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The severe mismatch between solid bioelectronics and dynamic biological tissues has posed enduring challenges in the biomonitoring community. Here, we developed a reconfigurable liquid cardiac sensor capable of adapting to dynamic biological tissues, facilitating ambulatory cardiac monitoring unhindered by motion artifacts or interference from other biological activities. We employed an ultrahigh-resolution 3D scanning technique to capture tomographic images of the skin on the wrist. Then, we established a theoretical model to gain a deep understanding of the intricate interaction between our reconfigurable sensor and dynamic biological tissues. To properly elucidate the advantages of this sensor, we conducted cardiac monitoring alongside benchmarks such as the electrocardiogram. The liquid cardiac sensor was demonstrated to produce stable signals of high quality (23.1 dB) in ambulatory settings.

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.

Leadless pacemakers (LPs) are self-contained pacemakers implanted inside the heart, providing a clinical strategy of pacing without pacemaker leads or a subcutaneous pocket. From an experimental therapy first used clinically in 2012, a decade later this technology is an established treatment option. Because of technologic advances and growing evidence, LPs are increasingly being used. Herein, the experience gained from a decade of leadless pacing is reviewed. We cover the safety and efficacy of single-chamber LPs, including comparisons with transvenous pacemakers and various models, and the initial clinical results of the first dual-chamber LP system. Furthermore, evidence and considerations regarding the optimal replacement strategy will be covered. Finally, we discuss future device developments that may broaden indications, such as LPs communicating with subcutaneous implantable cardiac defibrillators and energy-harvesting LPs. [Display omitted] • LPs have been designed to avoid lead- and pocket-related complications encountered with conventional transvenous pacemakers. • Single-chamber LPs seem to have less overall short- and long-term complications than transvenous pacemakers, but challenges exist. • The adoption of leadless pacing is dependent on clinical experience, evidence, and technologic advances. [ABSTRACT FROM AUTHOR]

CoVID-19 has been linked to long-term consequences on several human body organs, including lung ailments, kidney malfunctions, heart dysrhythmia, alterations in brain nutrient levels, psychological difficulties, abrupt changes in blood pressure, and more. Because of the considerable variety in the impacts on different body parts, researchers find it challenging to create models that can incorporate these effects for treatment recommendations and future disease prevention scenarios. Thus, this article examines some of the most recently proposed models for identifying the impacts of CoVID19 on various human organs. This review examines the underlying theories in terms of clinical nuances, functional advantages, contextual limits, and potential empirical applications. Based on this discussion, researchers will be able to find the best models for detecting particular diseases on specific body parts. It was discovered that hybrid bioinspired models, when paired with deep learning-based classification algorithms, can effectively detect these impacts. This text also parametrically analyses these models in terms of accuracy, precision, and recall, allowing readers to select the best models for their performance-specific use cases. To expand on this discussion, this book evaluates a unique CoVID19 Classification Rank Metric (CCRM) that integrates these factors for thorough model identification. Based on this criteria, researchers will be able to develop appropriate models for clinical scenarios that have high accuracy, low delay, and scalability while costing less. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether radiation therapy plans created using an automatic delineating system and a RapidPlan (RP) module could rapidly and accurately predict heart doses and benefit from deep inspiratory breath-hold (DIBH) in patients with left breast cancer. One hundred thirty-six clinically approved free breathing (FB) plans for patients with left breast cancer were included, defined as manual delineation–manual plan (MD–MP). A total of 104 of 136 plans were selected for RP model training. A total of 32 of 136 patients were automatically delineated by software, after which the RP generated plans, defined as automatic delineation–RapidPlan (AD–RP). In addition, 40 patients who used DIBH were included to analyze differences in heart benefits from DIBH. Two RP models were established for post–breast-conserving surgery (BCS) and post-modified radical mastectomy. There were no significant differences in most of the dosimetric parameters between the MD–MP and AD–RP. The heart doses of the 2 plans were strongly correlated in patients after BCS (0.80 ≤ r ≤ 0.88, P <.05) and moderately correlated in patients after postmodified radical mastectomy (0.46 ≤ r ≤ 0.58, P <.05). The RP model predicted the mean heart dose (MHD) within ± 59.67 cGy and ± 63.32 cGy for patients who underwent the 2 surgeries described above. The heart benefits from DIBH were significantly greater in patients with FB-MHD ≥ 4 Gy than in those with FB-MHD < 4 Gy. The combined automatic delineation RP model allows for the rapid and accurate prediction of heart dose under FB in patients with left breast cancer. FB-MHD ≥ 4 Gy can be used as a dose threshold to select patients suitable for DIBH. [ABSTRACT FROM AUTHOR]

Galactic cosmic radiation (GCR) is one of the most serious risks posed to astronauts during missions to the Moon and Mars. Experimental models capable of recapitulating human physiology are critical to understanding the effects of radiation on human organs and developing radioprotective measures against space travel exposures. The effects of systemic radiation are studied using a multi‐organ‐on‐a‐chip (multi‐OoC) platform containing engineered tissue models of human bone marrow (site of hematopoiesis and acute radiation damage), cardiac muscle (site of chronic radiation damage) and liver (site of metabolism), linked by vascular circulation with an endothelial barrier separating individual tissue chambers from the vascular perfusate. Following protracted neutron radiation, the most damaging radiation component in deep space, a greater deviation of tissue function is observed as compared to the same cumulative dose delivered acutely. Further, by characterizing engineered bone marrow (eBM)‐derived immune cells in circulation, 58 unique genes specific to the effects of protracted neutron dosing are identified, as compared to acutely irradiated and healthy tissues. It propose that this bioengineered platform allows studies of human responses to extended radiation exposure in an "astronaut‐on‐a‐chip" model that can inform measures for mitigating cosmic radiation injury. [ABSTRACT FROM AUTHOR]

The article discusses the importance of calcium flux balance in the heart, focusing on the equilibrium between calcium entering and leaving cardiac cells to prevent calcium overload. It highlights the role of various proteins and organelles in maintaining this balance, such as SERCA, NCX, LTCC, and RyR. The text responds to criticisms regarding the effects of caffeine on calcium release and emphasizes the necessity of considering calcium flux balance when studying the impact of drugs on calcium handling in the heart. [Extracted from the article]

ABSTRACT Cardiovascular disease (CVD) poses a major risk to human health and exert a heavy burden on individuals, society, and healthcare systems. Therefore, it is critical to identify CVD's underlying mechanism(s) and target them using effective agents. Natural compounds have shown promise as antioxidants with cardioprotective functions against CVD injuries due to their antioxidative solid capacity and high safety profile. Several CVDs, such as heart failure, ischemia/reperfusion, atherosclerosis, and cardiomyopathies, are closely linked to mitochondrial dysfunction. It is well established that activating the AMPK/SIRT1/PGC‐1α pathway during CVD promotes mitochondrial function. Therefore, targeting the AMPK/SIRT1/PGC‐1α pathway provides a foundation for novel therapeutic strategies to combat CVD. A key goal of our search was to find natural compounds that target this biological pathway and have beneficial effects on CVD. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular events secondary to stroke–collectively classified as stroke-heart syndrome–greatly impair the patient's prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model. Results: The specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment. Conclusion: This study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection. [ABSTRACT FROM AUTHOR]

Background: Aged heart is defined via structural and mitochondrial dysfunction of the heart. However, there is still no potent compound to improve cardiac function abnormalities in aged individuals. Olive oil (OLO), as an oil with monounsaturated fatty acids, has diverse protective effects on the cardiovascular system, including anti-inflammatory, anti-diabetic, and mitigating effects on blood pressure. In the present study, we evaluated the protective effects of OLO against aging-related cardiac dysfunction. Methods: Male Wistar rats were randomly divided into three groups: Control, D-galactose-induced aging rats (D-GAL group), and aging rats treated with OLO (D-GAL + OLO group). Aging in rats was induced by intraperitoneal injection of D-GAL at 150 mg/kg dose for eight weeks and the D-GAL + OLO group was treated with oral OLO by gavage for eight weeks. The heart tissues were harvested to assay the oxidative stress, molecular parameters, and histological analysis. Results: The D-GAL given rats indicated increased cardiomyocyte diameter as cardiac hypertrophy marker (21 ± 0.8, p < 0.001), an increased Malondialdehyde (MDA) level (27 ± 3, p < 0.001), a reduced Superoxide dismutase (SOD) (p < 0.001, 18.12 ± 1.3), and reduction in gene expression of Sirtuin 1 (SIRT1) (p < 0.05, 0.37 ± 0.06), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α (p < 0.001, 0.027 ± 0.04), and Transcription Factor A, Mitochondrial (TFAM) (p < 0.001, 0.023 ± 0.01), Bcl2 (p < 0.001, 0.04 ± 0.004) and an increase in gene expression of Bax (p < 0.001, 23.5 ± 5.4) in comparison with the control animals. Treatment with OLO improved cardiac hypertrophy (14 ± 0.4, p < 0.001), MDA (22 ± 2.5, p < 0.01), SOD (p < 0.001, 34.9 ± 2), SIRT1 (p < 0.05, 1.37 ± 0.46), PGC-1α (p < 0.001, 1.11 ± 0.1), TFAM (p < 0.01, 0.23 ± 0.02), Bcl2 (p < 0.05, 0.35 ± 0.05) and Bax genes (p < 0.01, 0.1 ± 0.03). Conclusions: Overall, OLO protects the heart against D-GAL-induced aging via increasing antioxidant effects, and enhancing cardiac expression of SIRT1, PGC-1α, TFAM, Bcl2 and Bax genes. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SZ) is characterized by abnormalities in self-representation, including a disturbed sense of agency (SoA). The continuous processing of sensory information concerning the internal state of the body (interoception) is argued to be fundamental to neural representations of the self. We, therefore, tested if aberrant interoception underpins disturbances in SoA in SZ, focusing on cardiac interoceptive signaling. Methods: Forty-two SZ and 29 non-clinical participants (healthy controls; HC) performed an intentional binding task to measure SoA during concurrent heartbeat recording. The effect of cardiac interoceptive signals on SoA was measured by the difference in intentional binding effect during systole and diastole. This measure was standardized based on the overall intentional binding effect to control for non-cardiac factors, and then compared between SZ and HC. Results: Our study revealed a significant difference between SZ and HC groups, with opposite effects of cardiac systole on SoA. Specifically, cardiac systole disrupted SoA in SZ, contrasting with the enhanced SoA in HC. Across the SZ group, the extent to which SoA was disrupted by cardiac systole correlated significantly with a clinical proxy for symptom instability, namely the number of hospital admissions for hallucinations and delusions. Furthermore, the disruption was particularly observed in patients with severe hallucinations. Conclusions: This study revealed a disturbance in the impact of cardiac interoceptive signals on an implicit index of SoA in schizophrenia. This supports the notion that pathophysiological disruption of the central integration of interoceptive information increases vulnerability to disturbances in self-representation and the associated expression of schizophrenic symptoms. [ABSTRACT FROM AUTHOR]

Adenosine receptors play pivotal roles in physiological processes. Adenosine A3 receptor (A3R), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of A3R-selective agents. Recently, we identified RNA-derived N6-methyladenosine (m6A) as an endogenous agonist for A3R, suggesting the relationship between RNA-derived modified adenosine and A3R. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of A3R, especially for A3R-selective agonists such as m6A and namodenoson, remained elusive. Here, we identify tRNA-derived N6-isopentenyl adenosine (i6A) as an A3R-selective ligand via screening of modified nucleosides against the adenosine receptors. Like m6A, i6A is found in the human body and may be an endogenous A3R ligand. Our cryo-EM analyses elucidate the A3R-Gi complexes bound to adenosine, 5'-N-ethylcarboxamidoadenosine (NECA), m6A, i6A, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (m6A), 3.28 Å (i6A), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of A3R. We further conduct structure-guided engineering of m6A-insensitive A3R, which may aid future research targeting m6A and A3R, providing a molecular basis for future drug discovery. Adenosine A3 receptor (A3R) plays important roles in neurons, heart, and immune cells, and is often overexpressed in tumors. Oshima et al. identify tRNA-derived i6A as an A3R-selective ligand and use cryo-EM to reveal A3R's selectivity and activation mechanisms. [ABSTRACT FROM AUTHOR]

Genetic modification in vivo could provide direct functions of genes that could potentially contribute to diverse areas of research including genetics, developmental biology, and physiology. It has been reported that genes of interest could be introduced via recombinant adenovirus type 5 (Ad5) in poultry. Successful gene delivery to mammal fetuses in utero promises substantial progress in clinical and developmental biology, but it is limited because of difficulties in injecting specific sites and invasiveness. On the other hand, developing avian embryos are easily accessible by making a window on the eggshell. Therefore, the objective of this study is to determine permissive embryonic stages for gene transfer into specific avian tissue/organs by injection of Ad5 containing the green fluorescent protein (GFP) gene into blood vessels. At 2 d of post-injection, a strong GFP signal was predominantly identified in the heart of chicken embryos injected at Hamilton–Hamburger (HH) 14, 15, 16 and17 stages with the percentages (44%, 53%, 25%, and 14%, respectively) of GFP positive embryos. In quail embryos, the injection at the HH 15 resulted in heart-specific expression of GFP. Western blot analysis revealed that GFP was exclusively expressed in the avian hearts. These results suggest that the GFP gene is specifically delivered to the avian embryonic hearts when Ad5 is injected through the blood vessel at HH 14–17. This adenoviral transduction of genes of interest in avian embryonic hearts can provide new models for understanding functions of genetic factors on embryonic heart development and unravel genetic etiology of congenital heart diseases. [ABSTRACT FROM AUTHOR]

The heart and kidney have a high energy requirement, but relatively little is known about their utilization of ketones as a potential energy source. We assessed the metabolism of the ketone tracer, carbon-11 acetoacetate (11C-AcAc), by the left and right ventricles of the heart and by the kidney using positron emission tomography (PET) in n = 10 healthy adults under four experimental conditions: a 4-h fast (fasted) ± a single 12 g oral dose of D-beta-hydroxybutyrate (D-BHB), and a single complete, liquid replacement meal (hereafter referred to as the "fed" condition) ± a single 12 g oral dose of D-BHB. Under these experimental conditions, the kinetics of 11C-AcAc metabolism fitted a two-compartment model in the heart and a three-compartment model in the kidney. Plasma ketones were about 10-fold higher with the oral dose of D-BHB. During the four conditions, tracer kinetics were broadly similar in the myocardium and kidney cortex. 11C-AcAc metabolism by the kidney pelvis was similar in three of the four study conditions but, later, peaked significantly higher than that in the cortex; the exception was that the tracer uptake was significantly lower in the fed condition without D-BHB. 11C-AcAc uptake was significantly inversely correlated with age in the kidney cortex, and its oxidative metabolism was significantly positively correlated with age in the left ventricle. D-BHB blunted the insulin, gastric inhibitory peptide, and C-peptide response to the meal. This PET methodology and these acute metabolic perturbations would be suitable for future studies assessing cardiorenal ketone metabolism in conditions in which heart and kidney functions are experimentally modified or compromised by disease. [ABSTRACT FROM AUTHOR]

Clozapine is an atypical antipsychotic (AAP) drug used in treatment-resistant schizophrenia patients. The adverse effects of clozapine on the heart may result in death and require drug discontinuation. Inflammatory mechanisms are thought to be responsible for the negative effect of clozapine on the heart. This suggests that using an agent with anti-inflammatory and antioxidant properties, which may be specific to clozapine-induced heart damage, may prevent possible damage. The aim of our study is to evaluate the effect of taxifolin (3 , 5 , 7 , 3 ', 4'-pentahydroxy flavanone), an agent with known antioxidant and anti-inflammatory effects, on myocardial damage caused by clozapine with biochemical and histopathological data. The rats were divided into three equal groups: healthy control group (HC), clozapine-treated group (CLN), and taxifolin + clozapine-treated group (TCL). To perform this experiment, taxifolin was administered to TCL (n-6) rats at a dose of 50 mg/kg orally by gavage into the stomach. In the HC (n-6) and CLN (n-6) groups, the same volume of distilled water was administered orally as a solvent. One hour after the administration of taxifolin and distilled water, clozapine was administered orally at a dose of 20 mg/kg to the TCL and CLN groups once a day for 28 days. At the end of the period, troponin I (TP I) and creatine kinase MB (CK-MB) levels were measured in the venous blood of each group. Malondialdehyde (MDA), total glutathione (tGSH), TNF-α, NF-▪B, and IL-1β levels were measured in samples taken from heart tissues. Additionally, heart tissues were evaluated histopathologically. Troponin I, CK-MB, MDA, TNF-α, NF-▪B, and IL-1β levels, myocardial degeneration, myofiber irregularity, and congestion scores were significantly higher and tGSH levels were lower in the clozapine group than in the healthy control and taxifolin + clozapine groups (P < 0.05). Compared with the healthy control group, troponin I, tGSH, and NF-KB levels were similar (P > 0.05), CK-MB, MDA, TNF-α, and IL-1β levels were higher in the taxifolin + clozapine group, while they were significantly lower than the clozapine group (P < 0.05). Histopathologically evaluated myocardial degeneration, myofiber irregularity, and congestion score were significantly lower in the taxifolin + clozapine group than in the clozapine group. In the clozapine group (CLN group), myofibers were found to have irregular patterns and were observed as irregular. In the taxifolin + clozapine group (TLC group), myofibrils generally showed a regular morphology. We found that taxifolin can ameliorate damage to myocardial tissue by regulating oxidant-antioxidant and proinflammatory cytokine levels. The data of our study suggest that taxifolin may be useful in the treatment of clozapine-induced myocardial injury. [ABSTRACT FROM AUTHOR]

Cardiometabolic disorders contribute to the global burden of cardiovascular diseases. Emerging sphingolipid metabolites like sphingosine‐1‐phosphate (S1P) and its receptors, S1PRs, present a dynamic signalling axis significantly impacting cardiac homeostasis. S1P's intricate mechanisms extend to its transportation in the bloodstream by two specific carriers: high‐density lipoprotein particles and albumin. This intricate transport system ensures the accessibility of S1P to distant target tissues, influencing several physiological processes critical for cardiovascular health. This review delves into the diverse functions of S1P and S1PRs in both physiological and pathophysiological conditions of the heart. Emphasis is placed on their diverse roles in modulating cardiac health, spanning from cardiac contractility, angiogenesis, inflammation, atherosclerosis and myocardial infarction. The intricate interplays involving S1P and its receptors are analysed concerning different cardiac cell types, shedding light on their respective roles in different heart diseases. We also review the therapeutic applications of targeting S1P/S1PRs in cardiac diseases, considering existing drugs like Fingolimod, as well as the prospects and challenges in developing novel therapies that selectively modulate S1PRs. [ABSTRACT FROM AUTHOR]

Introduction Warfighters are issued hard body armor designed to defeat ballistic projectiles. The resulting backface deformation can injure different thoracoabdominal organs. Developed over decades ago, the behind armor blunt impact criterion of maximum 44 mm depth in clay continues to be used independent of armor type or impact location on the thoracoabdominal region covered by the armor. Because thoracoabdominal components have different energy absorption capabilities, their mode of failures and mechanical properties are different. These considerations underscore the lack of effectiveness of using the single standard to cover all thoracoabdominal components to represent the same level of injury risk. The objective of this pilot study is to conduct cardiac impact tests with a live animal model and analyze biomechanical injury candidate metrics for behind armor blunt trauma applications. Materials and Methods Live swine tests were conducted after obtaining approvals from the U.S. DoD. Trachea tubes. An intravenous line were introduced into the swine before administering anesthesia. Pressure transducers were inserted into lungs and aorta. An indenter simulating backface deformation profiles produced by body armor from military-relevant ballistics to human cadavers delivered impact to the heart region. The approved test protocol included 6-hour monitoring and necropsies. Indenter accelerometer signals were processed to compute the velocity and deflection, and their peak magnitudes were obtained. The deflection-time signal was normalized with respect to chest depth along the impact axis. The peak magnitude of the viscous criterion, kinetic energy, force, momentum and stiffness were obtained. Results Out of the 8 specimens, 2 were sham controls. The mean total body mass and soft tissue thickness at the impact site were 81.1 ± 4.1 kg and 3.8 ± 1.1 cm. The peak velocities ranged from 30 to 59 m/s, normalized deflections ranged from 15 to 21%, and energies ranged from 105 to 407 J. The range in momentum and stiffness were 7.0 to 13.9 kg-m/s and 22.3 to 79.9 N/m. The maximum forces and impulse data ranged from 2.9 to 11.7 kN and 1.9 to 5.8 N-s. The peak viscous criterion ranged from 2.0 to 5.3 m/s. One animal did not sustain any injuries, 2 had cardiac injuries, and others had lung and skeletal injuries. Conclusions The present study applied blunt impact loads to the live swine cardiac region and determined potential candidate injury metrics for characterization. The sample size of 6 swine produced injuries ranging from none to pure skeletal to pure organ trauma. The viscous criterion metric associated with the response of the animal demonstrated a differing pattern than other variables with increasing velocity. These findings demonstrate that our live animal experimental design can be effectively used with testing additional samples to develop behind armor blunt injury criteria for cardiac trauma in the form of risk curves. Injury criteria obtained for cardiac trauma can be used to enhance the effectiveness of the body armor, reduce morbidity and mortality, and improve warfighter readiness in combat operations. [ABSTRACT FROM AUTHOR]

Context. The genotype of laying hens is one of the most important factors influencing their carcass composition and anatomical features. Aims. The aim of the present study was to compare two genotypes of laying hens, Lohmann Brown and Lohmann White, after the laying period. Methods. The experimental material consisted of 26 carcasses obtained after slaughtering spent laying hens at the age of 83 weeks. Key results. The genotype of the birds had a significant (P < 0.05) effect on carcass weight, and the proportion (%) of the breast muscle, leg muscle and gizzard weight. Significant correlations were also found between bodyweight and the weight of the stomach, proventriculus, liver and spleen. The origin of the laying hens also had a significant impact on the length of the sections on intestinal segments, namely, jejunum, ileum and colon. Significant differences in the correlations between bodyweight and length of duodenum, jejunum and rectum were also found. The compared hybrids of laying hens differed significantly in the dimensions of the femur and tibia. Lohmann Brown (LB) hens were characterized by higher greatest length, medial length, smallest breadth of the corpus, and greatest breadth of the distal end of the femur compared with Lohmann White (LW) hens. Dimensions of the tibia greatest length, axial length, smallest breadth of the corpus, greatest breadth of the distal end and greatest depth of the distal end in LB hens were also significantly (P < 0.05) higher than those in LW hens. Conclusions. The results showed that the genotype of laying hens tested after the laying period influenced carcass weight and muscle percentage, as well as differentiated the birds in terms of dimensions of individual segments of the digestive tract, femur, and tibia bones. Implications. The results of this research may be useful for consumers of laying hen carcasses and people interested in poultry anatomy. [ABSTRACT FROM AUTHOR]

L-type Ca2+ channels (CaV1.2/1.3) convey influx of calcium ions that orchestrate a bevy of biological responses including muscle contraction, neuronal function, and gene transcription. Deficits in CaV1 function play a vital role in cardiac and neurodevelopmental disorders. Here, we develop a genetically encoded enhancer of CaV1.2/1.3 channels (GeeCL) to manipulate Ca2+ entry in distinct physiological settings. We functionalized a nanobody that targets the CaV complex by attaching a minimal effector domain from an endogenous CaV modulator--leucine-rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeCL selectively increased L-type current amplitude. In neurons in vitro and in vivo, GeeCL augmented excitation-transcription (E-T) coupling. In all, GeeCL represents a powerful strategy to boost CaV1.2/1.3 function and lays the groundwork to illuminate insights on neuronal and cardiac physiology and disease. [ABSTRACT FROM AUTHOR]

Improving energy provision in the failing heart by augmenting the creatine kinase (CK) system is a desirable therapeutic target. However, over-expression of the creatine transporter (CrT-OE) has shown that very high creatine levels result in cardiac hypertrophy and dysfunction. We hypothesise this is due to insufficient endogenous CK activity to maintain thermodynamically favourable metabolite ratios. If correct, then double transgenic mice (dTg) overexpressing both CrT and the muscle isoform of CK (CKM-OE) would rescue the adverse phenotype. In Study 1, overexpressing lines were crossed and cardiac function assessed by invasive haemodynamics and echocardiography. This demonstrated that CKM-OE was safe, but too few hearts had creatine in the toxic range. In Study 2, a novel CrT-OE line was generated with higher, homogeneous, creatine levels and phenotyped as before. Myocardial creatine was 4-fold higher in CrT-OE and dTg hearts compared to wildtype and was associated with hypertrophy and contractile dysfunction. The inability of dTg hearts to rescue this phenotype was attributed to downregulation of CK activity, as occurs in the failing heart. Nevertheless, combining both studies in a linear regression analysis suggests a modest positive effect of CKM over a range of creatine concentrations. In conclusion, we confirm that moderate elevation of creatine is well tolerated, but very high levels are detrimental. Correlation analysis lends support to the theory that this may be a consequence of limited CK activity. Future studies should focus on preventing CKM downregulation to unlock the potential synergy of augmenting both creatine and CK in the heart. [Display omitted] • Improving cardiac energetics via the creatine kinase system can be cardioprotective. • Too much creatine (>2-fold increase) causes heart failure and is not rescued by CK. • LV dysfunction causes transcriptional and post-translational down-regulation of CK. • Aim for modest increases in creatine while preventing loss of CK activity. [ABSTRACT FROM AUTHOR]

Cardiac regeneration in newborn rodents depends on the ability of pre-existing cardiomyocytes to proliferate and divide. This capacity is lost within the first week of postnatal development when these cells rapidly switch from hyperplasia to hypertrophy, withdraw from the cell cycle, become binucleated, and increase in size. How these dynamic changes in cell size and nucleation impact cardiomyocyte proliferative potential is not well understood. In this study, we innovate the application of a commercially available digital holographic imaging microscope, the Holomonitor M4, to evaluate the proliferative responses of mononucleated and binucleated cardiomyocytes after CHIR99021 treatment, a model proliferative stimulus. This system enables long-term label-free quantitative tracking of primary cardiomyocyte dynamics in real-time with single-cell resolution. Our results confirm that chemical inhibition of glycogen synthase kinase 3 with CHIR99021 promotes complete cell division of both mononucleated and binucleated cardiomyocytes with high frequency. Quantitative tracking of cardiomyocyte volume dynamics during these proliferative events revealed that both mononucleated and binucleated cardiomyocytes reach a similar size-increase threshold prior to attempted cell division. Binucleated cardiomyocytes attempt to divide with lower frequency than mononucleated cardiomyocytes, which may be associated with inadequate increases in cell size. By defining the interrelationship between cardiomyocyte size, nucleation, and cell cycle control, we may better understand the cellular mechanisms that drive the loss of mammalian cardiac regenerative capacity after birth. Digital holographic imaging enables quantitative label-free three-dimensional tracking of cardiomyocyte and non-cardiomyocyte dynamics in vitro. Cardiomyocytes reach a size-increase threshold prior to cell division, which may be impaired by binucleation. Created with BioRender.com. [Display omitted] • Digital holographic imaging enables quantitative label-free three-dimensional monitoring of primary cardiac cultures in vitro. • Primary cardiomyocytes can be readily distinguished from non-cardiomyocytes based on their larger size and slower motility. • Mononucleated and binucleated cardiomyocytes reach a common size-increase threshold prior to cell division. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post‐MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High‐Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post‐exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin‐related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro‐fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. Key points: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia.Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart.Skeletal muscle shows an early mitochondrial pro‐fission response following exposure to moderate hypobaric hypoxia. [ABSTRACT FROM AUTHOR]

The use of 50+ year-old donors for heart transplant (HT) is rare in the United States. We assessed reasons for this—and whether it reflects concern about age itself or associated risk factors—using a survey of US HT centers. The Donor Heart Study enrolled US adult potential heart donors from 2015 to 2020. A total of 6,814 surveys across 2,197 donors cited, on average, 2.4 reasons (per donor) for offer refusal. Age was cited often (by ≥50% of centers surveyed) for 715 donors (33%). In this subgroup, accompanying donor-related reasons for refusal were infrequent, with no cardiac abnormality cited in most cases. Donor age showed associations with (1) age as a reason for refusal and (2) discard. Both abruptly increased at age 50: 55% of 50 to 51-year-old donors were refused often due to age (vs 38% of 48-49-year-olds), and 72% were discarded (vs 55% of 48-49-year-olds), despite no evidence of a threshold effect of age on outcomes. [ABSTRACT FROM AUTHOR]

The Canadian Association of Radiologists (CAR) Cardiovascular Expert Panel is made up of physicians from the disciplines of radiology, cardiology, and emergency medicine, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 30 clinical/diagnostic scenarios, a rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for one or more of these clinical/diagnostic scenarios. Recommendations from 48 guidelines and contextualization criteria in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) for guidelines framework were used to develop 125 recommendation statements across the 30 scenarios (27 unique scenarios as 2 scenarios point to the CAR Thoracic Diagnostic Imaging Referral Guideline and the acute pericarditis subscenario is included under 2 main scenarios). This guideline presents the methods of development and the referral recommendations for acute chest pain syndromes, chronic chest pain, cardiovascular screening and risk stratification, pericardial syndromes, intracardiac/pericardial mass, suspected valvular disease cardiomyopathy, aorta, venous thrombosis, and peripheral vascular disease. [ABSTRACT FROM AUTHOR]

Amyloidosis is triggered by the truncation of amyloid precursor proteins, causing organ damages. While previous studies found the truncation of amyloid A (AA) and amyloid transthyretin (ATTR) occurs in C- and N-terminal, respectively, the detailed mechanism of the fibril formation remains unclear. Liquid chromatography mass spectrometry is usually applied for a qualitative purpose, and thus quantification of tryptic peptide residue is difficult. We therefore employed a mass spectrometry-based quantification by isotope-labeled cell-free (MS-QBIC) to analyze the truncation processes in amyloid fibrillogenesis of AA and ATTR using the formalin-fixed paraffin-embedded tissues of autopsy cases. In this study, the process of transthyretin from an 'early fibril state' consisting of full-length ATTR to a 'mature ATTR amyloid fibril' with a truncated low-amyloidogenic segment has been mathematically revealed. The amount of full-length ATTR was nine times higher than in mature fibers. Large cohort studies using MS-QBIC may shed light on the clinical significance of amyloid fibrils. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of reduced k‐space sampling on B1+$$ {\mathrm{B}}_1^{+} $$ mapping and the resulting impact on phase shimming and dynamic/universal parallel transmit (pTx) RF pulse design. Methods: Channel‐wise 3D B1+$$ {\mathrm{B}}_1^{+} $$ maps were measured at 7 T in 35 and 23 healthy subjects for the heart and prostate region, respectively. With these B1+$$ {\mathrm{B}}_1^{+} $$ maps, universal phase shims optimizing homogeneity and B1+$$ {\mathrm{B}}_1^{+} $$ efficiency were designed for heart and prostate imaging. In addition, universal 4kT‐point pulses were designed for the heart. Subsequently, individual phase shims and individual 4kT‐pulses were designed based on B1+$$ {\mathrm{B}}_1^{+} $$ maps with different acceleration factors and tested on the original maps. The performance of the pulses was compared by evaluating their coefficients of variation (CoV), B1+$$ {\mathrm{B}}_1^{+} $$ efficiencies and specific energy doses (SED). Furthermore, validation measurements were carried out for one heart and one prostate subject. Results: For both organs, the universal phase shims showed significantly higher B1+$$ {\mathrm{B}}_1^{+} $$ efficiencies and lower CoVs compared to the vendor provided default shim, but could still be improved with individual phase shims based on accelerated B1+$$ {\mathrm{B}}_1^{+} $$ maps (acquisition time = 30 s). In the heart, the universal 4kT‐pulse achieved significantly lower CoVs than tailored phase shims. Tailored 4kT‐pulses based on accelerated B1+$$ {\mathrm{B}}_1^{+} $$ maps resulted in even further reduced CoVs or a 2.5‐fold reduction in SED at the same CoVs as the universal 4kT‐pulse. Conclusion: Accelerated B1+$$ {\mathrm{B}}_1^{+} $$ maps can be used for the design of tailored pTx pulses for prostate and cardiac imaging at 7 T, which further improve homogeneity, B1+$$ {\mathrm{B}}_1^{+} $$ efficiency, or SED compared to universal pulses. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin‐like growth factor‐II receptor α (IGF‐IIRα) acts as a stress‐inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF‐IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)‐induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF‐IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF‐IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy‐related and inflammation‐related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF‐IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS‐treated H9c2 cardiac myoblasts with IGF‐IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis‐related cardiac mechanisms. Our study suggests that under sepsis‐like conditions in the heart with IGF‐IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF‐IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function. [ABSTRACT FROM AUTHOR]

Clinical data: A nine-month-old female infant diagnosed with transposition of the great arteries with symptoms of heart failure associated with cyanosis and difficulty in gaining weight was referred to our center with late diagnosis (at nine months of age). Chest radiography: Cardiomegaly; attenuated peripheral vascular markings. Electrocardiography: Sinus rhythm with biventricular overload and aberrantly conducted supraventricular extra systoles. Echocardiography: Wide atrial septal defect, ventricular axis torsion with concordant atrioventricular connection and discordant ventriculoarterial connection. Computed tomography angiography: Concordant atrioventricular connection, right ventricle positioned superiorly and left ventricle positioned inferiorly; discordant ventriculoarterial connection with right ventricle connected to the aorta and left ventricle connected to pulmonary artery. Diagnosis: Crisscross heart is a rare congenital heart defect, accounting for 0.1% of congenital heart diseases. It consists of the 90° rotation of ventricles' axis in relation to their normal position; therefore, ventricles are positioned in the superior-inferior direction rather than anterior-posterior. Most cases have associated cardiac anomalies, and in this case, it is associated with transposition of the great arteries. The complexity and rarity of its occurrence make diagnosis and surgical treatment challenging. Operation: Modified Senning procedure using the pericardial sac in the construction of a tunnel from pulmonary veins to the right atrium. Cardiopulmonary bypass time of 147 minutes with nine minutes of total circulatory arrest. [ABSTRACT FROM AUTHOR]

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes. [ABSTRACT FROM AUTHOR]

Receptors for activated C kinases (RACKs) have been shown to coordinate PKC-mediated hypertrophic signalling in mice. However, little information is available on its participation in embryonic gene expression. This study investigated the involvement of RACK1 in the expression of embryonic genes in a zebrafish (ZF) ex vivo heart culture model by using phenylephrine (PE) or a growth factors cocktail (GFs) as a prohypertrophic/regeneration stimulus. Blebbistatin (BL) inhibition has also been studied for its ability to block the signal transduction actions of some PEs. qRT‒PCR and immunoblot analyses confirmed the upregulation of RACK1 in the PE- and GFs-treated groups. BL administration counteracted PE-induced hypertrophy and downregulated RACK1 expression. Immunohistochemical analyses of the heart revealed the colocalization of RACK1 and embryonic genes, namely, Gata4, Wt1, and Nfat2, under stimulation, whereas these genes were expressed at lower levels in the BL treatment group. Culturing ZF heart cells activated via GFs treatment increased the expression of RACK1. The overexpression of RACK1 induced by the transfection of recombinant RACK1 cDNA in ZF heart cells increased the expression of embryonic genes, especially after one week of GFs treatment. In summary, these results support the involvement of RACK1 in the induction of embryonic genes during cardiac hypertrophy/GFs stimulation in a fish heart model, which can be used as an alternative study model for mammals. [ABSTRACT FROM AUTHOR]

Background: Although the pathogenesis of essential hypertension is not clear, a large number of studies have shown that oxidative stress plays an important role in the occurrence and development of hypertension and target organ damage. Purpose: This paper systematically summarizes the relationship between oxidative stress and hypertension, and explores the potential mechanisms of Chinese herbal medicine (CHM) in the regulation of oxidative stress in hypertension, aiming to establish a scientific basis for the treatment of hypertension with CHM. Methods: To review the efficacy and mechanism by which CHM treat hypertension through targeting oxidative stress, data were searched from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the Chinese National Knowledge Infrastructure, the VIP Information Database, the Chinese Biomedical Literature Database, and the Wanfang Database from their inception up to January 2024. NPs were classified and summarized by their mechanisms of action. Results: In hypertension, the oxidative stress pathway of the body is abnormally activated, and the antioxidant system is inhibited, leading to the imbalance between the oxidative and antioxidative capacity. Meanwhile, excessive production of reactive oxygen species can lead to endothelial damage and vascular dysfunction, resulting in inflammation and immune response, thereby promoting the development of hypertension and damaging the heart, brain, kidneys, blood vessels, and other target organs. Numerous studies suggested that inhibiting oxidative stress may be the potential therapeutic target for hypertension. In recent years, the clinical advantages of traditional Chinese medicine (TCM) in the treatment of hypertension have gradually attracted attention. TCM, including active ingredients of CHM, single Chinese herb, TCM classic formula and traditional Chinese patent medicine, can not only reduce blood pressure, improve clinical symptoms, but also improve oxidative stress, thus extensively affect vascular endothelium, renin–angiotensin–aldosterone system, sympathetic nervous system, target organ damage, as well as insulin resistance, hyperlipidemia, hyperhomocysteinemia and other pathological mechanisms and hypertension related risk factors. Conclusions: CHM display a beneficial multi-target, multi-component, overall and comprehensive regulation characteristics, and have potential value for clinical application in the treatment of hypertension by regulating the level of oxidative stress. [ABSTRACT FROM AUTHOR]

AbstractAt the heart of Peter Abrahams’s 1946 novel Mine Boy is Xuma. He travels from the north (as we are often reminded) to Johannesburg in search of work after his farm has become infertile. It is an anxious transition for Xuma, who is quick to recognise the meaninglessness of his labour, and must adjust to a loud and alienating city. This article concerns the gendering of Xuma’s attitudes to both his work and his new surroundings. The women Xuma meets in Johannesburg (Leah, Eliza, Maisy), women he comes to rely on, are in some instances seen as instantiations of their place, where Xuma often reads their femininity into the places they inhabit. Abrahams, through Xuma, offers a portrayal of the city that is limited in its framing, and, as such, limited in how Johannesburg may be narrated. [ABSTRACT FROM AUTHOR]

Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis of the fasting heart and attempted to clarify the molecular basis of fasting-induced cardioprotection. Our investigation identified a total of 4,652 proteins, with 127 exhibiting downregulation and 118 showing upregulation after fasting. Annotation analysis highlighted significant changes in processes such as lipid metabolism, the peroxisome pathway, and reactive oxygen species metabolism. Notably, the HIF-1 signaling pathway emerged as one of the focal points, with various HIF-1 targets exhibiting differential responses to fasting. Further experiments demonstrated downregulation of HIF-1α at both transcript and protein levels. Intriguingly, while gene expression of Egln3 decreased, its protein product PHD3 remained unaffected by fasting. The unchanged levels of pro-inflammatory cytokines indicated that the observed reduction in Hif1a expression did not stem from a decrease in basal inflammation. These findings underscore the complex regulation of the well-established cardioprotective HIF-1 signaling within the heart during 3-day fasting. [ABSTRACT FROM AUTHOR]

Background and Aims This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone. Methods Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants. Results AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%–41.8%) vs. 29.3% (27.0%–31.5%) in UK Biobank, 36.5% (34.4%–38.5%) vs. 32.5% (30.4%–34.5%) in MGB, 41.8% (37.7%–45.9%) vs. 33.0% (28.9%–37.2%) in FHS, and 34.9% (28.8%–41.0%) vs. 28.9% (22.9%–35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P <.0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P <.0001), 0.856 vs. 0.818 in FHS (P <.0001), and 0.827 vs. 0.791 (P =.0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P =.0042) and All of Us (P =.049). Conclusions A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%–41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors. [ABSTRACT FROM AUTHOR]

Alternative splicing is an important process that contributes to highly diverse transcripts and protein products, which can affect the development of disease in various organisms. Cardiovascular disease (CVD) represents one of the greatest global threats to humans, particularly acute myocardial infarction (MI) and subsequent ischemic reperfusion (IR) injury, which involve complex transcriptomic changes in heart tissues associated with metabolic reshaping and immunological response. In this study, we used a newly developed ONT full-length transcriptomic approach and performed transcript-resolved differential expression profiling in murine models of MI and IR. We built an analytical pipeline to reliably identify and quantify alternative splicing products (isoforms), expanding on the currently available catalog of isoforms described in mice. The updated alternative splicing landscape included transcripts, genes, and pathways that were differentially regulated during IR and MI. Our study establishes a pipeline to profile highly diverse isoforms using state-of-the-art long-read sequencing, builds a landscape of alternative splicing in the mouse heart during MI and IR. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function, while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury, although its impact on diabetic cardiomyopathy remains elusive. Methods: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanisms involved. Adult mice were made diabetic using streptozotocin (STZ, 50 mg/kg, i.p., for 5 days) while receiving UCF101 (7.15 mg/kg, i.p.). Results: STZ evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin 1, elevated p62), mitophagy (FUNDC1 and Parkin with upregulated TOM20), increased left ventricular end systolic diameter, reduced fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/re-lengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effects from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMP-activated protein kinase (AMPK) (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, the mitophagy inhibitor liensinine, and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. Conclusion: These findings suggest that UCF101 rescues diabetes-mediated alterations in cardiac structure and function, likely through AMPK-mediated regulation of mitophagy. [ABSTRACT FROM AUTHOR]

Cellular heterogeneity is a well-accepted feature of tissues, and both transcriptional and metabolic diversity have been revealed by numerous approaches, including optical imaging. However, the high magnification objective lenses needed for high-resolution imaging provides information from only small layers of tissue, which can result in poor cell statistics. There is therefore an unmet need for an imaging modality that can provide detailed molecular and cellular insight within intact tissue samples in 3D. Using GFP-tagged GLUT4 as proof of concept, we present here a novel optical mesoscopy approach that allows precise measurement of the spatial location of GLUT4 within specific anatomical structures across the myocardium in ultrathick sections (5 mm x 5 mm x 3 mm) of intactmouse heart.We reveal distinct GLUT4 distribution patterns across cardiac walls and highlight specific changes in GLUT4 expression levels in response to high fat dietfeeding, and we identify sex-dependent differences in expression patterns. This method is applicable to any target that can be labelled for light microscopy, and to other complex tissues when organ structure needs to be considered simultaneously with cellular detail. [ABSTRACT FROM AUTHOR]

Resveratrol (RES) is a polyphenol with natural anti-inflammatory and antioxidant properties. It is found in abundance in plants, i.e., grapes and mulberry fruit. In addition, synthetic forms of RES exist. Since the discovery of its specific biological properties, RES has emerged as a candidate substance not only with modeling effects on the immune response but also as an important factor in preventing the onset and progression of cardiovascular disease (CVD). Previous research provided strong evidence of the effects of RES on platelets, mitochondria, cardiomyocytes, and vascular endothelial function. In addition, RES positively affects the coagulation system and vasodilatory function and improves blood flow. Not only in humans but also in veterinary medicine, cardiovascular diseases have one of the highest incidence rates. Canine and human species co-evolved and share recent evolutionary selection processes, and interestingly, numerous pathologies of companion dogs have a human counterpart. Knowledge of the impact of RES on the cardiovascular system of dogs is becoming clearer in the literature. Dogs have long been recognized as valuable animal models for the study of various human diseases as they share many physiological and genetic similarities with humans. In this review, we aim to shed light on the pleiotropic effects of resveratrol on cardiovascular health in dogs as a translational model for human cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) is known to induce oxidative stress and inflammation, leading to significant damage in cardiac tissues. This study investigates the protective effects of melatonin (MLT) against LPS-induced oxidative damage, inflammation, and apoptosis in rat heart tissue. Rats were divided into four groups (n = 6 per group): control, melatonin-treated, LPS-treated, and LPS + melatonin-treated. Oxidative stress markers, including thiobarbituric acid-reactive substances (TBARSs) and advanced oxidation protein products (AOPPs), were measured. Additionally, inflammatory markers, such as interleukin-6 (IL-6) levels, inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content, and apoptotic markers, caspase-3, caspase-9, and acidic DNase activity, were evaluated. LPS treatment significantly increased TBARS, AOPP, and IL-6 levels, as well as the activity of caspase-3, acidic DNase and iNOS and NO content compared to the control group. Co-treatment with melatonin significantly reduced the levels of TBARS and AOPP levels, and caspase-3 and acidic DNase activities nearly matched those of the control group, while caspse-9 was still slightly increased. Interestingly, IL-6, iNOS and NO levels were significantly decreased but did not fully match the values in the control group. Melatonin mitigates LPS-induced oxidative stress, inflammation, and apoptosis in rat heart tissue by affecting all studied parameters, demonstrating its potential as a therapeutic agent for conditions characterized by oxidative stress and inflammation. Further research is warranted to explore the clinical applications of melatonin in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is closely associated with most cardiovascular diseases. Experimental models are needed to analyze the potential impact of ED on cardioprotection in constant pressure Langendorff systems (CPLS). One cardioprotective strategy against ischemia/reperfusion injury (I/RI) is conditioning with the lipid emulsion Intralipid (IL). Whether ED modulates the cardioprotective effect of IL remains unknown. The aim of the study was to transfer a protocol using a constant flow Langendorff system for the induction of ED into a CPLS, without the loss of smooth muscle cell functionality, and to analyze the cardioprotective effect of IL against I/RI under ED. In isolated hearts of male Wistar rats, ED was induced by 10 min perfusion of a Krebs–Henseleit buffer containing 60 mM KCl (K+), and the vasodilatory response to the vasodilators histamine (endothelial-dependent) and sodium–nitroprusside (SNP, endothelial-independent) was measured. A CPLS was employed to determine cardioprotection of pre- or postconditioning with 1% IL against I/RI. The constant flow perfusion of K+ reduced endothelial response to histamine but not to SNP, indicating reduced vasodilatory functionality of endothelial cells but not smooth muscle cells. Preconditioning with IL reduced infarct size and improved cardiac function while postconditioning with IL had no effect. The induction of ED neither influenced infarct size nor affected the cardioprotective effect by preconditioning with IL. This protocol allows for studies of cardioprotective strategies under ED in CLPS. The protection by preconditioning with IL seems to be mediated independently of a functional endothelium. [ABSTRACT FROM AUTHOR]