into two groups, namely, groups A (n = 50) and B (n = 50), which were given 25 mg/day and 10 mg/day of empagliflozin, respectively. Cardiac function indexes at baseline and at the end of the third month were compared between the two groups, as well as adverse events during the 3-month follow-up period. The primary outcome of this study was the change in the left ventricular ejection fraction (LVEF), and the secondary outcomes were the change in the left ventricular end-diastolic diameter (LVEDD) and the incidences of hypotension, acute kidney injury (AKI), and genitourinary infections.At the end of the third month, the changes in the LVEF and LVEDD were greater in group A than those in group B (P < 0.05). During the 3-month follow-up period, the differences in the incidences of hypotension, AKI, and genitourinary infections between the two groups were statistically insignificant (P > 0.05).The results from this study suggested that 25 mg of empagliflozin might be better than 10 mg in improving heart function in HFrEF patients, and the safety profiles of 25 mg and 10 mg of empagliflozin are comparable. Further studies are expected to substantiate our speculations.

Runt-related transcription factor 1 (Runx1) aggravates pathological cardiac hypertrophy by promoting p53 expression.

Cardiac hypertrophy and the resultant heart failure are among the most common causes of morbidity and mortality worldwide; thus, identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Runx1 (Runt-related transcription factor 1) acts as an essential transcription factor that functions in a variety of cellular processes including differentiation, proliferation, tissue growth and DNA damage response. However, relatively little is known about the role of Runx1 in heart, especially cardiac hypertrophy and heart failure. In the present study, we investigated the role of Runx1 in experimentally pathological cardiac hypertrophy. The in vitro model was induced by Ang II exposure to cultured neonatal rat cardiomyocytes, and the in vivo pathological cardiac hypertrophy models were induced by chronic pressure overload in mice. Runx1 expression is increased in heart tissues from mice with pressure overload-induced cardiac hypertrophy and in neonatal rat cardiomyocytes in response to Ang II stimulation. Moreover, knockdown of cardiac Runx1 alleviates the pressure overload-induced cardiac hypertrophy. Mechanistically, Runx1 activates the p53 signalling by binding to the p53 gene and promotes its transcription. Rescue experiments indicate that Runx1 promotes cardiac hypertrophy in a p53-dependent manner. Remarkably, we demonstrated that Ro5-3335 (a Runx1 inhibitor) acts as a potential therapeutic drug for treating pathological cardiac hypertrophy. In summary, we conclude that Runx1 is a novel mediator and therapeutic target for pathological cardiac hypertrophy.

Dapagliflozin and Empagliflozin in Heart Failure with Reduced Ejection Fraction: A Retrospective Study.

Objective: Dapagliflozin 10 mg and empagliflozin 10 mg have been recommended to treat heart failure with reduced ejection fraction (HFrEF), and the purpose of this study was to compare the efficacy and safety of them in HFrEF. Methods: Two hundred and thirty-three patients with HFrEF admitted to a tertiary hospital of Zhengzhou and commenced to take dapagliflozin 10 mg/d or empagliflozin 10 mg/d were retrospectively included and separated into the dapagliflozin group (n=105) and the empagliflozin group (n=128). Their cardiac function indices before and after therapy were compared, together with the ratios of adverse events during therapy. Results: After 6 months of therapy, left ventricular ejection fraction was higher, and the ratio of New York Heart Association functional class III or IV, left ventricular end-diastolic diameter, and N-terminal pro-B-type natriuretic peptide were lower in the empagliflozin group than the dapagliflozin group (P<0.05). During 6 months of therapy, there were no statistically significant differences for the ratios of hypotension, deteriorating kidney function, and genitourinary infections between the dapagliflozin and empagliflozin groups (P>0.05). Conclusion: Despite its many limitations, this study suggested that different SGLT2 inhibitors might have differences regarding efficacy in HFrEF. We look forward to future studies to verify our conjectures.

Development and Validation of a Novel Nomogram to Predict Improved Left Ventricular Ejection Fraction in Patients With Heart Failure After Successful Percutaneous Coronary Intervention for Chronic Total Occlusion.

Background: Heart failure with improved left ventricular ejection fraction (HFiEF) is linked to a good clinical outcome. The purpose of this study was to create an easy-to-use model to predict the occurrence of HFiEF in patients with heart failure (HF), 1 year after successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) (CTO PCI). Methods: Patients diagnosed with HF who successfully underwent CTO PCI between January 2016 and August 2019 were included. To mitigate the effect of residual stenosis on left ventricular (LV) function, we excluded patients with severe residual stenosis, as quantitatively measured by a residual synergy between PCI with Taxus and Cardiac Surgery score (rSS) of >8. We gathered demographic data, medical history, angiographic and procedural characteristics, echocardiographic parameters, laboratory results, and medication information. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression models were used to identify predictors of HFiEF 1 year after CTO revascularization. A nomogram was established and validated according to the area under the receiver operating characteristic curve (AUC) and calibration curves. Internal validation was performed using bootstrap resampling. Results: A total of 465 patients were finally included in this study, and 165 (35.5%) patients experienced HFiEF 1 year after successful CTO PCI. According to the LASSO regression and multivariate logistic regression analyses, four variables were selected for the final prediction model: age [odds ratio (OR): 0.969; 95% confidence interval (CI): 0.952-0.988; p = 0.001], previous myocardial infarction (OR: 0.533; 95% CI: 0.357-0.796; p = 0.002), left ventricular end-diastolic dimension (OR: 0.940; 95% CI: 0.910-0.972; p < 0.001), and sodium glucose cotransporter two inhibitors (OR: 5.634; 95% CI: 1.756-18.080; p = 0.004). A nomogram was constructed to present the results. The C-index of the model was 0.666 (95% CI, 0.613-0.719) and 0.656 after validation. The calibration curve demonstrated that the nomogram agreed with the actual observations. Conclusions: We developed an simple and effective nomogram for predicting the occurrence of HFiEF in patients with HF, 1 year after successful CTO PCI without severe residual stenosis.

E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING.

Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase which is expressed in a variety of human tissues. RNF5 is involved in the regulation of endoplasmic reticulum stress, inflammation, and innate immunity and plays an important role in the occurrence and development of various tumors. However, the role of RNF5 in cardiac hypertrophy has not been reported. In this study, we found the expression of RNF5 was increased in the hearts of mice with pathological cardiac hypertrophy. The loss-of-function research demonstrated that RNF5 deficiency exacerbated cardiac hypertrophy, whereas gain-of-function studies revealed that overexpression of RNF5 had opposite effects. The stimulator of interferon genes (STING) is a signaling molecule that can activate type I interferon immunity, which can meditate inflammation and immune response in many diseases. The protein-protein interaction experiments confirmed that STING interacted with RNF5. Further studies showed that RNF5 inhibited cardiac hypertrophy by promoting STING degradation through K48-linked polyubiquitination. Therefore, we defined RNF5 as importantly regulated signaling for cardiac hypertrophy.

Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.

Background Restenosis is one of the main bottlenecks in restricting the further development of cardiovascular interventional therapy. New signaling molecules involved in the progress have continuously been discovered; however, the specific molecular mechanisms remain unclear. MTMR14 (myotubularin-related protein 14) is a novel phosphoinositide phosphatase that has a variety of biological functions and is involved in diverse biological processes. However, the role of MTMR14 in vascular biology remains unclear. Herein, we addressed the role of MTMR14 in neointima formation and vascular smooth muscle cell (VSMC) proliferation after vessel injury. Methods and Results Vessel injury models were established using SMC-specific conditional MTMR14-knockout and -transgenic mice. Neointima formation was assessed by histopathological methods, and VSMC proliferation and migration were assessed using fluorescence ubiquitination-based cell cycle indicator, transwell, and scratch wound assay. Neointima formation and the expression of MTMR14 was increased after injury. MTMR14 deficiency accelerated neointima formation and promoted VSMC proliferation after injury, whereas MTMR14 overexpression remarkably attenuated this process. Mechanistically, we demonstrated that MTMR14 suppressed the activation of PLK1 (polo-like kinase 1) by interacting with it, which further leads to the inhibition of the activation of MEK/ERK/AKT (mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase/protein kinase B), thereby inhibiting the proliferation of VSMC from the medial to the intima and thus preventing neointima formation. Conclusions MTMR14 prevents neointima formation and VSMC proliferation by inhibiting PLK1. Our findings reveal that MTMR14 serves as an inhibitor of VSMC proliferation and establish a link between MTMR14 and PLK1 in regulating VSMC proliferation. MTMR14 may become a novel potential therapeutic target in the treatment of restenosis.