Prognostic significance of preoperative nutritional status for heart transplantation patients.

BACKGROUND: The association between malnutrition and outcomes of heart transplantation (HTx) has not been well studied. The purpose of this article was to evaluate the prognostic value of three different nutrition indices in HTx, including CONUT (Controlling Nutritional Status), NRI (Nutritional Risk Index) and GNRI (Geriatric Nutritional Risk Index). METHODS: A total of 438 patients who underwent THx from January 2015 to December 2020 were included in this study. The nutritional status of the patients was evaluated by CONUT, NRI and GNRI. Kaplan-Meier (KM) curves were constructed to compare the difference in overall survival (OS) between the normal and malnutrition groups in each index. Cox regression analysis was used to identify the independent risk factors of OS. The predictive power was compared by time-dependent ROC and time-dependent ccurves. Logistic regression model was used to evaluate the relationship between these three nutrition indices and postoperative clinical events. RESULTS: 336 (76.7%), 183 (43.8%), and 190 (43.4%) patients had malnutrition according to CONUT, NRI and GNRI calculations. 102 (23.3%) patients had died at the end of follow-up. After adjustment for confounding variables, multivariate Cox analysis showed that CONUT [HR 1.286 (95%CI 1.166 ~ 1.419); p < 0.001], NRI [HR 0.942 (95%CI 0.923 ~ 0.962); p < 0.001] and GNRI [HR 0.959 (95%CI 0.939 ~ 0.979); p < 0.001] were all independent predictors for OS. The predictive power of CONUT score was higher than that of NRI (p = 0.045) and GNRI (p < 0.001). Regarding the postoperative complications, multivariate logistic regression model showed that malnutrition assessed by CONUT [HR 1.156 (95%CI 1.032 ~ 1.294); p = 0.012] and NRI [HR 1.543 (95%CI 1.008 ~ 2.362); p = 0.046] was independent risk factors for posttransplant infections. CONCLUSION: Poor nutritional status, as assessed by CONUT, NRI and GNRI, was associated with an increased risk of mortality after HTx. CONUT displayed the highest predictive power compared to the other two indices. CONUT and NRI were also independently associated with posttransplant infections.

Schisandrol B inhibits calcification of aortic valve by targeting p53 related inflammatory and senescence.

Calcific aortic valve disease (CAVD) primarily involves osteogenic differentiation in human aortic valve interstitial cells (hVICs). Schisandrol B (SolB), a natural bioactive constituent, has known therapeutic effects on inflammatory and fibrotic disorders. However, its impact on valve calcification has not been reported. We investigated the effect of SolB on osteogenic differentiation of hVICs. Transcriptome sequencing was used to analyze potential molecular pathways affected by SolB treatment. The study also included an in vivo murine model using aortic valve wire injury surgery to observe SolB's effect on valve calcification. SolB inhibited the osteogenic differentiation of hVICs, reversing the increase in calcified nodule formation and osteogenic proteins. In the murine model, SolB significantly decreased the peak velocity of the aortic valve post-injury and reduced valve fibrosis and calcification. Transcriptome sequencing identified the p53 signaling pathway as a key molecular target of SolB, demonstrating its role as a molecular glue in the mouse double minute 2 (MDM2)-p53 interaction, thereby promoting p53 ubiquitination and degradation, which further inhibited p53-related inflammatory and senescence response. These results highlighted therapeutic potential of SolB for CAVD via inhibiting p53 signaling pathway and revealed a new molecular mechanism of SolB which provided a new insight of theraputic mechanism for CAVD.

Beyond VICs: Shedding light on the overlooked VECs in calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is prevalent in developed nations and has emerged as a pressing global public health concern due to population aging. The precise etiology of this disease remains uncertain, and recent research has primarily focused on examining the role of valvular interstitial cells (VICs) in the development of CAVD. The predominant treatment options currently available involve open surgery and minimally invasive interventional surgery, with no efficacious pharmacological treatment. This article seeks to provide a comprehensive understanding of valvular endothelial cells (VECs) from the aspects of valvular endothelium-derived nitric oxide (NO), valvular endothelial mechanotransduction, valvular endothelial injury, valvular endothelial-mesenchymal transition (EndMT), and valvular neovascularization, which have received less attention, and aims to establish their role and interaction with VICs in CAVD. The ultimate goal is to provide new perspectives for the investigation of non-invasive treatment options for this disease.

FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease.

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

Morusin Alleviates Aortic Valve Calcification by Inhibiting Valve Interstitial Cell Senescence Through Ccnd1/Trim25/Nrf2 Axis.

The senescence of aortic valve interstitial cells (VICs) plays a critical role in the progression of calcific aortic valve disease (CAVD). However, the precise mechanisms underlying the senescence of VICs remain unclear, demanding the identification of a novel target to mitigate this process. Previous studies have highlighted the anti-aging potential of morusin. Thus, this study aimed to explore the therapeutic potential of morusin in CAVD. Cellular experiments reveal that morusin effectively suppresses cellular senescence and cause a shift toward osteogenic differentiation of VICs in vitro. Mechanistically, morusin activate the Nrf2-mediated antiaging signaling pathway by downregulating CCND1 expression and aiding Keap1 degradation through Trim 25. This activation lead to the upregulated expression of antioxidant genes, thus reducing reactive oxygen species production and thereby preventing VIC osteogenic differentiation. In vivo experiments in ApoE-/- mice on a high-fat Western diet demonstrate the positive effect of morusin in mitigating aortic valve calcification. These findings emphasize the antiaging properties of morusin and its potential as a therapeutic agent for CAVD.

Elevated serum albumin-to-creatinine ratio as a protective factor on outcomes after heart transplantation.

Background: The purpose of this study was to investigate the prognostic significance of serum albumin to creatinine ratio (ACR) in patients receiving heart transplantation of end-stage heart failure. Methods: From January 2015 to December 2020, a total of 460 patients who underwent heart transplantation were included in this retrospective analysis. According to the maximum Youden index, the optimal cut-off value was identified. Kaplan-Meier methods were used to describe survival rates, and multivariable analyses were conducted with Cox proportional hazard models. Meanwhile, logistic regression analysis was applied to evaluate predictors for postoperative complications. The accuracy of risk prediction was evaluated by using the concordance index (C-index) and calibration plots. Results: The optimal cut-off value was 37.54 for ACR. Univariable analysis indicated that recipient age, IABP, RAAS, BB, Hb, urea nitrogen, D-dimer, troponin, TG, and ACR were significant prognostic factors of overall survival (OS). Multivariate analysis showed that preoperative ACR (HR: 0.504, 95% = 0.352-0.722, P < 0.001) was still an independent prognostic factor of OS. The nomogram for predicting 1-year and 5-year OS in patients who underwent heart transplantation without ACR (C-index = 0.631) and with ACR (C-index = 0.671). Besides, preoperative ACR level was a significant independent predictor of postoperative respiratory complications, renal complications, liver injury, infection and in-hospital death. Moreover, the calibration plot showed good consistency between the predictions by the nomogram for OS and the actual outcomes. Conclusion: Our research showed that ACR is a favorable prognostic indicator in patients of heart transplantation.

Regulation of BCRP expression and sulfasalazine pharmacokinetics by the nuclear receptor REV-ERBα.

BCRP (breast cancer resistance protein) is a crucial efflux transporter involved in the regulation of the pharmacokinetics and pharmacodynamics of a wide range of drugs. Herein, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in the regulation of BCRP expression and sulfasalazine (a BCRP probe substrate) pharmacokinetics.Regulation of BCRP expression by REV-ERBα was assessed using Rev-erbα-/- mice and AML12 and CT26 cells. Pharmacokinetic analysis was performed with Rev-erbα-/- and wild-type mice after sulfasalazine administration.We found that the expression levels of BCRP mRNA and protein were downregulated in the liver and small intestine of Rev-erbα-dificient mice. In line with this, Rev-erbα ablation increased the systemic exposures of oral sulfasalazine.Positive regulation of BCRP expression and function by REV-ERBα was furtherly confirmed in AML12 and CT26 cells. Moreover, indirect regulation of Bcrp expression by REV-ERBα was potentially mediated by a negative transcription factor DEC2, which is a downstream target of REV-ERBα.In conclusion, REV-ERBα positively regulates BCRP expression in mice, thereby affecting sulfasalazine pharmacokinetics.

Multi-weight susceptible-infected model for predicting COVID-19 in China.

The mutant strains of COVID-19 caused a global explosion of infections, including many cities of China. In 2020, a hybrid AI model was proposed by Zheng et al., which accurately predicted the epidemic in Wuhan. As the main part of the hybrid AI model, ISI method makes two important assumptions to avoid over-fitting. However, the assumptions cannot be effectively applied to new mutant strains. In this paper, a more general method, named the multi-weight susceptible-infected model (MSI) is proposed to predict COVID-19 in Chinese Mainland. First, a Gaussian pre-processing method is proposed to solve the problem of data fluctuation based on the quantity consistency of cumulative infection number and the trend consistency of daily infection number. Then, we improve the model from two aspects: changing the grouped multi-parameter strategy to the multi-weight strategy, and removing the restriction of weight distribution of viral infectivity. Experiments on the outbreaks in many places in China from the end of 2021 to May 2022 show that, in China, an individual infected by Delta or Omicron strains of SARS-CoV-2 can infect others within 3-4 days after he/she got infected. Especially, the proposed method effectively predicts the trend of the epidemics in Xi'an, Tianjin, Henan, and Shanghai from December 2021 to May 2022.