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During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. We sought to elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb after treatment with serum or the α-adrenergic agonist phenylephrine. Depletion of Bmal1 decreased the expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by micrococcal nuclease-quantitative PCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting natriuretic peptide B transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented phenylephrine-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

The heart, which is the first organ to develop, is highly dependent on its form to function1,2. However, how diverse cardiac cell types spatially coordinate to create the complex morphological structures that are crucial for heart function remains unclear. Here we integrated single-cell RNA-sequencing with high-resolution multiplexed error-robust fluorescence in situ hybridization to resolve the identity of the cardiac cell types that develop the human heart. This approach also provided a spatial mapping of individual cells that enables illumination of their organization into cellular communities that form distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, which support their specialization according to the cellular ecosystem and anatomical region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities using in vivo conditional genetic mouse models and in vitro human pluripotent stem cell systems revealed multicellular signalling pathways that orchestrate the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. These detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodelling the human heart offer new insights into structural heart diseases and the engineering of complex multicellular tissues for human heart repair.

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating avatars (herein defined as an extension of digital twins) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1 apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to apo SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is the most common type of myocardial dysfunction, affecting mostly young adults, but its therapeutic diagnosis and biomarkers for prognosis are lacking. This study aimed to investigate the possible effect of the common food additive monosodium glutamate (MSG) and tannic acid (TA), a phenolic compound, on the key molecular actors responsible for DCM. DCM‐related publicly available microarray datasets (GSE120895, GSE17800, and GSE19303) were downloaded from the comprehensive Gene Expression Omnibus (GEO) database, and analyzed to identify differentially expressed genes (DEGs). By integrating DEGs and gene‐disease validity curation results, overlapping genes were screened and identified as hub genes. Protein‐protein interaction (PPI) network and ontology analysis were performed to make sense of the identified biological data. Finally, mRNA expression changes of identified hub genes in the heart tissues of rats treated with MSG and TA were measured by the qPCR method. Six upregulated (IGF1, TTN, ACTB, LMNA, EDN1, and NPPB) DEGs were identified between the DCM and healthy control samples as the hub genes. qPCR results revealed that the mRNA levels of these genes involved in DCM development increased significantly in rat heart tissues exposed to MSG. In contrast, this increase was remarkably alleviated by TA treatment. Our results provide new insights into critical molecular mechanisms that should be focused on in future DCM studies. Moreover, MSG may play a critical role in DCM formation, and TA may be used as a promising therapeutic agent in DCM. [ABSTRACT FROM AUTHOR]

Machine perfused ex-vivo organs offer an excellent experimental platform, e.g., for studying organ physiology and for conducting pre-clinical trials for drug delivery. One main challenge in machine perfusion is the accurate assessment of organ condition. Assessment is often performed using viability markers, i.e., lactate concentrations and blood gas analysis. Nonetheless, existing markers for condition assessment can be inconclusive, and novel assessment methods remain of interest. Over the last decades, several imaging modalities have given unique insights into the assessment of organ condition. A systematic review was conducted according to accepted guidelines to evaluate these medical imaging methods, focussed on literature that use machine perfused human-sized organs, that determine organ condition with medical imaging. A total of 18 out of 1,465 studies were included that reported organ condition results in perfused hearts, kidneys, and livers, using both conventional viability markers and medical imaging. Laser speckle imaging, ultrasound, computed tomography, and magnetic resonance imaging were used to identify local ischemic regions and quantify intraorgan perfusion. A detailed investigation of metabolic activity was achieved using 31P magnetic resonance imaging and near-infrared spectroscopy. The current review shows that medical imaging is a powerful tool to assess organ condition. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Hypertension is a chronic disease with high morbidity and mortality. Previously, we screened a walnut meal peptide FDWLR (PEP) with significant angiotensin‐converting enzyme inhibitory activity. The present study further investigated the anti‐hypertensive effects of PEP in vivo using spontaneously hypertensive rats.The results indicated that PEP reduced blood pressure and the indices in the renin–angiotensin–aldosterone system (RAAS) including angiotensin‐converting enzyme (ACE) (decreased by 15.36%), angiotensin II (Ang II) (decreased by 31.56%), angiotensinogen (AGT) (decreased by 58.84%) and aldosterone (ALD) (decreased by 18.27%), whereas NO levels increased by 54.96%. The pathological analysis showed that PEP relieved cardiac and renal damage. PEP also alleviated oxidative stress, inflammation and fibrosis in the heart and kidney. Mechanistically, PEP mitigated cardiac and renal damage by simultaneously regulating ACE‐Ang II‐AT1R and the ACE2‐Ang (1–7)‐MAS axis. Additionally, PEP increased the levels of short chain fatty acids by 224.16% and improved gut microbiota by increasing the abundance of Prevotella, Phascolarctobacterium, Clostridium_sensu_stricto and Bifidobacterium, at the same time as decreasing Bacteroides and Alistipes abundances.This study indicated that PEP prevented hypertension and associated heart and kidney damage by modulating the RAAS system and gut microbiota, which is valuable in guiding future development and optimal utilization of walnut meal. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Summary Patients with AL amyloidosis can have persistent organ dysfunction despite achieving a haematological complete response (hemCR). We aimed to identify factors for organ non‐response among 143 patients who achieved hemCR for ≥6 months. Kidney, heart and liver non‐response were observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) patients respectively. Predisposing factors varied by organ system. Kidney non‐responders had more advanced organ dysfunction at diagnosis, whereas heart non‐responders had disproportionately more lambda‐typic amyloidogenic light chains. Most patients without an apparent reason for organ non‐response had detectable residual clonal disease. The interplay of factors impeding organ recovery in AL amyloidosis is complex. [ABSTRACT FROM AUTHOR]

In The Culmination, Robert Pippin offers a stunning reassessment of the achievements of absolute idealism. Having developed some of the most persuasive defenses of Hegel's absolute idealism to date, Pippin now argues that Heidegger's trenchant critique of Hegel has revealed a dogmatism at the very heart of absolute idealism: an unwarranted identification of what is with what is discursively knowable. This dogmatic identification leads to a distorted understanding of the meaning of Being, a reifying account of beings, and a neglect of our own finitude. In this article, I defend Hegel against these charges. The upshot of this discussion is twofold. Rather than evading the question of the exteriority of being, I argue, Hegel in fact aims to reveal that this exteriority is internal to thinking itself. And rather than identifying the meaning of being with discursive knowability, Hegel shows that the meaning of being resides in a form of freedom that goes beyond the self‐transparency of knowing. [ABSTRACT FROM AUTHOR]

Background: The incidence and mortality rates of cardiovascular disease worldwide are a major concern in the healthcare industry. Precise prediction of cardiovascular disease is essential, and the use of machine learning and deep learning can aid in decision-making and enhance predictive abilities. Objective: The goal of this paper is to introduce a model for precise cardiovascular disease prediction by combining machine learning and deep learning. Method: Two public heart disease classification datasets with 70,000 and 1190 records besides a locally collected dataset with 600 records were used in our experiments. Then, a model which makes use of both machine learning and deep learning was proposed in this paper. The proposed model employed CNN and LSTM, as the representatives of deep learning models, besides KNN and XGB, as the representatives of machine learning models. As each classifier defined the output classes, majority voting was then used as an ensemble learner to predict the final output class. Result: The proposed model obtained the highest classification performance based on all evaluation metrics on all datasets, demonstrating its suitability and reliability in forecasting the probability of cardiovascular disease. [ABSTRACT FROM AUTHOR]

This paper presents an inverse problem of identifying two ionic parameters of a nonlocal reaction-diffusion system in cardiac electrophysiology modelling. We used a nonlocal FitzHugh-Nagumo monodomain model which describes the electrical activity in cardiac tissue with the diffusion rate assumed to depend on the total electrical potential in the heart. We established at first, the global Carleman estimate adapted to nonlocal diffusion to obtain our main result which is the uniqueness and the Lipschitz stability estimate for two ionic parameters (k , γ) . [ABSTRACT FROM AUTHOR]

Objective: To analyze the influencing factors of postoperative thrombocytopenia in critically ill patients with heart disease and construct a nomogram prediction model. Methods: From October 2022 to October 2023, 319 critically ill patients with heart disease who visited our hospital were collected and separated into postoperative thrombocytopenia group (n = 142) and no postoperative thrombocytopenia group (n = 177) based on their postoperative thrombocytopenia, Logistic regression analysis was applied to screen risk factors for postoperative thrombocytopenia in critically ill patients with heart disease; R software was applied to construct a nomogram for predicting postoperative thrombocytopenia in critically ill patients with heart disease, and ROC curves, calibration curves, and Hosmer-Lemeshow goodness of fit tests were applied to evaluate nomogram. Results: A total of 142 out of 319 critically ill patients had postoperative thrombocytopenia, accounting for 44.51%. Logistic regression analysis showed that gender (95% CI 1.607–4.402, P = 0.000), age ≥ 60 years (95% CI 1.380–3.697, P = 0.001), preoperative antiplatelet therapy (95% CI 1.254–3.420, P = 0.004), and extracorporeal circulation time > 120 min (95% CI 1.681–4.652, P = 0.000) were independent risk factors for postoperative thrombocytopenia in critically ill patients with heart disease. The area under the ROC curve was 0.719 (95% CI: 0.663–0.774). The slope of the calibration curve was close to 1, and the Hosmer-Lemeshow goodness of fit test was χ2 = 6.422, P = 0.491. Conclusion: Postoperative thrombocytopenia in critically ill patients with heart disease is influenced by gender, age ≥ 60 years, preoperative antiplatelet therapy, and extracorporeal circulation time > 120 min. A nomogram established based on above multiple independent risk factors provides a method for clinical prediction of the risk of postoperative thrombocytopenia in critically ill patients with heart disease. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary artery hypertension (PAH) poses a significant challenge due to its limited therapeutic options and high mortality rates. The ACE2-Ang- (1-7)-Mas axis plays a pivotal role in regulating blood pressure and inhibiting myocardial remodeling. However, the precise mechanistic links between the ACE2-Ang-(1-7)-Mas axis and PAH remain poorly understood. This study aimed to elucidate the involvement of the ACE2-Ang-(1-7)-Mas axis in the development of PAH. Methods: PAH was induced in mice using Sugen5416/hypoxia, PAAT/PET ratio and PA were detected using cardiac ultrasound; inflammation related factors such as MCP-1, TNF, IL-10and IL-12p70 were detected in intestines using cytometric bead array (CBA) kits; histopathological and morphological changes in lung and intestinal tissues were assessed via HE staining and Masson staining to evaluate the progression of PAH. Immunohistochemistry and western blotting were employed to determine the expression levels of two tight junction proteins, occludin and ZO-1, in intestinal tissues. Additionally, 16SrRNA sequencing and non-targeted metabolomics by LC-MS/MS techniques were utilized to investigate the impact of the ACE2-Ang-(1-7)-Mas axis on microbial diversity and metabolomics of intestinal contents. Results: Activation of the ACE2-Ang-(1-7)-Mas axis improves heart function, reduces intestines inflammatory factors and ameliorates pathological and histological alterations in SuHx mice. This activation notably upregulated the expression of occludin and ZO-1 proteins in intestinal tissues and promoted the proliferation of SCFA-producing bacteria genera, such as g_Candidatus_ Saccharimonas. Furthermore, it enhanced the abundance of beneficial metabolites, including tryptophan and butyric acid. Conclusion: The findings suggest that modulation of the ACE2-Ang-(1-7)-Mas axis can alleviate PAH by regulating intestinal microbes and metabolites. These results highlight the potential of the ACE2-Ang-(1-7)-Mas axis as a promising therapeutic target for clinical management of PAH. [ABSTRACT FROM AUTHOR]

Introduction Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome. Currently, there is no radiation medical countermeasure approved by the U.S. FDA which can be used before radiation exposure to protect exposed individuals. Here we aimed to evaluate the therapeutic potential of an aqueous suspension of synthetic genistein nanoparticles (BIO 300) as a radioprotectant in a pilot efficacy study using a nonhuman primate model of total body irradiation. Materials and Methods Eight rhesus macaques were divided into two groups; four received vehicle and four received BIO 300 Injectable Suspension 24 h before 5.8 Gy total-body irradiation. Survival, blood cell counts, blood chemistry, and clinical parameters were monitored over the 60 days of the study. Tissues were collected at necropsy 60 days post-irradiation or from animals that met unscheduled euthanasia criteria and subjected to histopathological analysis. Tissues analyzed included the duodenum, jejunum, ileum, sternum, lung, heart, liver, kidney, spleen, gut-associated lymphoid tissue, and urinary bladder. Results In this pilot study, all BIO 300 Injectable Suspension treated animals survived to day 60, while only 50% of the vehicle-treated animals survived. We found that BIO 300 Injectable Suspension did not mediate an improvement in blood cell counts (e.g. neutrophils, platelets, white blood cells). However, BIO 300 Injectable Suspension treated animals had a lower incidence of fever and febrile neutropenia, were able to better maintain their body weight post radiation exposure, and exhibited less anemia and faster recovery from anemia. Histopathological analysis revealed that BIO 300-treated animals had less irradiation-induced damage to the sternum and other tissues compared to vehicle controls. Conclusions BIO 300's mechanism of action is complex and protection against irradiation is attainable without much improvement in the complete blood count (CBC) profile. BIO 300's mechanism for radioprotection involves multiple biological pathways and systems. [ABSTRACT FROM AUTHOR]

Introduction Non-compressible torso hemorrhagic (NCTH) shock is the leading cause of potentially survivable trauma on the battlefield. New hypotensive drug therapies are urgently required to resuscitate and protect the heart and brain following NCTH. Our aim was to examine the strengths and limitations of permissive hypotension and discuss the development of small-volume adenosine, lidocaine, and Mg2+ (ALM) fluid resuscitation in rats and pigs. Materials and Methods For review of permissive hypotension, a literature search was performed from inception up to November 2023 using PubMed, Cochrane, and Embase databases, with inclusion of animal studies, clinical trials and reviews with military and clinical relevance. For the preclinical study, adult female pigs underwent laparoscopic liver resection. After 30 minutes of bleeding, animals were resuscitated with 4 mL/kg 3% NaCl ± ALM bolus followed 60 minutes later with 4 h 3 mL/kg/h 0.9% NaCl ± ALM drip (n  = 10 per group), then blood transfusion. Mean arterial pressure (MAP) and cardiac output (CO) were continuously measured via a left ventricular pressure catheter and pulmonary artery catheter, respectively. Systemic vascular resistance (SVR) was calculated using the formula: 80 × (MAP − CVP)/CI. Oxygen delivery was calculated as the product of CO and arterial oxygen content. Results Targeting a MAP of ∼50 mmHg can be harmful or beneficial, depending on how CO and SVR are regulated. A theoretical example shows that for the same MAP of 50 mmHg, a higher CO and lower SVR can lead to a nearly 2-fold increase in O2 supply. We further show that in animal models of NCTH, 3% NaCl ALM bolus and 0.9% NaCl ALM drip induce a hypotensive, high flow, vasodilatory state with maintained tissue O2 supply and neuroprotection. ALM therapy increases survival by resuscitating the heart, reducing internal bleeding by correcting coagulopathy, and decreasing secondary injury. Conclusions In rat and pig models of NCTH, small-volume ALM therapy resuscitates at hypotensive pressures by increasing CO and reducing SVR. This strategy is associated with heart and brain protection and maintained tissue O2 delivery. Translational studies are required to determine reproducibility and optimal component dosing. ALM therapy may find wide utility in prehospital and far-forward military environments. [ABSTRACT FROM AUTHOR]

Cardiovascular manifestations of coronavirus disease 2019 (COVID-19) include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26loxP-STOP-loxP-hACE2 mice with an ancestral, non-mouse-adapted strain of SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced macrophage accumulation, suppressed the development of LV systolic dysfunction, and promoted viral clearance in the heart. These findings establish a mouse model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both viral replication and resultant innate immune responses contribute to cardiac pathology. IMPORTANCE Heart involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs in multiple ways and is associated with worse outcomes in coronavirus disease 2019 (COVID-19) patients. It remains unclear if cardiac disease is driven by primary infection of the heart or immune response to the virus. SARS-CoV-2 is capable of entering contractile cells of the heart in a culture dish. However, it remains unclear how such infection affects the function of the heart in the body. Here, we designed a mouse in which only heart muscle cells can be infected with a SARS-CoV-2 strain to study cardiac infection in isolation from other organ systems. In our model, infected mice show viral infection, worse function, and accumulation of immune cells in the heart. A subset of immune cells facilitates such worsening heart function. As this model shows features similar to those observed in patients, it may be useful for understanding the heart disease that occurs as a part of COVID-19. [ABSTRACT FROM AUTHOR]

Background: One of the special anatomical structures in sturgeons is the pericardioperitoneal canal (PPC), which has not been studied much. Considering that the presence and absence of this channel and its morphometry have not been investigated in this type of fish, this study was conducted. Objective: The purpose of present study was to obtain a complete understanding about anatomical features and ultrasonography of PPC in the heart of immature beluga species in order to provide standard approaches for performing sonography and echocardiography on this sturgeon species. Methods: Ten immature belugas (Huso huso) were used to perform ultrasonography with Sonosite MicroMaxx ultrasonography machine of ventral approach between two pectoral fins. After performing the steps of ultrasonographic study, gross anatomical studies were also performed, and the morphometric measurement of the canal was also performed. Results: A small PPC was observed, which communicated between the pericardial cavity, and the peritoneal (coelomic) cavity. The cranial part of this channel, which was located immediately after the transverse septum, was on the midline of the body and was seen in midsagittal ultrasonograms. On average, the length of this canal was 3.23 ± 0.05 cm, and its diameter (cranial part) was 0.24 ± 0.04 cm. Conclusions: In the present study on immature beluga, it was observed that the canal is located behind the sinus venosus and is caudoventral to it, though behind the transverse septum. It has been mentioned that this PPC establishes a connection between the pericardial cavity and the peritoneal cavity, so this connection is between the peritoneal cavity and the space between the two layers of the pericardium and has no connection with the pericardial sac (the space where the heart is located). In this study, the anatomical structure and morphometry of the PPC in immature beluga were investigated, and some approaches were presented to observe the canal in ultrasonography. [ABSTRACT FROM AUTHOR]

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KOb/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KOb/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure–volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KOb/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca2+ transients in paced KOb/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KOb/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Understanding the precise anatomy of the left and right subvalvular apparatus in the domestic horse can contribute to the development of normal and comparative animal anatomy, as well as surgery, internal medicine, and biology. This study conducts such an analysis, taking into account the thickness of the left ventricular wall, the right ventricular wall, the interventricular septum, the ventricle's length, and the entire heart's width. Additionally, it examines the number of muscle bellies of the papillary muscles, the type of connection between the muscle and the heart wall, the height of muscle origin, and the length of the papillary muscle. This study calculates various proportions and compares them with descriptions of subvalvular apparatuses in other animal species, including humans, available in the literature. Due to the growing interest among veterinarians and the increasing market demands, the development of equine cardiology is necessary. Currently, veterinary medicine for companion animals needs to catch up to human medicine—equine medicine included. A common condition in older horses is aortic valve regurgitation resulting from fibrosis, while its more severe form occurs in younger horses or develops due to a bacterial infection. Mitral valve regurgitation, especially dangerous due to the possibility of sudden death, has a better prognosis if the horse has valve prolapse. Tricuspid valve regurgitation usually does not pose a clinical problem, although its severe cases may lead to heart failure. Some pathologies can be treated surgically, which requires excellent knowledge of anatomy. The object of this study consisted of twenty domestic horse hearts. The focus was on the normal and comparative anatomy of the left and right subvalvular apparatus. The number of muscular bellies of the papillary muscles and the type of connection of the muscles were analysed. Moreover, the height of muscle originating from the ventricle wall was determined, the morphological regularity of the papillary muscle was assessed, and the chordae tendineae originating from the papillary muscles were examined. The conducted research allowed for comparing domestic horses with different species through other studies, the authors of which described this particular aspect. Interspecies similarities which may be correlated with the evolutionary relatedness, as well as differences that could reflect adaptation to different lifestyles, environmental conditions, or metabolic requirements of the animals, have been found. This study expands the knowledge of animals' normal and comparative anatomy, and contributes to the development of veterinary surgery, internal medicine, and biology. [ABSTRACT FROM AUTHOR]

Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (n = 15) and healthy organ donors (n = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including CD34 and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway. NEW & NOTEWORTHY: Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways. [ABSTRACT FROM AUTHOR]

Atrioventricular (AV) accessory pathways (APs) provide additional electrical connections between the atria and ventricles, resulting in severe electrical disturbances. It is generally accepted that APs originate in the altered annulus fibrosus maturation in the late prenatal and perinatal period. However, current experimental methods cannot address their development in specific locations around the annulus fibrosus because of the inaccessibility of late fetal hearts for electrophysiological investigation under physiological conditions. In this study, we describe an approach for optical mapping of the retrogradely perfused chick heart in the last third of the incubation period. This system showed stability for electrophysiological measurement for several hours. This feature allowed analysis of the number and functionality of the APs separately in each clinically relevant position. Under physiological conditions, we also recorded the shortening of the AV delay with annulus fibrosus maturation and analyzed ventricular activation patterns after conduction through APs at specific locations. We observed a gradual regression of AP with an area-specific rate (left-sided APs disappeared first). The results also revealed a sudden drop in the number of active APs between embryonic days 16 and 18. Accessory myocardial AV connections were histologically documented in all positions around the annulus fibrosus even after hatching. The fact that no electrically active AP was present at this stage highlights the necessity of electrophysiological evaluation of accessory atrioventricular connections in studying AP formation. NEW & NOTEWORTHY: We present the use of retrograde perfusion and optical mapping to investigate, for the first time, the regression of accessory pathways during annulus fibrosus maturation, separately examining each clinically relevant location. The system enables measurements under physiological conditions and demonstrates long-lasting stability compared with other approaches. This study offers applications of the model to investigate electrical and/or functional development in late embryonic development without concern about heart viability. [ABSTRACT FROM AUTHOR]

The balancing of freedom of contract against fundamental values seems to be a classic subject. It is commonly taught in contract law that fundamental principles may constitute a limit on freedom of contract, and justify infringement of the freedom of choice of the contracting party or, above all, of the freedom to determine the content of the contract. There are indeed a number of values that may justify infringement: the protection of the weaker party, but also other more contemporary issues such as environmental protection. It therefore appears that the heart of freedom of contract, the only intangible value that must be constitutionally protected, is the freedom to enter into or not to enter into a contract. In our view, however, the subject should also be taken in the other direction: certain fundamental values must in fact be protected because they are the very conditions under which freedom of contract is possible. In other words, certain limits on freedom of contract serve not only to protect fundamental values but also to protect freedom of contract itself. To forget this could lead to a reversal of that freedom and thus to a collapse of the legal framework necessary for the protection of constitutional values. [ABSTRACT FROM AUTHOR]

Background Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. Objective This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). Methods This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Results Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Conclusion Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Modelling [18F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain" published in the European Journal of Nuclear Medicine & Molecular Imaging. The correction notice addresses errors in the original article and provides the accurate information. The corrections include changes to numerical values and clarifications in the text. Additionally, some figures in the original article were incorrect and have been corrected in the notice. The publisher, Springer Nature, remains neutral and unbiased in relation to jurisdictional claims and institutional affiliations. [Extracted from the article]

To understand the information processing mechanism of the brain, it is important to decode the bidirectional communication between the brain and organs. For this purpose, computational models were proposed to simulate brain–organ interfaces at different levels of abstraction. Conventional computational models can be modified to understand the bidirectional interactions for further clarification and treatment of morbidity. In this work, a unified model of excitable cells (brain, heart, and pancreatic cells) is proposed that can predict the electrical response with adrenergic features. This enables us to activate the sparsely coupled cardio-neural network to estimate the heart rate variability, one of the key features to identify a healthy heart. The recent advancements in nano- and bioelectronics will make it possible to build and deploy the brain–heart interface as a nanochip in the body to monitor and control the electrophysiological abnormality of the brain and heart by integrating nano-regulators with ion channels for stimulation. [ABSTRACT FROM AUTHOR]

Obesity-induced cardiac dysfunction is growing at an alarming rate, showing a dramatic increase in global prevalence. Mitochondrial translocation of miR-181c in cardiomyocytes results in excessive reactive oxygen species (ROS) production during obesity. ROS causes Sp1, a transcription factor for MICU1, to be degraded via post-translational modification. The subsequent decrease in MICU1 expression causes mitochondrial Ca2+ accumulation, ultimately leading to a propensity for heart failure. Herein, we hypothesized that phosphorylation of Argonaute 2 (AGO2) at Ser 387 (in human) or Ser 388 (in mouse) inhibits the translocation of miR-181c into the mitochondria by increasing the cytoplasmic stability of the RNA-induced silencing complex (RISC). Initially, estrogen offers cardioprotection in pre-menopausal females against the consequences of mitochondrial miR-181c upregulation by driving the phosphorylation of AGO2. Neonatal mouse ventricular myocytes (NMVM) treated with insulin showed an increase in pAGO2 levels and a decrease in mitochondrial miR-181c expression by increasing the binding affinity of AGO2-GW182 in the RISC. Thus, insulin treatment prevented excessive ROS production and mitochondrial Ca2+ accumulation. In human cardiomyocytes, we overexpressed miR-181c to mimic pathological conditions, such as obesity/diabetes. Treatment with estradiol (E 2) for 48 h significantly lowered miR-181c entry into the mitochondria through increased pAGO2 levels. E 2 treatment also normalized Sp1 degradation and MICU1 transcription that normally occurs in response to miR-181c overexpression. We then investigated these findings using an in vivo model, with age-matched male, female and ovariectomized (OVX) female mice. Consistent with the E 2 treatment, we show that female hearts express higher levels of pAGO2 and thus, exhibit higher association of AGO2-GW182 in cytoplasmic RISC. This results in lower expression of mitochondrial miR-181c in female hearts compared to male or OVX groups. Further, female hearts had fewer consequences of mitochondrial miR-181c expression, such as lower Sp1 degradation and significantly decreased MICU1 transcriptional regulation. Taken together, this study highlights a potential therapeutic target for conditions such as obesity and diabetes, where miR-181c is upregulated. In this study, we show that the phosphorylation of Argonaute 2 (AGO2) stabilizes the RNA-induced silencing complex in the cytoplasm, preventing miR-181c entry into the mitochondria. Furthermore, we demonstrate that treatment with estradiol can inhibit the translocation of miR-181c into the mitochondria by phosphorylating AGO2. This ultimately eliminates the downstream consequences of miR-181c overexpression by mitigating excessive reactive oxygen species production and calcium entry into the mitochondria. [Display omitted] • Pre-menopausal females show reduced risk of obesity-induced heart disease than males and post-menopausal women. • AGO2 phosphorylation stabilizes the RISC in the cytoplasm, preventing miR-181c entry into the mitochondria. • Offers a potential therapeutic approach for conditions like diet-induced obesity and diabetes by limiting miR-181c mobility. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance. [Display omitted] • OGG1 is upregulated in cardiac tissue in diabetic cardiomyopathy. • Deletion of OGG1 exacerbates heart dysfunction in in diabetic cardiomyopathy. • OGG1 plays a role in regulating insulin resistance and glucose uptake. • OGG1 modulates insulin resistance and glucose uptake by interacting with PPAR-γ. • Overexpression of OGG1 alleviates cardiac dysfunction and exhibits a therapeutic effect in diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Introduction While previous studies have analyzed military surgeon experience within military–civilian partnerships (MCPs), there has never been an assessment of how well military providers are integrated within an MCP. The Center for Sustainment of Trauma and Readiness Skills, Cincinnati supports the Critical Care Air Transport Advanced Course and maintains the clinical skills of its staff by embedding them within the University of Cincinnati Medical Center. We hypothesized that military trauma surgeons are well integrated within University of Cincinnati Medical Center and that they are exposed to a similar range of complex surgical pathophysiology as their civilian partners. Materials and Methods After Institutional Review Board approval, Current Procedural Terminology (CPT) codes were abstracted from billing data for trauma surgeons covering University of Cincinnati Hospitals in 2019. The number of trauma resuscitations and patient acuity metrics were abstracted from the Trauma Registry and surgeon Knowledge, Skills, and Abilities clinical activity (KSA-CA) scores were calculated using their CPT codes. Finally, surgeon case distributions were studied by sorting their CPT codes into 23 categories based on procedure type and anatomic location. Appropriate, chi-squared or Mann–Whitney U-tests were used to compare these metrics between the military and civilian surgeon groups and the metrics were normalized by the group's full-time equivalent (FTE) to adjust for varying weeks on service between groups. Results Data were available for two active duty military and nine civilian staff. The FTEs were significantly lower in the military group: military 0.583-0.583 (median 0.583) vs. civilian 0.625-1.165 (median 1.0), P  = 0.04. Per median FTE and surgeon number, both groups performed a similar number of trauma resuscitations (civilian 214 ± 54 vs. military 280 ± 13, P  = 0.146) and KSA-CA points (civilian 55,629 ± 25,104 vs. military 36,286 ± 11,267; P  = 0.582). Although the civilian surgeons had a higher proportion of hernia repairs (P  < 0.001) and laparoscopic procedures (P  = 0.006), the CPT code categories most relevant to combat surgery (those relating to solid organ, hollow viscus, cardiac, thoracic, abdominal, and tissue debridement procedures) were similar between the surgeon groups. Finally, patient acuity metrics were similar between groups. Conclusion This is the first assessment of U.S. Air Force trauma surgeon integration relative to their civilian partners within an MCP. Normalized by FTE, there was no difference between the two groups' trauma experience to include patient acuity metrics and KSA-CA scores. The proportion of CPT codes that was most relevant to expeditionary surgery was similar between the military and civilian partners, thus optimizing the surgical experience for the military trauma surgeons within University of Cincinnati Medical Center. The methods used within this pilot study can be generalized to any American College of Surgeons verified Trauma Center MCP, as standard databases were used. [ABSTRACT FROM AUTHOR]

In the domain of anatomy, some Chinese characters in anatomical terms possess distinctive morphological significance. Chinese characters evolved from pictographic characters, with some of these pictographs being created by ancient people based on their own body structure. This implies that the comprehension and depiction of the human body structure have been integral since the inception of Chinese characters, and this knowledge has been passed down and developed through the continued inheritance of Chinese characters. Even today, certain characters retain the appearance to reflect the shape of the human body structure. By examining the characters related to vertebrae, cranial fontanel and heart, we can find the unique and enduring link between Chinese characters and the fields of anatomy as well as Chinese traditional medicine. [ABSTRACT FROM AUTHOR]

Breast cancer radiotherapy can increase the risks of heart disease, lung cancer and oesophageal cancer. At present, the best dosimetric predictors of these risks are mean doses to the whole heart, lungs and oesophagus, respectively. We aimed to estimate typical doses to these organs and resulting risks from UK breast cancer radiotherapy. A systematic review and meta-analysis was conducted of planned or delivered mean doses to the whole heart, lungs or oesophagus from UK breast cancer radiotherapy in studies published during 2015–2023. Average mean doses were summarised for combinations of laterality and clinical targets. Heart disease and lung cancer mortality risks were then estimated using established models. For whole heart, thirteen studies reported 2893 doses. Average mean doses were higher in left than in right-sided radiotherapy and increased with extent of clinical targets. For left-sided radiotherapy, average mean heart doses were: 2.0 Gy (range 1.2–8.0 Gy) breast/chest wall, 2.7 Gy (range 0.6–5.6 Gy) breast/chest wall with either axilla or supraclavicular nodes and 2.9 Gy (range 1.3–4.7 Gy) breast/chest wall with nodes including internal mammary. For right-sided radiotherapy, average mean heart doses were: 1.0 Gy (range 0.3–1.0 Gy) breast/chest wall and 1.2 Gy (range 1.0–1.4 Gy) breast/chest wall with either axilla or supraclavicular nodes. There were no whole heart dose estimates from right internal mammary radiotherapy. For whole lung, six studies reported 2230 doses. Average mean lung doses increased with extent of targets irradiated: 2.6 Gy (range 1.4–3.0 Gy) breast/chest wall, 3.0 Gy (range 0.9–5.1 Gy) breast/chest wall with either axilla or supraclavicular nodes and 7.1 Gy (range 6.7–10.0 Gy) breast/chest wall with nodes including internal mammary. For whole oesophagus, two studies reported 76 doses. Average mean oesophagus doses increased with extent of targets irradiated: 1.4 Gy (range 1.0–2.0 Gy) breast/chest wall with either axilla or supraclavicular nodes and 5.8 Gy (range 1.9–10.0 Gy) breast/chest wall with nodes including internal mammary. The typical doses to these organs may be combined with dose-response relationships to estimate radiation risks. Estimated 30-year absolute lung cancer mortality risks from modern UK breast cancer radiotherapy for patients irradiated when aged 50 years were 2–6% for long-term continuing smokers, and <1% for non-smokers. Estimated 30-year mortality risks for heart disease were <1%. • Average mean whole organ doses were ∼2 Gy for heart, 3 Gy lung, and 4 Gy oesophagus. • Organ doses increased with increasing targets irradiated. • Estimated absolute 30-year radiation heart disease mortality risks were 0.2%–0.7%. • Equivalent lung cancer risks were 0.2%–0.4% for non-smokers and 2.3%–6.2% for smokers. [ABSTRACT FROM AUTHOR]

LUZP1 expression was increased in pressure overload-induced cardiac hypertrophy in postnatal mice. By constructing cardiac-specific Luzp1 knockout and transgenic mice, we demonstrated that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-induced cardiac hypertrophy and dysfunction. Mechanistically, LUZP1 elevated SHP1 expression to inactivate Stat3 pathway, thereby preventing pathological cardiac hypertrophy. Accordingly, SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. [Display omitted] • LUZP1 expression was progressively increased in hearts after TAC surgery. • Cardiac-specific LUZP1 deficiency aggravated pressure overload-induced cardiac hypertrophy. • Cardiac-specific LUZP1 overexpression attenuated pressure overload-induced cardiac hypertrophy. • Stat3 pathway was a downstream target of LUZP1 in regulating pathological cardiac hypertrophy. • LUZP1 elevated SHP1 expression to inactivate Stat3 pathway. Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive. This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach. Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro. LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

The article explores the potential benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of acute myocardial infarction (AMI). SGLT2i medications have shown promise in reducing cardiovascular events in patients with diabetes. Observational studies and recent trials have shed light on the role of SGLT2i in this critical setting. While SGLT2i have positive effects on various organs, potential side effects should be acknowledged and patients should be monitored carefully. The trials evaluated the efficacy of dapagliflozin and empagliflozin in AMI patients, with dapagliflozin showing statistically superior outcomes in cardio-metabolic factors and empagliflozin showing a significant reduction in heart failure hospitalization rates. Further research is needed to fully understand the potential benefits of SGLT2 inhibitors in AMI patients. [Extracted from the article]

Bacterial lipopolysaccharides belong to the group of pathogen-associated molecular patterns such as alarmins. They can cause various dysfunctions of the cardiovascular system, including arrhythmia, myocardial hypertrophy, myocarditis, and heart failure. The damaging effect of lipopolysaccharides on the myocardium can be a result of their direct action or ensured by uncontrolled secretion of endogenous alarmins and cytotoxic shock. Lipopolysaccharides are perceived by specific caspases of host cells and activate the release of interleukins, and in maximum stimulation they lead to necrosis and/or pyroptosis of cells. The mechanism of the action of bacterial lipopolysaccharide on the functional activity of the heart was studied in vitro using an isolated frog heart model. By the method of pharmacological blockade, the participation of calcium and potassium channels, phosphodiesterase and Na+-K+-ATPase in the mechanism of the lipopolysaccharide influence on the inotropic and chronotropic activity of the heart was revealed. In our experiments, we observed a dose-dependent negative effect of lipopolysaccharide on the inotropic and chronotropic functions of isolated frog heart, as well as a significant reduction in its viability. It is assumed that the mechanism of the action of lipopolysaccharide on the heart involves calcium and potassium ions, Na+-K+-ATPase and cAMP. The study investigated the role of the calcium-regulating hormonal system (including parathyroid hormone, parathyroid hormone-related protein, calcitonin, and vitamin D3) in preventing disturbances in the functional parameters of the isolated heart induced by bacterial lipopolysaccharide. The protective role of these hormones in preserving the pacemaker and contractile functions of the heart under the influence of bacterial lipopolysaccharide has been shown. A particularly significant effect is exerted by vitamin D3, parathyroid hormone and parathyroid hormone-related protein, which maintain the functional activity of the isolated heart for a long time. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading contributor of mortality worldwide. Accurate cardiovascular disease prediction is crucial, and the application of machine learning and data mining techniques could facilitate decision-making and improve predictive capabilities. This study aimed to present a model for accurate prediction of cardiovascular diseases and identifying key contributing factors with the greatest impact. The Cleveland dataset besides the locally collected dataset, called the Noor dataset, was used in this study. Accordingly, various data mining techniques besides four ensemble learning-based models were implemented on both datasets. Moreover, a novel model for combining individual classifiers in ensemble learning, wherein weights were assigned to each classifier (using a genetic algorithm), was developed. The predictive strength of each feature was also investigated to ensure the generalizability of the outcomes. The ultimate ensemble-based model achieved a precision rate of 88.05% and 90.12% on the Cleveland and Noor datasets, respectively, demonstrating its reliability and suitability for future research in predicting the likelihood of cardiovascular diseases. Not only the proposed model introduces an innovative approach for specifying cardiovascular diseases by unraveling the intricate relationships between various biological variables but also facilitates early detection of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Due to the discrepancy between patients awaiting a heart transplant and the availability of donor hearts, strategies to expand the donor pool and improve the transplant's success are crucial. This review aims to summarize current knowledge on the ex vivo heart preservation (EVHP) experience as an alternative to standard cold static storage (CSS). EVHP techniques can improve the preservation of the donor's heart before transplantation and allow for pre-transplant organ evaluation. [ABSTRACT FROM AUTHOR]

Legubicin is a novel conjugate of doxorubicin and a legumain‐cleavable peptide linker. It has been developed to ameliorate the side effects of doxorubicin. Biodistribution in tumor‐bearing mice, acute tolerance, and potential systemic toxic effects in Sprague–Dawley rats and beagle dogs of legubicin were assessed. Legubicin exists mainly as a protein complex in plasma after entering the circulation. Compared with conventional doxorubicin at an equal molar dose in mice, we found higher exposure to doxorubicin in tumor (approximately 1.7‐fold increase) while lower exposure in normal tissues (an ~3.26‐, 3.46‐, and 1.29‐fold reduction in heart, kidney, and plasma, respectively) in tumor‐bearing mice after intravenous injection of legubicin. The acute maximum tolerance dose (MTD) of legubicin was >16 mg/kg doxorubicin equivalent in female rats, 11 mg/kg doxorubicin equivalent in male rats (LD50 of conventional doxorubicin is 10.51 mg/kg), and >8 mg/kg doxorubicin equivalent in dogs (MTD of conventional doxorubicin is 1.5 mg/kg). Four‐week repeat‐dose toxicity studies of intravenous legubicin were conducted in rats (5, 10, and 25 mg/kg/dose once weekly) and dogs (3/1.5, 10/5, and 20/10 mg/kg/dose once weekly); the dose levels were reduced from the second dose due to intolerable legubicin‐associated toxicity at 20 mg/kg. Major organs of toxicity included the gastrointestinal tract, lymphoid and hematopoietic organs, kidney, skin, liver, reproductive organs, and peripheral nerves, which are all associated with doxorubicin. However, cardiotoxicity was only noted at MTD dose levels. Altogether, our results confirm an improved safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer. In the present investigation, a biodistribution study in tumor‐bearing mice and toxicity studies in rats and dogs of legubicin under GLP conditions were performed. Our results show that legubicin causes doxorubicin selectivity to accumulate in tumor tissues, markedly improves acute tolerability of doxorubicin, and significantly attenuates doxorubicin‐induced cardiotoxicity. Altogether, our results confirm the safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer. [ABSTRACT FROM AUTHOR]

In order to facilitate cardiovascular research to develop non-invasive optical heart pacing methods, we have generated a double-transgenic Drosophila melanogaster (fruit fly) model suitable for optogenetic pacing. We created a fly stock with both excitatory H134R-ChR2 and inhibitory eNpHR2.0 opsin transgenes. Opsins were expressed in the fly heart using the Hand-GAL4 driver. Here we describe Hand > H134R-ChR2; eNpHR2.0 model characterization including bi-directional heart control (activation and inhibition) upon illumination of light with distinct wavelengths. Optical control and real-time visualization of the heart function were achieved non-invasively using an integrated light stimulation and optical coherence microscopy (OCM) system. OCM produced high-speed and high-resolution imaging; simultaneously, the heart function was modulated by blue (470 nm) or red (617 nm) light pulses causing tachycardia, bradycardia and restorable cardiac arrest episodes in the same animal. The irradiance power levels and illumination schedules were optimized to achieve successful non-invasive bi-directional heart pacing in Drosophila larvae and pupae. Optical control and real-time beating heart visualization of Hand > H134R-ChR2; eNpHR2.0 Drosophila were achieved non-invasively using an integrated light stimulation and optical coherence microscopy (OCM) system. [ABSTRACT FROM AUTHOR]