Structural Remodeling Research Articles

Intermittent hypoxia is significantly associated with low-voltage areas in patients with atrial fibrillation complicated by obstructive sleep apnea

Abstract Background Obstructive sleep apnea (OSA) is one of risk factors for atrial fibrillation (AF); however, how OSA affects the structural and electrical atrial remodeling is not well described. This study aimed to determine the association of OSA with left atrial (LA) size and LA low-voltage area (LVA), a known arrhythmogenic substrate for AF. Methods Eighty-three patients undergoing catheter ablation of AF (forty-nine with OSA [apnea–hypopnea index: AHI ≥ 5/h] and thirty-four control patients without OSA by full polysomnography or portable monitor) were studied. In all cases, LA maps were created using a three-dimensional electro-anatomical mapping system in sinus rhythm or pacing from the right atrium. LVA was defined as a bipolar voltage < 0.5 mV. %LVA is defined as ratio of LVA to LA area. Results LVA and %LVA were larger in OSA group as compared to Control group (6.0 ± 6.6 vs. 2.6 ± 3.2 cm2, P = 0.003 and 7.5 ± 8.5 vs. 3.5 ± 4.6 %, P = 0.008, respectively). On the other hand, there was no difference in LA size between the two groups. In addition, 3% oxygen desaturation index (ODI) was significantly correlated with %LVA (r = 0.282, P = 0.010), but not with LA size (r = 0.053, P = 0.637). Multiple regression analysis demonstrated that 3%ODI ≥ 30 (3.088, 1.078-8.851, P = 0.036) was significantly associated with %LVA after adjustment. Conclusion In patients with AF complicated by OSA, significant enlargement of the LVA was observed, but there was no evidence of enlargement in LA size. Intermittent hypoxia may be one of the mechanisms of this atrial electro-anatomical remodeling.figure 1figure 2

Left atrial strain measurement in patients with heart failure and atrial fibrillation compared to a control group

Abstract Background Left atrial (LA)-strain measurement is a non-invasive and widely available echocardiographic method to detect atrial cardiomyopathy as a process of structural and functional remodeling. The aim of this study is to measure LA-strain in patients with heart failure (HF) and atrial fibrillation (AF), compared to patients without structural heart disease and to evaluate whether or not LA-Strain could be part of a multi-modality assessment that influences therapy strategies and prognosis in patients suffering AF. Methods This study includes 18 patients with HF in sinus rhythm who underwent CRT implantation (HF group), 25 patients with persistent AF and preserved ejection fraction (EF) who underwent left atrial catheter ablation (AF group) and 22 patients without structural heart disease or AF who underwent electrophysiological study (control group). All subjects received measurement of reservoir (LASr), conduit (LAScd) and contraction (LASct) LA strain imaging using two-dimensional speckle tracking echocardiography (2D-STE). Results Patient characteristics in the HF-group showed mean age 68y (SD 10,6), mean EF 29% (SD 6,8), 66% male compared to the AF-group with mean age 66y (SD 8.0), mean EF 60% (SD 5.1), 68% male. The control-group showed mean age 55y (SD 13.8), mean EF 60% (SD 5.4), 55% male. For LASr we found normal values in the control groups and reduced values in the HF und AF group (HF: mean 20% [9 – 45%], AF: mean 24% [7 – 52%], control: mean 42% [30 – 67%]). In LASr, LAScd and LASct there was a statistically significant difference between the HF and the control group (p < 0.001) as well as the AF and control group (p < 0.001), whereas there was no difference between AF and HF group (p = 0.444). Discussion Patients with persistent AF show similar LA-strain compared to patients with HF and patients without structural heart disease present significant better LA strains. The findings of this study suggest, that LA strain analysis might contribute to comprehensive assessment of patients with AF especially as a simple imaging method. A limitation of our results could be the significant younger age of our control group (p = 0.004) as fibrotic remodeling increases in advanced age. It remains to be analyzed whether early AF treatment could prevent further fibrotic remodeling and whether measuring LA strain could provide further information for risk stratification and the definition of therapeutic intervention strategies.

Cardiovascular magnetic resonance 3D LGE imaging for atrial fibrillation ablation

Abstract Objective To assess feasibility and reliability of cardiac magnetic resonance (CMR) imaging in visualizing left atrial (LA) structural changes that patients with paroxysmal atrial fibrillation (PAF) undergo acutely and long-term post ablation. Two different ablation methods i.e pulsed filed ablation (PFA) and cryoablation were studied. Background Pulmonary vein (PV) isolation has become the cornerstone technique for catheter ablation in patients with drug-refractory atrial fibrillation (AF). At present, almost all ablation technologies are mediated by a thermal effect. Recently, pulsed field ablation (PFA) has been introduced as a new energy source. PFA is a non-thermal ablative modality in which high voltage ultra-short pulses are applied to target tissue, while preserving the extracellular matrix architecture, nerves, and microvascular structures. Few data exist showing different structural LA changes between the two methods using Three-Dimensional (3D) Late Gadolinium Enhancement (LGE) Imaging. Methods CMR imaging was performed pre-ablation, acutely (<24 h), and 3 months post-ablation in 10 patients with paroxysmal atrial fibrillation (AF) undergoing pulmonary vein (PV) isolation with PFA (n = 5) or cryoablation (n = 5). 3D LGE and T2-weighted images were analysed. We obtained two data sets of 3D whole heart LGE imaging with high resolution, 20minutes post gadolinium injection. Patients underwent two acquisitions: the conventional respiratory navigated, electrocardiographically-gated 3D fast gradient echo (1.3slice thickness, 256x256 matrix acquisition) and the image-navigated isotropic high resolution 3D LGE with Dixon water-fat separation. 3D LGE data were analysed using a dedicated (ADAS LA) software in order to produce a 3D-LA model visualization of LGE areas. Results In the acute stage, LGE volume was 50% larger after PFA vs. cryoablation (P < 0.001), and oedema on T2 imaging was significantly smaller (visual estimation) on PFA cases. LGE rings surrounding PV ostia were more homogeneous after PFA, with no sign of microvascular damage or intramural hemorrhage as compared to cryoablation cases. In the chronic stage, the majority of acute LGE had disappeared after PFA, whereas most LGE persisted after cryo-ablation. The two 3D LGE sequences used for analysis showed complete agreement in the visualization of atrial scar with superior image quality of the novel sequence. The mean acquisition time for 3D LGE imaging was 11±4minutes for the conventional fast gradient echo sequence, and 5±2minutes for the novel 3D self-image navigated LGE sequence. Conclusions CMR imaging may help in visualization and understanding of LA structural remodeling post different ablation techniques.

Left atrial wall thickness measured by a machine learning method predicts AF recurrence after pulmonary vein isolation

Abstract Background Left atrial (LA) remodeling plays a significant role in the progression of atrial fibrillation (AF). Although LA wall thickness (LAWT) has emerged as an indicator of structural remodeling, its impact on AF outcomes remains unclear. We aimed to determine the association between LAWT and AF recurrence after pulmonary vein isolation (PVI). Methods Single-center registry of patients enrolled for radiofrequency PVI from 2016 to 2018. In all cases, a pre-ablation CT scan was performed within less than 48 hours. Mean LAWT was retrospectively determined by a semi-automated machine learning method with minimal human intervention (ADAS 3D®). Additionally, regional tissue thickness was assessed in four locations: roof and inferior, posterior, and anterior walls. In a subgroup of patients, a pre-ablation cardiac magnetic resonance (CMR) was also performed within the same week. LA functional parameters and fibrosis, using 3D delayed gadolinium enhancement, were analyzed. The primary endpoint was AF recurrence after a 3-month blanking period. Results A total of 439 patients (mean age 61±12years, 62% male, 78% with paroxysmal AF) were included. The mean LAWT was 1.4±0.2mm (ranging from 0.9 to 1.9mm). Software processing duration was 8.2±0.4 min, and the mean human input time was 1.3±0.1 min. There was no correlation between LAWT and CT-derived LA-indexed volume (Spearman –0.01, p=0.845). During a median follow-up of 5.8 (IQR 4.9–6.6) years, 238 patients (54%) had an AF relapse. LAWT was an independent predictor of recurrence, after adjusting for known confounders including age, non-paroxysmal AF, LA-indexed volume, and chronic kidney disease (adjusted HR 6.49 [95% CI 2.70-15.49], p<0.001). AF recurrence rates were 11%, 15%, and 21%/year across terciles of increasing LAWT (log-rank p<0.001) – Figure. The posterior LAWT revealed the strongest association with the study endpoint (HR 1.93 [95% CI 1.24-3.02], p=0.004). In the cohort of 62 patients with both CT and CMR, LAWT showed weak correlations with LA ejection fraction and LA coupling index (Spearman <0.25; p=0.054 and p=0.093, respectively), and a moderate correlation with LA fibrosis (Spearman 0.468; p<0.001). Conclusions Mean LAWT, easily assessed by commercially available machine learning software, is an independent predictor of AF recurrence after PVI in the long-term follow-up. This association is mainly driven by the posterior LAWT. Whether patients with increased LAWT should receive tailored therapy deserves further investigation.Figure

#326 Features of intrarenal hemodynamics in patients with chronic glomerulonephritis on the background of taking anticoagulants

Abstract Background and Aims Chronic glomerulonephritis (CGN)-glomerular, autoimmune kidney disease, where baseline therapy is clinically proven to be successful. The study evaluates hemodynamic disorders of renal blood flow in patients with CGN on the background of baseline treatment with the inclusion of rivaroxaban. Method We researched108 patients CGN against the background of 3-month basic therapy with the inclusion of rivaroxaban (group AC+, 55 patients) and without anticoagulant (group AC-, 53 patients). Initial and after 3 months evaluation in the mode of color Doppler mapping and pulse-wave doppler. Results In the course of 3-month therapy, the performance of dopplerography of renal arteries in patients with CGN did not change reliably. But there was a credible and clinically significant increase in the systolic blood flow rate at the level of the Interregional Artery (IA), both compared to the baseline data and towards the end of hospitalization (by 9.27 2.58% p < 0.001 the validity of the difference with the raw data, by 8.60 2.53%, p < 0.01 with the 10th day of therapy), remaining reliably lower than in control group (p < 0.001). The speed at the arc artery (АА) also increased slightly (by 2.46 1.03%, p < 0.05 reliability of the difference with the original data and the end of hospitalization), but although statistical reliability was achieved, the dynamics was clinically insignificant and was less than 2.5%. The resistivity index (RI) at both IA and AA levels did not change reliably. Conclusion In CGN patients, intrarenal hemodynamics change with decreased blood flow rates in IA and AA. In the future, against the background of 3-month basic HGH therapy, there was some improvement in blood flow at the IA level but not AA, but no qualitative changes in intrarenal hemodynamics were achieved. The supplementation of long-term anticoagulation therapy with rivaroxaban has increased the effect of therapy on hemodynamic rates, resulting in some improvement in blood flow at both IA and AA levels, but no qualitative improvement has been achieved, possible due to pronounced structural remodeling of kidney vessels in patients with CGN.

Effects of different sodium–glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis

BackgroundThis systematic review and meta-analysis aimed to explore the effects of different sodium–glucose cotransporter-2 inhibitors (SGLT2i) on prognosis and cardiac structural remodeling in patients with heart failure (HF).MethodsRelevant studies published up to 20 March 2024 were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library CNKI, China Biomedical Literature Service, VIP, and WanFang databases. We included randomized controlled trials of different SGLT2i and pooled the prognosis data of patients with HF. We compared the efficacy of different SGLT2i in patients with HF and conducted a sub-analysis based on left ventricular ejection fraction (LVEF).ResultsWe identified 77 randomized controlled trials involving 43,561 patients. The results showed that SGLT2i significantly enhanced outcomes in HF, including a composite of hospitalizations for HF and cardiovascular death, individual hospitalizations for HF, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, left atrial volume index (LAVi), and LVEF among all HF patients (P < 0.05) compared to a placebo. Sotagliflozin was superior to empagliflozin [RR = 0.88, CI (0.79–0.97)] and dapagliflozin [RR = 0.86, CI (0.77–0.96)] in reducing hospitalizations for HF and CV death. Dapagliflozin significantly reduced hospitalizations [RR = 0.51, CI (0.33–0.80)], CV death [RR = 0.73, CI (0.54–0.97)], and all-cause mortality [RR = 0.69, CI (0.48–0.99)] in patients with HF with reduced ejection fraction (HFrEF). SGLT2i also plays a significant role in improving cardiac remodeling and quality of life (LVMi, LVEDV, KCQQ) (P < 0.05). Among patients with HF with preserved ejection fraction (HFpEF), SGLT2i significantly improved cardiac function in HFpEF patients (P < 0.05). In addition, canagliflozin [RR = 0.09, CI (0.01–0.86)] demonstrated greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF patients.ConclusionOur systematic review showed that SGLT2i generally enhances the prognosis of patients with HF. Sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in a composite of hospitalization for HF and CV death in the overall HF patients. Canagliflozin exhibited greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF. Overall, the efficacy of SGLT2i was greater in HFrEF patients than in HFpEF patients.

Dynamics of mature myelin.

Myelin, which is produced by oligodendrocytes, insulates axons to facilitate rapid and efficient action potential propagation in the central nervous system. Traditionally viewed as a stable structure, myelin is now known to undergo dynamic modulation throughout life. This Review examines these dynamics, focusing on two key aspects: (1) the turnover of myelin, involving not only the renewal of constituents but the continuous wholesale replacement of myelin membranes; and (2) the structural remodeling of pre-existing, mature myelin, a newly discovered form of neural plasticity that can be stimulated by external factors, including neuronal activity, behavioral experience and injury. We explore the mechanisms regulating these dynamics and speculate that myelin remodeling could be driven by an asymmetry in myelin turnover or reactivation of pathways involved in myelin formation. Finally, we outline how myelin remodeling could have profound impacts on neural function, serving as an integral component of behavioral adaptation.

CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/β-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-β1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/β-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

Structural, Functional, and Electrical Remodeling of the Atria With Reduced Cardiorespiratory Fitness: Implications for AF

BackgroundReduced cardiorespiratory fitness (CRF) is an independent risk factor for the progression of atrial fibrillation (AF). We hypothesized that reduced CRF is associated with structural, functional, and electrical remodeling of the left atrium. ObjectivesThis study sought to correlate objectively assessed CRF with functional and electrical left atrial (LA) parameters using invasive and noninvasive assessments. MethodsConsecutive patients with symptomatic AF undergoing catheter ablation were recruited. CRF was objectively quantified pre-ablation by using cardiopulmonary exercise testing. Using peak oxygen consumption, participants were classified as preserved CRF (>20 mL/kg/min) or reduced CRF (<20 mL/kg/min). LA stiffness was assessed invasively with hemodynamic monitoring and imaging during high-volume LA saline infusion. LA stiffness was calculated as ΔLA diameter/ΔLA pressure over the course of the infusion. LA function was assessed with echocardiographic measures of LA emptying fraction and LA strain. Electrical remodeling was assessed by using high-density electroanatomical maps for LA voltage and conduction. ResultsIn total, 100 participants were recruited; 43 had reduced CRF and 57 had preserved CRF. Patients with reduced CRF displayed elevated LA stiffness (P = 0.004), reduced LA emptying fraction (P = 0.006), and reduced LA reservoir strain (P < 0.001). Reduced CRF was also associated with reduced LA voltage (P = 0.039) with greater heterogeneity (P = 0.027) and conduction slowing (P = 0.04) with greater conduction heterogeneity (P = 0.02). On multivariable analysis, peak oxygen consumption was independently associated with LA stiffness (P = 0.003) and LA conduction velocities (P = 0.04). ConclusionsReduced CRF in patients with AF is independently associated with worse LA disease involving functional and electrical changes. Improving CRF may be a target for restoring LA function in AF.

BETWEEN SCYLLA AND CHARYBDIS: MULTIPLE LEFT ATRIAL THROMBI DESPITE ORAL ANTICOAGULATION AND ANTIPLATELET THERAPY IN A PATIENT CANDIDATE FOR LEFT ATRIAL APPENDAGE OCCLUSION

Abstract Introduction Left atrial (LA) thrombosis usually occurs in patients affected by atrial fibrillation (AF), generally involving the left atrial appendage (LAA). We present the unexpected echocardiographic finding of multiple LA thrombi despite an adequate antithrombotic strategy. Case Presentation A 76–year–old lady underwent transesophageal echocardiographic examination (TOE) to assess eligibility for percutaneous LAA occlusion (LAAO) procedure due to high bleeding risk. Her medical history included AF and a recent percutaneous coronary revascularization; therefore, her antithrombotic therapy included apixaban 2.5 mg bid and clopidogrel 75 mg od. The TOE showed LA structural and functional remodeling with spontaneous echo contrast and multiple thrombi involving the LAA (one [12 x 9 mm] overflowing the orifice and attached to the Coumadin Ridge and the second [12 x 7 mm] attached and arising from the tunnel of patent foramen ovale). Mitral valve stenosis was excluded (Fig.1). Due to TOE findings, the patient was not considered eligible for percutaneous LAAO. Due to the concomitant very high thromboembolic risk, despite the previous intracranial bleeding, we decided to stop apixaban and to start parenteral anticoagulation for 3 weeks with low–molecular weight heparin (100 UI/kg bid) followed by the switch to a vitamin k antagonist (VKA). We also prescribed a hematological evaluation to exclude a hypercoagulability disorder. Our patient’s daughter was a carrier of a mutation in both the methylenetetrahydrofolatereductase and Thrombin genes. A TOE after 30 days showed the persistence of LA thrombi, although with significantly reduced size and mobility (Fig.2). The follow–up was clinically uneventful. We suggested to continue anticoagulation therapy with VKA, and we planned a new TOE after 4 weeks. Discussion Although proper anticoagulation decreases cardioembolic risk in patients with AF, atrial thrombosis may occur due to LA remodeling, high CHA2DS2–VASc score and other factors, including hypercoagulability disorders. The presence of multiple LA thrombi represents a challenge for clinicians, especially in case of concomitant high thromboembolic and bleeding risk. However, the best treatment strategies for these extreme conditions are not defined, so far. Therefore, the therapeutic choice is often tailored to the single patient and based on the clinical judgment, bearing in mind that avoiding Charybdis means passing to close to Scylla and vice versa.

Single-cell 3D genome structure reveals distinct human pluripotent states

BackgroundPluripotent states of embryonic stem cells (ESCs) with distinct transcriptional profiles affect ESC differentiative capacity and therapeutic potential. Although single-cell RNA sequencing has revealed additional subpopulations and specific features of naive and primed human pluripotent stem cells (hPSCs), the underlying mechanisms that regulate their specific transcription and that control their pluripotent states remain elusive.ResultsBy single-cell analysis of high-resolution, three-dimensional (3D) genomic structure, we herein demonstrate that remodeling of genomic structure is highly associated with the pluripotent states of human ESCs (hESCs). The naive pluripotent state is featured with specialized 3D genomic structures and clear chromatin compartmentalization that is distinct from the primed state. The naive pluripotent state is achieved by remodeling the active euchromatin compartment and reducing chromatin interactions at the nuclear center. This unique genomic organization is linked to enhanced chromatin accessibility on enhancers and elevated expression levels of naive pluripotent genes localized to this region. In contradistinction, the primed state exhibits intermingled genomic organization. Moreover, active euchromatin and primed pluripotent genes are distributed at the nuclear periphery, while repressive heterochromatin is densely concentrated at the nuclear center, reducing chromatin accessibility and the transcription of naive genes.ConclusionsOur data provide insights into the chromatin structure of ESCs in their naive and primed states, and we identify specific patterns of modifications in transcription and chromatin structure that might explain the genes that are differentially expressed between naive and primed hESCs. Thus, the inversion or relocation of heterochromatin to euchromatin via compartmentalization is related to the regulation of chromatin accessibility, thereby defining pluripotent states and cellular identity.

Re-dating Roman Karanis, Egypt: radiocarbon evidence for prolonged occupation until the seventh century AD

One century after its initial excavation, this article presents the first absolute chronology for the settlement of Karanis in Egypt. Radiocarbon dates from crops retrieved from settlement structures suggest that the site was inhabited beyond the middle of the fifth century AD, the time at which it was previously believed to have been abandoned. These dates add to the complex picture of population fluctuations and the remodelling and reuse of structures at Karanis. Two dates reach into the middle of the seventh century, placing the abandonment of the site in a period of political and environmental transition that changed the physical and social landscape of the Fayum region and beyond.

Constraint-Induced Movement Therapy Modulates Neuron Recruitment and Neurotransmission Homeostasis of the Contralesional Cortex to Enhance Function Recovery after Ischemic Stroke.

Stroke often results in long-term and severe limb dysfunction for a majority of patients, significantly limiting their activities and social participation. Constraint-induced movement therapy (CIMT) is a rehabilitation approach aimed explicitly at enhancing upper limb motor function following a stroke. However, the precise mechanism remains unknown. This study explores how CIMT may alleviate forelimb paralysis in ischemic mice, potentially through structural and functional remodeling of brain regions beyond the infarct area, especially the contralateral cortex. We demonstrated that CIMT recruits neurons from the contralesional cortex into the network that innervates the affected forelimb, as evidenced by PRV retrograde nerve tracing. Additionally, we investigated how CIMT influences synaptic plasticity in the contralateral cortex by evaluating synaptic growth marker levels and neurotransmission's homeostatic regulation. Our findings uncover a rehabilitative mechanism by which CIMT treats ischemic stroke, characterized by increased recruitment of neurons from the contralateral cortex into the network that innervates the affected forelimb, facilitated by homeostatic regulation of neurotransmission.

Infliximab Limits Injury in Myocardial Infarction.

The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Coronary thrombus aspirates were collected from patients at the time of ST-segment-elevation myocardial infarction and subjected to array-based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1-year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor-α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor-α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab-mediated immune modulation impacts post-MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P<0.01). Concomitantly, immunoassays of coronary sinus samples quantified lower troponin I levels (41.72±7.34 pg/mL versus 58.11±10.75 pg/mL; P<0.05) and secreted protein analysis revealed upregulation of injury-modifying interleukin-2, -4, -10, -12, and -18 cytokines in the infliximab-treated cohort. At 4 weeks (n=12), infliximab treatment resulted in significant protective influence, improving left ventricular ejection fraction (53.9%±5.4% versus 36.2%±5.3%; P<0.001) and reducing scar size (8.31%±10.9% versus 17.41%±12.5%; P<0.05). Profiling of coronary thrombus aspirates in patients with ST-segment-elevation MI revealed highest association for tumor necrosis factor-α in injury risk. Infliximab-mediated immune modulation offers an actionable pathway to alter MI-induced inflammatory response, preserving contractility and limiting adverse structural remodeling.

Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity

BackgroundObesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. ObjectiveThe purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). MethodsSixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m2) had ECGi pre–bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. ResultsObesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. ConclusionObesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.

Electrical pulse stimulation protects C2C12 myotubes against H2O2-induced injury via activating Nrf2/antioxidant pathway

Background: In response to various physiological stimuli during exercise, skeletal muscle (SkM), a highly plastic tissue, is capable of functional and structural remodeling. The present study aimed to elucidate antioxidant adaptation of SkM to contraction by exposing C2C12 myotubes to electrical pulse stimulation (EPS). Methods: C2C12 myoblasts were differentiated to myotubes by changing the media from complete media (DMEM/High Glucose, 10% fetal bovine serum, and 1% antibiotics) to differentiation media (DMEM/High Glucose, 5% horse serum, and 1% antibiotics). The myotubes were seeded at 50,000 cells/well in a 6-well plate where they underwent EPS at 10 V, 10 ms, 50 Hz, 0.3 sec/3 sec for 1 hour/day for 4 days. Results: (1) By completing experiments for time-course (0 – 6 days) and dose-effect (0 – 10 voltage) tests, we found that NQO1 and GSTA2 proteins, two well-known targets of Nrf2, were maximally upregulated with 3.3 and 12.1 fold increase, respectively, by an EPS at 10 voltage for 4 days; therefore, these parameters were used in the following experiments. (2) MitoSOX-Red, CM-H2DCFDA, confocal microscopy, and EPR assay revealed significantly higher ROS levels in mitochondria, cytosol, and whole cell of EPS-cells than control-cells. Western blot data suggests that EPS-cells express significantly higher Nrf2 and a broad array of downstream antioxidant enzymes (SOD1, SOD2, Cat, GPX, NQO1, GSTA2, GSTA4, PRX1, and TRX). This phenomenon was completely abolished by pretreatment with N-acetylcysteine, a ROS scavenger. These data suggest that contraction enhances muscle antioxidant defense through ROS-dependent, Nrf2-activated multi-antioxidant mechanisms, including the first line of antioxidant components, glutathione system, thioredoxin system, and peroxiredoxin system. (3) We further found that EPS significantly upregulated expression of mitochondrial complexes I/V, mitofusin-1, and mitochondrial fission factor, and significantly increased mitochondrial basal oxygen consumption rate and ATP-linked respiration, suggesting an enhanced mitochondrial function and biogenesis. (4) A post-stimulation time-course experiment demonstrated that the upregulated NQO1 and GSTA2 protein expression lasts at least 24 hours after EPS, suggesting that EPS induces antioxidant preconditioning in the cells. (5) A cell viability study using CCK-8 assay demonstrated that EPS-cells have a significantly higher survival rate than control cells in response to H2O2 treatment. Conclusion: We found that EPS dramatically upregulated a large group of antioxidant enzymes in C2C12 myotubes via activating Nrf2. These cells display an increased mitochondrial function and enhanced tolerance to oxidative challenge. These data suggest that contraction can evoke antioxidant adaptation in muscle via mitochondrion-ROS-Nrf2 pathway, which provides myocytes with protection against oxidative stress-associated injury. This project is funded by NIH R01 HL 160820. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Structure-Function Relationship of Respiratory Muscles in the mdx Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder, characterized by severe and progressive skeletal muscle weakness, which extends to the respiratory muscles. We have determined that peak inspiratory pressure-generating capacity is preserved in early dystrophic disease in the mdx mouse model of muscular dystrophy, but this early compensation is lost as disease progressesa. We sought to examine the structure-function relationship of obligatory and accessory respiratory muscles in early (4-month) and advanced (16-month) disease. Ex vivo muscle function of obligatory (diaphragm and parasternal) and accessory (sternomastoid, cleidomastoid and scalene) respiratory muscles was assessed in wild-type and mdx mice in early dystrophic disease (n = 8-15 per group). Diaphragm and scalene ex vivo muscle function was assessed in advanced dystrophic disease (n = 10-14 per group). Histology (sirius red, and haematoxylin and eosin) and immunofluorescence (laminin) were used to assess the form of obligatory (diaphragm, parasternal and intercostal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscles (n=6 per group). Pro-inflammatory cytokine concentrations were examined in muscle homogenates of obligatory and accessory respiratory muscles of wild-type and mdx mice in early and advanced dystrophic disease (n=10 per group). Our study revealed obligatory (diaphragm and parasternal) and accessory (sternomastoid and cleidomastoid) muscle weakness evident in early dystrophic disease. Scalene muscle function is preserved in mdx mice in early disease but is weak in mdx mice in advanced dystrophic disease. Structural remodelling by way of increased collagen deposition (fibrosis), increased central nucleation, increased area of inflammatory cell infiltrate and reduced mean minimal Feret’s diameter (relative atrophy) was evident in obligatory and accessory respiratory muscles in early dystrophic disease. The relative area of collagen deposition in obligatory and accessory respiratory muscles increased with disease progression, but interestingly the increase was most pronounced in the diaphragm muscle. Increased concentration of pro-inflammatory cytokines (IFN-γ, IL-1β, IL-6, KC/GRO, TNF-α, MCP-1, IL-33, MIP-1α, IP-10, MIP-2) was observed in mdx obligatory and accessory muscle homogenates compared to wild-type in early and advanced dystrophic disease. These data widen characterisation of the respiratory control system in mdx mice, potentially revealing novel therapeutic targets. References a O'Halloran KD, Maxwell MN, Marullo AL, Hamilton CP, Ó Murchú SC, Burns DP, Mahony CM, Slyne AD, Drummond SE (2023). Loss of compensation afforded by accessory muscles of breathing leads to respiratory system compromise in the mdx mouse model of Duchenne muscular dystrophy. J Physiol. 601(19):4441-4467. Eli Lilly &amp; Science Foundation Ireland (19/FFP/6628). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Coronary Sinus Metabolite 12,13-diHOME Is a Novel Biomarker for Left Atrial Remodeling in Patients With Atrial Fibrillation.

12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) has shown potential in protecting against heart disease, but its relationship with atrial fibrillation (AF) remains unknown. Coronary sinus (CS) and femoral vein blood samplings were synchronously collected from AF and non-AF subjects (paroxysmal supraventricular tachycardia or idiopathic premature ventricular complexes) who underwent catheter ablation. First, untargeted metabolomic profiling was performed in a discovery cohort (including 12 AF and 12 non-AF subjects) to identify the most promising CS or femoral vein metabolite. Then, the selected metabolite was further measured in a validation cohort (including 119 AF and 103 non-AF subjects) to confirm its relationship with left atrium remodeling and 1-year postablation recurrence of AF. Finally, the biological function of the selected metabolite was validated in a rapid-paced cultured HL-1 atrial cardiomyocytes model. Metabolomic analysis identified CS 12,13-diHOME as the most pronounced change metabolite correlated with left atrium remodeling in the discovery cohort. In the validation cohort, CS 12,13-diHOME was significantly lower in patients with AF than non-AF controls (84.32±20.13 versus 96.24±23.56 pg/mL; P<0.01), and associated with worse structural, functional, and electrical remodeling of left atrium. Multivariable regression analyses further demonstrated that decreased CS 12,13-diHOME was an independent predictor of 1-year postablation recurrence of AF (odds ratio, 0.754 [95% CI, 0.648-0.920]; P=0.005). Biological function validations showed that 12,13-diHOME treatment significantly protect the cell viability, improved the expression of MHC (myosin heavy chain) and Cav1.2 (L-type calcium channel α1c), and attenuated mitochondrial damage in the rapid-paced cultured HL-1 cardiomyocytes model. CS metabolite 12,13-diHOME is decreased in patients with AF and can serve as a novel biomarker for left atrium remodeling.

Adropin Treatment Restores Cardiac Function and Metabolic Flexibility in Diabetic Cardiomyopathy

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and has been recognized as a cause of heart failure independent of other common risk factors. Metabolic inflexibility is a hallmark feature, where increased free fatty acid availability and decreased myocardial glucose uptake lead to an over-reliance on fatty acid oxidation, reducing cardiac work effciency. Energetic ineffciency in diabetic hearts may have profound implications for cardiac function under conditions of increased workload, and therefore therapeutic approaches are warranted. Adropin is a liver- and brain-secreted peptide hormone shown to regulate fuel metabolism in the heart. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity, insulin resistance, and impaired glucose tolerance. Our lab recently showed that acute adropin treatment restores glucose oxidation activity in the hearts of prediabetic obese mice. However, the effects of chronic adropin exposure in the heart remains unknown. Hypothesis: We hypothesize that adropin treatment will exhibit beneficial effects on cardiac fuel metabolism that may lead to long-term improvements in functional output. Methods: We used a preclinical model of DCM to investigate the effects of long-term adropin treatment on cardiac structural and metabolic remodeling. Mice were treated with adropin daily for four weeks, and subjected to echocardiography, glucose tolerance tests, histopathology, RNA-sequencing, and metabolomics. Results: We report that long-term adropin treatment restores normal cardiac structure and metabolic function in the diabetic heart, by inhibiting flux of non-oxidative glycolytic intermediates into the hexosamine biosynthetic pathway. Conclusions: Our findings highlight the therapeutic potential of adropin signaling to attenuate cardiac remodeling in DCM. The project described was supported by NIDDK 1F31DK134089 and NHLBI R01HL147861. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Morphology engineering and electronic structure remodeling of manganese-incorporated VN for boosting urea-assisted energy-saving hydrogen production

Urea-assisted water electrolysis offers a promising route to reduce energy consumption for hydrogen production and meanwhile treat urea-rich wastewater. Herein, we devised a shear force-involved polyoxometalate-organic supramolecular self-assembly strategy to fabricate 3D hierarchical porous nanoribbon assembly Mn-VN cardoons. A bimetallic polyoxovanadate (POV) with the inherent structural feature of Mn surrounded by [VO6] octahedrons was introduced to trigger precise Mn incorporation in VN lattice, thereby achieving simultaneous morphology engineering and electronic structure modulation. The lattice contraction of VN caused by Mn incorporation drives electron redistribution. The unique hierarchical architecture with modulated electronic structure that provides more exposed active sites, facilitates mass and charge transfer, and optimizes the associated adsorption behavior. Mn-VN exhibits excellent activity with low overpotentials of 86 mV and 1.346 V at 10 mA/cm2 for hydrogen evolution reaction (HER) and urea oxidation reaction (UOR), respectively. Accordingly, in the two-electrode urea-assisted water electrolyzer utilizing Mn-VN as a bifunctional catalyst, hydrogen production can occur at low voltage (1.456 V@10 mA/cm2), which has the advantages of energy saving and competitive durability over traditional water electrolysis. This work provides a simple and mild route to construct nanostructures and modulate electronic structure for designing high-efficiency electrocatalysts.