Pump Function Research Articles

Expression of ABCB1, ABCC1, and LRP in Mesenchymal Stem Cells from Human Amniotic Fluid and Bone Marrow in Culture—Effects of In Vitro Osteogenic and Adipogenic Differentiation

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into various lineages. They have also the potential to protect themselves against harmful stimuli to maintain their functional integrity. Drug resistance-related transporters such as ABCB1 (P-glycoprotein; P-gp), ABCC1 (MRP1; multidrug resistance-related Protein 1), and LRP (lung resistance protein) may protect MSCs against toxic substances such as chemotherapeutic agents. This study evaluated ABCB1, ABCC1, and LRP before and after the differentiation of MSCs derived from human amniotic fluid (AF) and bone marrow (BM). P-gp expression in both AFMSCs and BMMSCs was analyzed by immunocytochemistry, and pump function was analyzed by cell viability assay with doxorubicin (DOX) and Rhodamine 123 (Rh 123) dye exclusion. ABCB1, ABCC1, and LRP gene expression was determined by RT-PCR both before and after osteogenic and adipogenic differentiation. The MES-SA/DX5 cell line was used as a model of resistance to DOX and the overexpression of P-gp. Both AFMSCs and BMMSCs displayed a high P-gp expression, although lower than MES-SA/DX5 control cells. It was shown that both, undifferentiated AFMSCs and BMMSCs, have high cell viability in response to DOX, similar to the MES-SA/DX5 lineage. ABCB1 was less expressed in BM than in AFMSCs in undifferentiated samples, while no differences were observed in the expression of ABCC1 and LRP. AFMSCs showed an increase in ABCB1 after osteogenic differentiation, whereas BMMSCs exhibited lower ABCB1 and ABCC1 expression after osteogenic and adipogenic differentiation. The findings suggest that ABCB1, ABCC1, and LRP gene expression in AFMSCs and BMMSCs is influenced by differentiation processes and further support the concept that these transporters modulate MSC differentiation in a cell source-dependent way.

Left Atrial Mechanics and Atrioventricular Coupling in Hypertension With Supra-Normal Left Ventricular Ejection Fraction.

Supra-normal left ventricular ejection fraction (snLVEF) represents a heterogeneous group with distinct prognoses. Left atrial (LA) strain, measured by speckle tracking echocardiography (STE), is a validated prognostic indicator. This study aimed to evaluate LA and left ventricular (LV) mechanical strains in hypertensive patients with snLVEF. This retrospective study included 101 patients (mean age 59.7 ± 8.4 years; 61.4% men) with primary arterial hypertension and preserved LVEF (≥50%). Patients were categorized into low-normal LVEF (lnLVEF; 50%-59%), mid-normal LVEF (mnLVEF; 60%-69%), and snLVEF (≥70%). LV global longitudinal strain (LVGLS) and LA strains during reservoir (LASr), conduit (LAScd), and contraction (LASct) phases were measured using STE. Relative wall thickness was significantly higher in snLVEF patients compared to mnLVEF (p < 0.01), with no difference in LVGLS (p = 0.933). Compared to mnLVEF, snLVEF patients had reduced LASr and LAScd (both p<0.01) but preserved LASct (p=0.057). In contrast, lnLVEF patients showed greater reductions in all phasic LA strains (all p<0.01). Loess regression revealed an inverted U-shaped relationship between LASr and LVEF, peaking at LVEF 65%-70%. The mitral E/e'mean ratio and LVGLS correlated moderately to strongly with LASr (r = -0.39 and r = -0.65, respectively; both p < 0.001). Hypertensive patients with snLVEF exhibit impaired LA reservoir and conduit functions while maintaining pump function, suggesting snLVEF may be an intermediate stage between mnLVEF and lnLVEF as hypertension progresses. Further studies are needed to explore the prognostic potential of LA strain in this population.

Impact of glucagon-like peptide-1 receptor agonists on axonal function in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) affects approximately half of the 500 million people with type 2 diabetes worldwide. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) receptors in the peripheral nervous system may be a suitable target for DPN treatment. Fourteen participants were consecutively recruited after being prescribed either semaglutide or dulaglutide as part of standard clinical care for type 2 diabetes. Participants underwent clinical assessment, nerve conduction studies, and axonal excitability assessment at baseline and at 3 mo following commencement of GLP-1 receptor agonist (GLP-1RA) therapy. These data were combined with 10 participants who had previously received exenatide therapy, and mathematical modeling of excitability data was undertaken. Clinical neuropathy scores improved at 3 mo following commencement of GLP-1 (baseline TNS 3.7 ± 4.5, posttreatment TNS 2.3 ± 3.4, P = 0.005). Nerve conduction studies demonstrated an improvement in sural amplitude at 3 mo (baseline 11.9 ± 8.5 μV, posttreatment 14.2 ± 9.2 μV; P = 0.013). Axonal excitability studies revealed changes consistent with improvements in Na+/K+-ATPase pump function and Na+ permeability, and this was supported by mathematical modeling. GLP-1RA therapy improves clinical and neurophysiological outcomes in DPN. Treatment with GLP-1RA may reverse axonal dysfunction by improving Na+/K+-ATPase pump function.NEW & NOTEWORTHY Diabetic peripheral neuropathy is known to be relentlessly progressive and irreversible. Prospective studies in 24 participants with diabetic peripheral neuropathy (DPN) treated with glucagon-like peptide-1 receptor agonists (GLP-1RA) demonstrated improvements in clinical neuropathy scores, nerve conduction studies, and axonal excitability recordings. Analysis of axonal excitability recordings revealed the mechanism for GLP-1RA improvement in DPN were changed consistent with improvements in Na+/K+-ATPase pump function, and this was supported by mathematical modeling.

"Form follows function": the developmental morphology of the cardiac atria.

Although the heart atria have a lesser functional importance than the ventricles, atria play an important role in the pathophysiology of heart failure and supraventricular arrhythmias, particularly atrial fibrillation. In addition, knowledge of atrial morphology recently became more relevant as cardiac electrophysiology and interventional procedures in the atria gained an increasingly significant role in the clinical management of patients with heart disease. The atrial chambers are thin-walled, and several vessels enter at the level of the atria. The left and right atrium have different structures and shape. In general, both atrial chambers have the venous part, the appendage, and the vestibule; different aspects of each part allow us to distinguish morphologically between the left and right atrium. The human atrial conduction system consists of the sinus node and the atrioventricular node with no histologically specialized conduction pathways in the atrial chamber and an interatrial connection. The data show that the propagation of the impulse depends mainly on the myocardial architecture in the atria and the orientation of the myocytes plays a significant role in conduction. To complete the picture, it is also important to know how the atria develop and what is the embryonic origin of its different structures, as this may play a role in the development of some pathological conditions such as atrial fibrillation or certain types of congenital heart defects. Functional impairment of the atria can in some situations severely compromise heart pumping function, and conversely, can support it if other areas are damaged, balancing the blood flow to the body for some time. Key words Morphology of atrial chambers, Pectinate muscles, Atrial function.

O TRÍCEPS SURAL COMO UMA BOMBA CARDIOVASCULAR

Objective: This study aims to carry out an integrative review on the anatomy of the calf, highlighting its function as a “second heart” and the muscular pump mechanisms, as well as the implications for venous circulation. Methodology: An integrative review was carried out with a selection of information published between 2020 and 2024. The research was carried out in virtual libraries, using the descriptors “anatomy”, “calf”, “second heart”, “venous circulation”, “function”. Only texts in Portuguese and English were included. Results: Data analysis revealed that the calf functions as a muscular pump, as it is essential for venous return from the lower extremity and influences preload and cardiac output. A survey was carried out in which 2,728 adult patients who underwent venous strain gauge plethysmography were analyzed, excluding those with conditions that could interfere with the results. The results showed that patients with impaired calf muscle pump (CMP) were older, predominantly female and had greater comorbidity. Conclusion: The muscular structure and function of the calf muscle pump are crucial for physical performance and the prevention of complications, especially in elderly populations and in patients with chronic conditions such as venous insufficiency and arterial claudication.

Esomeprazole inhibits liver inflammation and carcinogenesis by suppressing farnesoid X receptors and NF-κB signaling.

The activity of proton pump inhibitors (PPIs) hinders the function of proton pumps that generate stomach acid. Nuclear factor kappa B (NF-κB) is a transcriptional factor engaged in inflammation, immunity and the formation of cancer. The farnesoid X receptor (FXR) is a nuclear receptor that governs the metabolism of bile acids and the metabolic functioning of the liver. The impact of PPIs on the signaling of FXRs and NF-κB is not well understood. We aimed to study the effects of esomeprazole on FXRs and NF-κB signaling in liver cells. For the liver cell model, we used the human liver cell line HepaG2. Cells were treated with lipopolysaccharides (LPS) and esomeprazole, and then we assessed the effects of esomeprazole on inflammatory and carcinogenic markers, NF-κB and FXR. We applied the techniques of western blotting, reverse-transcription polymerase chain reaction (RT-PCR), confocal microscopic imaging, and electrophoretic mobility shift assay (EMSA). Lipopolysaccharides-induced FXRs and NF-κB signaling upregulated the NF-κB-associated cytokines interleukin 6 (IL-6), cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-α). Esomeprazole inhibited the upregulation of all these cytokines. Additionally, esomeprazole inhibited LPS-induced FXR expression and NF-κB signaling in HepaG2 cells. The net effect on FXRs and NF-κB signaling was the lower levels of the associated inflammatory and carcinogenic cytokines. Our study provides insight into the potential therapeutic effects of esomeprazole on hepatic inflammation and carcinogenesis by inhibiting LPS-induced NF-κB and FXR expression in HepG2 cells.

A021: Hypoxic Complex Exercise Promotes HIF-1Α Expression to Improve Drosophila Cardiac Pumping Function

Background: Some studies have shown that the stability and transcription of HIF-1Α significantly increases under hypoxic conditions, and HIF and its downstream targets are becoming a new choice for the treatment of various organ injuries to improve physical function. Combined with the team's pre-screening of suitable hypoxic compound exercise protocols, this study aimed to explore the link between the expression of exercise HIF-1Α under hypoxic conditions and cardiac function, in order to provide a realistic and theoretical basis for the improvement of cardiac function by hypoxic compound exercise. Methods: 300 Drosophila flies of wild-type W11188 strain feathered within 12 hours were collected and randomly divided into control (NC), hypoxic quiet (HC), normoxic exercise (NE), and intermittent hypoxic training (HE) groups, with 100 Drosophila in each group, and were subjected to intermittent hypoxic, normoxic and hypoxic combined exercise interventions for 5 consecutive days, lasting for one hour per day, at the age of 7 days, respectively. The gas used in both HC and HE groups was a mixture of 6% O2 and 94% N2. At 24 h after the intervention, the changes of cardiac actin were observed by F-actin staining, the changes of HIF-1Α expression level in the heart were detected by RT-qPCR, and 30 s of Drosophila heart beats were captured by an EM-CCD digital video camera (130 frames/s) to quantify the indexes of Drosophila cardiac pumping function. Results: Compared with the NC group, HIF-1Α expression increased in the heart after hypoxic compound exercise (P &lt; 0.001), the diameter of the heart tube became larger, the arrangement of cardiac myofilaments was tighter and neater, the systolic diameter of the heart increased (P &lt; 0.05), the diastolic diameter increased (P &lt; 0.001), and the shortening fraction improved (P &lt; 0.001). Compared with the NC group, HIF-1Α expression did not change significantly in the NE group, and the heart had an increased systolic diameter (P &lt; 0.05), an increased diastolic diameter (P &lt; 0.001), and a slightly improved shortening fraction. Compared with the NC group, after intermittent hypoxic exposure, cardiac HIF-1Α expression was elevated, the diameter of the heart became smaller, myocardial myofilaments were irregularly arranged, the systolic and diastolic diameters did not change significantly, and the shortening fraction was slightly increased. Conclusion: Hypoxic compound exercise promoted HIF-1Α expression in the heart and improved cardiac pumping function.

Cardiac effects of OPA1 protein promotion in a transgenic animal model.

Mitochondria form a dynamic network in cells, regulated by the balance between mitochondrial fusion and fission. The inhibition of mitochondrial fission can have positive effects in acute ischemic/reperfusion injury models by preventing the fall in mitochondrial membrane potential associated with fission processes. However, inhibition of fission in chronic models is disadvantageous because it obstructs the elimination of damaged mitochondrial fragments. OPA1, in view of previous results, is a possible therapeutic target as a fusion promoter and structure stabilizer protein. We used transgenic mice in which the OMA1 cleavage sites of OPA1 were deleted. This resulted in a higher representation of L-OPA1 compared to S-OPA1. After genotyping and model validation, all animals were examined by echocardiograph on two occasions, at weeks 11 and 36. Histological samples were taken from hearts to examine mitochondrial morphology and structure remodeling. The signaling pathways related to mitochondrial dynamic processes were evaluated. Cardiomyocytes were isolated from neonatal mice to determine the efficiency of mitochondrial respiration using the SeaHorse assay method. OPA1 protein promotion has a negative effect on systolic function during aging. We confirmed that volume overload and ventricular remodeling did not manifest. The reason behind the loss of pump function might be, at least partly, due to the energy deficit caused by mitochondrial respiratory failure and damage in mitochondrial quality control pathways.

Abstract 4125500: Obesity-Related Left Atrial Functional Change Becomes Apparent in Infancy

Background: Impaired left atrial (LA) function is observed in obese patients, however, there is little information on when LA dysfunction begins to appear. To clarify this issue, we assessed LA volume and function in obese infants. Methods: Two-dimensional speckle-tracking echocardiography was performed in 96 infants aged 4 months. Subjects were divided into 3 groups according to body mass index (BMI): normal (n=53), &lt;17 kg/m 2 ; overweight (n=28), 17 to 19.9 kg/m 2 ; obese (n=15), ≧20 kg/m 2 . LA maximal volume, LA minimal volume, and LA pre-atrial contraction volume and LA longitudinal strain (reservoir, conduit, and booster) were measured. LA total emptying fraction, passive emptying fraction, and active emptying fraction were calculated. Results: Systolic blood pressure was significantly higher in the obese group than in the normal group (Table). LA maximal volume, minimal volume, and pre-atrial contraction volume increased significantly with increasing BMI (r = 0.53, 0.54, and 0.63, respectively, p &lt;0.01). Compared with the normal group, reservoir LA strain was significantly lower in the overweight and obese groups. Conduit LA strain and passive emptying fraction were significantly lower in the overweight and obese groups than those in the normal group (Table). Reservoir LA strain, conduit LA strain, and passive emptying fraction decreased significantly with increasing BMI (r = -0.28, -0.27, and -0.33, respectively, p &lt;0.01). There was no significant difference in booster LA strain among the 3 groups. Compared with the normal group, LA active emptying fraction was significantly higher in the obese group (Table). Conclusions: Higher BMI is associated with impaired reservoir and conduit LA function and higher booster LA pump function, which may be compensatory. Thus, obesity-related changes in LA functional begin to appear in infancy. Our data support prevention of obesity in early childhood because higher BMI is responsible for significant changes in LA function in early life.

Abstract 4146301: Relationship Between Calf Muscle Pump Function and Exercise Stress Testing

Background: Exercise stress testing uses metabolic equivalents of tasks (METs) to measure the energy cost of activities, aiding in the assessment of exercise capacity and cardiovascular health. Despite its significance, the correlation between calf muscle pump function (CPF) and exercise stress testing remains unexplored. We aimed to evaluate the relationship between CPF and peak METs as determined by cardiopulmonary treadmill exercise stress testing. Methods: The study included adults who underwent exercise cardiopulmonary stress testing and venous plethysmography at Mayo Clinic between April 2017 and March 2020. The protocols other than Bruce, Mayo, Modified Naughton, and Naughton protocols were excluded. The CPF ejection fraction (EF) was calculated per leg based on refill volumes post-exercise as a percentage of passive drain refill. The classification of CEAP (Clinical-Etiology-Anatomy-Pathophysiology) was utilized to better understand chronic venous insufficiency (CVI). Results: A total of 155 patients who underwent both exercise stress testing and venous plethysmography were included, with a mean age of 61.31 ± 14.03 years, and 84 (54.2%) were male. The peak measured METs for normal, unilaterally reduced, and bilaterally reduced CPF were 8.5 (2.5), 7.3 (2.1), and 7.1 (2.4), respectively (p=0.004, Figure 1). Multiple linear regression models were developed with METs as the outcome to determine if CPF was an independent predictor of METs on cardiopulmonary exercise stress testing. IIn model 1, the following independent variables were included: resting heart rate, peak heart rate, peak systolic blood pressure, recovery heart rate at minute 1, and worst EF (Table 1). In model 1, with only exercise parameters, lower EF was associated with lower METs (p=0.03). In a second analysis, variables identified as statistically significant with METs in the initial model were included, along with CEAP class (model 2) and CCI (model 3) (Table 2). In model 2, CEAP class 3 or higher was associated with decreased METs on the exercise stress test. This correlation implies that individuals with moderate to severe CVI may influence exercise capacity, demonstrating the interconnectedness of the cardiovascular system. Moreover, in model 3, the CCI, a predictor for mortality, was not significantly associated with METs. Conclusion: Our findings revealed that more severe CVI (CEAP class and reduced CPF) was associated with reduced exercise capacity after accounting for other factors.

A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that α-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. α-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.

Multicentre, randomized, double-blind, prospective study on the effects of ImmunoAdSorptiOn on cardiac function in patients with Dilated CardioMyopathy (IASO-DCM): Rationale and design.

Pilot studies indicate that immunoadsorption with subsequent IgG substitution (IA/IgG) induces beneficial effects in patients with dilated cardiomyopathy (DCM) and heart failure. This placebo-controlled study investigates whether IA/IgG treatment enhances left ventricular (LV) systolic function as compared to a control group receiving pseudo-treatment. This multicentre, randomized, double-blind, parallel-group trial aims to include 200 patients with heart failure due to DCM (LV ejection fraction [LVEF] <40%) on optimized guideline-directed heart failure medication. Participants are randomly assigned in a 1:1 ratio to IA/IgG using protein-A columns, or to pseudo-immunoadsorption followed by an intravenous infusion without IgG. Follow-up visits take place by telephone after 1 and 3 months and at the study centres after 6, 12 and 24 months. The primary efficacy endpoint is the change in LVEF from baseline to 6 months determined by contrast echocardiography, analysed at a core lab. In addition, LV end-diastolic and end-systolic volumes will be analysed as secondary endpoints over the entire study period to assess whether IA/IgG affects LV remodelling. As main secondary outcome, a composite of all-cause death, cardiac resuscitation, hospitalization for heart failure, and need for cardiac surgery to improve myocardial pump function will be evaluated after 24 months. In addition, exploratory outcomes as well as safety endpoints related to the treatment will be assessed throughout the whole study period. IASO-DCM is a randomized study which will provide comprehensive insights into the effects of immunoadsorption with subsequent IgG substitution in patients with DCM.

Research on Predicting Survival in Heart Failure Patients of Logistic Regression Models

Abstract. The purpose of this paper is to study a logistic regression model for predicting the survival of patients with heart failure. Heart failure is a serious clinical syndrome that usually develops from multiple heart diseases, and its inadequate pumping function of the heart poses a significant threat to the life and health of the patient and a significant economic burden on the healthcare system. Using medical record data from 299 patients with heart failure in the UCI database, this research utilized logistic regression models to identify the critical factors influencing the survival of heart failure patients and to forecast their survival outcomes. This paper found that age, ejection fraction, serum creatinine concentration and follow-up period are significant factors affecting survival in patients with heart failure. By adopting backward elimination method to optimize the model, the accuracy of prediction is further improved. The optimized logistic regression model yields an area under the Receiver Operating Characteristic (ROC) curve of 0.845, showing high prediction accuracy. The conclusions of this study provide a new perspective for the early diagnosis, risk assessment and personalized treatment of heart failure.

Is left atrial reservoir strain a superior modality to predict acute left ventricular failure in hypertensive patients

Abstract Background The left atrium (LA) plays an important role in the pathophysiology of heart failure. Left Atrial function has 3 components and their relative contributions, under normal circumstance, include reservoir(40%), conduit (35%), and active pump(25%) function(1). All these functions can be assessed by their respective strain, measured in trans thoracic echocardiography usually by speckle tracking, from apical 4 and 2 chamber views. Of the 3 types of LA strain, LA reservoir strain (LAS-r), is the best reflection of atrial function(2). LA strain can detect LA dysfunction even before obvious LA enlargement, aiding preclinical diagnosis of cardiac dysfunction. Purpose To assess if Left atrial reservoir strain was a superior modality to predict acute Left Ventricular Failure in hypertensive patients. Methodology Our study cohort consisted of 200 hypertensive patients, 84 females and 116 males, 40 to 71 years old with hypertension duration of 6 months to 21 years .Patients with other co morbidities were excluded. All were on treatment and had BP ranging from normal to high. Sixty two (31%) had experienced one or more episodes of acute left ventricular failure(LVF). Patients underwent in addition to routine investigations, detailed ECHO including measurement of left ventricular global longitudinal strain(LVGLS- normal &amp;gt; -18) and LAS-r (Normal &amp;gt;35). Results and Discussions All patients had normal ejection fraction. 128 (64%) had LVDD. 102(79.8%) had grade 1 LVDD, 24 (18.6%) had grade II LVDD and 2 (1.6%) had Grade III. Forty eight (37.5%) of the 128 with LVDD experienced acute LVF and 23(47.9%) of them had grade 11 LVDD or more. Forty two (21%) had reduced LVGLS, of these, 18(42.9%) experienced acute LVF and of these, 14(77.8%) had in addition reduced LAS-r. One hundred and two (51%) had reduced LAS-r (LAS-r &amp;lt;25), of which 61(59.8%) had experienced acute LVF. 63(31.5%) had increased LA volume of which 37( 58.7%) had experienced acute LVF. 5.7% of patients with BP &amp;lt;150/90 had reduced LAS-r, 69.5% with BP between 150/90- 169/100 had reduced LAS-r and 85.4% with BP &amp;gt; 170 had reduced LAS-r. Of the 62 patients with acute LVF, 18(29%) showed reduced LVGLS, 48(77.4%) had LVDD, 37(59.7%) had increased LA volume and 61(98.4%) had reduced LAS-r indicating that the latter was an earlier, better predictor of acute LVF than the former three. Although there were no age or gender differences in the findings, the prevalence of reduced LAS-r was higher with less well controlled BP. Conclusions In our study, LAS-r, irrespective of the age or sex, was an earlier better predictor of acute LVF than reduction of LVGLS, LVDD or increased LA volumes, in hypertensive patients. The prevalence of reduced LAS-r was higher in patients with poorly controlled BP. Prognostic significance of LAS-r can help influence early clinical decision making and for defining early management.TABLE 1TABLE 2

Reduced stroke volume by resting 2-dimensional echocardiography negatively affects survival in patients with abnormal ejection fraction

Abstract Background Abnormal (&amp;lt;50%) ejection fraction (EF) is a cornerstone of risk stratification and therapy, but also an imperfect proxy of left ventricular (LV) cardiac pump function, better assessed with stroke volume (SV). Aim To assess the value of SV in stratifying risk of patients with abnormal EF. Methods In a prospective, observational, multicenter study, we recruited 746 patients (age 66± 11 years, 536 males, 72%, 359 with previous myocardial infarction, 48%) with chronic coronary syndromes (CCS) and EF &amp;lt;50% referred for resting transthoracic echocardiography with technically successful 2-dimensional volumetric echocardiography in 17 accredited laboratories. We quantitatively assessed LV end-diastolic volume (EDV) and end-systolic volume (ESV) by Simpson’s biplane method. EF (EDV-ESV/EDV) and SV (EDV-ESV) were calculated from LV volumes. The outcome end-point was all-cause death. Results EF was 39±9%, SV 48±20 ml. There were 100 all-cause deaths during a median follow-up of 796 days (interquartile range 420-1286 days). Receiver-operating curve analysis identified SV≤31.4 ml/b as the best cut-off for predicting mortality. At multivariable analysis, after adjustment for age and prior myocardial infarction, EF &amp;lt;40% and SV ≤31.4 ml/b were significantly associated with decreased survival (HR 2.09, 95%, confidence intervals 1.09-4.01, p=0.024). The annual mortality was lowest (3.19%) in the group with mildly reduced (40-49%) EF and normal (&amp;gt;31.4 ml) SV, and highest (8.30%) in patients with both reduced EF and abnormal SV: see figure. Conclusion Patients with CCS and abnormal EF are a prognostically heterogeneous group, and the mortality rate is almost 3-times worse in patients with reduced EF and abnormal SV compared to patients with mildly reduced EF and normal SV. A simple resting volumetric two-dimensional echocardiography can offer an efficient risk stratification, beyond EF, with no extra imaging or analysis time.Figure

Right atrial and ventricular function in risk stratification of patients with pulmonary artery hypertension

Abstract Background Right atrial (RA) phasic function was proved to be impaired in individuals with pulmonary arterial hypertension (PAH), the awareness of the nonnegligible involvement of RA in the clinical course of PAH was raised. However, evidence for the clinical significance of the RA strain in prognostication and risk stratification for PAH patients was limited. Method Participants diagnosed with PAH from June 2013 to December 2022 in West China Hospital were prospectively and continuously recruited. The primary endpoint was all-cause mortality, and the second endpoint was a combination of all-cause mortality and heart failure-related repeat hospitalization. Cox regression analysis and Kaplan Meier survival analysis were performed to identify the association between variables and outcomes. C-index, 1-year mortality, and annual event rate were performed to confirm the value of RA strain in PAH patients’ risk stratification. Result A total of 283 participants (mean age, 38 ± 14 years, 84 male) were finally included, following a median follow-up duration of 31.5 months (interquartile range: 15.1-53.9 months). Significant decreases in RA reservoir (p&amp;lt;.001), conduit (p&amp;lt;.001), booster pump function (p&amp;lt;.001), right ventricular global longitudinal strain (RVGLS, p&amp;lt;.001), and free-wall longitudinal strain (RV-FWLS, p&amp;lt;.001) were observed in participants with all-cause mortality than those who survived. Using 16.1% and 23.6% as thresholds for RA reservoir strain, PAH patients could be divided into low-, intermediate, and high-risk groups well, with calculated 1-year mortality of 1.8%, 6.9%, and 21.4%. Moreover, RA reservoir strain presented with better 1-year mortality predictive performance than RV-FWLS (C-index, 0.82 [0.72-0.92] vs 0.72 [0.62-0.82], p&amp;lt;.001). The addition of RA reservoir strain had significantly increased the power of both REVEAL Lite2 and Comparative, Prospective Registry of Newly initiated Therapies for Pulmonary Hypertension (COMPERA) models (both p&amp;lt;.001). Conclusion RA reservoir strain was an independent predictor of all-cause mortality in individuals with pulmonary arterial hypertension and could be used to stratify participants into different risk stratification stratum.

Clustering analysis based on clinically available data for improving risk stratification and outcome prediction of hypertension

Abstract Background Hypertension (HTN) is a heterogeneous condition with several factors contributing to adverse outcomes. Machine learning can harness complex data to unveil outcome predictors and guide prevention. Purpose To use clustering analysis on clinical data to identify HTN risk profiles and their associations with cardiovascular abnormalities and clinical outcomes. Methods A cohort of 14,840 UK Biobank hypertensive participants without pre-existing heart failure (HF) who underwent cardiovascular magnetic resonance (CMR) assessment was examined using K-means clustering on 79 clinical attributes. The clusters’ association with incident HF, mortality, atrial fibrillation (AF), and major adverse cardiovascular events (MACE) were evaluated, alongside imaging characteristics, with mediation analysis probing the role of imaging in risk differentiation. All post-hoc analyses were adjusted for vascular risk factors (VRFs), including diabetes, hypercholesterolaemia, previous myocardial infarction. Results Three distinct clusters differing considerably in lifestyle habits, cardiovascular risk factors, electrocardiographic parameters, and cardiometabolic profiles were identified. Cluster 1 (lowest risk), predominantly females, exhibited the most favourable metabolic profile and outcomes. Cluster 2 (highest risk), predominantly males, had the most adverse metabolic and cardiovascular profiles, and the highest risk of all adverse outcomes, especially AF and HF (hazard ratio (HR) 1.80 [1.45–2.25] and 1.85 [1.39–2.46]; p &amp;lt;0.005). This group was associated with more eccentric LV hypertrophy (LVH), overall poorer left atrial emptying function (LAEF), bi-ventricular systolic function and LV mechanics, and higher systemic vascular resistance (Figure 1). Cluster 3 (intermediate risk) was a more heterogeneous group with the highest burden of diabetes and adiposity and a moderate rise in AF and MACE risk (HR 1.61 [1.12-2.32] and 1.30 [1.07-1.58]; p &amp;lt;0.05). This cluster was associated with concentric LV remodelling and better indices of cardiac mechanics, but greater impairment in LA booster pump function (active LAEF) than Cluster 2 (Figure 1). Cluster 2's effect on MACE was mostly mediated through LV mass increase (proportion mediated, 67%), followed by changes (reducing) in LV global longitudinal strain (33%), and ejection fraction (25.4%). The indirect effect of CMR changes in the association between cluster 3 and MACE was much smaller with the highest proportion of the effects mediated through increased myocardial wall thickness (26%) but not LV mass, and changes in all the components of LA function. Conclusions Clinical data clustering provides insight into distinct HTN risk profiles, each with specific imaging characteristics and clinical trajectories, hinting at different pathophysiological mechanisms. Enhanced phenotyping can facilitate tailored interventions based on the disease subtype and improve clinical outcomes.Figure 1.

A BPTF Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Murine Triple-Negative Breast Cancer Cells to Chemotherapy.

Triple-negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger-containing transcription factor), was capable of sensitizing preclinical models of TNBC to chemotherapy in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with the inhibition of the P-glycoprotein (P-gp) efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump in a manner consistent with the inhibition of the pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in TNBC, that has not yet been successfully addressed by clinical efforts.

Deciphering the inhibitory mechanism of antimicrobial peptide pexiganan conjugated with sodium-alginate chitosan-cholesterol nanoparticle against the opportunistic pathogen Acinetobacter baumannii

The emergence of antibiotic resistance is one of the most challenging problems of modern times as the armory of conventional antibiotics is quickly exhausting due to the rapid rise of resistance in pathogenic microorganisms. Acinetobacter baumannii, a potential member of ESKAPE group of bacteria, has a great deal of clinical importance causing severe nosocomial infections which often become life-threatening. According to the World Health Organization (WHO), antimicrobial resistance accounts for 2–3 million deaths every year across the world. Since the pathogen has the remarkable ability to acquire or upregulate various resistant determinants in the form of secreting of β-lactamase, aminoglycoside modifying enzymes, uplifting the function of efflux pumps or altering the target sites of different antibiotics; conventional antibiotic therapy often falls short to eradicate the infection. As a possible solution, the application of alternative therapy is therefore the need of the hour. Here we emphasize potentiating the antimicrobial efficacy of pexiganan, a well-known antimicrobial peptide against Gram-negative bacteria. Conjugation with nanoparticles composed of sodium-alginate and chitosan-cholesterol has increased the antimicrobial effect of the peptide on this opportunist pathogen. The evaluation of the bactericidal analysis and minimum inhibitory concentration indicates this nanocomposite can kill the bacteria at a very low concentration (3 μg/ml). When applied to the bacterial biofilm, the key factor for producing recalcitrant infection; our synthesized complex could effectively reduce the biomass in a dose-dependent manner. Later we enfold the mechanism of killing by measuring oxidative stress, cell membrane perforation by biochemical analysis. Our analysis indicates this unique nanocomposite can bypass the need of antibiotic treatment by its pore-forming ability on bacterial membrane. The nominal in-vivo toxicity and non-specific mode of action make it an interesting candidate for future therapeutics.

Ultra-Low-Field Portable MRI and Extracorporeal Membrane Oxygenation: Preclinical Safety Testing.

Conventional MRI is incompatible with extracorporeal membrane oxygenation (ECMO) cannulas and pumps. Ultra-low-field portable MRI (ULF-pMRI) with 0.064 Tesla may provide a solution, but its safety and compatibility is unknown. ULF-pMRI does not cause significant displacement and heating of ECMO cannulas and does not affect ECMO pump function. ECMO cannulas in various sizes were tested ex vivo using phantom models to assess displacement force and heating according to the American Society for Testing and Materials criteria. ECMO pump function was assessed by pump flow and power consumption. In vivo studies involved five female domestic pigs (20-42 kg) undergoing different ECMO configurations (peripheral and central cannulation) and types of cannulas with an imaging protocol consisting of T2-weighted, T1-weighted, FLuid-Attenuated Inversion Recovery, and diffusion-weighted imaging sequences. Phantom models demonstrated that ECMO cannulas, both single lumen with various sizes (15-24-Fr) and double lumen cannula, had average displacement force less than gravitational force within 5 gauss safety line of ULF-pMRI and temperature changes less than 1°C over 15 minutes of scanning and ECMO pump maintained stable flow and power consumption immediately outside of the 5 gauss line. All pig models showed no visible motion due to displacement force or heating of the cannulas. ECMO flow and the animals' hemodynamic status maintained stability, with no changes greater than 10%, respectively. ULF-pMRI is safe and feasible for use with standard ECMO configurations, supporting its clinical application as a neuroimaging modality in ECMO patients.