Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy.

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. OBJECTIVES: This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. METHODS: SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. RESULTS: Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61). CONCLUSIONS: The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.

BACKGROUND: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. OBJECTIVES: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. METHODS: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. RESULTS: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area. CONCLUSIONS: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).

OsPLDα1 mediates cadmium stress response in rice by regulating reactive oxygen species accumulation and lipid remodeling.

Lipid remodeling is crucial for various cellular activities and the stress tolerance of plants; however, little is known about the lipid dynamics induced by the heavy metal cadmium (Cd). In this study, we investigated the phospholipid profiles in rice (Oryza sativa) under Cd exposure. We observed a significant decline in the total amounts of phosphatidylcholine and phosphatidylserine, contrasted with an elevation in phosphatidic acid (PA) due to Cd stress. Additionally, Cd stress prompted the activation of phospholipase D (PLD) and induced the expression of PLDα1. OsPLDα1 knockout mutants (Ospldα1) showed increased sensitivity to Cd, characterized by a heightened accumulation of hydrogen peroxide in roots and diminished PA production following Cd treatment. Conversely, PLDα1-overexpressing (OsPLDα1-OE) lines demonstrated enhanced tolerance to Cd, with suppressed transcription of the respiratory burst oxidase homolog (Rboh) genes. The transcription levels of genes associated with Cd uptake and transport were accordingly modulated in Ospldα1 and OsPLDα1-OE plants relative to the wild-type. Taken together, our findings underscore the pivotal role of OsPLDα1 in conferring tolerance to Cd by modulating reactive oxygen species homeostasis and lipid remodeling in rice.

Non-Invasive Imaging for Native Aortic Valve Regurgitation.

Aortic regurgitation (AR) is associated with left ventricular volume and pressure overload, resulting in eccentric left ventricular (LV) remodeling and enlargement. This condition may be well tolerated for years before the onset of myocardial dysfunction and symptoms. Echocardiography plays a crucial role in the diagnosis of AR, assessing its mechanism and severity, and detecting LV remodeling. The assessment of AR severity is challenging and frequently requires the integration of information from multiple different measurements to assess the severity. Recent data suggests that echocardiographically derived LV volumes (end-systolic volume index > 45 ml/m2), an ejection fraction threshold of <60%, and abnormal global longitudinal strain may help identify early dysfunction and may be used to improve clinical outcomes. Consequently, these parameters can identify candidates for surgery. Cardiac magnetic resonance imaging is emerging as a valuable tool for assessing severity when it remains unclear after an echocardiographic evaluation. This review emphasizes the importance of imaging, particularly echocardiography, in the evaluation of AR. It focuses on various echocardiographic parameters, including technical details, and how to integrate them for assessing the mechanism and severity of AR, as well as LV remodeling.

A morpho-viscoelasticity theory for growth in proliferating aggregates.

Despite significant research efforts in the continuum modeling of biological growth, certain aspects have been overlooked. For instance, numerous investigations have examined the influence of morphogenetic cell behaviors, like division and intercalation, on the mechanical response of passive (non-growing) tissues. Yet, their impact on active growth dynamics remains inadequately explored. A key reason for this inadequacy stems from challenges in the continuum treatment of cell-level processes. While some coarse-grained models have been proposed to address these shortcomings, a focus on cell division and cell expansion has been missing, rendering them unusable when it comes to modeling growth. Moreover, existing studies are limited to two-dimensional tissues and are yet to be formally extended to three-dimensional multicellular systems. To address these limitations, we here present a generalized multiscale model for three-dimensional aggregates that accounts for complex morphogenetic movements that include division, expansion, and intercalation. The proposed continuum theory thus allows for a comprehensive exploration into the growth and dissipation mechanics of proliferating aggregates, such as spheroids and organoids.

Establishment and identification of the gill cell line from the blunt snout bream (Megalobrama amblycephala) and its application in studying gill remodeling under hypoxia.

To probe the mechanisms of gill remodeling in blunt snout bream under hypoxic conditions, we selected gill tissue for primary cell culture to establish and characterize the first blunt snout bream gill cell line, named MAG. The gill cells were efficiently passaged in M199 medium supplemented with 8% antibiotics and 15% fetal bovine serum at 28 °C, exhibiting primarily an epithelial-fibroblast mixed type. Additionally, the MAG cells (17th generation) were subjected to four experimental conditions-normoxia, hypoxia 12 h, hypoxia 24 h, and reoxygenation 24 h (R24h)-to evaluate the effects of hypoxia and reoxygenation on MAG cells during gill remodeling. We found that the MAG cell morphology underwent shrinkage and mitochondrial potential gradually lost, even leading to gradual apoptosis with increasing hypoxia duration and increased reactive oxygen species (ROS) activity. Upon reoxygenation, MAG cells gradually regain cellular homeostasis, accompanied by a decrease in ROS activity. Analysis of superoxide dismutase (SOD), glutathione (GSH), lactate dehydrogenase (LDH), catalase (CAT), anti-superoxide anion, and other enzyme activities revealed enhanced antioxidant enzyme activity in MAG cells during hypoxia, aiding in adapting to hypoxic stress and preserving cell morphology. After reoxygenation, the cells gradually returned to normoxic levels. Our findings underscore the MAG cells can be used to study hypoxic cell apoptosis during gill remodeling. Therefore, the MAG cell line will serve as a vital in vitro model for exploring gill remodeling in blunt snout bream under hypoxia.

Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension.

AIMS: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction. MAIN METHODS: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain. KEY FINDINGS: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it. SIGNIFICANCE: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction.

Computed tomography-based measurements associated with rapid lung function decline in severe asthma.

BACKGROUND: Severe asthma patients are susceptible to lung function decline (LFD), but biomarkers that reliably predict an accelerated LFD have not been fully recognized. OBJECTIVE: In this study, we explored the computed tomography (CT) imaging features within pre-defined LFD groups to identify variables associated with previous LFD occurrences in severe asthma patients. METHODS: We obtained inspiratory and expiratory CT image of 102 severe asthma patients and derived two airway structural parameters (wall thickness [WT] and hydraulic diameter [Dh]) and two parenchymal variables (functional small airway disease [fSAD] and emphysema [Emph]). We retrospectively calculated the annual changes in forced expiratory volume in 1 second and grouped participants by their values determined. The four-imaging metrics, along with levels of several biomarkers were compared among LFD groups. RESULTS: Severe asthma patients with enhanced LFD exhibited significantly lower WT and smaller Dh compared to those with minimal change or slight decline in lung function, after an adjustment of smoking status. Conversely, CT-based percentages of Emph and fSAD did not significantly differ according to LFD. Furthermore, fractional exhaled nitric oxide (FeNO) level and the blood matrix metalloproteinase-9/TIMP metallopeptidase inhibitor 1 ratio were significantly higher in severe asthma patients with enhanced LFD compared to those in the others. CONCLUSION: Lower WT on CT scans with increased FeNO that may represent increased airway inflammation significantly correlated with enhanced LFD in severe asthma patients. Consequently, active management plans may help to attenuate LFD for severe asthma patients with lower WT and high FeNO.

Integration of cross-links, discrete fiber distributions and of a non-local theory in the Homogenized Constrained Mixture Model to Simulate Patient-Specific Thoracic Aortic Aneurysm Progression.

Thoracic aortic aneurysms (TAA) represent a critical health issue for which computational models can significantly contribute to better understand the physiopathology. Among different computational frameworks, the Homogenized Constrained Mixture Theory has shown to be a computationally efficient option, allowing the inclusion of several mechanically significant constituents into a layer-specific mixture. Different patient-specific Growth and Remodeling (G&R) models correctly predicted TAA progression, although simplifications such as the inclusion of a limited number of collagen fibers and imposed boundary conditions might limit extensive analyses. The current study aims to enhance existing models by incorporating several discrete collagen fibers and to remove restrictive boundary conditions of the previous models. The implementation of discretized fiber dispersion presents a more realistic description of the vessel, while the removal of boundary conditions was addressed by including cross-links in the model to provide a supplemental stiffness against through-thickness shearing, a feature that was previously absent, and by the development of a non-local framework that ensures the stable deposition and degradation of collagen fibers. With these improvements, the current model represents a step forward towards more robust and comprehensive simulations of TAA growth.

Intermittent hypoxia by obstructive sleep apnea is significantly associated with electro-anatomical remodeling of the left atrium preceding structural remodeling in patients with atrial fibrillation.

Background: Obstructive sleep apnea (OSA) is one of the risk factors for atrial fibrillation (AF). However, the mechanism underlying the atrial structural and electro-anatomical remodeling by OSA has not yet been clearly elucidated. Methods: This study was conducted in 83 patients who had undergone catheter ablation for AF (49 with OSA and 34 Controls without OSA). The left atrial (LA) maps were created in all the patients using a three-dimensional electro-anatomical mapping system. The LA with a bipolar voltage of <0.5 mV was defined as the low voltage area (LVA); %LVA was defined as the ratio of the LVA to the total surface area of the LA. Results: The LVA and %LVA were significantly greater in the OSA group as compared with the Control group, however, there was no difference in the LA area. The 3 % oxygen desaturation index (ODI) was significantly correlated with the %LVA (r = 0.268, P = 0.014), but not with the LA area. Multiple regression analysis with adjustments identified 3 %ODI ≥30 (3.088, 1.078-8.851, P = 0.036) as being significantly associated with the %LVA. Conclusions: In patients with AF complicated by OSA, significant increase of the LVA, but not of the LA area, was observed. The intermittent hypoxia severity was significantly associated with the LVA. These results suggest that intermittent hypoxia by OSA might be one of the mechanisms of electro-anatomical remodeling of the LA, possibly preceding structural remodeling represented by LA enlargement, in patients with AF.

Mesenchymal stem cells arouse myocardial NAD+ metabolism to alleviate microgravity-induced cardiac dysfunction.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

A proposal for analyzing the inflammatory and remodeling processes of mucosa in chronic rhinosinusitis with nasal polyposis through MRI.

OBJECTIVES: Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) is a disease characterized by chronic inflammation and tissue remodeling process. The remodeling process in nasal polyps has mainly been studied by histology analysis. However, it is limited to a polyp fragment and requires tissue removal. The present study aims to evaluate the ability of Magnetic Resonance Imaging (MRI) to depict and characterize the remodeling process in patients with CRSwNP. METHODS: 30 patients that met clinical diagnostic criteria for CRSwNP, without previous history of rhinosinusitis surgery were submitted to MRI scan (conventional, diffusion-weighted and DCE MRI) and compared with polyp tissue histological findings, IL-6 concentrations in the tissue and eosinophil count in the blood. The examinations were evaluated, independently, by two radiologists blinded to other radiological and histological data. The pathologist, blinded to MRI results, also compared the tissue sample from the most central and the most peripheral portion of the polypoid tissue adjacent to the floor of the nasal fossa. RESULTS: This study demonstrated a characteristic pattern of nasal polyps, whose peripheral portions of nasal polypoid tissue are edematous, whereas the central portions in the middle meatus and in the middle and upper ethmoid are predominantly fibrotic. ADC values found in the most anterior portion of the polyps may be a marker for radiological phenotyping the remodeling process. This non-invasive analysis presented a high degree of agreement in the fibrosis and edema rating by two radiologists and the histological analysis was concordant with the MRI findings. The polyps were characterized as eosinophilic, and no relationship was found between the severity of the eosinophilic inflammatory process or concentration of IL-6 and the remodeling process. CONCLUSION: MRI by using T2-weighted imaging sequence and ADCs values allows tissue characterization and is an effective tool for the differentiation of edematous and fibrotic components in CRSwNP.

Trajectory of Postpartum Cervical Remodeling in Women Delivering Full-Term and Spontaneous Preterm: Sensitivity to Quantitative Ultrasound Biomarkers.

OBJECTIVE: Women with a history of spontaneous preterm birth (sPTB) face an increased risk of recurrence. Yet, the factors contributing to the increased risk are unknown, hampering the development of targeted interventions. Noninvasive quantitative ultrasound (QUS) has been validated in the characterization of cervical tissue and has the potential to provide information about postpartum cervical remodeling. The objective of this study was to determine the postpartum cervical remodeling trajectories of women over 12 mo post-delivery and to determine whether there were differences between women who delivered full-term and spontaneous preterm that were sensitive to QUS biomarkers. METHODS: Data were collected prospectively from 55 women: 41 who delivered full-term and 14 who delivered spontaneously preterm at 6 wk, 3, 6, 9 and 12 mo (±2 wk) postpartum. Data from QUS biomarkers: Attenuation Coefficient; Backscatter Coefficient; Shear Wave Speed; and Lizzi-Feleppa Slope, Intercept and Midband were analyzed from the acquired radiofrequency data using a Siemens S2000 ultrasound system with a transvaginal MC 9-4 MHz probe. The biomarkers were analyzed using descriptive statistics and linear mixed-effects models. RESULTS: QUS biomarkers, Backscatter Coefficient and Lizzi-Feleppa Intercept showed significant differences during the year after delivery between women who had a full-term birth and sPTB (p < 0.05), suggesting that there are differences in the cervical remodeling trajectories between the two groups. All QUS biomarkers demonstrated significant variations between the full-term birth and sPTB groups over time (p < 0.05), indicating ongoing cervical remodeling for both groups during the 12-mo postpartum period. CONCLUSION: QUS biomarkers identified cervical microstructure differences and trajectories in the year after delivery between women who delivered full-term and spontaneous preterm.

Features of the regulation of reparative processes of chronic wounds in response to the effect of photobiomodulation therapy on a wound defect. Photobiomodulation therapy for chronic wounds.

BACKGROUND: One of the promising methods of influencing the wound process is photobiomodulation (PBM) therapy. The optimal parameters of PBM therapy have not yet been found because the molecular mechanisms of light interaction with tissue are not fully understood. OBJECTIVE: Studying the influence of PBM of various parameters on the regulation of reparative process- es of chronic wounds using the example of indicators of aggregation activity of platelets, platelet-derived growth factor (PDGF), interleukin-8 (IL-8), and amino-terminal propeptide of type III procollagen (PIIINP) at the remodeling stage. And also the study of the structural and functional features of chronic wound heal- ing in an experiment under various parameters of PBM therapy. METHODS: Experiments were carried out on Wistar rats. Chronic wounds were simulated. Experimental animals were exposed to PBM at a wavelength of 660 nm and an energy density of 1 J/cm2. In serum, PDGF, IL-8, and PIIINP levels were measured by enzyme-linked immunosorbent assay. The functional activity of platelets was measured using the turbidimetric method. Histological analysis was performed. RESULTS: The work noted the dose-dependent effect of PBM using the example of platelet aggregation at the remodeling stage during the healing of chronic wounds. The use of PBM therapy resulted in increased serum PDGF levels. Histological examination data indicate a positive effect of PBM therapy on the wound healing process. CONCLUSIONS: The effectiveness of the use of PBM therapy for the healing of chronic wounds to regulate reparative processes has been proven.

Tudor-SN exacerbates pathological vascular remodeling by promoting the polyubiquitination of PTEN via NEDD4-1.

BACKGROUND: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear. METHODS: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro. RESULTS: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice. CONCLUSIONS: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases.

Nominal and achieved stromal ablation depth after myopic transepithelial photorefractive keratectomy: implications for residual stromal thickness calculation.

BACKGROUND: The primary objective of this investigation was to compare the nominal central ablation depth with the achieved central corneal stromal ablation depth after StreamLight transepithelial photorefractive keratectomy (tPRK) for myopia with WaveLight® laser by Alcon Laboratories, TX, USA. METHODS: This ambispective study encompassed a retrospective analysis of 40 eyes who underwent treatment for myopia and astigmatism, followed by a prospective examination conducted 6-9 months postoperatively. Pre- and postoperative Avanti spectral-domain optical coherence tomography (SD-OCT; Optovue Inc., CA, USA) provided stromal and epithelial thickness maps. The difference between pre- and postoperative central stromal thicknesses at the corneal vertex was used to calculate the achieved stromal thickness ablation depth. This value was then compared with the corresponding central nominal depth on the laser ablation planning map. RESULTS: A total of 40 eyes (OD/OS:18/22) of 40 patients (31.4 ± 9.2 years) were available for evaluation. The mean treated spherical equivalent was - 2.98 ± 1.46 D. The mean nominal and achieved central stromal ablation depths were 51.22 µm and 59.67 µm, respectively, showing a mean stromal excessive ablation of 16.50%. The mean pre- and postoperative central epithelial thicknesses were 53.74 µm and 59.31 µm, respectively, showing a mean postoperative thickness increase of 10.46%. This increase in the epithelial thickness rendered the mean postoperative pachymetry reduction to 54.11 µm, only 2.33% greater than the mean nominal ablation depth. CONCLUSIONS: The study revealed a central stromal ablation 16.50% greater than the nominal ablation depth. This excessive stromal removal was largely compensated for by the increase in epithelial thickness, resulting in a mean difference between the nominal ablation depth and the achieved central corneal pachymetry reduction of only 2.33%. This significant excessive central stromal ablation must be taken into consideration in the calculation of the residual stromal thickness.

Gene therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Current limitations of pharmacological and ablative therapies motivate the development of novel therapies as next generation treatments for AF. The arrhythmia mechanisms creating and sustaining AF are key elements in the development of this novel treatment. Gene therapy provides a useful platform that allows us to regulate the mechanisms of interest using a suitable transgene(s), vector, and delivery method. Effective gene therapy strategies in the literature have targeted maladaptive electrical or structural remodeling that increase vulnerability to AF. In this review, we will summarize key elements of gene therapy for AF, including molecular targets, gene transfer vectors, atrial gene delivery and preclinical efficacy and toxicity testing. Recent advances and challenges in the field will be also discussed.

The Pathological Mechanisms and Therapeutic Molecular Targets in Arteriovenous Fistula Dysfunction.

The number of patients with end-stage renal disease (ESRD) requiring hemodialysis is increasing worldwide. Although arteriovenous fistula (AVF) is the best and most important vascular access (VA) for hemodialysis, its primary maturation failure rate is as high as 60%, which seriously endangers the prognosis of hemodialysis patients. After AVF establishment, the venous outflow tract undergoes hemodynamic changes, which are translated into intracellular signaling pathway cascades, resulting in an outward and inward remodeling of the vessel wall. Outward remodeling refers to the thickening of the vessel wall and the dilation of the lumen to accommodate the high blood flow in the AVF, while inward remodeling is mainly characterized by intimal hyperplasia. More and more studies have shown that the two types of remodeling are closely related in the occurrence and development of, and jointly determining the final fate of, AVF. Therefore, it is essential to investigate the underlying mechanisms involved in outward and inward remodeling for identifying the key targets in alleviating AVF dysfunction. In this review, we summarize the current clinical diagnosis, monitoring, and treatment techniques for AVF dysfunction and discuss the possible pathological mechanisms related to improper outward and inward remodeling in AVF dysfunction, as well as summarize the similarities and differences between the two remodeling types in molecular mechanisms. Finally, the representative therapeutic targets of potential clinical values are summarized.

Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein-Cannabinoid Type 1 Receptor Double Knockout Animals.

Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB1Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB1Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB1R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB1R gene. However, with the defect of the CB1R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB1R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB1R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB1Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB1R gene significantly attenuates vascular damage in hypercholesterolemic mice.

The role of body composition in left ventricular remodeling, reverse remodeling, and clinical outcomes for heart failure with mildly reduced ejection fraction: more knowledge to the "obesity paradox".

BACKGROUND: Although the "obesity paradox" is comprehensively elucidated in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the role of body composition in left ventricular (LV) remodeling, LV reverse remodeling (LVRR), and clinical outcomes is still unclear for HF with mildly reduced ejection fraction (HFmrEF). METHODS: Our study is a single-centre, prospective, and echocardiography-based study. Consecutive HFmrEF patients, defined as HF patients with a left ventricular ejection fraction (LVEF) between 40 and 49%, between January 2016 to December 2021 were included. Echocardiography was re-examined at 3-, 6-, and 12-month follow-up to assess the LVRR dynamically. Body mass index (BMI), fat mass, fat-free mass, percent body fat (PBF), CUN-BAE index, and lean mass index (LMI) were adopted as anthropometric parameters in our study to assess body composition. The primary outcome was LVRR, defined as: (1) a reduction higher than 10% in LV end-diastolic diameter index (LVEDDI), or a LVEDDI < 33 mm/m2, (2) an absolute increase of LVEF higher than 10 points compared with baseline echocardiogram, or a follow-up LVEF ≥50%. The secondary outcome was a composite of re-hospitalization for HF or cardiovascular death. RESULTS: A total of 240 HFmrEF patients were enrolled in our formal analysis. After 1-year follow-up based on echocardiography, 113 (47.1%) patients developed LVRR. Patients with LVRR had higher fat mass (21.7 kg vs. 19.3 kg, P = 0.034) and PBF (28.7% vs. 26.6%, P = 0.047) compared with those without. The negative correlation between anthropometric parameters and baseline LVEDDI was significant (all P < 0.05). HFmrEF patients with higher BMI, fat mass, PBF, CUN-BAE index, and LMI had more pronounced and persistent increase of LVEF and decline in LV mass index (LVMI). Univariable Cox regression analysis revealed that higher BMI (HR 1.042, 95% CI 1.002-1.083, P = 0.037) and fat mass (HR 1.019, 95% CI 1.002-1.036, P = 0.026) were each significantly associated with higher cumulative incidence of LVRR for HFmrEF patients, while this relationship vanished in the adjusted model. Mediation analysis indicated that the association between BMI and fat mass with LVRR was fully mediated by baseline LV dilation. Furthermore, higher fat mass (aHR 0.957, 95% CI 0.917-0.999, P = 0.049) and PBF (aHR 0.963, 95% CI 0.924-0.976, P = 0.043) was independently associated with lower risk of adverse clinical events. CONCLUSIONS: Body composition played an important role in the LVRR and clinical outcomes for HFmrEF. For HFmrEF patients, BMI and fat mass was positively associated with the cumulative incidence of LVRR, while higher fat mass and PBF predicted lower risk of adverse clinical events but not LMI.