Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles.

The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, "undruggable" KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the "undruggable" KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.

The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients.

Objective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients. Materials and Methods: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry. Results: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 µg/mL, or the VCZ CN was lower than 1.7 µg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased. Conclusion: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.

H-assisted CO2 dissociation on PdnPt(4-n)/In2O3 catalysts: a density functional theory study.

CO2 hydrogenation into valuable chemical compounds can effectively address the issues of greenhouse gas emissions and energy scarcity. The activation and dissociation processes of CO2 are crucial for its reduction reactions, but the effects of *H adatoms on the C-O cleavage are still confusing. This study investigates the H-assisted CO2 dissociation pathways on the PdnPt(4-n)/In2O3 (n = 0-4) catalysts via DFT calculation. Initially, the adsorption properties of *H2, *COOH, and *HCOO species are calculated. Then, two H-assisted CO2 dissociation channels, i.e., *CO2 + *H → *COOH → *CO + *OH and *CO2 + *H → *HCOO → *CHO + *O, are studied. Results show that Pt and Pd promote the CO2 hydrogenation and C-O bond cleavage reactions, respectively. In comparison to CO2 direct dissociation, the COOH-mediated and HCOO-mediated channels facilitate and impede the C-O bond cleavage, respectively. Overall, the Pd3Pt/In2O3 constituent is suggested for the H-assisted CO2 dissociation reaction. The electronic effects of the PdnPt(4-n) bimetals adjust the stabilities of the intermediates and barriers of the elementary steps, and the interactions between PdnPt(4-n) and In2O3 provide extra sites for the adsorbates and reaction steps. This study reveals the effects of *H on the C-O bond dissociation processes and provides useful insight into designing PdPt/In2O3 catalysts for CO2 hydrogenation reactions.

Understanding the textural enhancement of low-salt myofibrillar protein gels filled with pea protein pre-emulsions through interfacial behavior: Effects of structural modification and oil phase polarity.

This study investigated the effects of pea protein pre-emulsions containing triglyceride- or diglyceride-oil on the emulsifying and gelling properties of low-salt myofibrillar protein (MP). Pea protein isolates treated with pH12-shifting (PPIpH) or ultrasonication (PPIU) demonstrated superior initial interfacial adsorption and higher final interfacial pressure than native pea protein. Within MP/PPI blends, an increased ratio of MP led to a decrease in interfacial pressure, while simultaneously enhancing film elasticity at both polar and non-polar interfaces. Polar diglyceride promoted protein adsorption and fostered interfacial interactions between modified pea proteins and MP, enhancing the cross-linking of transglutaminase (TG) in the composite emulsion gels. Combining diglyceride-type PPIU and PPIpH emulsions with TG increased gel strength to 0.58 N and 0.63 N, respectively, from an initial 0.33 N, yielding a denser protein network with uniformly dispersed oil droplets. Therefore, the utilization of diglyceride and modified PPI can serve as structural enhancers in comminuted meat products.

Strategies for improving photocatalytic performance of g-C3N4 by modulating charge separation and current research status.

Graphitic carbon nitride (g-C3N4) has been extensively investigated over the past decade for its potential utilizations in photocatalytic energy generation and pollutant degradation. To better meeting the requirements for practical utilizations, it is crucial to address the issue of poor charge separation properties in g-C3N4, which origin from the strong interactions in photogenerated electron-hole pairs. In this review, we summarized the pertinent studies on developing strategies to promote the charge separation properties of g-C3N4. The strategies can be categorized into two categories of promoting the surface migration of charge carriers and prolonging the lifetime of surface charge. Finally, we present potential challenges in promoting charge separation and offer feasible suggestions to face these challenges.

Isolation, Purification of Phenolic Glycoside 1 from Moringa oleifera Seeds and Formulation of Its Liposome Delivery System.

In this study, N, N '-bis {4- [(α-L- rhamnosyloxy) benzyl]} thiourea (PG-1), a phenolic glycoside compound was purified from Moringa seed. The PG-1 has attracted extensive attention due to its anti-cancer, antioxidant, anti-inflammatory and hypoglycemic properties. However, some of its physicochemical properties such as oral bioavailability has not been studied. Herein, a highly purified PG-1 was extracted and incorporated in multiple layered liposomes (PG-1-L) to avoid its burst release and enhance oral bioavailability. After appropriate characterization, it was discovered that the obtained PG-1-L was stable, homogeneous and well dispersed with the average particle size being 89.26 ± 0.23 nm. Importantly, the in vitro release and in vivo oral bioavailability of PG-1-L were significantly improved compared with PG-1. In addition, MTT results showed that compared with the free PG-1, PG-1-L displayed obvious inhibitory effect on the HepG2 cells, while the inhibitory effect on healthy non-malignant 3T6 and LO-2 cells was not significant, indicating that PG-1-L had high safety. In conclusion, PG-1-L can be used as a promising delivery system and an ideal novel approach to improve the oral bioavailability and anticancer activity of PG-1.

Multiple Mechanisms of Haematococcus pluvialis-Derived Carotenoids to Inhibit Glycidyl Ester Formation in Rice Oil and a Chemical Model at High Temperatures.

The common presence of glycidyl esters (GEs) in refined vegetable oils has been a concern for food safety. The present study aimed to investigate the inhibitory effects of three carotenoids derived from Haematococcus pluvialis microalga on GE formation in both rice oil and a chemical model during heating. The addition of astaxanthin (AS), lutein (LU), and ß-carotene (CA) at 0.6 mg/g in rice oil can reduce GE formation by 65.0%, 57.1%, and 57.5%, respectively, which are significantly higher than those achieved by common antioxidants such as l-ascorbyl palmitate (39.0%), α-tocopherol (18.5%), tert-butyl hydroquinone (42.7%), and quercetin (26.2%). UPLC-Q-TOF-MS/MS analysis showed that two new compounds, that is, propylene glycol monoester and diester of palmitic acid, were formed in the CA-added chemical model, which provided direct experimental evidence for the inhibition of antioxidants including AS, LU, and CA against GE formation not only by indirect antioxidative action but also by direct radical reactions to competitively prevent the formation of cyclic acyloxonium intermediates. Furthermore, it was interestingly found that only AS could react with the GEs. The adduct of AS with GEs, astaxanthin-3-O-propanetriol esters, was preliminarily identified using Q-TOF-MS/MS in the heated AS-GE model, suggesting that reacting with GEs might represent another distinct mechanism of AS to eliminate GEs.

Causal association between triglycerides and cholesterol-lowering medication with non-rheumatic valve disease: A 2-sample Mendelian randomization study.

Previous studies have found a possible causal relationship between triglycerides and lipid-lowering drugs and valvular disease. The aim of this study was to explore the potential causal relationship between triglycerides and lipid-lowering drugs and valvular disease using Mendelian randomization (MR) analysis. Data sets associated with triglycerides (441,016 participants and 12,321,875 single nucleotide polymorphisms [SNPs]) and cholesterol-lowering drugs (209,638 participants and 9851,867 SNPs) were retrieved from the Genome-Wide Association Study (GWAS) database. A total of 297 and 49 SNPs significantly associated with triglycerides and cholesterol-lowering drugs, respectively (P < 5 × 10-8), were identified. Similarly, data sets for non-rheumatic valve diseases (NVDs) (361,194 participants and 10,080,950 SNPs) were obtained from the GWAS database. Inverse variance weighting was used as the primary method for calculating the odds ratio (OR) and 95% confidence intervals (CI). The MR-Egger, weighted median, and weighted mode analyses were also used to test the robustness of the main results. The MR-Egger intercept test and the MR-PRESSO test were used to evaluate horizontal pleiotropy. Inverse variance weighted (IVW) results showed that both triglyceride and cholesterol-lowering medication were positively associated with NVDs (OR = 1.001, 95% CI 1.000-1.0012, P = 0.006; OR = 1.007, 95% CI 1.003-1.010; P = 0.002). This study suggests that both triglyceride and cholesterol-lowering medications are positively associated with NVDs, suggesting that lowering triglyceride levels or the use of cholesterol-lowering medications may reduce the incidence of NVDs. However, larger samples are required for further validation.

Longitudinal measurement invariance and psychometric properties of the Patient Health Questionnaire-Four in China.

BACKGROUND: Depression and anxiety symptoms among medical students are often a concern. The Patient Health Questionnaire-Four (PHQ-4), an important tool for depression and anxiety screening, is commonly used and easy to administer. This study aimed to assess and update the longitudinal measurement invariance and psychometric properties of the simplified Chinese version. METHODS: A three-wave longitudinal survey was conducted among healthcare students using the PHQ-4. Structural validity was based on one-factor, two-factor, and second-order factor models, construct validity was based on the Self-Rated Health Questionnaire (SRHQ), Sleep Quality Questionnaire (SQQ), and Rosenberg Self-Esteem Scale (RSES), and longitudinal measurement invariance (LMI), internal consistency, and test-retest reliability were based on structural consistency across three time points. RESULTS: The results of the confirmatory factor analysis indicated that two-factor model was the best fit, and LMI was supported at three time points. Inter-factor, factor-total, and construct validity correlations of the PHQ-4 were acceptable. Additionally, Cronbach's alpha, McDonald's omega, and the intraclass correlation coefficient demonstrated acceptable/moderate to excellent reliability of the PHQ-4. CONCLUSIONS: This study adds new longitudinal evidence that the Chinese version of the PHQ-4 has promising LMI and psychometric properties. Such data lends confidence to the routine and the expanded use of the PHQ-4 for routine screening of depression and anxiety in Chinese healthcare students.

OrganogenesisDB: A Comprehensive Database Exploring the Cell-Type Identities and Gene Expression Dynamics during Organogenesis.

Organogenesis, the phase of embryonic development that starts at the end of gastrulation and continues until birth is the critical process for understanding cellular differentiation and maturation during organ development. The rapid development of single-cell transcriptomics technology has led to many novel discoveries in understanding organogenesis while also accumulating a large quantity of data. To fill this gap, OrganogenesisDB (http://organogenesisdb.com/), which is a comprehensive database dedicated to exploring cell-type identification and gene expression dynamics during organogenesis, is developed. OrganogenesisDB contains single-cell RNA sequencing data for more than 1.4 million cells from 49 published datasets spanning various developmental stages. Additionally, 3324 cell markers are manually curated for 1120 cell types across 9 human organs and 4 mouse organs. OrganogenesisDB leverages various analysis tools to assist users in annotating and understanding cell types at different developmental stages and helps in mining and presenting genes that exhibit specific patterns and play key regulatory roles during cell maturation and differentiation. This work provides a critical resource and useful tool for deciphering cell lineage determination and uncovering the mechanisms underlying organogenesis.

The effect of residential greenness on cardiovascular mortality from a large cohort in South China: An in-depth analysis of effect modification by multiple demographic and lifestyle characteristics.

BACKGROUND: The potential for residential greenness to improve cardiovascular health through both physical and psychological mechanisms is well recognized. However, evidence from rapidly urbanizing developing countries and cohort-based causal inference approaches, remains limited. We aim to examine the effect of residential greenness and time to cardiovascular mortality in South China. METHODS: We utilized data from a community-based population survey involving 748,209 participants at baseline from 2009 to 2015, followed up until 2020. Residential greenness exposure was assessed by the annual Normalized Difference Vegetation Index (NDVI) in the 500 m radius of each participant's residence. We used time-varying proportional hazard Cox models coupled with inverse probability weighting to fit marginal structural models and obtain hazard ratios (HRs) for cardiovascular disease (CVD) mortality after adjusting for confounders. Multiple effect modifiers on both additive and multiplicative scales were further explored. RESULTS: A total of 15,139 CVD-related deaths were identified during a median of 7.9 years of follow-up. A protective effect was found between higher greenness exposure and reduced CVD mortality, with a 9.3 % lower rate of total CVD mortality (HR 0.907, 95 % CI 0.859-0.957) based on a 0.1 increase in annual average NDVI. Demographic (age, marital status) and lifestyle factors (smoking, drinking status) were found to modify the association between residential greenness and CVD mortality (all P interaction values < 0.05 or 95 %CI for RERI excluded the value 0). Notably, this effect was more pronounced among older adults, married, and individuals having healthier lifestyles, indicating a greater benefit from greenness for these subgroups. CONCLUSIONS: Our findings support a causal link between increased residential greenness exposure and a reduced risk of CVD mortality in South China with marked heterogenous effects, which has public health implications for cultivating greener urban environments to mitigate the impact of CVD within the context of rapid urbanization.

In silico fragment-based discovery of CIB1-directed anti-tumor agents by FRASE-bot.

Chemical probes are an indispensable tool for translating biological discoveries into new therapies, though are increasingly difficult to identify since novel therapeutic targets are often hard-to-drug proteins. We introduce FRASE-based hit-finding robot (FRASE-bot), to expedite drug discovery for unconventional therapeutic targets. FRASE-bot mines available 3D structures of ligand-protein complexes to create a database of FRAgments in Structural Environments (FRASE). The FRASE database can be screened to identify structural environments similar to those in the target protein and seed the target structure with relevant ligand fragments. A neural network model is used to retain fragments with the highest likelihood of being native binders. The seeded fragments then inform ultra-large-scale virtual screening of commercially available compounds. We apply FRASE-bot to identify ligands for Calcium and Integrin Binding protein 1 (CIB1), a promising drug target implicated in triple negative breast cancer. FRASE-based virtual screening identifies a small-molecule CIB1 ligand (with binding confirmed in a TR-FRET assay) showing specific cell-killing activity in CIB1-dependent cancer cells, but not in CIB1-depletion-insensitive cells.

Targeted metabolomics revealed the seasonal plasticity of skin color and pigment metabolites in ornamental koi carp.

The koi carp is an ornamental fish that was obtained through artificial selection from the common carp (Cyprinus carpio L.). The most economically important traits of koi are their beautiful skin patterns in bright colors. As seasonality is an important factor in the biology and ecology of fish, we thus assumed that seasonal changes are involved in regulating the formation of skin color and patterns of koi carp. The white, red, cyan, and black skin colors from four varieties of scaleless koi carp (Doitsu Shiromuji (W), Doitsu Kohaku (WR), Doitsu Showa Sanke (WRI), and Kumonryu (WI)) were evaluated using the CIELab color space (lightness, redness, and yellowness) in different seasons. Compared to winter, the yellowness of the white color in all koi varieties decreased in summer and autumn. The black skin color areas in WRI and WI koi increased in summer and autumn compared to winter. The yellowness of the red color decreased only in WRI koi, while no changes were observed in WR koi. Targeted metabolomics analysis revealed that the levels of the structural pigment guanine of all koi varieties showed significant seasonal variation. Of seven detected carotenoids, the zeaxanthin and tunaxanthin contents in W, WI, and WRI koi changed with the seasons, while none of the carotenoids in WR koi were altered. Of the seven potential regulatory metabolites, epinephrine, melatonin, and cyclic adenosine monophosphate (cAMP) in all four koi varieties showed the highest levels in winter. A correlation analysis suggested that the seasonal changes in white skin color occurred through the epinephrine-cAMP pathway; melanin-dependent and carotenoid-dependent skin color changes occurred through melatonin in koi carp. This study demonstrated the seasonal plasticity of skin color in koi carp regulated by melatonin and epinephrine, associating with variety and color specificity.

Transcription factor OsNF-YC1 regulates grain size by coordinating the transcriptional activation of OsMADS1 in Oryza sativa L.

Grain weight, grain number per panicle, and the number of panicles are the three factors that determine rice (Oryza sativa L.) yield. Of these, grain weight, which not only directly determines rice yield but also influences appearance and quality, is often considered the most important for rice production. Here, we describe OsNF-YC1, a member of the NF-Y transcription factor family that regulates rice grain size. OsNF-YC1 knockout plants (osnf-yc1), obtained using CRISPR-Cas9 technology, showed reduced grain weight due to reduced width and thickness, with no change in grain length, leading to a slenderer grain shape. Downregulation of OsNF-YC1 using RNA interference resulted in similar grain phenotypes as osnf-yc1. OsNF-YC1 affects grain formation by regulating both cell proliferation and cell expansion. OsNF-YC1 localizes in both the nucleus and cytoplasm, has transcriptional activation activity at both the N-terminus and C-terminus, and is highly expressed in young panicles. OsNF-YC1 interacts with OsMADS1 both in vivo and in vitro. Further analysis showed that the histone-like structural CBFD-NFYB-HMF domain of OsNF-YC1 conserved in the OsNF-YC transcription factor family can directly interact with the MADS-box domain of OsMADS1 to enhance its transcriptional activation activity. This interaction positively regulates the expression of OsMADS55, the direct downstream target of OsMADS1. Therefore, this paper reveals a potential grain size regulation pathway controlled by an OsNF-YC1-OsMADS1-OsMADS55 module in rice.

Constructing and validating a predictive nomogram for osteoporosis risk among Chinese single-center male population using the systemic immune-inflammation index.

Osteoporosis (OP) is a bone metabolism disease that is associated with inflammatory pathological mechanism. Nonetheless, rare studies have investigated the diagnostic effectiveness of immune-inflammation index in the male population. Therefore, it is interesting to achieve early diagnosis of OP in male population based on the inflammatory makers from blood routine examination. We developed a prediction model based on a training dataset of 826 Chinese male patients through a retrospective study, and the data was collected from January 2022 to May 2023. All participants underwent the dual-energy X-ray absorptiometry (DXEA) and blood routine examination. Inflammatory markers such as systemic immune-inflammation index (SII) and platelet-to-lymphocyte ratio (PLR) was calculated and recorded. We utilized the least absolute shrinkage and selection operator (LASSO) regression model to optimize feature selection. Multivariable logistic regression analysis was applied to construct a predicting model incorporating the feature selected in the LASSO model. This predictive model was displayed as a nomogram. Receiver operating characteristic (ROC) curve, C-index, calibration curve, and clinical decision curve analysis (DCA) to evaluate model performance. Internal validation was test by the bootstrapping method. This study was approved by the Ethic Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (Ethic No. JY2023012) and conducted in accordance with the relevant guidelines and regulations. The predictive factors included in the prediction model were age, BMI, cardiovascular diseases, cerebrovascular diseases, neuropathy, thyroid diseases, fracture history, SII, PLR, C-reactive protein (CRP). The model displayed well discrimination with a C-index of 0.822 (95% confidence interval: 0.798-0.846) and good calibration. Internal validation showed a high C-index value of 0.805. Decision curve analysis (DCA) showed that when the threshold probability was between 3 and 76%, the nomogram had a good clinical value. This nomogram can effectively predict the incidence of OP in male population based on SII and PLR, which would help clinicians rapidly and conveniently diagnose OP with men in the future.

Low-coordinated copper facilitates the *CH2CO affinity at enhanced rectifying interface of Cu/Cu2O for efficient CO2-to-multicarbon alcohols conversion.

The carbon-carbon coupling at the Cu/Cu2O Schottky interface has been widely recognized as a promising approach for electrocatalytic CO2 conversion into value-added alcohols. However, the limited selectivity of C2+ alcohols persists due to the insufficient control over rectifying interface characteristics required for precise bonding of oxyhydrocarbons. Herein, we present an investigation into the manipulation of the coordination environment of Cu sites through an in-situ electrochemical reconstruction strategy, which indicates that the construction of low-coordinated Cu sites at the Cu/Cu2O interface facilitates the enhanced rectifying interfaces, and induces asymmetric electronic perturbation and faster electron exchange, thereby boosting C-C coupling and bonding oxyhydrocarbons towards the nucleophilic reaction process of *H2CCO-CO. Impressively, the low-coordinated Cu sites at the Cu/Cu2O interface exhibit superior faradic efficiency of 64.15 ± 1.92% and energy efficiency of ~39.32% for C2+ alcohols production, while maintaining stability for over 50 h (faradic efficiency >50%, total current density = 200 mA cm-2) in a flow-cell electrolyzer. Theoretical calculations, operando synchrotron radiation Fourier transform infrared spectroscopy, and Raman experiments decipher that the low-coordinated Cu sites at the Cu/Cu2O interface can enhance the coverage of *CO and adsorption of *CH2CO and CH2CHO, facilitating the formation of C2+ alcohols.

The developmental pattern related to fatty acid uptake and oxidation in the yolk sac membrane and jejunum during embryogenesis in Muscovy duck.

This study aimed to investigate the developmental change of body growth and gene expression related to fatty acid uptake and oxidation in the yolk sac membrane (YSM) and jejunum during embryogenesis in Muscovy ducks. The weights of embryos and yolk sac (YS) (5 embryos per replicate, n = 6) were recorded on embryonic days (E)16, E19, E22, E25, E28, E31, and the day of hatch (DOH). The fat and fatty acid contents in YSM, jejunal histology, and gene expression related to fatty acid metabolism in YSM and jejunum were determined in each sampling time. Among the nonlinear models, the maximum growth is estimated at 2.83 (E22.5), 2.67 (E22.1), and 2.60 (E21.3) g/d using logistic, Gompertz, and Von Bertalanffy models, respectively. The weight of YS, and ether extract-free YS as well as the amounts of fat and fatty acids in YS decreased (P < 0.05) linearly, whereas the villus height, crypt depth, villus height/crypt depth, and musculature thickness in jejunum increased (P < 0.05) linearly during embryogenesis. The mRNA expression of CD36, SLC27A4, and FABP1 related to fatty acid uptake as well as the mRNA and protein expressions of PPARα and CPT1 related to fatty acid oxidation increased in a quadratic manner (P < 0.05) in both YS and jejunum, and the maximum values were achieved during E25 to E28. In conclusion, the maximum growth rate of Muscovy duck embryos was estimated at 2.60 to 2.83 g/d on E21.3 to E23.5, while the accumulations of lipid and fatty acid in YS were decreased in association with the increased absorptive area of morphological structures in jejunum. The gene and protein expression involved in fatty acid metabolism displayed a similar enhancement pattern between YSM and jejunum during E25 to E28, suggesting that fatty acid utilization could be strengthened to meet the energy demand for embryonic development.

Cardiovascular-kidney-metabolic overlap in heart failure with preserved ejection fraction: Cardiac structure and function, clinical outcomes, and response to sacubitril/valsartan in PARAGON-HF.

AIMS: Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. METHODS AND RESULTS: In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). CONCLUSIONS: Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01920711.