Remodeling Changes Research Articles

A multi-stack registration technique to improve measurement accuracy and precision across longitudinal HR-pQCT scans.

Recent applications of high-resolution peripheral quantitative computed tomography (HR-pQCT) have demonstrated that changes in local bone remodelling can be quantified in vivo using longitudinal three-dimensional image registration. However, certain emerging applications, such as fracture healing and joint analysis, require larger multi-stack scan regions that can result in stack shift image artifacts. These artifacts can be detrimental to the accurate alignment of the bone structure across multiple timepoints. The purpose of this study was to establish a multi-stack registration protocol for evaluating longitudinal HR-pQCT images and to assess the accuracy and precision error in comparison with measures obtained using previously established three-dimensional longitudinal registration. Three same day multi-stack HR-pQCT scans of the radius (2 stacks in length) and tibia (3 stacks in length) were obtained from 39 healthy individuals who participated in a previous reproducibility study. A fully automated multi-stack registration algorithm was developed to re-align stacks within a scan by leveraging slight offsets between longitudinal scans. Stack shift severity before and after registration was quantified using a newly proposed stack-shift severity score. The false discovery rate for bone remodelling events and precision error of bone morphology and micro-finite element analysis parameters were compared between longitudinally registered scans with and without the addition of multi-stack registration. Most scans (82%) improved in stack alignment or maintained the lowest stack shift severity score when multi-stack registration was implemented. The false discovery rate of bone remodelling events significantly decreased after multi-stack registration, resulting in median false detection of bone formation and resorption fractions between 3.2 to 7.5% at the radius and 3.4 to 5.3% at the tibia. Further, precision error was significantly reduced or remained unchanged in all standard bone morphology and micro-finite element analysis parameters, except for total and trabecular cross-sectional areas. Multi-stack registration is an effective strategy for accurately aligning multi-stack HR-pQCT scans without modification of the image acquisition protocol. The algorithm presented here is a viable approach for performing accurate morphological analysis on multi-stack HR-pQCT scans, particularly for advanced application investigating local bone remodelling in vivo.

A female Bullmastiff with calvarial hyperostosis syndrome and concurrent hyperostotic changes affecting the mandible and cervical vertebrae

AbstractAn immature female Bullmastiff presented for assessment of swelling of the right dorsal orbital region, causing discomfort. Computed tomography showed osseous proliferation of the calvarium, frontal bone and concurrent unilateral osseous changes at the level of the left mandible. Ventral new bone formation and remodelling changes were noted between vertebrae C7 and T1. The vertebral bodies of C5, C6 and C7 were fused. Histopathology was consistent with calvarial hyperostosis syndrome. Subsequently, the dog developed neurological signs: proprioceptive ataxia and lower motor neuron ambulatory tetraparesis. Magnetic resonance imaging showed mild osseous spinal cord compression at C7 level. Calvarial hyperostosis syndrome described in this report is the first recorded case of a dog having concurrent hyperostotic changes affecting the calvarium, mandible and cervical vertebrae in a dog.

Application and underlying mechanism of acupuncture for the nerve repair after peripheral nerve injury: remodeling of nerve system.

Peripheral nerve injury (PNI) is a structural event with harmful consequences worldwide. Due to the limited intrinsic regenerative capacity of the peripheral nerve in adults, neural restoration after PNI is difficult. Neurological remodeling has a crucial effect on the repair of the form and function during the regeneration of the peripheral nerve after the peripheral nerve is injured. Several studies have demonstrated that acupuncture is effective for PNI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve the nervous system remodeling in the process of nerve repair. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating related neurotrophins retrograde transport, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), N-cadherin, and MicroRNAs. Peripheral nerve injury enhances the perceptual response of the central nervous system to pain, causing central sensitization and accelerating neuronal cell apoptosis. Together with this, the remodeling of synaptic transmission function would worsen pain discomfort. Neuroimaging studies have shown remodeling changes in both gray and white matter after peripheral nerve injury. Acupuncture not only reverses the poor remodeling of the nervous system but also stimulates the release of neurotrophic substances such as nerve growth factors in the nervous system to ameliorate pain and promote the regeneration and repair of nerve fibers. In conclusion, the neurological remodeling at the peripheral and central levels in the process of acupuncture treatment accelerates nerve regeneration and repair. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of PNI.

Mechanisms and therapeutic strategies to combat the recurrence and progression of hepatocellular carcinoma after thermal ablation

Thermal ablation (TA), including radiofrequency ablation (RFA) and microwave ablation (MWA), has become the main treatment for early-stage hepatocellular carcinoma (HCC) due to advantages such as safety and minimal invasiveness. However, HCC is prone to local recurrence, with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition (EMT) and remodeling of the tumor microenvironment (TME). According to many studies, various components of the TME undergo complex changes after TA, such as the recruitment of innate and adaptive immune cells, the release of tumor-associated antigens (TAAs) and various cytokines, the formation of a hypoxic microenvironment, and tumor angiogenesis. Changes in the TME after TA can partly enhance the anti-tumor immune response; however, this response is weak to kill the tumor completely. Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions, leading to tumor recurrence and progression. How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear. Thus, in this review, we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.

Comparative assessment of echocardiographic parameters in persons without diagnosed chronic non-communicable diseases depending on body mass index

Aim: To compare the indicators of structural remodeling and intracardiac hemodynamics in people without previously diagnosed chronic non-communicable diseases, depending on body mass index (BMI).Material and Methods. We analyzed the data of 123 people aged 21 to 59 years who did not have chronic non-infectious diseases and did not take any drug therapy that affects the indicators of central and peripheral hemodynamics, as well as lipid, carbohydrate and fat metabolism. All the examined persons were divided depending on the BMI into 2 groups, comparable in sex, but with age differences. The first group consisted of 60 people (75% women) with a BMI < 30 kg/m2, whose median age was 40 years (Q1–Q3: 35–48 years). The second group included 63 subjects (76.1% women) with BMI ≥ 30 kg/m2 at the age of 48.5 years (Q1–Q3: 38–54 years). Structural and functional parameters of the heart were assessed during transthoracic echocardiography, which was performed on the Philips EPIQ CVx 2D ultrasound machine by one specialist.Results. In the group of persons with increased BMI, the average values of the left ventricular relative wall thickness (RWT LV) were higher – 0.37 [0.34; 0.40] versus 0.41 [0.37; 0.47], p = 0.01; left ventricular mass index (LVMI) – 64.0 [53.0; 76.5] g/m2 and 27.0 [23.1; 30.9] g/m2,7 vs. 82.0 [70.0; 92.0] g/m2 and 38.1 [34.5; 46.5] g/m2,7, p = 0.01; epicardial fat (EF) – 5 [4; 6] mm vs. 8 [5; 10] mm, p = 0.01, left ventricular global longitudinal strain (LV GLS) –21.8 [–23.6…–19.7]% vs. –19.2 [–21.2…–18.2] %, p = 0.01. Statistically direct correlations of BMI with LVMI g/m2,7 (ρ = 0.746; p = 0.01), EF (ρ = 0.563; p = 0.01), LV GLS (ρ = 0.418; p = 0 .01), RWT (ρ = 0.438; p = 0.01). With an increase in BMI by 1 kg/m2, one should expect an increase in the thickness of EF by 0.172 mm, longitudinal deformation of the LV by 0.151%, RWT by 0.003, LVMI, g/m2 by 1.200, LVMI g/m2,7 by 1.116.Conclusion. The increase in BMI is associated with changes in structural remodeling and systolic function of the LV. In individuals with increased BMI, to determine structural remodeling and changes in the geometry of the heart chambers, it is necessary to use growth indexing, to determine indicators of GLS LV, to determine the thickness of EF in order to detect intracardiac hemodynamic disorders in the early stages and timely prevention of complications.

Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release

Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.

NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.

E-cadherin adhesion dynamics as revealed by an accelerated force ramp are dependent upon the presence of α-catenin

Tissue remodeling and shape changes often rely on force-induced cell rearrangements occurring via cell-cell contact dynamics. Epithelial cell-cell contact shape changes are particularly dependent upon E-cadherin adhesion dynamics which are directly influenced by cell-generated and external forces. While both the mobility of E-cadherin adhesions and their adhesion strength have been reported before, it is not clear how these two aspects of E-cadherin adhesion dynamics are related. Here, using magnetic pulling cytometry, we applied an accelerated force ramp on the E-cadherin adhesion between an E-cadherin-coated magnetic microbead and an epithelial cell to ascertain this relationship. Our approach enables the determination of the adhesion strength and force-dependent mobility of individual adhesions, which revealed a direct correlation between these key characteristics. Since α-catenin has previously been reported to play a role in both E-cadherin mobility and adhesion strength when studied independently, we also probed epithelial cells in which α-catenin has been knocked out. We found that, in the absence of α-catenin, E-cadherin adhesions not only had lower adhesion strength, as expected, but were also more mobile. We observed that α-catenin was required for the recovery of strained cell-cell contacts and propose that the adhesion strength and force-dependent mobility of E-cadherin adhesions act in tandem to regulate cell-cell contact homeostasis. Our approach introduces a method which relates the force-dependent adhesion mobility to adhesion strength and highlights the morphological role played by α-catenin in E-cadherin adhesion dynamics.

Sensitivity Analysis of CMAP Scan Step Index to Different Stimulation Parameters and Examination of Muscles Affected by Spinal Cord Injury.

Step index (STEPIX) is a recently developed compound muscle action potential (CMAP) scan method for evaluating motor unit loss and remodeling changes. This study investigates the influence of different stimulation parameters during CMAP scan on STEPIX and its examination of muscles affected by spinal cord injury (SCI). CMAP scan of the first dorsal interosseous (FDI) muscle was performed using different stimulus pulse widths (0.1 ms, 0.2 ms) and different numbers of stimuli (500, 1000) in 12 neurologically intact subjects. STEPIX was derived from each CMAP scan of all subjects. A significantly higher STEPIX was obtained using 1000 stimuli than 500 stimuli, while no significant difference in STEPIX was observed using 0.1 and 0.2 ms stimulus pulse widths. STEPIX was further applied to process CMAP scans of the FDI muscle from 13 tetraplegia and 13 healthy control subjects using the same stimulation parameter setting (0.1 ms, 500 stimuli), along with other methods including MScanFit motor unit number estimation (MUNE) and D50. STEPIX was significantly lower for the SCI subjects compared with the healthy control subjects. STEPIX was significantly correlated with MscanFit MUNE and D50, but had a smaller relative width of the overlapping zone (WOZ%) between tetraplegic and healthy control groups compared with MScanFit MUNE and D50. The findings of the study highlight the importance of maintaining a consistent stimulation parameter setting in CMAP scan studies and confirm the usefulness of STEPIX as a convenient CMAP scan parameter for examination of motor unit number changes.

Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity.

Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis, including zygotic genome activation (ZGA) during maternal-to-zygotic transition, influence such remodeling remains unknown. Here, we have investigated the establishment of nuclear architecture, focusing on the remodeling of lamina-associated domains (LADs) during this transition. We report that LADs reorganize gradually in two-cell embryos and that blocking ZGA leads to major changes in nuclear organization, including altered chromatin and genomic features of LADs and redistribution of H3K4me3 toward the nuclear lamina. Our data indicate that the rearrangement of LADs is an integral component of the maternal-to-zygotic transition and that transcription contributes to shaping nuclear organization at the beginning of mammalian development.

Cardiovascular Insights for the Appropriate Management of Chronic Venous Disease: A Narrative Review of Implications for the Use of Venoactive Drugs.

Evidence suggests that chronic venous disease (CVD) may be a cardiovascular disorder, as patients with CVD are prone to developing arterial (atherosclerosis) and venous (thromboembolism) diseases. This may be partly explained by shared risk factors. Thus, patients with CVD or cardiovascular disease require careful history-taking and physical assessment to identify coexisting pathologies and risk factors. This article summarises a symposium at the XIX World Congress of the International Union of Phlebology held in Istanbul, Turkey, in September 2022. Common pathophysiological features of CVD and cardiovascular disease are endothelial injury, hypercoagulability and systemic inflammation. In CVD, inflammation primarily affects the microcirculation, with changes in capillary permeability, vein wall and valve remodelling and increase in oxidative stress. Once patients develop symptoms/signs of CVD, they tend to reduce their physical activity, which may contribute to increased risk of cardiovascular disease. Data show that the presence of CVD is associated with an increased risk of cardiovascular disease, including peripheral arterial disease and heart failure (HF), and the risk of adverse cardiovascular events increases with CVD severity. In addition, patients with cardiovascular disease, particularly those with HF, are at increased risk of venous thromboembolism (VTE) and should be assessed for VTE risk if they are hospitalised with cardiovascular disease. Therefore, CVD management must include a multi-specialty approach to assess risk factors associated with both the venous and arterial systems. Ideally, treatment should focus on the resolution of endothelial inflammation to control both CVD and cardiovascular disease. International guidelines recommend various conservative treatments, including venoactive drugs (VADs), to improve the symptoms/signs of CVD. Micronized purified flavonoid fraction (MPFF) is a VAD, with high-quality evidence supporting its use in relieving symptoms/signs of CVD and improving quality of life. Moreover, in large-scale observational studies, MPFF has shown superior effectiveness in real-world populations compared with other VADs. Video Abstract. (MP4 97173 kb).

Appreciating the links between heart failure and depression.

Depression and heart failure frequently occur together, symptoms overlap and the prognosis is worsened. Both conditions share biopsychosocial risk factors and are accompanied by behavioural/lifestyle, neurohormonal, inflammatory and autonomic changes that are implicated aetiologically. Depression has been conceptualized as a decompensated response to allostatic overload, wherein adaptive psychological, behavioural and physiological responses to chronic and/or severe stress, become unsustainable. Heart failure can similarly be viewed as a decompensated response to circulatory overload, wherein adaptive functional (neurohormonal effects on circulation, inotropic effects on heart) and structural (myocardial remodelling) changes, become unsustainable. It has been argued that the disengaged state of depression can initially be protective, limiting an individual's exposure to external challenges, such that full recovery is often possible. In contrast, heart failure, once past a tipping-point, can progress relentlessly. Here, we consider the bidirectional interactions between depression and heart failure. Targeted treatment of depression in the context of heart failure may improve quality of life, yet overall benefits on mortality remain elusive. However, effective treatment of heart failure typically enhances function and improves key psychological and behavioural determinants of low mood. Prospectively, research that examines the mechanistic associations between depression and heart failure offers fresh opportunity to optimize personalized management in the advent of newer interventions for both conditions.

Omega-3 Fatty Acids as Antiarrhythmic Drugs: Upstream Target Modulators Affecting Acute and Long-Term Pathological Alterations in Cardiac Structure and Function.

Postoperative atrial fibrillation (POAF) is a common complication in the acute care period following coronary artery bypass grafting (CABG) surgery that is associated with significant morbidity and mortality in both short-term and long-term settings. Recently, the Vaughn Williams Classification of antiarrhythmic agents, first proposed in 1975 and widely viewed as the authoritative description of their electrophysiologic actions, was updated and notably omega-3 fatty acids (Ω-3 fatty acids) have been included in class VII, described as "upstream target modulators," to mitigate pathological structural and electrophysiological remodeling changes in the aged and/or injured myocardium. A PubMed literature search was performed. Studies examining the significance of complications in patients undergoing isolated CABG surgery were selected for inclusion. Relevant data were qualitatively assessed and narratively summarized. POAF occurs in approximately 30% of patients, and inflammation from chronic coronary artery disease preoperatively, as well as acute atrial inflammation from surgery postoperatively are the leading causes. Inflammation underlies its pathophysiology; therefore Ω-3 fatty acids not only exhibit antiarrhythmic properties but are an effective anti-inflammatory treatment that may reduce the clinical risks of POAF. At present no effective prophylaxis is available to address POAF following CABG surgery. Clinical approaches that focus on the inflammatory response in this setting may optimize the response to treatment. The current literature supports the hypothesis that Ω-3 fatty acids may acutely reduce the inflammatory response via favorable alterations in the metabolism of prostaglandins and leukotrienes (eicosanoids) and specialized pro-resolving mediators.

Live-bearing cockroach genome reveals convergent evolutionary mechanisms linked to viviparity in insects and beyond

Live birth (viviparity) has arisen repeatedly and independently among animals. We sequenced the genome and transcriptome of the viviparous Pacific beetle-mimic cockroach and performed comparative analyses with two other viviparous insect lineages, tsetse flies and aphids, to unravel the basis underlying the transition to viviparity in insects. We identified pathways undergoing adaptive evolution for insects, involved in urogenital remodeling, tracheal system, heart development, and nutrient metabolism. Transcriptomic analysis of cockroach and tsetse flies revealed that uterine remodeling and nutrient production are increased and the immune response is altered during pregnancy, facilitating structural and physiological changes to accommodate and nourish the progeny. These patterns of convergent evolution of viviparity among insects, together with similar adaptive mechanisms identified among vertebrates, highlight that the transition to viviparity requires changes in urogenital remodeling, enhanced tracheal and heart development (corresponding to angiogenesis in vertebrates), altered nutrient metabolism, and shifted immunity in animal systems.

Vascular phenotyping of the invasive front in breast cancer using a 3D angiogenesis atlas.

Vascular remodeling at the invasive tumor front (ITF) plays a critical role in progression and metastasis of triple negative breast cancer (TNBC). Therefore, there is a crucial need to characterize the vascular phenotype (i.e. changes in the structure and function of vasculature) of the ITF and tumor core (TC) in TNBC. This requires high-resolution, 3D structural and functional microvascular data that spans the ITF and TC (i.e. ∼4-5mm from the tumor's edge). Since such data are often challenging to obtain with most conventional imaging approaches, we employed a unique "3D whole-tumor angiogenesis atlas" derived from orthotopic xenografts to characterize the vascular phenotype of the ITF and TC in TNBC. First, high-resolution (8μm) computed tomography (CT) images of "whole-tumor" microvasculature were acquired from eight orthotopic TNBC xenografts, of which three tumors were excised at post-inoculation day 21 (i.e. early-stage) and five tumors were excised at post-inoculation day 35 (i.e. advanced-stage). These 3D morphological CT data were combined with soft tissue contrast from MRI as well as functional data generated in silico using image-based hemodynamic modeling to generate a multi-layered "angiogenesis atlas". Employing this atlas, blood vessels were first spatially stratified within the ITF (i.e. ≤1mm from the tumor's edge) and TC (i.e. >1mm from the tumor's edge) of each tumor xenograft. Then, a novel method was developed to visualize and characterize microvascular remodeling and perfusion changes in terms of distance from the tumor's edge. The angiogenesis atlas enabled the 3D visualization of changes in tumor vessel growth patterns, morphology and perfusion within the ITF and TC. Early and advanced stage tumors demonstrated significant differences in terms of their edge-to-center distributions for vascular surface area density, vascular length density, intervessel distance and simulated perfusion density (p≪0.01). Elevated vascular length density, vascular surface area density and perfusion density along the circumference of the ITF was suggestive of a preferential spatial pattern of angiogenic growth in this tumor cohort. Finally, we demonstrated the feasibility of differentiating the vascular phenotypes of ITF and TC in these TNBC xenografts. The combination of a 3D angiogenesis atlas and image-based hemodynamic modeling heralds a new approach for characterizing the role of vascular remodeling in cancer and other diseases.

A 3-D Visualization Technique for Bone Remodeling in a Suture Expansion Mouse Model.

Craniofacial sutures play a crucial role beyond being fibrous joints connecting craniofacial bones; they also serve as the primary niche for calvarial and facial bone growth, housing mesenchymal stem cells and osteoprogenitors. As most craniofacial bones develop through intramembranous ossification, the sutures' marginal regions act as initiation points. Due to this significance, these sutures have become intriguing targets in orthopedic therapies like spring-assisted cranial vault expansion, rapid maxillary expansion, and maxillary protraction. Under orthopedic tracing force, suture stem cells are rapidly activated, becoming a dynamic source for bone remodeling during expansion. Despite their importance, the physiological changes during bone remodeling periods remain poorly understood. Traditional sectioning methods, primarily in the sagittal direction, do not capture the comprehensive changes occurring throughout the entire suture. This study established a standard mouse model for sagittal suture expansion. To fully visualize bone remodeling changes post-suture expansion, the PEGASOS tissue clearing method was combined with whole-mount EdU staining and calcium chelating double labeling. This allowed the visualization of highly proliferating cells and new bone formation across the entire calvarial bones following expansion. This protocol offers a standardized suture expansion mouse model and a 3-D visualization method, shedding light on the mechanobiological changes in sutures and bone remodeling under tensile force loading.

Obesity dominates early effects on cardiac structure and arterial stiffness in people with type 2 diabetes.

Type 2 diabetes (T2D) and obesity are global epidemics leading to excess cardiovascular disease (CVD). This study investigates standard and novel cardiac MRI parameters to detect subclinical cardiac and central vascular dysfunction in inactive people with and without T2D. Physically inactive age and BMI-similar premenopausal women and men with ( n = 22) and without [ n = 34, controls with overweight/obesity (CWO)] uncomplicated T2D were compared to an age-similar and sex-similar reference control cohort ( n = 20). Left ventricular (LV) structure, function, and aortic stiffness were assessed by MRI. Global arterial pulse wave velocity (PWV) was assessed using carotid-to-femoral applanation tonometry. Regional PWV was measured via 2D phase-contrast MRI and 4D flow MRI. Global arterial PWV did not differ between CWO and T2D. 2D PC-MRI PWV in the ascending aorta was higher in people with T2D compared with CWOs ( P < 0.01). 4D flow PWV in the thoracic aorta was higher in CWO ( P < 0.01), and T2D ( P < 0.001) compared with RC. End-diastolic volume, end-systolic volume, stroke volume, and cardiac output were lower in CWO and T2D groups compared with reference control. Subclinical changes in arterial stiffening and cardiac remodeling in inactive CWO and T2D compared with reference control support obesity and/or physical inactivity as determinants of incipient CVD complications in uncomplicated T2D. Future studies should determine the mechanistic causes of the CVD complications in greater detail in order to create therapeutic targets. Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (NCT03419195).

Long-term changes in heart rate and electrical remodeling contribute to alternans formation in heart failure: a patient-specific in silico study.

Individuals with chronic heart failure (CHF) have an increased risk of ventricular arrhythmias, which has been linked to pathological cellular remodeling and may also be mediated by changes in heart rate. Heart rate typically fluctuates on a timescale ranging from seconds to hours, termed heart rate variability (HRV). This variability is reduced in CHF, and this HRV reduction is associated with a greater risk for arrhythmias. Furthermore, variations in heart rate influence the formation of proarrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD), or intracellular calcium (Ca). In this study, we investigate how long-term changes in heart rate and electrical remodeling associated with CHF influence alternans formation. We measure key statistical properties of the RR-interval sequences from ECGs of individuals with normal sinus rhythm (NSR) and CHF. Patient-specific RR-interval sequences and synthetic sequences (randomly generated to mimicking these statistical properties) are used as the pacing protocol for a discrete time-coupled map model that governs APD and intracellular Ca handling of a single cardiac myocyte, modified to account for pathological electrical remodeling in CHF. Patient-specific simulations show that beat-to-beat differences in APD vary temporally in both populations, with alternans formation more prevalent in CHF. Parameter studies using synthetic sequences demonstrate that increasing the autocorrelation time or mean RR-interval reduces APD alternations, whereas increasing the RR-interval standard deviation leads to higher alternans magnitudes. Importantly, we find that although both the CHF-associated changes in heart rate and electrical remodeling influence alternans formation, variations in heart rate may be more influential.NEW & NOTEWORTHY Using patient-specific data, we show that both the changes in heart rate and electrical remodeling associated with chronic heart failure influence the formation of proarrhythmic alternans in the heart.

Leukemic Transformation of Longstanding Essential Thrombocythemia

Acute Myeloid Leukemia (AML) represents only 1% of all cancers, despite being the most frequent type of leukemia [1]. Multiple genetic pathways are associated with AML, causing various changes in genetic transcription, apoptosis, chromatin remodeling, and protein levels. One such pathway, the JAK-STAT pathway, governs cellular proliferation, differentiation, and apoptosis, and is linked to both AML and myeloproliferative neoplasms due to mutations [2]. The JAK V617F mutation is the most common mutation in this pathway, occurring in about 50% of Essential Thrombocythemia (ET) patients, as described in this report [2]. While rare, transformation of Essential Thrombocythemia (ET) to AML occurs in 1-4% of cases [3]. This report presents a case of AML in a 76-year-old male with a medical history of ET. Following an abnormal peripheral blood smear, bone marrow biopsy confirmed the diagnosis. The current report aims to emphasize the significance of regular screening and monitoring for patients with long-standing Essential Thrombocythemia (ET), especially those under suppressive therapy. The transformation of ET to acute leukemia is associated with an unfavorable prognosis, underscoring the importance of early diagnosis. Therefore, this case serves to draw attention to the criticality of timely intervention through routine follow-up to achieve optimal outcomes for patients with ET.

Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.

Mitochondrion, known as the "powerhouse" of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K+ and Ca2+, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes.