Disease Models Research Articles

Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium

IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration. MethodsThirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis. ResultsSGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes. ConclusionsSGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.

Retracted] Brain cell apoptosis inhibition by butylphthalide in Alzheimer's disease model in rats.

[This retracts the article DOI: 10.3892/etm.2017.4322.].

Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models

Computer-vision and machine-learning (ML) approaches are being developed to provide scalable, unbiased, and sensitive methods to assess mouse behavior. Here, we used the ML-based variational animalmotion embedding (VAME) segmentation platform to assess spontaneous behavior in humanized App knockin and transgenic APP models of Alzheimer's disease (AD) and to test the role of AD-related neuroinflammation in these behavioral manifestations. We found marked alterations in spontaneous behaviorin AppNL-G-F and 5xFAD mice, including age-dependent changes in motif utilization, disorganized behavioral sequences, increased transitions, and randomness. Notably, blocking fibrinogen-microglia interactions in 5xFAD-Fggγ390-396A mice largely prevented spontaneous behavioral alterations, indicating akey role for neuroinflammation. Thus, AD-related spontaneous behavioral alterations are prominent in knockin and transgenic models and sensitive to therapeutic interventions. VAME outcomes had higherspecificity and sensitivity than conventional behavioral outcomes. We conclude that spontaneous behavior effectively captures age- and sex-dependent disease manifestations and treatment efficacy in AD models.

Echocardiographic Screening Model for Improved Assessment of Atrial Septal Defect Closure: A Multicenter Retrospective Study.

Atrial septal defect (ASD) is a prevalent congenital heart condition in adults, which finally leads to pulmonary hypertension and right heart failure if left untreated. Right heart catheterization (RHC), the current gold standard for determining ASD closure feasibility, is invasive. Thus, a noninvasive prescreening tool is urgently needed. In a multicenter, retrospective study, we assessed 924 ASD patients (2012-2022) to determine their suitability for ASD closure. Using LASSO regression, we identified predictors for a correctable shunt, enabling us to create the ASD model. The ASD model, comprising of estimated pulmonary artery systolic pressure (ePASP), peak velocity through the pulmonary valve (PV), peak E-wave velocity through the tricuspid valve (TVE), and right atrial longitudinal dimension (RA) by echocardiography, was constructed and exhibited favorable discriminative capability with an area under the curve (AUC) of 0.941 (95% CI: 0.920-0.961) in the derivation group. The model also demonstrated good calibration and discriminative abilities in the validation cohort. When juxtaposed with the earlier congenital heart disease (CHD) model, the newly developed ASD model demonstrated superior predictive capabilities for correctable shunt, supported by the net reclassification index (NRI) [0.063 (95% CI: 0.001-0.127, p = 0.047)] and integrated discrimination improvement (IDI) [0.023 (95% CI: 0.011-0.036, p <0.001)]. In summary, our research advocates the ASD model as a superior tool for screening suitable ASD defect closure candidates.

Insights into the Therapeutic and Pharmacological Properties of Resveratrol as a Nutraceutical Antioxidant Polyphenol in Health Promotion and Disease Prevention.

Resveratrol (3, 5, 4'-trihydroxystilbene) is a polyphenolic derivative with herbal origin. It has attracted considerable attention in recent decades. Many studies have revealed the benefits of Resveratrol over several human disease models, including heart and neurological diseases, nephroprotective, immune regulation, antidiabetic, anti-obesity, age-related diseases, antiviral, and anticancer in experimental and clinical conditions. Recently, the antioxidant and anti-inflammatory activities of Resveratrol have been observed, and it has been shown that Resveratrol reduces inflammatory biomarkers, such as tissue degradation factor, cyclooxygenase 2, nitric oxide synthase, and interleukins. All of these activities appear to be dependent on its structural properties, such as the number and position of the hydroxyl group, which regulates oxidative stress, cell death, and inflammation. Resveratrol is well tolerated and safe even at higher pharmacological doses and desirably affects cardiovascular, neurological, and diabetic diseases. Consequently, it is plausible that Resveratrol can be regarded as a beneficial nutritional additive and a complementary drug, particularly for therapeutic applications. The present review provides an overview of currently available investigations on preventive and therapeutic characteristics and the main molecular mechanisms of Resveratrol and its potent derivatives in various diseases. Thus, this review would enhance knowledge and information about Resveratrol and encourage researchers worldwide to consider it as a pharmaceutical drug to struggle with future health crises against different human disorders.

Role of local angiotensin II signaling in bladder function.

Angiotensin II signaling plays a crucial role in many different diseases. Although it has been known for several decades that local angiotensin II signaling molecules are present in the bladder, the understanding of their functions there is still limited, especially compared with other organ systems such as cardiovascular and respiratory systems. This article reviews current literature regarding local angiotensin II signaling in the urinary bladder. By reviewing several decades of literature, the field has provided strong evidence to support the presence of local angiotensin II signaling in the bladder, including the expression of angiotensin type 1 receptor and angiotensin type 2 receptor in both human and animal tissues. In addition, evidence suggests a functional role of angiotensin type 1 receptor in mediating bladder contractions. In bladder disease models, angiotensin II signaling can be upregulated, and angiotensin type 1 receptor activity is associated with increases in inflammation, fibrosis, and oxidative stress. We also address the gaps in knowledge that remain in understanding local angiotensin II signaling in the bladder, including limitations on clinical translatability. Although there is a strong foundation regarding the local presence and role of angiotensin II signaling in the bladder, further research is needed to support translational applications.

Nathan Lo—translating infectious disease models into policy

Nathan Lo—translating infectious disease models into policy

ВОЗМОЖНОСТИ ПРИМЕНЕНИЯ НЕИНВАЗИВНЫХ ОФТАЛЬМОЛОГИЧЕСКИХ МЕТОДОВ ДИАГНОСТИКИ ПАТОЛОГИЧЕСКИХ СОСТОЯНИЙ ПРОЦЕССА РАННЕГО СТАРЕНИЯ НА МОДЕЛИ ПРИМАТОВ

Currently, there is an urgent need for early diagnostics, searching for means of predicting the development of cognitive deficit, and assessing the dynamics of changes during treatment. Given the common origin of the brain and eye, which undergo the same onto- and phylogenetic development, some researchers have suggested that the eye can act as a “window” for easily accessible and non-invasive methods for studying brain pathology [3]. The popularity of fundamental research is growing, and interest in creating disease models in primates is becoming more relevant. The creation of such models will significantly expand the possibilities of obtaining the most reliable information, especially in the field of gerontology and brain pathology (cataract, senile ring, age-related changes in the fundus and other signs of early aging). In this part of the work, approaches to studying the fundus, physiological parameters of the structures and functions of the visual organ in rhesus macaques and hamadryas baboons of different ages are developed; potential ophthalmological biomarkers for diagnosing early aging processes are considered. A combined approach using ophthalmological markers, including non-invasive visualization of the retina and detection of pathological proteins in the intraocular fluid, lens or retina, in combination with biomarkers of oxidative stress (malondialdehyde, lipofuscin, protein carbonyls, 8-OH-deoxyguanosine) will allow us to develop a methodology for diagnosing the development and correction of early aging in humans on a primate model.

Establishing disease models for the Belgian national burden of disease study: challenges and perspectives

Abstract The Belgian national burden of disease study (BeBOD) was launched in 2022, and currently provides disease burden estimates for 38 key diseases. The calculation of the non-fatal component of the disease burden, the Years Lived with Disability (YLD), follows a stepwise approach that aims to establish priority outcomes; quantify prevalence “best estimates”; establish disease models; and perform expert evaluation of methods and results. The disease models visualize the relationship between the different health states associated with a given outcome. Health states include the different acute and chronic stages of the outcome (including complications), which may be stratified in different severity levels (e.g., mild, moderate, severe). Disease models used in burden of disease studies primarily aim to document the considered health states, and do not aim at a representation of the complete clinical picture of the condition. The disease models instead help in understanding how the number of cases for each health state is calculated. Models typically start with one “parent node”, which contains all cases. This parent node then gives rise to multiple “child nodes”, with the terminal child nodes representing the individual health states. In BeBOD, disease models and severity distributions are adapted from the Global Burden of Disease (GBD) study, and complemented with local data where possible. This process ensures consistency with available disability weights, while still allowing for local data to feed into the calculations. In this presentation, we will demonstrate the BeBOD process for establishing disease models based on a number of archetypical examples, which represent varying challenges linked to disease model complexity, clarity and completeness of the GBD disease model documentation, and availability of local data. Future perspectives will be discussed, including the improved leveraging of local clinical data, and the implementation of tailored active data collection.

Inhibiting chondroitin sulfate synthase 1 ameliorates hyperplastic arterial remodelling

Abstract Introduction Hyperplastic arterial remodelling is characterized by intima-media thickening, lumen narrowing, inflammation and increased extracellular matrix (ECM) deposition. Chondroitin sulfate (CS) glycosaminoglycans, the unbranched polysaccharide chains of proteoglycans, are important components of ECM. We previously found CS accumulated in adversely remodelled heart and artery, aggravating cardiac deterioration. Objective We aim to explore a therapeutic strategy to interfere with CS synthesis and investigate its potential in ameliorating hyperplastic arterial remodelling. Methods Through single-cell RNA sequencing of non-cardiomyocytes cardiac cells from mouse myocardial infarction model, chondroitin sulfate synthase 1 (CHSY1) was identified as the primary CS synthase and was increased during disease progression. A Chsy1 knockout (KO) mouse strain was generated. Fibrosis and arterial remodelling were induced using: (i) 4 weeks of angiotensin II/phenylephrine (AngII/PE) infusion through subcutaneous osmotic minipumps; and (ii) transverse aortic constriction surgery. To assess the therapeutic potential of CHSY1 inhibition in ameliorating hyperplastic arterial remodelling, Chsy1 was knockdown by dsiRNA post disease onset. Mechanism of action was investigated using primary vascular smooth muscle cells (VSMCs). Results Chsy1 KO reduced CS and its stereoisomer dermatan sulfate in the heart to 42 ± 22% and 36 ± 7% respectively, whereas other types of glycosaminoglycans remain intact. KO mice were protected against phenotypes of hyperplastic arterial remodelling induced by the two disease models in both the coronary and carotid arteries. For example, 90.1% of coronary arterial fibrosis and 79.7% of macrophage infiltration induced by AngII/PE was declined in KO mice compared to WT mice, while cardiac function as stroke volume was augmented by 41.3%. Concomitantly, carotid arterial wall thickening was lower by 36.5% and distensibility was higher by 36.7%, validating Chsy1 as a potent target. As a therapeutic approach, weekly intravenous injection of dsiRNA achieved Chsy1 reduced to 30.2 ± 5.5% in the carotid artery and 72.5 ± 4.7% in the heart. Post disease onset, Chsy1 KD therapy reduced fibrosis by 59.9% in the coronary artery (P = 0.006) and improved stroke volume by 25.6% (P = 0.036). The structural integrity and function of carotid arteries were well-reserved, manifesting as improved distensibility (29%, P = 0.016), increased elastin/perimeter ratio (15%, P = 0.002), and reduced macrophage infiltration (38%, P = 0.029). In vitro, CHSY1 inhibition suppressed migration and cytokine production of macrophages, fibroblast-to-myofibroblast transition, and VSMC hyperproliferation. NOTCH3 signalling was found to be positively correlated with CHSY1 modulation. Conclusions We demonstrated that inhibiting CHSY1 is necessary and sufficient to block CS synthesis. Chsy1 KD by dsiRNA is an effective therapy to ameliorate hyperplastic arterial remodelling.

Impaired right ventricular strain is associated with worse prognosis in patients with liver cirrhosis

Abstract Introduction Cirrhotic cardiomyopathy is a complication of liver cirrhosis accounting for significant morbidity and associated with reduced patient survival. It is characterized by reduced afterload, increased cardiac output, and diastolic dysfunction. However, there are limited data regarding the prognostic significance of right ventricular (RV) mechanics. Novel echocardiographic techniques such as speckle tracking echocardiography can detect subclinical myocardial dysfunction early in the course of non-ischemic myocardiopathies. Purpose To investigate the prognostic role of RV free wall strain (RVFWS) in patients with liver cirrhosis. Methods We prospectively enrolled 70 patients with liver cirrhosis in stable clinical condition. Patients with coronary artery disease, valvular heart disease, ongoing alcohol consumption or poor acoustic window were excluded from the study. Transthoracic echocardiography was performed and RVFWS was calculated from RV focused 4-chamber views using a dedicated software. Since RVFWS was as expected negative in all patients, absolute values were used for all calculations. Clinical and laboratory examination was also performed in all patients and the Model for End-Stage Liver Disease (MELD) score a widely used tool for assessing liver disease severity was calculated. All-cause mortality at 24 months was the primary endpoint and was available in all patients. Results Mean RVFWS in the cohort was 27.4±6.3% and using a lower normal limit of 20%, reduced RVFWS was detected in six patients. According to the Spearman coefficient analysis, RVFWS was correlated with MELD (rho=0.274, p=0.023) indicating increased values in patients with more advanced liver disease. According to the univariate Cox-regression proportion hazard models RVFWS as a continuous variable was not significantly correlated with worse two year survival (HR: 1.01 (0.95-1.08, p=0.658). Interestingly, among conventional echocardiographic parameters basal RV diameter (p=0.004) and right atrial end-systolic area (p=0.008) were associated with increased risk for the primary endpoint. The association of the primary endpoint with other parameters of RV systolic function was also not statistically significant. The Multivatiate Cox Regression survival analysis, which incorporated age, sex, MELD, hemoglobin, systolic blood pressure and cardiac output, showed that among echocardiographic parameters for the evaluation of the RV, only RVFWS showed a tendency to be associated with worse survival (p=0.062). When patients were stratified into tertiles according to RVFWS values, those in the first tertile (with lower absolute RVFWS values) had significantly increased hazard for the primary endpoint (HR: 5.82, 2.18-15.8, P&amp;lt;0.001) (figure 1). Conclusions RVFWS values are within normal limits in most patients with liver cirrhosis. When adjusted for the severity of the liver disease, reduced RVFWS values are associated with worse prognosis in cirrhotics.

ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease

Abstract Background Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include ERBB4 stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. Objectives To assess the effect NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Methods Hypertensive heart disease was induced in 12 Aachener minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 weeks and compared to 6 controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method. Results DOCA significantly increased microvascular resistance compared to controls (from 14.5 to 19.9 mmHg.s, p = 0.028). This increase was abrogated by JK07 (11.3 mmHg.s, p = 0.018 vs DOCA). dP/dtmax increased by DOCA compared to controls (from 2415.5 to 4455.5 mmHg/s, p = 0.011), which was also abrogated by JK07 (3107.3 mmHg/s, p = 0.055 vs DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared to DOCA only (2.1 vs. 5.4 %, p = 0.026), but without difference in perivascular fibrosis (p = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, or microvascular vessel thickness. Conclusions ERBB4 activation by JK07 is capable to prevent CMD in a DOCA hypertensive pig model. Functional rather than structural alterations may explain the protective effects of JK07 on microvascular resistance.Visual summaryJK07 decreases microvascular resistance

Comparative analysis of multi-organ failure trajectories reflected by the MELD-3.0 following heart transplantation and heartmate 3 implantation

Abstract Background Multi-organ failure (MOF) frequently complicates advanced heart failure (HF), substantially impacting patient prognosis. The Model of End-Stage Liver Disease 3.0 (MELD-3.0) scale, encompassing liver and kidney function parameters, is a valuable tool for assessing the severity of organ dysfunction. Purpose This study aims to elucidate the trajectory of MOF in individuals undergoing either heart transplantation (HTx) or left ventricular assist device (LVAD) - HeartMate 3 implantation, utilizing the MELD-3.0 scale, over a 1-year follow-up period. Methods A comprehensive analysis was conducted, examining data from 1 month preceding to 1 year subsequent to the HTx or LVAD implantation. The MELD-3.0 score was calculated using the average values of international normalized ratio, bilirubin, creatinine, sodium, and albumin levels during this timeframe. Comparative assessments of the average MELD-3.0 scores were performed between the HTx and LVAD groups at 1 month pre-procedure, as well as at 1 week, 1 month, 3 months, 6 months, and 1 year post-procedure. Results The analysis included 107 patients undergoing HTx and 31 patients undergoing HMi, with a median age of 54 years (47-62), 85% were male. There was no difference in MELD-3.0 between HTx and LVAD patients in the pre-procedure period: 12.3 (7.3-15.9) vs 13.1 (7.7-16.6), p=0.95. There was also no difference in MELD-3.0 at 1 week and 1 month post-procedure. However, in the 3rd month, the difference gained statistical significance: 7.3 (4.6-9.4) vs 13.8 (11.5-19.7), p&amp;lt;0.01 and continued to be significant in the next follow-ups: 12-month 5.4 (3.1-10.2) vs 11.1 (6.7—15.1), p&amp;lt;0.01, comparing respectively HTx vs LVAD. In both groups of patients, a significant decrease in MELD-3.0 score from 3-month follow-up when compared to 1 month preceding the procedure was observed. Within 12 months post-procedure, 30 patients (22%) died (19 in HTx group and 11 in LVAD group), 8 LVAD patients (26%) had HTx. Conclusion The utilization of the MELD-3.0 scale reveals significant differences in the trajectory of multi-organ failure between HTx and LVAD patients. Both forms of advanced HF therapy result in an improvement of liver and kidney condition, while HTx patients' benefits are larger and last longer, highlighting the distinct impacts of this intervention on organ function.MELD 3.0 score in time

Elafibranor: A promising treatment for alcoholic liver disease, metabolic-associated fatty liver disease, and cholestatic liver disease

Liver diseases pose a significant threat to human health. Although effective therapeutic agents exist for some liver diseases, there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes. This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease (ALD), as reported by Koizumi et al in the World Journal of Gastroenterology . We summarize the impact and mechanisms of Elafibranor on ALD, metabolic-associated fatty liver disease, and cholestatic liver disease based on current research. We also explore its potential as a dual agonist of PPARα/δ, which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis. Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

Thyroglobulin measurement is the most powerful outcome predictor in differentiated thyroid cancer: a decision tree analysis in a European multicenter series.

An accurate prognostic assessment is pivotal to adequately inform and individualize follow-up and management of patients with differentiated thyroid cancer (DTC). We aimed to develop a predictive model for recurrent disease in DTC patients treated by surgery and 131I by adopting a decision tree model. Age, sex, histology, T stage, N stage, risk classes, remnant estimation, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), administered 131I activities and post-therapy whole body scintigraphy (PT-WBS) were identified as potential predictors and put into regression algorithm (conditional inference tree, c-tree) to develop a risk stratification model for predicting persistent/recurrent disease over time. The PT-WBS pattern identified a partition of the population into two subgroups (PT-WBS positive or negative for distant metastases). Patients with distant metastases exhibited lower disease-free survival (either structural, DFS-SD, and biochemical, DFS-BD, disease) compared to those without metastases. Meanwhile, the latter were further stratified into three risk subgroups based on their Tg values. Notably, Tg values >63.1 ng/mL predicted a shorter survival time, with increased DFS-SD for Tg values <63.1 and <8.9 ng/mL, respectively. A comparable model was generated for biochemical disease (BD), albeit different DFS were predicted by slightly different Tg cutoff values (41.2 and 8.8 ng/mL) compared to DFS-SD. We developed a simple, accurate and reproducible decision tree model able to provide reliable information on the probability of structurally and/or biochemically persistent/relapsed DTC after a TTA. In turn, the provided information is highly relevant to refine the initial risk stratification, identify patients at higher risk of reduced structural and biochemical DFS, and modulate additional therapies and the relative follow-up.

Prognostic value of MELD-XI score and hemodynamic parameters in patients undergoing transcatheter tricuspid valve intervention

Abstract Background Hepatorenal dysfunction is a strong prognostic predictor in patients with tricuspid regurgitation. Patients are often hospitalized with acute heart failure due to volume overload and peripheral hypoperfusion. End-organ dysfunction is associated with the development of right ventricular failure related to hemodynamic changes such as low cardiac output and passive congestion from increased right ventricular filling pressures. Purpose This study aimed to investigate the prognostic value of hepatorenal dysfunction using the Model for End-stage Liver Disease (MELD) Score, the modified version of the score, MELD-XI, and of parameters determined during right-heart catheterization in patients undergoing transcatheter tricuspid valve intervention. Methods In this single-center prospective cohort study, data from patients undergoing edge-to-edge repair or heterotopic minimal invasive tricuspid valve repair were analyzed. Serum creatinine, INR and bilirubin were measured and the MELD score as well as the MELD XI score was calculated. All patients underwent right heart catheterization before the intervention. Receiver operator characteristics with calculation of the area under the curve (AUC) were performed to determine the predictive value of MELD (XI) score and hemodynamic parameters for the combined endpoint of rehospitalization due to decompensated heart failure and mortality within 3 months. Results Data from 36 consecutive patients were analyzed. 28 patients underwent edge-to-edge repair and 8 patients heterotopic minimal invasive tricuspid valve repair. Mean age of patients was 80.2 ± 5.9 years; 33.3% (12/36) were male. Baseline characteristics are shown in table 1. Rehospitalization due to decompensated heart failure occurred in 9/36 patients (25%). Mortality within the first 3 months was 11% (4/36). The predictive value for the composite endpoint of the modified MELD IX score was AUC 0.82 (95 % CI 0.63-0.99; p=0.009), while the conventional MELD score had an AUC of 0.77 (95 % CI 0.55-0.99; p = 0.059) (figure 1). RV pressure (AUC 0.84, 95% CI 0.66-1.00, p= 0.012) and RA pressure (AUC 0.83, 95% CI 0.67-0.98, p=0.016) showed a good predictive value for the composite endpoint (figure 2). The combination of MELD XI (at admission) and RV or PA pressure improved the AUC (MELD XI + RV: AUC 0.85; MELD XI + PA: AUC 0.84). Conclusion In this pilot-study, the modified MELD XI score, as indicator of hepatorenal dysfunction, was identified as a potential marker for short-term outcome after interventional tricuspid valve treatment.

Targeting BRD4-HK2 reverses the meta-inflammatory shift in perivascular adipose tissue and rescues cardiometabolic vascular dysfunction

Abstract Background/Introduction Reducing vascular inflammation is crucial to halt and reverse cardiometabolic damage. BRD4, an epigenetic pan-inflammatory activator whose inhibition has shown promising results in cancer, may play an important role in this context. However, its role in cardiometabolic disease remains unclear. Purpose To investigate BRD4-related transcriptional programmes and therapeutic modulation in translational models of cardiometabolic disease. Methods We dissected small arteries (100-300 μM) from visceral fat biopsies in healthy volunteers (n=16) and patients with obesity and hypertension (n=16), a highly prevalent cardiometabolic phenotype. We assessed the ex vivo effects of BRD4 inhibition on vascular function by pressure myography in the presence or absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 or with anti-inflammatory/anti-metabolic drugs. We used a cardiometabolic mouse model (high-fat diet+L-NAME supplementation) that mirrored our human phenotype and orally administered RVX-208 (150 mg/kg) or vehicle for 5 days (n=6 per group) to confirm the in vivo effect of chronic BRD4 inhibition. Finally, we investigated the molecular pathways involved in the perivascular cross-talk in an in vitro model of human adipocytes (hADSCs) and endothelial cells (HAECs) using gene overexpression/silencing strategies. We assessed ROS and nitric oxide levels (confocal microscopy), protein and gene expressions (Western blot; qPCR), transcriptional (custom qPCR array; chromatin immunoprecipitation (ChIP)) and metabolic changes (metabolomics, lipidomics, mitochondrial swelling). Results Vascular inflammation, remodeling and function were altered in cardiometabolic patients/mice. RVX-208 attenuated ex vivo vascular dysfunction to a greater extent than anti-IL-1β, anti-IL-6 receptor and anti-TNF-α. In vessels with intact PVAT we observed a stronger effect, due to the restoration of healthy PVAT phenotype (Figure 1). In PVAT, Hexokinase-2 (Hk2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - was the top downregulated gene by RVX-208 treatment; ChIP confirmed increased binding of BRD4 to the Hk2 promoter. In line, metabolomics and lipidomics assays revealed a PVAT glycolytic shift with increased fatty acid storage in disease states, which was reversed by BRD4 inhibition. The in vitro study showed that: i) healthy adipocytes overexpressing HK2 shift to an inflammatory phenotype; ii) their secretome induces an inflammatory phenotype in HAECs; iii) ex vivo PVAT-selective inhibition of HK2 ameliorates vascular dysfunction (Figure 2). Conclusions We identified BRD4-HK2 interaction at the PVAT level as a novel mediator of cardiometabolic damage. Its targeting rescues vascular dysfunction by reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammation may represent a promising strategy in patients with obesity and hypertension.

Early detection of liver fibrosis in patients with Fontan circulation using multiparametric magnetic resonance imaging

Abstract Introduction Fontan procedure (FP), serving as the palliative intervention for complex congenital heart diseases characterized by single-ventricle physiology, precipitates a spectrum of late-stage complications. Fontan-associated liver disease (FALD) encompassing liver fibrosis (LF) which may progress to liver cirrhosis (LC) and thereby hepatocellular carcinoma (HCC) is among the most serious. Despite its importance, optimal surveillance of FALD remains undefined. Multiparametric Liver Multiscan (LMS) with corrected T1 (cT1) value emerges as a novel magnetic resonance (MRI) based non-invasive quantitative tool for liver inflammation and fibrosis evaluation. Aim of this study was to ascertain prevalence and severity of LF utilizing LMS, alongside identifying contributory risk factors for LF in adults post-FP. Material and methods Our cohort included 29 adult patients after FP who underwent LMS. Median age was 25y (20-43y) 54% were females. Liver morphology was assessed by ultrasound (USG) and MRI-based LMS protocol. Hepatic scoring systems, including the Aspartate Aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4) Index, and Model for End-Stage Liver Disease (MELD), were computed. Additionally, presence of fenestrations in the Fontan circulation, hemoglobin levels (Hb), and blood oxygen saturation both at rest and during exercise (SatO2%) were evaluated. Results Median cT1 was 914 (±207) ms, in 87% exceeding normal threshold . In those with elevated cT1, LF was undetected by USG in 38%. LC was identified in 27% of the cohort by USG. LC group exhibited significantly higher cT1 values (P&amp;lt;0.001) compared to non-LC group. cT1 value &amp;gt;933ms was associated with a sensitivity of 89% and a specificity of 80% for diagnosing LC (AUC 0.92). Significant correlation was found between cT1 values and Hb (P=0.01) and desaturation (SatO2 &amp;lt;90%/ interventional closure of fenestration, P=0.004). Conventional liver tests and hepatic scoring systems (APRI/FIB-4/MELD) did not predict cT1 nor LC. Conclusion Our study confirmed that LF is almost widely prevalentamong adult patients with single-chamber circulation. Risk factors for LF are systemic desaturation (SatO2 &amp;lt;90% or interventional closure of fenestration) and polyglobulia. However, reliable FALD surveillance remains challenging. Conventional liver assessments and scoring algorithms fall short in delineating the full scope of LF or LC. Consequently, the integration of non-invasive LMS into routine follow-up regimens is advocated, given its pronounced sensitivity for detecting subclinical FALD manifestations and predicting LC. The LMS-derived cT1 value &amp;gt;933ms is a critical predictor for LC, underscoring its importance in guiding further patient monitoring, treatment, and facilitating early HCC detection.

MELD-albumin score is strongly associated with all-cause mortality in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Background Kidney and liver injury are frequent complications in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) because of hypoperfusion and venous congestion. Model of End-Stage Liver Disease replacing INR with albumin (MELD-Albumin) score quantifies liver and kidney function and has been associated with mortality in acute heart failure. Higher MELD-albumin score indicates particularly more severe hepatic dysfunction. The predictive value of MELD-albumin score has yet to be assessed in AMICS. Methods This is a retrospective, multicenter observational cohort study of 1,716 patients admitted with AMICS at two tertiary facilities in Denmark between 2010 and 2017. MELD-albumin was calculated for each patient individually from 0–72-hour peak s-albumin, s-creatinine and s-bilirubin values in patients alive beyond day 2. Patients were stratified into groups according to score (Low: 1-10, Intermediate: 11-25, High: &amp;gt;25). Using national health registries, we performed follow-up until a maximum of 5 years (median 3.4 years). The primary outcome was all-cause mortality. Results Of 1716 patients in the cohort, 1284 (75%) were alive beyond admission day 2. Albumin, creatinine, and bilirubin measurements were available in 764 patients (60%). The median MELD-albumin score was 17. In the comparison across high vs. intermediate vs. low score groups, the high score group revealed a significantly higher prevalence of hypertension (61 vs. 49 vs. 39%, p=0.038), diabetes mellitus (33 vs. 18 vs. 13%, p=0.003), and history of acute myocardial infarction (24 vs. 13 vs. 17%, p=0.026). Fewer had suffered out-of-hospital cardiac arrest (34 vs. 52 vs. 48%, p=0.014) and revascularization attempts (82 vs. 93 vs. 92%, p=0.007) in the high score group. No significant differences were observed in the initial hemodynamic pressures, lactate levels, left ventricular ejection fraction (LVEF), number of diseased vessels and culprit lesions between the three groups. Patients in the high score group had a 30-day mortality rate of 58%, which was higher compared to 40% in the medium- and 17% in the low score group (Figure 1, p&amp;lt;0.001, using the log-rank test). These findings were still significant when excluding s-creatinine from the calculations. In a Cox Regression analysis, a MELD-albumin score of &amp;gt;25 was associated with a hazard ratio (HR) of 4.34 for 5-year mortality (p &amp;lt; 0.001), whereas a score of 11-25 was associated with a HR of 2.52 (p &amp;lt; 0.001). When adjusting for age, diabetes, hypertension, dyslipidemia, peripheral arterial disease, STEMI, left ventricular ejection fraction and baseline lactate, scores of &amp;gt;25 and 11-25 were still associated with similar 4- to 2.5-fold increases in 5-year mortality risks. Conclusions This study revealed a strong association between MELD-albumin score and all-cause mortality among patients with AMICS, supporting kidney and liver function inclusion in future risk stratification models.

Investigation of an optimal control strategy for a cholera disease transmission model with programs

Cholera is a disease of poverty affecting people with inadequate access to safe water and basic sanitation. Conflict, unplanned urbanization and climate change all increase the risk of cholera. In this article, an optimal control deterministic mathematical model of cholera disease with cost-effectiveness analysis is developed and analyzed considering both direct and indirect contact transmission pathways. The model qualitative behaviors, such as the invariant region, the existence of a positive invariant solution, the two equilibrium points (disease-free and endemic equilibrium), and their stabilities (local as well as global stability) of the model are studied. Moreover, the basic reproduction number of the model is obtained. We also performed sensitivity analysis of the basic parameters of the model. Then an optimal control problem is designed with a control functional having five controls: vaccination, treatment, environment sanitation and personal hygiene, and water quality improvement program. We examined the existence and uniqueness of the optimal controls of the system. Through the implementation of Pontryagin's maximum principle, the characterization of the optimal controls optimality system is established. The numerical simulation results the integrated control strategies demonstrated that strategy 2, 7, and 12 are effective programs to combat cholera disease from the community. Based on the local circumstances, available funds, and resources, it is recommended to the government stakeholders and policymakers to execute any one of the three integrated intervention programs.