Structural Remodeling Research Articles

The impact of diabetes mellitus on cardiac function assessed by magnetic resonance imaging in patients with hypertrophic cardiomyopathy

BackgroundThe adverse prognostic impact of diabetes on hypertrophic cardiomyopathy (HCM) is poorly understood. We sought to explore the underlying mechanisms in terms of structural and functional remodelling in HCM patients with coexisting diabetes (HCM-DM).MethodsA total of 45 HCM-DM patients were retrospectively included. Isolated HCM controls (HCM patients without diabetes) were matched to HCM-DM patients in terms of maximal wall thickness, age, and gender distribution. Left ventricular (LV) and atrial (LA) performance were evaluated using cardiac magnetic resonance feature tracking strain analyses. The associations between diabetes and LV/LA impairment were investigated by univariable and multivariable linear regression.ResultsCompared with the isolated HCM controls, the HCM-DM patients had smaller end-diastolic volume and stroke volume, lower ejection fraction, larger mass/volume ratio and impaired strains in all three directions (all P < 0.05). In terms of the LA parameters, HCM-DM patients presented impaired LA reservoir and conduit strain/strain rate (all P < 0.05). Among all HCM patients, comorbidity with diabetes was independently associated with a low LV ejection fraction (β = − 6.05, P < 0.001) and impaired global longitudinal strain (β = 1.40, P = 0.007). Moreover, compared with the isolated HCM controls, HCM-DM patients presented with more myocardial fibrosis according to late gadolinium enhancement, which was an independent predictor of impaired LV global radial strain (β = − 45.81, P = 0.008), LV global circumferential strain (β = 18.25, P = 0.003), LA reservoir strain (β = − 59.20, P < 0.001) and strain rate (β = − 2.90, P = 0.002).ConclusionsDiabetes has adverse effects on LV and LA function in HCM patients, which may be important contributors to severe manifestations and outcomes in those patients. The present study strengthened the evidence of the prevention and management of diabetes in HCM patients.

Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 (TcBDF2) using a fluorescence polarization-based high-throughput assay.

Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress

Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, invivo and invitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Abstract Mo037: Cardiac-Selective TRPV1 Afferent Ablation in Subacute Myocardial Infarction Ameliorates Adverse Remodeling and Ventricular Arrhythmogenesis

Background: Ventricular arrhythmias (VT/VF), the most common cause of sudden death after myocardial infarction (MI), can be ameliorated by cardiac-selective transient receptor potential cation channel subfamily V member 1 (TRPV1) afferent ablation at the time of infarction in animal models. To enable translation to human, it remains unknown whether afferent depletion in the subacute phase of MI will reduce arrhythmias and mitigate long-term structural remodeling. Objectives: To assess the role of cardiac-selective TRPV1 afferent ablation two weeks after MI on the long-term ventricular arrhythmogenesis and adverse structural remodeling. Methods: Yorkshire pigs were randomized to resiniferatoxin (RTX 5.0µg/ml: n=10) or vehicle(n=6) 14days after the left anterior descending artery infarct. Four weeks later, terminal experiments were conducted to evaluate the effect of RTX on cardiac structural and functional remodeling, ventricular arrhythmogenesis, and autonomic reflex function. Results: Cardiac afferent depletion via RTX administration was confirmed by diminished sympathetic response to TRPV1 agonists (bradykinin and capsaicin) and by immunohistochemical analysis of ventricular innervation. Compared to the vehicle treated group, the RTX administration reduced LV dimension (p&lt;0.01), repolarization heterogeneity (p&lt;0.01) and ventricular arrhythmogenesis (program stimulation; p=0.01 and CsCl induced PVCs;p&lt;0.01). In the scar-border zone, myocytolysis and nerve sprouting, which are associated with VT/VF, were attenuated in the RTX group (abnormality score; p=0.01 and nerve sprouting index; p &lt; 0.01). T cell infiltration in dorsal root ganglia was suppressed in the RTX group (p = 0.02). RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes tyrosine hydroxylase and neuropeptide-Y in the RTX group. Taken together, these results suggest that cardiac afferent ablation in subacute MI alleviates adverse structural remodeling and ventricular arrhythmogenesis by targeting neuroinflammation and reducing stellate ganglion sympathetic overexcitation. Conclusion: Cardiac TRPV1 afferent depletion in subacute MI is a promising disease altering treatment for patients suffering from MI.

Abstract Mo047: DNA METHYLATION AND TRANSCRIPTIONAL MARKERS OF MYOCARDIAL REVERSE REMODELING IN HF PATIENTS ON LVAD SUPPORT

Heart failure (HF) involves global genome modifications. Adverse structural and function remodeling that occurs in HF was initially considered to be irreversible. However, ~15% of HF patients on left ventricular assist device (LVAD) support show significant structural and functional reverse remodeling, distinguishing them as responders (R), while ~85% are non-responders (NR). DNA methylation and transcriptional changes that exert myocardial recovery is not well understood. To address this, we performed whole-genome bisulphite sequencing and RNA sequencing on paired myocardial biopsies from HF patients (n=84) before (pre-LVAD) and after LVAD unloading (post-LVAD). Post-LVAD samples showed activation of pathways including TGFβ signaling, PTEN and Fatty acid oxidation compared to pre. Integrating DNA methylation and transcriptomics data revealed hypomethylation (upregulation) of genes including Scaper, Frat1 and Magi1 and hypermethylation (downregulation) of Tpp3 and Icam. Overall, suggesting a unique ECM-specific stabilization pathway post-LVAD unloading. Segregating samples based on their response to LVAD unloading, pathways such as inflammation and fibrotic signaling were activated in postNR compared to preNR. Hypomethylation of Magi1 and hypermethylation of Tppp3 was observed in postNR suggesting cross-linking proteins and destabilization of microtubule formation as potential mechanisms of functional regression in NR. Conversly, postR showed activation of deubiquitination, oxidative phosphorylation and NLR signaling compared to preR. Finally, we observed integrin signaling, syndecan interaction, collagen degradation and wound healing pathways were activated in postR compared to postNR. Hypomethylation of actin cytoskeleton ( Myl12a ), microtubule/motor proteins ( Kif5b ) and tropomyosin ( Tpm3 ) were observed in postR, suggesting a plausible reverse remodeling mechanism mediated by ECM degradation and stabilization of myocardium in these patients. Western blot analysis also showed a trend towards an increase in collagen in postNR compared to postR (n=4, p=0.06). Finally, a mouse model of HF and recovery was used and pathways including ECM degradation and cardioprotective signaling were activated in mice that recovered from HF compared to mice that did not. Overall, our data suggests a unique ECM regulation pathway to contribute towards myocardial reverse remodeling in HF patients.

Abstract We073: CLEC4E Signaling in Myocardial Ischemia-Reperfusion Injury

Background: The innate immune receptor CLEC4E (C-type lectin domain family 4 member E) in cardiac resident cells and circulating leukocytes contributes to ischemic myocardial damage and adverse LV remodeling following ischemia reperfusion injury (I/R). Mice with loss of CLEC4E gene function show reduced cardiac injury and better LV remodeling but the mechanisms of this cardioprotection remain unknown. Aims: We investigated whether Clec4e gene function in cardiac resident cells vs infiltrating immune cells mediates cardioprotection during myocardial ischemia-reperfusion injury. Methods: We generated chimeric mice by IV infusion of 5 x 10 6 bone marrow cells originating from C57Bl6/J CLEC4E -/- and C57Bl6/J wild-type (WT) donor mice in 8w-old lethally irradiated (9.5 Gy) WT (n=36) and CLEC4E -/- (n=50) receptor mice, respectively. After 4 w, mice were subjected to ischemia reperfusion injury (I/R) by 60 min LAD occlusion. Troponin levels (TnI) were measured at 90 min post I/R and 7T-magnetic resonance imaging with late gadolinium enhancement (LGE) for infarct size evaluation was performed at 24 h and 28 d post I/R. Mice were euthanized at 28 days for immunohistochemistry and analysis of BM chimerism. Results: Immunohistochemistry for CLEC4E expression on bone marrow smears confirmed successful BM chimerism. At 24h post I/R, TnI levels and LGE-assessed infarct size on MRI were not significantly different between groups (42.1 vs 48.4 ng/ml, and 25.2% vs 31.5% of LVmass in CLEC4E -/- &amp; WT BM versus in WT &amp; CLEC4E -/- BM, respectively) suggesting similar myocardial damage . After 28 d, LV end-diastolic volumes (43µL vs 55µL), and end-systolic volumes (13µL vs 25µL) were significantly smaller in CLEC4E -/- &amp; WT BM than in WT &amp; CLEC4E -/- BM mice (P&lt;0.05 for both), resulting in better preserved global LV function (LVEF 62% vs 47%, P&lt;0.05) . Infarct size, semiquantitatively assessed using planimetry on Sirius red stains, was smaller in CLEC4E -/- &amp; WT BM than in WT &amp; CLEC4E -/- BM (6.9% vs 19.8%, P&lt;0.01). Conclusion: CLEC4E gene deletion in cardiac resident cells, but not in infiltrating hematopoietic immune cells is associated with better functional and structural remodelling after myocardial I/R. Inhibition of CLEC4E signaling via blocking antibodies or small molecule inhibitors in cardiac myocytes might be a promising cardioprotective strategy.

Abstract Or105: Constitutive Deletion of the Obscurin Ig58/59 Domains Induces Structural and Electrophysiological Remodeling in Atria

Introduction: Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments and regulates contraction. In the ObscnΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, aging males exhibit irregular heart rhythm with prominent atrial fibrillation, atrial enlargement, and progressive remodeling of the ventricles. A mechanistic basis for the emergence of arrhythmia early on could not be identified in ObscnΔIg58/59 ventricles, suggesting that the atria are preferentially impacted by deletion of the obscurin Ig58/59 module prior to the ventricles. Hypothesis: We hypothesize that Ig58/59 deletion elicits unique structural, electrical, and functional consequences in the atria preceding ventricular maladaptation. Aims: I. Examine the structural organization of ObscnΔIg58/59 atria II. Assess Ca 2+ handling in isolated atrial cardiomyocytes and determine molecular alterations. Methods: Electron microscopy and super resolution microscopy were utilized to visualize sarcomeric ultrastructure and the transverse-axial tubule (TAT) network, respectively. Ca 2+ handling activity and synchrony were also resolved, while Phos-Tag gels were used to quantify T-cap phospho-species. Results: ObscnΔIg58/59 atria exhibited misalignment of Z-disks. Spontaneous and stimulated Ca 2+ cycling behavior were [AB1] differentially disrupted in atrial cardiomyocytes in 6- and 12-month ObscnΔIg58/59 males. Relatedly, atrial cells showed an age-dependent deterioration in TAT architecture. Finally, as a function of aging, ObscnΔIg58/59 atria displayed alterations in the expression and phosphorylation of T-cap, a Z-disk protein implicated in the integration of t-tubules with the sarcomeric cytoskeleton. Conclusions: The structural and electrical alterations that arise in ObscnΔIg58/59 atria precede ventricular dysfunction and coincide with the emergence of atrial fibrillation. Collectively, our work indicates that the atria are principally affected by Ig58/59 elimination, instigating arrhythmias and morphological alterations with age. The ObscnΔIg58/59 mouse model has thus emerged as a proxy for atrial cardiomyopathy.

Abstract Tu072: O-GlcNAcylation underlies the activation of sodium-glucose cotransporter 1 in diabetic hearts

Rationale: Type-2 diabetes (T2D) greatly increases the risk for developing heart failure. Recent evidence indicates that the cardiac expression and function of the sodium-glucose cotransporter 1 (SGLT1) is elevated in disease states, including T2D, leading to structural and functional remodeling of the heart. The mechanisms underlying SGLT1 activation in the diabetic heart are currently unknown. Objective: To investigate if SGLT1 undergoes the O-linked attachment of β- N -acetylglucosamine (O-GlcNAcylation), a post-translational modification that is exacerbated in T2D, and its effect on SGLT1 activity in diabetic hearts. Methods/Results: SGLT1 co-immunoprecipitates with O-GlcNAc in heart homogenates and HL-1 cardiomyocyte lysates. Enhancing global protein O-GlcNAcylation in HL-1 cells via si-RNA-mediated silencing of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc from proteins, resulted in increased amounts of O-GlcNAc that precipitate with SGLT1. SGLT1 function, measured as the SGLT1-mediated Na + influx, was significantly increased in HL-1 cells with silenced OGA. These data suggest that SGLT1 undergoes O-GlcNAcylation and this modification results in SGLT1 activation. Using rats that express human amylin in the pancreatic β-cells (HIP rats) as a model of late-onset T2D and their wild-type littermates as controls, we found that a larger fraction of SGLT1 co-immunoprecipitates with O-GlcNAc in hearts from T2D rats compared to controls. The SGLT1-mediated Na + influx was larger in myocytes from T2D vs . control rats. Increasing total O-GlcNAcylation with Thiamet-G in control myocytes resulted in larger Na + influx. In reverse experiments, inhibition of O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine crystalline reduced SGLT1-mediated Na + uptake in myocytes from T2D rats. Inhibition of O-GlcNAcylation in T2D myocytes reduced Ca 2+ spark frequency and this effect was significantly less pronounced with SGLT1 blocked. These results suggest that O-GlcNAcylation affects myocyte Na + regulation by activating SGLT1, which contributes to myocyte Na + overload and its downstream effects on sarcoplasmic reticulum Ca 2+ leak in T2D. Conclusion: Exacerbated O-GlcNAcylation underlies SGLT1 activation in diabetic hearts. Preventing O-GlcNAcylation may limit myocyte Na + overload and the frequency of pro-arrhythmogenic Ca 2+ sparks in myocytes from T2D rats.

Abstract Tu125: Loss of mitochondrial magnesium leads to hepatic ketogenic insufficiency and accelerates the progression of cardiac hypertrophy

Magnesium (Mg 2+ ) is an abundant intracellular divalent cation and is an important co-factor. Like calcium, Mg 2+ is also compartmentalized to mitochondria. Mrs2 is the only known molecular machinery associated with mitochondrial Mg 2+ influx. Although we know that Mg 2+ plays a crucial role in cellular homeostasis, our understanding of how mMg 2+ homeostasis alters the metabolic state of the cell remains incomplete. To begin elucidating the importance of mMg 2+ , we made a liver-specific Mrs2 knockout mouse model (Mrs2 Dhep ) using the Cre-loxP system. Since liver is the central hub of lipid metabolism, we hypothesized that loss of mitochondrial Mg 2+ could alter hepatic lipid homeostasis. Enigmatically we observed increased hepatic lipid accumulation, in spite of increased PPARa activation and Fatty acid oxidation (FAO). In our previous work we showed in Mrs2 Dhep the FAO-derived acetyl CoA to be channeled to de novo lipogenesis (DNL) via cataplerosis, instead of ketogenesis. Further, our results show markedly blunted ketonemia in Mrs2 Dhep revealing a state of ketogenic insufficiency. In the presence of increased ketone bodies (KB), normal hearts preferentially use both KB and FAO while glucose metabolism tend to be reduced. During the progression of heart failure (HF), the failing heart depends on alternate ATP generating substrates like KB as there is a metabolic deficit in both FAO and glucose metabolism. Because we saw a decrease in the KB, we hypothesize that hepatic ketogenic insufficiency will lead to cardiac hypertrophy and heart failure in pressure overload model due to energy insufficiency. Interestingly we found the heart weight and the heart to body weight ratio, left ventricular (LV) wall thickness, expression of genes linked to cardiac hypertrophy to be increased in Mrs2 Dhep compared to control. We also observed an adverse structural remodeling of LV and LV dysfunction. Masson’s trichrome staining showed increased collagen deposition and fibrosis in the Mrs2 Dhep mice when compared to the control. Our results show altered hepatic mitochondrial Mg 2+ homeostasis to have profound direct effect on hepatic lipid metabolism and indirect inter-organ effect on the heart following pressure overload.

Calcium-mediated DAD in membrane potentials and triggered activity in atrial myocytes of ETV1f / fMyHCCre /+ mice.

The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.

ARRHYTHMIAS IN HEART FAILURE: PATHOPHYSIOLOGY

Heart failure is a medical condition caused by various factors and is associated with significant morbidity and mortality. Significantly, heart failure provokes changes in the expression and regulation of ion channels, leading to electrical remodelling that can increase the risk of arrhythmias. Structural remodelling in heart failure, which involves myocardial hypertrophy, fibrosis, and scar formation, is crucial in the development of arrhythmogenic conditions. This article examines the mechanisms contributing to increased susceptibility to arrhythmias and associated ion channel expression, function, and calcium homeostasis alterations in heart failure. Understanding the mechanisms of arrhythmogenic remodelling is essential to improve arrhythmia treatment and prevent sudden cardiac death in patients with heart failure.

Contrastive Disentanglement for Quantitative Ultrasound Muscle Atrophy Evaluation.

Muscleatrophy reduces the quality of life and increases morbidity and mortality from other diseases. The development of non-invasive muscle atrophy evaluation method is of great practical value. The lack of gold standard for pathological grading usually allows only the duration of weightlessness as a criterion for the degree of atrophy. However, the adaptive reductive remodeling of muscle physiology and structure shows a trend of nonlinear changes in time. Consequently, using weightlessness time as a benchmark for the degree of atrophy is inaccurate. This paper proposes a new ultrasound imaging-based method for quantifying muscle atrophy that utilizes weakly supervised information between multiple data partitions with controlled variance components, overcoming the limitations of using the weightlessness time as a criterion. We introduce a group-supervised contrastive disentanglement network (GCDNet) to disentangle the individual variances, muscle growth and atrophy components of ultrasound images, and quantify the degree of atrophy using the disentangled atrophy component. The feasibility of GCDNet is validated by the separability, independence, and representativeness of the disentangled components. To simplify the application of GCDNet, a muscle atrophy scoring network requiring no reference images is developed by distilling the GCDNet's knowledge of muscle atrophy quantization. The strength of the proposed methodology allows us, for the first time to our knowledge, to study the muscle growth attribute during hind-limb unloading and the spatial distribution of muscle atrophy.

Pulmonary artery aneurysm: computed tomography (CT) imaging findings and diagnosis.

Pulmonary artery aneurysm (PAA) is a rare pulmonary vascular disease with nonspecific symptoms and various etiologies. As the disease progresses, in addition to the dilation of the pulmonary arteries, it may be accompanied by remodeling of the cardiac structure and changes in the morphology of the aorta. Recognizing the cause of PAA is therefore a clinically challenging task. In this review article, we provide an overview of various causes of PAA with the support of corresponding imaging findings on computed tomography pulmonary angiography (CTPA) examination. Firstly, from the perspective of hemodynamics, a logical diagnosis is provided according to whether the main pulmonary artery (MPA) is dilated, and whether the PA is dilated locally or diffusely. Secondly, for the imaging examination of vascular wall lesions, due to the limitations of ultrasound examination and interventional procedures, the irreplaceability of dual-phase CTPA examination in disease assessment is especially emphasized. Finally, for highly suspected disorders, it is necessary to comprehensively check with the patient whether there is a family history or past medical history. For patients with PAA, especially those with Marfan syndrome (MFS) or arteritis, adequate preoperative imaging evaluation, regular postoperative radiographic follow-up, and concurrent treatment of the underlying disease (if necessary) are crucial, which are related to the prognosis and long-term quality of life of such patients. Despite the nonspecific features of PAA presentation, a thorough examination of the patient's clinical history and imaging characteristics will play an important role in diagnosing PAA and planning patient management strategies.

Advanced myocardial deformation echocardiography for evaluation of the athlete's heart: Functional and mechanistic analysis

BackgroundAssessment of the athlete's heart is challenging because of a phenotypic overlap between reactive physiological adaptation and pathological remodelling. The potential value of myocardial deformation remains controversial in identifying early cardiomyopathy. AimTo identify the echocardiographic phenotype of athletes using advanced two-dimensional speckle tracking imaging, and to define predictive factors of subtle left ventricular systolic dysfunction. MethodsIn total, 191 healthy male athletes who underwent a preparticipation medical evaluation at Nancy University Hospital between 2013 and 2020 were included. Clinical and echocardiographic data were compared with 161 healthy male subjects from the STANISLAS cohort. Borderline global longitudinal strain value was defined as<17.5%. ResultsAthletes demonstrated lower left ventricular ejection fraction (57.9±5.3% vs. 62.6±6.4%; P<0.01) and lower global longitudinal strain (17.5±2.2% vs. 21.1±2.1%; P<0.01). No significant differences were found between athletes with and without a borderline global longitudinal strain value regarding clinical characteristics, structural echocardiographic features and exercise capacity. A borderline global longitudinal strain value was associated with a lower endocardial global longitudinal strain (18.8±1.2% vs. 22.7±1.9%; P=0.02), a lower epicardial global longitudinal strain (14.0±1.1% vs. 16.6±1.2%; P<0.01) and a higher endocardial/epicardial global longitudinal strain ratio (1.36±0.07 vs. 1.32±0.06; P<0.01). No significant difference was found regarding mechanical dispersion (P=0.46). ConclusionsBorderline global longitudinal strain value in athletes does not appear to be related to structural remodelling, mechanical dispersion or exercise capacity. The athlete's heart is characterized by a specific myocardial deformation pattern with a more pronounced epicardial layer strain impairment.

Dynamic remodeling of septin structures fine-tunes myogenic differentiation

Controlled myogenic differentiation is integral to the development, maintenance and repair of skeletal muscle, necessitating precise regulation of myogenic progenitors and resident stem cells. The transformation of proliferative muscle progenitors into multinuclear syncytia involves intricate cellular processes driven by cytoskeletal reorganization. While actin and microtubles have been extensively studied, we illuminate the role of septins, an essential yet still often overlooked cytoskeletal component, in myoblast architecture. Notably, Septin9 emerges as a critical regulator of myoblast differentiation during the initial commitment phase. Knock-down of Septin9 in C2C12 cells and primary mouse myoblasts accelerates the transition from proliferation to committed progenitor transcriptional programs. Furthermore, we unveil significant reorganization and downregulation of Septin9 during myogenic differentiation. Collectively, we propose that filmamentous septin structures and their orchestrated reorganization in myoblasts are part of a temporal regulatory mechanism governing the differentiation of myogenic progenitors. This study sheds light on the dynamic interplay between cytoskeletal components underlying controlled myogenic differentiation.

Light-Driven H2 Production in Chlamydomonas reinhardtii: Lessons from Engineering of Photosynthesis.

In the green alga Chlamydomonas reinhardtii, hydrogen production is catalyzed via the [FeFe]-hydrogenases HydA1 and HydA2. The electrons required for the catalysis are transferred from ferredoxin (FDX) towards the hydrogenases. In the light, ferredoxin receives its electrons from photosystem I (PSI) so that H2 production becomes a fully light-driven process. HydA1 and HydA2 are highly O2 sensitive; consequently, the formation of H2 occurs mainly under anoxic conditions. Yet, photo-H2 production is tightly coupled to the efficiency of photosynthetic electron transport and linked to the photosynthetic control via the Cyt b6f complex, the control of electron transfer at the level of photosystem II (PSII) and the structural remodeling of photosystem I (PSI). These processes also determine the efficiency of linear (LEF) and cyclic electron flow (CEF). The latter is competitive with H2 photoproduction. Additionally, the CBB cycle competes with H2 photoproduction. Consequently, an in-depth understanding of light-driven H2 production via photosynthetic electron transfer and its competition with CO2 fixation is essential for improving photo-H2 production. At the same time, the smart design of photo-H2 production schemes and photo-H2 bioreactors are challenges for efficient up-scaling of light-driven photo-H2 production.

Tannic acid/non-covalent interaction-mediated modification of hemp seed proteins: Focused on binding mechanisms, oil-water interface behavior, and rheological properties

In this study, hemp seed protein (HSP) was treated to prepare a hemp seed protein-tannic acid non-covalent complex (Nov-HSP). To obtain an emulsifier with excellent properties at the oil-water interface and to propose a potential mechanism of action. The results showed that the α-helix and β-sheet content of Nov-HSP decreased and the intensity of the UV absorption peak increased, respectively, compared with that of HSP. The positions of the maximum fluorescence emission peaks of the synchronized fluorescence spectra were red-shifted to 301.8 nm and 340.6 nm, respectively. Fluorescence quench analysis revealed that static quench occurred between tannins and HSP, with ΔH of −16.138 kJ/mol and ΔS of −0.1073 kJ/mol. The physicochemical and functional properties of HSP and Nov-HSP were analyzed, and it was found that the volume mean diameter of Nov-HSP was 449.28 nm, the absolute value of zeta potential was 20.52 mV, and the solubility was 33.42% at a tannic acid concentration of 1.0 mg/mL. Focusing on the oil-water interfacial properties of Nov-HSP as an emulsifier, it was found that having non-covalent binding effectively increased the diffusion rate of HSP at the interface, thus enhancing the rheological properties of the emulsion. And the emulsification activity index and emulsion stability index were improved to 71.67 m2/g and 32.01 min. These findings provide new perspectives for the phenolic compound-mediated structural remodeling of HSP, expanding its application in emulsion food production.

The role of NETosis in heart failure.

The hallmark of heart failure (HF) is structural myocardial remodeling including cardiomyocyte hypertrophy, fibrosis, cardiomyocyte cell death, and a low-grade aseptic inflammation. The initiation and maintenance of persistent chronic low-grade inflammation in HF are not fully understood. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. In the settings of myocardial infarction, myocarditis, or cardiomyopathies, neutrophils infiltrate the cardiac tissue and undergo NETosis that further aggravate the inflammation. A number of stimuli may cause NETosis that is a form of programmed cell death of neutrophils that is different from apoptosis of these cells. Whether NETosis is directly involved in the pathogenesis and development of HF is still unclear. In this review, we analyzed the mechanisms and markers of NETosis, especially placing the accent on the activation of the neutrophil-specific myeloperoxidase (MPO), elastase (NE), and peptidylarginine deiminase 4 (PAD4). These conclusions are supported by the recent genetic and pharmacological studies which demonstrated that MPO, NE, and PAD4 inhibitors are effective at least in the settings of post-myocardial infarction adverse remodeling, cardiac valve diseases, cardiomyopathies, and decompensated left ventricular hypertrophy whose deterioration can lead to HF. This is essential for understanding NETosis as a contributor to pathophysiology of HF and developments of new therapies of HF.

A correctable immune niche for epithelial stem cell reprogramming and post-viral lung diseases.

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.

β-catenin mediates monocrotaline-induced pulmonary hypertension via glycolysis in rats

BackgroundMetabolic abnormalities and immune inflammation are deeply involved in pulmonary vascular remodelling and the development of pulmonary hypertension (PH). However, the regulatory mechanisms of glycolysis in macrophages are still elusive. Cumulative evidence indicates that β-catenin plays a crucial role in metabolic reprogramming. This study aimed to investigate the effect of β-catenin on macrophage glycolysis in PH.MethodsLPS-induced BMDMs were generated via in vitro experiments. A monocrotaline (MCT)-induced PH rat model was established, and the β-catenin inhibitor XAV939 was administered in vivo. The role of β-catenin in glycolysis was analysed. The degree of pulmonary vascular remodelling was measured.Resultsβ-catenin was significantly increased in both in vitro and in vivo models. In LPS-induced BMDMs, β-catenin increased the levels of hexokinase 2 (HK2), phosphofructokinase (PFK), M2-pyruvate kinase (PKM2), lactate dehydrogenase (LDH), and lactate (LA) and the expression of inflammatory cytokines and promoted PASMC proliferation and migration in vitro. XAV939 decreased the level of glycolysis and downregulated the expression of inflammatory cytokines in vivo. MCT promoted pulmonary arterial structural remodelling and right ventricular hypertrophy, and XAV939 alleviated these changes.ConclusionsOur findings suggest that β-catenin is involved in the development of PH by promoting glycolysis and the inflammatory response in macrophages. Inhibition of β-catenin could improve the progression of PH.