Liver Function Research Articles

Impact of Intermediate-term Oral Contraceptive Use on Oxidative Stress, Lipid Profile, and Liver Function in Iraqi Women: A Comprehensive Biochemical Assessment

Impact of Intermediate-term Oral Contraceptive Use on Oxidative Stress, Lipid Profile, and Liver Function in Iraqi Women: A Comprehensive Biochemical Assessment

Unveiling the Dark Side of Flavonoid: Rutin Provokes Hepatotoxicity in Low-Dose 2-Amino-3-methylimidazo [4,5-f] Quinoline-Exposed Mice via Regulating Gut Microbiota and Liver Metabolism.

2-Amino-3-methylimidazole [4,5-f] quinoline (IQ) is a kind of heterocyclic amine (HCAs) with high carcinogenicity in hot processed meat. Rutin (Ru) is a flavonoid compound with anti-inflammatory and antioxidant properties. However, whether Ru is scatheless under IQ-stimulated potential unhealthy conditions, especially liver function, in vivo, is unknown. In this study, we explored the effects and underlying mechanism of Ru on liver injury induced by a low dose of IQ in mice. Results showed that Ru supplement led to liver injury upon low-dose IQ alone administration, as shown by histological analysis, inflammatory, and serum biochemical indexes. Additionally, nontargeted metabolomics analysis revealed that coexposure of Ru and IQ disrupted liver metabolic balance, leading to significant changes in metabolites and metabolic pathways, hinting at a possible relationship with intestinal microbiota. Furthermore, the 16S rRNA sequencing data indicated that a combination of Ru and IQ caused gut microbiota dysbiosis and decreased the level of short-chain fatty acids (SCFAs). Correlation analysis between gut microbiota, SCFAs, liver metabolites, and liver damage markers highlighted the crucial role of the gut-liver axis in IQ and Ru coexposure-induced liver injury in vivo. In general, this study offers a valuable perspective on flavones and HCA compounds in the realms of food safety and human health.

Evaluation of drug-drug interaction between rosuvastatin and tacrolimus and the risk of hepatic injury in rats.

Multimorbidity, therapeutic complexity, and polypharmacy, which greatly increases the risk of drug-drug interactions (DDIs) and adverse medical outcomes, have become important and growing challenges in clinical practice. Statins are frequently prescribed to manage post-transplant dyslipidemia and reduce overall cardiovascular risk in solid organ transplant recipients. This study aimed to determine whether rosuvastatin has significant DDIs with tacrolimus (the first-line immunosuppressant) and to evaluate the risk of hepatotoxicity associated with concomitant therapy. We first studied whether a rat model could be established to assess the magnitude of rosuvastatin-tacrolimus DDI. The liver function index and histopathological examination were performed to investigate the characteristics of hepatotoxicity in the presence and absence of DDI. The clinical DDI potential between rosuvastatin and tacrolimus was also explored. Single-dose intravenous administration of tacrolimus did not significantly affect the area under the plasma concentration-time curve (AUC0-∞), clearance (CL), and volume of distribution at steady-state (Vss) of rosuvastatin in rats, despite a 96.7% increase in the rosuvastatin maximum plasma concentration (P = 0.024). Multiple doses of intravenous tacrolimus had no effect on the systemic disposition of rosuvastatin, but significantly increased aspartate transaminase (AST) by 42.6% (P = 0.043). Multiple doses of intravenous tacrolimus and rosuvastatin significantly altered the disposition of rosuvastatin, reducing alanine aminotransferase(ALT) and AST by 38.3% (P = 0.040) and 31.6% (P = 0.019), respectively. Histological evaluation of the liver specimens revealed patterns of drug-induced liver injury in rats. At clinically relevant doses, tacrolimus was predicted to be unable to cause pharmacokinetic interactions with rosuvastatin through basic models. The concomitant administration of tacrolimus and rosuvastatin has a minor impact on rosuvastatin pharmacokinetics; however, mild hepatotoxicity has been observed in rats.

Effect of Target-Mediated Disposition on Iptacopan Clinical Pharmacokinetics in Participants with Normal or Impaired HepaticFunction.

Iptacopan, a first-in-class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement-mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma-based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target-mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug-target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38- to 3.72-fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two-site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small-molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small-molecule drug development.

Alkaline phosphatase of late pregnancy promotes the prediction of adverse birth outcomes.

Adverse birth outcomes (ABO), such as preterm birth (PTB), small and large for gestational age (SGA/LGA), can compromise both the short- and long-term health of mothers and their foetuses. The purpose of this observational study was to investigate the association between maternal serum alkaline phosphatase (ALP) levels in late pregnancy and the risk of ABO, and to evaluate its predictive value of maternal ALP levels for ABO in women with singleton pregnancies. A total of 11 853 consecutive pregnant women underwent hepatic and renal function tests, lipid profile assessments, ALP and high-sensitivity C-reactive protein levels measurements upon admission for labour. Their clinical perinatal parameters and outcomes were also analysed. The prevalence of PTB, SGA, and LGA in this study was 7.2% (n = 849), 8.9% (n = 1053), and 15.6% (n = 1844), respectively. With increasing quartiles of maternal serum ALP levels, the foetal gestational age increased by 0.58 weeks (95% confidence interval (CI) = 0.50-0.66), 0.78 weeks (95% CI = 0.70-0.86), and 0.98 weeks (95% CI = 0.90-1.06), respectively, and the birth weight increased by 62.91 g (95% CI = 43.96-81.86), 91.54 g (95% CI = 72.41-110.67), and 117.92 g (95% CI = 98.18-137.67), respectively. Compared to women in the bottom quartile of ALP, those in the top quartile had a lower risk of PTB (adjusted odds ratio (OR) = 0.14; 95% CI = 0.11-0.18), a lower risk of SGA (adjusted OR = 0.65; 95% CI = 0.53-0.80), and a higher risk of LGA (adjusted OR = 1.92; 95% CI = 1.62-2.28). Sensitivity analyses conducted among individuals without advanced maternal age, obesity, multiparity, pregnancy complications, and PTB (for SGA/LGA) validated the consistency of these results. More importantly, adding ALP to the established model significantly increased the area under the curve (AUC) for predicting adverse birth outcomes: for PTB, the AUC increased from 0.761 to 0.809 (P < 0.001); for SGA, it increased from 0.754 to 0.759 (P = 0.014); and for LGA, it increased from 0.750 to 0.755 (P < 0.001). Maternal serum ALP levels in late pregnancy are significantly associated with the risk of ABO. When combined with clinical characteristics and routine laboratory results, ALP has incremental predictive value for ABO, particularly for PTB.

Selenomethionine Attenuates Aflatoxin B1-induced Liver Injury by Modulating the Gut Microbiota and Metabolites in Rabbits.

Dietary contamination with aflatoxin B1 (AFB1), which can lead to severe liver damage, poses a great threat to livestock and poultry breeding and has detrimental impacts on food safety. Selenomethionine (SeMet), with anti-inflammatory, antioxidative, and detoxifying effects, is regarded as a beneficial food additive. However, whether SeMet can reduce AFB1-induced liver injury and intestinal microbial disorders in rabbits remains to be revealed. Forty 35-day-old rabbits were randomly divided into a control group, an AFB1 group, and 0.2 mg/kg Se and 0.4 mg/kg Se groups. The SeMet treatment group was fed different doses of the SeMet diet every day for 21 days. On Days 17-21, the AFB1 group, 0.2 mg/kg Se, and 0.4 mg/kg Se groups were intragastrically administered 0.3 mg AFB1/kg b.w. Results showed that SeMet restored alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviating AFB1-induced liver function damage. This was linked to changes in intestinal metabolites and activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. In this study, the relationships between intestinal microorganisms and their metabolites and AFB1-induced liver injury are investigated, and the potential protective role of SeMet against liver damage induced by AFB1 offers novel insights into strategies for the prevention and treatment of AFB1-related toxicity.

Palbociclib Is Safe for Breast Cancer Patients With Mild Hepatic Impairment: A Multicenter Retrospective Study Using Real-World Data.

The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real-world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression-free survival (PFS) of palbociclib in advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, using the National Cancer Institute scoring system, in a large real-world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (n = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (n = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83-1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93-1.42). In real-world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib-induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.

Lactobacillus acidophilus YL01 and its exopolysaccharides ameliorate obesity and insulin resistance in obese mice via modulating intestinal specific bacterial groups and AMPK/ACC signaling pathway.

Probiotics intervention by Lactobacillus acidophilus has potential effect on alleviating obesity and insulin resistance. However, the limited knowledge of functional substances and potential regulatory mechanisms hinder their widespread application. Herein, L. acidophilus YL01 was firstly isolated from Chinese traditional yogurt, demonstrating inhibitory activities on amylase and glucosidase that are comparable to those of L. rhamnosus LGG. Besides, the oral administration of L. acidophilus YL01 and its EPS significantly reduced body weight in high-fat mice (p < 0.05), as well as fat accumulation in liver and adipocytes. Moreover, they not only reduced fasting blood glucose and glucose/insulin resistance, but also improved dyslipidemia, liver function and inflammation. Further high-performance liquid chromatography analysis and Fourier transform infrared spectroscopy indicated that EPS is an acidic polysaccharide, characterized by a molecular weight of 952 kDa and predominantly composed of glucose. Additionally, the mechanism investigation revealed that the L. acidophilus YL01 and EPS demonstrated limited efficacy in restoring the composition of gut microbiota, but rather exerted an influence on the abundance of specific bacterial groups. The enrichment of the bacterial groups resulted in the increase of acetic acid and butyric acid, which further mediates the gut-liver crosstalk in regulating lipid metabolism by the activation of AMPK/ACC pathway.

Nanoenzyme-based sensors for the detection of anti-tumor drugs.

Natural enzymes are a class of biological catalysts that can catalyze a specific substrate. Although natural enzymes have catalytic activity, they are susceptible to the influence of external environment such as temperature, and storage requirementsare more stringent. Since the first discovery of magnetic Fe3O4 nanoparticles with peroxidase-like activity in 2007, the research on nanoenzymes has entered a rapid development stage. Nanoenzymes synthesized by chemical methods not only have the catalytic activity of natural enzymes but also are more stable, easy to store, and convenient to prepare. Anthracyclines, as a commonly used anti-tumor chemotherapy drug, will produce many side effects such as myelosuppression and liver function damage after long-term use, which will affect its therapeutic effects. This paper reviews the characteristics, classification, and mechanisms of nanoenzymes. The detection of anti-tumor drugs, especially anthracycline drugs, using a nanoenzyme-based sensor was emphatically introduced. On this basis, the application of nanoenzyme-based sensors in the detection of anti-tumor drugs is prospected.

Spinal cord injury induces transient activation of hepatic stellate cells in rat liver

Spinal cord injury (SCI) causes abnormal liver function, the development of metabolic dysfunction-associated steatotic liver disease features and metabolic impairment in patients. Experimental models also demonstrate acute and chronic changes in the liver that may, in turn, affect SCI recovery. These changes have collectively been proposed to contribute to the development of a SCI-induced metabolic dysfunction-associated steatohepatitis (MASH). However, none of the existent studies have focused on hepatic stellate cells (HSCs), liver resident cells that are the primary drivers of collagen deposition and fibrosis following sustained liver damage. Here, we describe the transient activation of HSCs after a thoracic contusion in rats, considered a clinically relevant model of experimental SCI. We studied HSC during the time course of SCI, from 1 to 45 days post injury. We found a transient activation of HSCs after SCI, beginning with the acute downregulation of Glial Fibrillar Acidic Protein 1dpi. This is followed by a morphological and phenotypical transformation into alpha-smooth muscle actin (ACTA2/SMA) immunoreactive myofibroblast-like cells, peaking at 14 days post-injury and returning to control-like levels at later timepoints (45 days post-injury). These changes are not accompanied by fibrosis development but collagen deposition in peri-portal areas is observed at 45 days.

Hepatoprotective effect of the Sechium HD-Victor hybrid extract in a model of liver damage induced by carbon tetrachloride in mice.

Sechium spp., is a vegetable species renowned for its pharmacological properties, including hepatoprotective activity. This species can crossbreed with its wild relatives, leading to the creation of an HD-Victor hybrid with higher levels of flavonoids, cucurbitacins, and phenolic acids compared to the Sechium edule. However, the antioxidant and hepatoprotective properties of this hybrid are not well-known. We investigated the hepatoprotective effect of HD-Victor hybrid extract on a hepatic-damage mouse model induced by carbon tetrachloride (CCl₄). We conducted a phytochemical characterization and quantified its antioxidant activity. Subsequently, we evaluated the extract at different concentrations, testing the potential to mitigate liver damage induced by CCl₄. After, we performed tests to assess liver function through AST, ALT, ALP and albumin, antioxidant levels, and histopathological examination. Our findings reveal that HD-Victor hybrid extract is rich in flavonoids, phenolic acids, and cucurbitacins and shows DPPH-free radical inhibition, protection in liver function, and increased antioxidant levels. Therefore, the Sechium HD-Victor hybrid extract exerts a protective effect against hepatic damage induced by oxidative stress, showing its potential as a hepatoprotective agent.

Mechanism of TGIF1 on glycolipid metabolism disorders in mice with type 2 diabetes

IntroductionType 2 diabetes (T2D) is a chronic condition characterized by high levels of blood glucose resulting from the inefficiency of insulin. This study aims to explore the mechanism of TGFB-induced...

Therapeutic Potential of Rosmarinic Acid in Tramadol-Induced Hepatorenal Toxicity: Modulation of Oxidative Stress, Inflammation, RAGE/NLRP3, ER Stress, Apoptosis, and Tissue Functions Parameters.

Tramadol (TRM), a widely used opioid analgesic for moderate to severe pain, is associated with liver and kidney toxicity at high doses or prolonged use. This study investigates the protective role of rosmarinic acid (RA), a natural phenolic compound known for its antioxidant, anti-inflammatory, and cell-protective properties, against TRM-induced hepatorenal toxicity. Thirty-five male Wistar rats were divided into five groups: Control, TRM, RA, TRM+RA25, and TRM+RA50. Rats received TRM (50 mg/kg) and RA (25 or 50 mg/kg), with liver and kidney function tests, oxidative stress, inflammation, ER stress, apoptosis, and tissue damage indicators assessed through qRT-PCR, ELISA, Western blotting, H&E, and immunohistochemical analysis. TRM induced liver and kidney dysfunctions, evident from increased ALT, AST, ALP, urea, creatinine, nephrin, TIM-1 and 8-OHdG levels, along with activated oxidative stress, inflammation, ER stress, and apoptosis pathways. RA significantly reduced these effects, ameliorating histologic and immunohistochemical markers of tissue damage and inflammation. RA demonstrates therapeutic potential by mitigating TRM-induced hepatorenal toxicity and preserving tissue integrity.

A preliminary study of combined toxicity and underlying mechanisms of imidacloprid and cadmium coexposure using a multiomics integration approach.

Imidacloprid (IMI) and cadmium (Cd) have been shown to be harmful to mammals separately, but their combined toxicity to mammals remains largely unknown. In this study, biochemical analysis (oxidative stress and serum indicators of liver and kidney function), pathological sections and multiomics (metabolomics and transcriptomics) methods were used to investigate the changes and mechanisms of liver and kidney in mice coexposed to IMI and Cd. Biochemical analysis and pathological section results showed that oxidative stress, organ function, and cell damage were aggravated after the combination of the two methods. Omics results revealed the following mechanism: When mouse liver and kidney cells were threatened by the external environment, mitochondrial DNA was inhibited, which leads to changes in energy metabolism. In this process, lipid metabolism and amino acid metabolism were disordered, resulting in the inhibition of substances related to lipid metabolism and amino acid metabolism that protect the body from oxidative damage, and then showed more serious liver and kidney oxidative stress and liver and kidney function and cell damage. This research offers novel insights for the assessment of the safety profile associated with the concurrent exposure of the two chemicals in mammalian species.

Oral supplementation of curcumin-encapsulated chitosan nanoconjugates as an innovative strategy for mitigating nickel-mediated hepatorenal toxicity in rats.

Nickel pollution adversely affects human health and causes various disorders, mainly hepatic and renal dysfunction. The present work focused on a comparative evaluation of the pure form of curcumin (CU) with curcumin-encapsulated chitosan nanoconjugates (CS/CU NCs), on mitigation of the delirious effects of Ni on hepatorenal tissue. Forty-two male rats were allocated into 6 groups (n = 7 for each) as follows: (1) control, (2) CU, (3) CS/CU NCs, (4) Ni, (5) Ni + CU, (6) Ni + CS/CU NCs. After 30days, blood and tissue (liver and kidneys) were collected to measure hepatorenal biomarkers, oxidant/antioxidant balance, inflammatory gene expression, liver and kidney histopathology, and immunohistochemistry. Results revealed disruption of hepatorenal functions, oxidative stress, and inflammatory markers at biochemical and molecular levels associated with severe hepatorenal histopathological alterations and abnormal immunohistochemical tissue expression for caspase-3 and cyclooxygenase-2. On the contrary, the treatment of Ni-intoxicated rats with CS/CU NCs markedly mitigated the adverse effect of Ni on hepatorenal tissue via regulation of oxidative stress, inflammatory, and apoptotic markers. The present study provides a novel nanoformulation for curcumin using CS NPs encapsulation that selectively targets the injured cells and improves the beneficial effect of CU via enhancing the antioxidant activity and regulating both inflammatory and apoptotic markers.

Chlorogenic Acid Ameliorates CCl4-induced Liver Fibrosis by Modulating the PI3K/AKT/mTOR Autophagy Pathway.

Liver fibrosis represents a serious risk to global health by impairing quality of life and elevating the chances of hepatocellular carcinoma, while the intricate role of autophagy can either alleviate or worsen fibrosis depending on its functioning. Herein, we aimed to investigate the therapeutic effect of chlorogenic acid in CCl4-induced hepatic fibrosis and explore the autophagy pathway as the possible molecular target of chlorogenic acid. Rats were injected with carbon tetrachloride (1ml/kg) to induce liver fibrosis for 10 weeks. In the current study, the liver fibrosis rats were treated daily with chlorogenic acid (20, 40, and 60 mg/kg) for 30 days. Liver function tests, renal function tests, lipid peroxidation, antioxidant enzyme, anti-inflammatory NF-κB level, and autophagy pathway parameters (PI3K, AKT, mTOR, LC3, and Beclin-1) were assessed. CCl4 elevated serum AST and ALT activity, and hepatic malondialdehyde, PI3K, AKT, and mTOR expressions. It decreased LC3, Beclin-1 expression, and hepatic glutathione level. The results indicated that chlorogenic acid treatment ameliorated the hepatic functions. It declined serum AST and ALT activities, improved hepatic GSH concentration, decreased lipid peroxidation, and downregulated PI3K, AKT, and mTOR protein expressions in hepatic tissue. Moreover, chlorogenic acid increased the hepatic expression of LC3 and Beclin-1. It also significantly decreased NF-kB expression. Chlorogenic acid showed promise in reducing liver damage in rats caused by CCl4 by influencing the autophagy process and adjusting levels of antioxidant and inflammatory markers.

SERT-Deficient Mice Fed Western Diet Reveal Altered Metabolic and Pro-Inflammatory Responses of the Liver: A Link to Abnormal Behaviors.

The inheritance of the short SLC6A4 allele, encoding the serotonin transporter (SERT) in humans, increases susceptibility to neuropsychiatric and metabolic disorders, with aging and female sex further exacerbating these conditions. Both central and peripheral mechanisms of the compromised serotonin (5-HT) system play crucial roles in this context. Previous studies on SERT-deficient (Sert-/-) mice, which model human SERT deficiency, have demonstrated emotional and metabolic disturbances, exacerbated by exposure to a high-fat Western diet (WD). Growing evidence suggests the significance of hepatic regulatory mechanisms in the neurobiology of central nervous system disorders, supporting the 'liver-brain' concept. However, the relationship between aberrant behavior and hepatic alterations under conditions of SERT deficiency remains poorly investigated. One-year-old female Sert-/- mice and their wild-type (WT) littermates were subjected to a control diet (CD) or the WD for a duration of three weeks. The WD had a higher caloric content and was characterized by an elevated saturated fat content (21%) compared to the CD (4.5%) and contained 0.2% cholesterol. Mice were evaluated for anxiety-like behavior, exploration and locomotor activity in the open field test, as well as glucose tolerance and histological indicators of hepatic steatosis. Hepatic pro-inflammatory and metabolism-related gene expression and markers of nitrosative stress, were analyzed utilizing real-time polymerase chain reaction (RT-PCR) and correlated with behavioral and histological outcomes. In comparison to unchallenged mice, Sert-/-/WD mutants, but not the WT/WD group, had increased locomotion and anxiety-like behavior, increased hepatic steatosis, and elevated expression of insulin receptor B and pro-inflammatory cytokines interleukin-1β (Il-1β) and Tnf, as well as decreased expression of leptin receptor B. The two genotypes displayed distinct gene expression patterns of nitric oxide (NO)-related molecules inducible NO synthase (iNos) and arginase (Arg2), insulin receptor-related signaling factors: cluster of differentiation 36 (Cd36), ecto-nucleotide pyrophosphatase/phosphodiesterase (Enpp), protein tyrosine phosphatase N1 (Ptpn1), cytochrome P450 omega-hydroxylase 4A14 (Cyp4a14), acyl-CoA synthetase 1 (Acsl1) and phosphatase and tensin homolog (Pten). Furthermore, there were profound differences in correlations between molecular, histological, and behavioral measurements across the two genotypes. Our findings suggest that the genetic deficiency of SERT results in abnormal hepatic pro-inflammatory and metabolic adaptations in response to WD. The significant correlations observed between behavioral measures and pro-inflammatory and metabolic alterations in WD-fed mice suggest the importance of liver-brain interactions and their role in the aberrant behaviors exhibited by Sert-/- mutants. This study presents the first evidence that altered liver functions are associated with pathological behaviors arising from genetic SERT deficiency.

Predicting right ventricular failure after left ventricular assist device implant: A novel approach.

Right ventricular (RV) failure (RVF) after left ventricular assist device (LVAD) implant is an important cause of morbidity and mortality. Modern, data-driven approaches for defining and predicting RVF have been under-utilized. Two hundred thirty-two patients were identified with a mean age of 55years; 40 (17%) were women, 132 were (59%) Caucasian and 74 (32%) were Black. Patients were split between Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Classes 1, 2 and 3 (25%, 38% and 34%, respectively). Within this group, 'provisional RVF' patients were identified, along with 'no RVF' patients. 'No RVF' patients were defined as patients who never demonstrated more than moderate RV dysfunction on a post-LVAD transthoracic echocardiogram (TTE) (ordinal RV function <3), never required an RV assist device (RVAD), were not discharged on sildenafil and were not on a pulmonary vasodilator or inotropic medication at 3months after LVAD implant. In total, n=67 patients were defined as 'no RVF'. The remaining patients represented the 'provisional RVF' population (n=165). Extensive electronic health records queries yielded >1200 data points per patient. Using <1 and >1month post-LVAD time windows motivated by established, expert-consensus definitions of 'early' and 'late' post-implant RVF, unbiased clustering analysis was performed to identify hidden patient 'phenogroups' within these two established RVF populations. Clusters were compared on post-implant clinical metrics and 1year outcomes. Lastly, pre-implant metrics were used to generate models for predicting post-implant RVF phenogroup. Within the 'early RVF' time window, distinct 'well' and 'sick' patient phenogroup clusters were identified. These clusters had similar RV function and pulmonary vasodilator usage during the first month after LVAD but differed significantly in heart failure therapy tolerance, renal (P<0.001) and hepatic (P=0.013) function, RVAD usage (P=0.001) and 1year mortality (P=0.047). Distinct 'well' and 'sick' phenogroups were also identified in the 'late RVF' time window. These clusters had similar RV function (P=0.111) and RVAD proportions (P=0.757) but differed significantly in heart failure medication tolerance, pulmonary vasodilator usage (P=0.001) and 1year mortality (P<0.001). Prediction of phenogroup clusters from the 'early RVF' population achieved an area under the receiver operating characteristic curve (AUROC) of 0.84, with top predictors including renal function, liver function, heart rate and pre-LVAD RV function. Distinct, potentially predictable phenogroups of patients who have significantly different long-term outcomes exist within consensus-defined post-LVAD RVF populations.

Sacubitril/valsartan on right ventricular-pulmonary artery coupling and albumin-bilirubin score in heart failure in Chinese patients with reduced ejection fraction

ObjectiveImpaired right ventricular (RV)-pulmonary arterial (PA) coupling, calculated by measuring the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP), can be used as an early indicator of right ventricular dysfunction (RVD) in patients with heart failure with a reduced ejection fraction (HFrEF). Patients suffering from HFrEF experience improvements in left ventricular (LV) function through the administration of sacubitril/valsartan therapy. In addition, the albumin-bilirubin (ALBI) score was associated with the fluid overload status and adverse clinical outcomes in patients with heart failure. This study aimed to assess whether angiotensin receptor-neprilysin inhibitor (ARNI) affects the TAPSE /PASP in patients with HFrEF, and whether there is a correlation between changes in the ALBI score and ARNI treatment.MethodsA retrospective observational study was conducted on 305 patients with HFrEF and RVD who were hospitalized between June 2020 and December 2021. One year after treatment, laboratory test results, ALBI score, transthoracic echocardiography (TTE), New York Heart Association classification, Minnesota Living with Heart Failure Questionnaire scores and changes in relevant variables were reevaluated.ResultsCompared to before sacubitril/valsartan treatment, the ALBI was found to be significantly reduced after one year of follow-up (-2.42 ± 0.37 vs. -2.51 ± 0.32, p < 0.001). Additionally, A significant improvement was demonstrated in the following echocardiography parameters assessing RV function after 1 year of treatment with sacubitril/valsartan: TAPSE (15 ± 1 vs. 18 ± 2 mm, p < 0.001), PASP (45 ± 8 vs. 40 ± 9 mmHg, p < 0.001), pulmonary artery diastolic pressure (PADP) (22 ± 4 vs. 19 ± 4 mmHg, p < 0.001), RV-PA coupling (0.35 ± 0.08 vs. 0.48 ± 0.12, p < 0.001), and RV s’(8.7 ± 2.2 vs. 9.5 ± 2.6 cm/s, p < 0.001). Multivariate analysis showed that the improvement of RV-PA coupling was associated with baseline PASP (r: -0.45, p < 0.001) and PADP (r: -0.45, p < 0.001).ConclusionsSacubitril/valsartan improves RV-PA conjugation in patients with RVD and HFrEF, and has a positive impact on the ALBI score by improving liver function in patients with HFrEF.

Vascular flow alteration is a dominant pattern of liver pathology in patients with orthotopic lung transplants: a retrospective observational study.

The number of orthotopic lung transplants (OLT) has skyrocketed since the 1960s, generating an ever-increasing cohort of post-OLT patients. Many challenges exist in the post-OLT timeframe, including donor graft dysfunction, infection, malignancy, and immunosuppression-related conditions. A rather elusive topic in the posttransplant setting remains the impact of the underlying disease process and donor lungs on other organ systems and the complications arising from the complex physiologic interactions. The liver represents a vital organ often impacted in many ways by the lung transplant procedure. Also, there is a higher likelihood of adverse outcomes in OLT recipients who have significant liver pathology. Yet little is known about the morphologic changes in liver after patients have received an OLT. In this study we retrospectively reviewed liver pathology cases obtained after the patient received an OLT. Histology was reviewed by three pathologists and evaluated with a standardized checklist format. In our cohort, we found morphologic features of hepatic injury in the form of vascular outflow obstruction, nodular regenerative hyperplasia, portal vessel changes, and steatosis/steatohepatitis, but there was a striking absence of advanced fibrosis in our cohort. Here we present the first comprehensive account of morphologic changes in livers of post-OLT patients. We believe that this information will aid clinical decision-making during monitoring of hepatic function and fibrosis in patients with OLT and other complex pulmonary diagnoses.