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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.

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]

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.

Key points Previous studies demonstrated that the mitochondrial Ca2+ uniporter MCU and the Na+‐Ca2+ exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria‐SR Ca2+ interaction. However, the physiological relevance of the mitochondria‐SR Ca2+ interaction has remained unsolved. Furthermore, although mitochondrial Ca2+ has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH‐producing dehydrogenases, the contribution of the Ca2+‐dependent regulatory mechanisms to cellular functions under physiological conditions has been controversial. In this study, we constructed a new integrated model of human ventricular myocyte with excitation‐contraction‐energetics coupling and investigated systematically the contribution of mitochondria‐SR Ca2+ interaction, especially focusing on cardiac energetics during dynamic workload transitions in exercise. Simulation analyses revealed that the spatial coupling of mitochondria and SR, particularly via mitochondrial Ca2+ uniport activity‐RyR, was the primary determinant of mitochondrial Ca2+ concentration, and that the Ca2+‐dependent regulatory mechanism facilitated mitochondrial NADH recovery during exercise and contributed to the stability of NADH in the workload transition by about 40%, while oxygen consumption rate and cytoplasmic ATP level were not influenced. We concluded that the mitochondria‐SR Ca2+ interaction, created via the uneven distribution of Ca2+ handling proteins, optimizes the contribution of the mitochondrial Ca2+‐dependent regulatory mechanism to stabilizing NADH during exercise. The mitochondrial Ca2+ uniporter protein MCU and the Na+‐Ca2+ exchanger protein NCLX are reported to exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria‐SR Ca2+ interaction in cardiomyocytes. Mitochondrial Ca2+ (Ca2+mit) has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH‐producing dehydrogenases. Here we constructed an integrated model of a human ventricular myocyte with excitation‐contraction‐energetics coupling and investigated the role of the mitochondria‐SR Ca2+ interaction in cardiac energetics during exercise. Simulation analyses revealed that the spatial coupling particularly via mitochondrial Ca2+ uniport activity‐RyR is the primary determinant of Ca2+mit concentration, and that the activation of NADH‐producing dehydrogenases by Ca2+mit contributes to NADH stability during exercise. The mitochondria‐SR Ca2+ interaction optimizes the contribution of Ca2+mit to the activation of NADH‐producing dehydrogenases. [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]

There is a lack of in-depth research on the impacts and changes in chronic psychological stress (CPS) on the cardiovascular system after acute myocardial infarction (AMI). This study aims to explore the comorbid mechanism and dynamic evolution of AMI exposed to CPS. 120 Wistar rats were randomly divided into Sham Operation group, Sham Operation + Chronic Unpredictable Mild Stress (CUMS) group, AMI group and AMI + CUMS group, with each group further divided into subgroups at days 7, 14, and 28. The AMI model was created by ligating the left anterior descending coronary artery, and CUMS model was used to induce CPS in rats. Behavioral changes were assessed through open field tests and sucrose preference tests. Cardiac function and structure were evaluated via echocardiography. The serum levels of TNFα, IL-6, NO, ET, CK-MB, cTNT, and ANP were measured using assay kits. Pathological changes in cardiac and brain tissues were observed under an optical microscope. Comparative analysis across different models revealed that CUMS significantly reduced behavioral activities in rats, with an interaction between CUMS and AMI affecting total distance (P < 0.05). Both CUMS and AMI significantly reduced cardiac function indicators, with their interaction effects on LVEF, LVFS, and CO (P < 0.05). AMI significantly altered cardiac structural parameters, particularly on day 28 (P < 0.05); while the impact of CUMS on cardiac structure was not significant, except for a notable reduction in LVAW/s on day 7 in AMI + CUMS group (P < 0.05). AMI caused significant changes in the serum biomarkers, while CUMS only significantly increased cTnT on day 7, ANP, TNFα, and IL-6 on day 14, and CK-MB on day 28, with their interaction effects on the three myocardial injury markers and TNFα (P < 0.05). Comparative analysis across different time points demonstrated that behavioral activity, cardiac function, CK-MB, cTnT, ANP, TNFα, and ET levels decreased significantly over time in the AMI model rats, while the left ventricular mass increased significantly (P < 0.05). Pathologically, compared with stress or AMI alone, the AMI + CUMS group exhibited more severe myocardia cellular degeneration and inflammatory infiltration, causing larger infract areas in myocardial tissue, as well as cell number decreases and morphological changes in hippocampal tissue. AMI with CPS exacerbates myocardial injury through sustained inflammation and endothelial dysfunction, leading to heart-brain pathology manifestations characterized by decreased cardiac function and hippocampal tissue damage. [ABSTRACT FROM AUTHOR]

Stereotactic ablative body radiotherapy (SABR) is increasingly used for early-stage lung cancer, however the impact of dose to the heart and cardiac substructures remains largely unknown. The study investigated doses received by cardiac substructures in SABR patients and impact on survival. SSBROC is an Australian multi-centre phase II prospective study of SABR for stage I non-small cell lung cancer. Patients were treated between 2013 and 2019 across 9 centres. In this secondary analysis of the dataset, a previously published and locally developed open-source hybrid deep learning cardiac substructure automatic segmentation tool was deployed on the planning CTs of 117 trial patients. Physical doses to 18 cardiac structures and EQD2 converted doses (α/β = 3) were calculated. Endpoints evaluated include pericardial effusion and overall survival. Associations between cardiac doses and survival were analysed with the Kaplan–Meier method and Cox proportional hazards models. Cardiac structures that received the highest physical mean doses were superior vena cava (22.5 Gy) and sinoatrial node (18.3 Gy). The highest physical maximum dose was received by the heart (51.7 Gy) and right atrium (45.3 Gy). Three patients developed grade 2, and one grade 3 pericardial effusion. The cohort receiving higher than median mean heart dose (MHD) had poorer survival compared to those who received below median MHD (p = 0.00004). On multivariable Cox analysis, male gender and maximum dose to ascending aorta were significant for worse survival. Patients treated with lung SABR may receive high doses to cardiac substructures. Dichotomising the patients according to median mean heart dose showed a clear difference in survival. On multivariable analyses gender and dose to ascending aorta were significant for survival, however cardiac substructure dosimetry and outcomes should be further explored in larger studies. • Eighteen cardiac structure automatic segmentation tool deployed on planning datasets. • Data from phase II multicentre trial of stereotactic lung radiotherapy. • Dichotomising patients according to mean heart dose showed a difference in survival. • Gender and maximum dose to ascending aorta were significant on multivariable analysis. [ABSTRACT FROM AUTHOR]

Objectives: Observational studies have suggested an association between age at natural menopause (ANM) and ventricular structure and function. Nevertheless, the causal relationship remains unclear. This study aimed to evaluate the causal effects of ANM on ventricular structure and function by Mendelian randomization (MR) analysis. Methods: Genome-wide association summary statistics for ANM and 16 ventricular structures and functions were obtained. The inverse variance weighted (IVW) method was the primary MR approach for assessing causal associations. In addition, three additional MR methods (MR-Egger, weighted median and weighted mode) were performed to complement the IVW method. Furthermore, various sensitivity tests were conducted to evaluate the reliability of the MR results. Results: The IVW method identified no causal association between ANM and all 16 ventricular structures or functions (p > 0.05). Three additional MR methods yielded parallel results to the IVW approach (p > 0.05). Various sensitivity tests revealed stability of the MR results, indicating no heterogeneity or horizontal pleiotropy. Conclusion: The present MR study indicated that ANM would not causally affect ventricular structure or function. Therefore, the correlation between ANM and ventricular characteristics in previous observational studies might be attributed to shared upstream cardiovascular risk factors or unidentified genetic mutations that simultaneously affect both ANM and ventricular structure and function. [ABSTRACT FROM AUTHOR]

S‐Limonene (s‐Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s‐Lim exerts its antiarrhythmic effect, focusing on the blockade of β‐adrenoceptor (β‐AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the β‐adrenergic pathway, sarcomeric shortening and L‐type calcium current (ICa,L). In isolated hearts, 10 μM of s‐Lim did not alter the ECG profile or LVPD. s‐Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 μM and reduced heart rate at the concentrations of 30 (12.4%) and 50 μM (16.6%). s‐Lim (10 μM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 μM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s‐Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker β1‐AR). In vivo, s‐Lim antagonized the effect of ISO (agonists β1‐AR), presenting a similar effect to propranolol (a non‐selective blocker β‐AR). In ventricular cardiomyocyte, s‐Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s‐Lim did not affect changes in the ECG effect mediated by 5 μM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO‐induced arrhythmia model, s‐Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s‐Lim is related to blockade of β‐AR in the heart. [ABSTRACT FROM AUTHOR]

Mild hyperbaric oxygen therapy (mHBOT) is an adjuvant therapy used in conditions where tissue oxygenation is reduced and is implemented using pressures less than 1.5 ATA and 100% O2 (instead of the classical HBOT at 1.9–3 ATA) which results in cheaper, easier to implement, and equally effective. mHBOT is offered for wellness and beauty and as an anti-aging strategy, in spite of the absence of studies on the cardiovascular system. Consequently, we investigated the impact of mHBOT on the cardiovascular system. Mechanical and energetic parameters of isolated heart submitted to ischemia/reperfusion injury and arterial contractile response from mHBOT-exposed rats were evaluated. In the heart, mHBOT increased pre-ischemic velocity of contraction and ischemic end-diastolic pressure and developed pressure and contractile economy during reperfusion. mHBOT decreased infarct size and increased the plasma nitrite levels. In the artery, mHBOT increased acetylcholine sensitivity. mHBOT protects the heart during ischemia/reperfusion and affects vascular relaxation. [ABSTRACT FROM AUTHOR]

Revascularization of ischemic myocardium following cardiac damage is an important step in cardiac regeneration. However, the mechanism of arteriogenesis has not been well described during cardiac regeneration. Here we investigated coronary artery remodeling and collateral growth during cardiac regeneration. Neonatal MI was induced by ligature of the left descending artery (LAD) in postnatal day (P) 1 or P7 pups from the Cx40-GFP mouse line and the arterial tree was reconstructed in 3D from images of cleared hearts collected at 1, 2, 4, 7 and 14 days after infarction. We show a rapid remodeling of the left coronary arterial tree induced by neonatal MI and the formation of numerous collateral arteries, which are transient in regenerating hearts after MI at P1 and persistent in non-regenerating hearts after MI at P7. This difference is accompanied by restoration of a perfused or a non-perfused LAD following MI at P1 or P7 respectively. Interestingly, collaterals ameliorate cardiac perfusion and drive LAD repair, and lineage tracing analysis demonstrates that the restoration of the LAD occurs by remodeling of pre-existing arterial cells independently of whether they originate in large arteries or arterioles. These results demonstrate that the restoration of the LAD artery during cardiac regeneration occurs by pruning as the rapidly forming collaterals that support perfusion of the disconnected lower LAD subsequently disappear on restoration of a unique LAD. These results highlight a rapid phase of arterial remodeling that plays an important role in vascular repair during cardiac regeneration. [Display omitted] • Rapid remodeling of the arterial tree is induced by myocardial infarction. • The endocardial response to ischemia differs between regenerated and non-regenerated hearts following myocardial infarction. • Collateral growth is rapid and transient in regenerated hearts while delayed and persistent in non-regenerated hearts. • Collateral arteries ameliorate cardiac perfusion and drive LAD repair. • The restoration of the LAD occurs by remodeling of pre-existing arterial cells. [ABSTRACT FROM AUTHOR]

In 2016, we initiated a quality improvement endeavor to increase pediatric heart offer acceptance. This study assessed the effect of these interventions at our center. We evaluted pre- and postimplementation cohorts (January 1, 2008-December 31, 2016 vs January 1, 2017-July 1, 2023) comparing donor heart utilization. Six interventions were iterated over time to increase offer acceptance ("extended criteria"): ABO-incompatible transplant, ex vivo perfusion for distanced donors, 3-dimensional total cardiac volume (TCV) assessment, acceptance of hepatitis-C or Severe Acute Respiratory Syndrome Coronavirus 2 infected donors, and institutional culture change favoring consideration of donors previously considered unacceptable. Outcomes studied included annual HT volume, median waitlist duration, sequence number at acceptance, and post-transplant clinical outcomes. During the study period, annual transplant volume increased from 16/year to 25/year pre- and postimplementation. Three hundred thirteen of 389 (80%) listed patients were transplanted. Waitlist duration shortened postimplementation (p = 0.01), as did the percentage of accepted heart offers utilizing at least 1 extended criterion (p < 0.001). Institutional culture change and TCV assessment had the largest impact on donor heart utilization (p = 0.04 and p < 0.001). There was no difference in post-HT intubation or intensive care unit days (p = 0.05-0.9), though post-transplant hospitalization duration (p < 0.001) increased. Post-transplant survival was unaffected by the use of extended criteria hearts (p = 0.3). We report a successful longitudinal, multifaceted effort to increase organ offer utilization, with institutional culture change and TCV assessments most impactful. The use of extended criteria hearts was not associated with inferior survival. [ABSTRACT FROM AUTHOR]

An 11-year-old, female, spayed, soft-coated Wheaten terrier presented for acute onset of neurological signs. On presentation, neurological examination showed right thoracic and pelvic limb proprioceptive deficits, absent right menace reflex, and weak right nasal septum response. A left thalamocortical lesion was localized. On thoracic auscultation, an arrhythmia was noted, and electrocardiography showed frequent ventricular premature complexes and rare runs of ventricular tachycardia. Echocardiography identified an interventricular septal mass extending into the lumen of the left ventricle. Thalamocortical metastasis secondary to the cardiac mass was suspected to be the cause of the patient's neurological signs. Humane euthanasia was elected by the owner due to the patients clinical status and poor prognosis. A postmortem examination diagnosed hemangiosarcoma of the interventricular septum, the right ventricular free wall, and left ventricular free wall. The left ventricle adjacent to the paraconal groove showed myocardial necrosis and inflammation. Metastases to the brain and secondary intracranial hemorrhage were found which were suspected to be the cause of the antemortem neurological signs. Concurrent pulmonary and hepatic metastases were noted. This report describes a rare presentation of an intracardiac hemangiosarcoma of the interventricular septum, right ventricle, and left ventricle in a patient presenting with neurological signs. [ABSTRACT FROM AUTHOR]

Background: Chronic Rapid eye movement (REM) sleep deprivation has been associated with various cardiovascular alterations, including disruptions in antioxidant defense mechanisms, lipid metabolism, and inflammatory responses. This study investigates the therapeutic potential of green tea extract (GTE) in mitigating these adverse effects. Methods: A total of 24 male Wistar albino rats were used in this study and divided into the control group (n = 8), Chronic-REM Sleep Deprivation (CRSD) Group (n = 8) and Chronic-REM SD + Green Tea 200 (CRSD + GTE200) Group (n = 8). After 21 days, a comprehensive analysis of paraoxonase (PON1), arylesterase (ARE), malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), proinflammatory cytokines, and lipid profiles in aortic tissue, heart tissue, and serum was conducted in a sleep-deprived rat model. Results: Chronic REM sleep deprivation led to a significant reduction in PON1 and ARE levels in aortic (p = 0.046, p = 0.035 respectively) and heart tissues (p = 0.020, p = 0.019 respectively), indicative of compromised antioxidant defenses. MDA levels increased, and NOx levels decreased, suggesting oxidative stress and impaired vascular function. Lipid profile alterations, including increased triglycerides and total cholesterol, were observed in serum. Elevated levels of inflammatory cytokines (IL-6 and TNF-alpha) further indicated an inflammatory response (p = 0.007, p = 0.018 respectively). GTE administration demonstrated a protective role, restoring antioxidant enzyme levels, suppressing lipid peroxidation, and improving NOx levels. Conclusion: These findings suggest the therapeutic potential of GTE in alleviating the cardiovascular impairments of chronic REM sleep deprivation, emphasizing its candidacy for further clinical exploration as a natural intervention in sleep-related disorders and associated cardiovascular risks. [ABSTRACT FROM AUTHOR]

Cardiovascular functions in diabetes greatly depend on constitutive NOS (cNOS) activity. A comparative study of the effects of a steroid hormone ecdysterone and enalapril, an ACE inhibitor widely used to treat cardiac disorders on cNOS, inducible NOS (iNOS), xanthine oxidoreductase (XOR) activity, RNS, ROS, and lipid peroxidation in heart tissue in experimental diabetes was conducted. The rat model of diabetes was established by streptozotocin injection. NOS activity, NO2−, NO3−, uric acid, nitrosothiols, hydroperoxide, superoxide, and diene conjugate formation were studied spectrophotomerically. In diabetes, cNOS downregulation correlated with a dramatic fall of NO2− production and ~4.5-fold elevation of nitrosothiols, which agreed with a steep rise of iNOS activity, while NO3− remained close to control. Dramatic activation of XOR was observed, which correlated with the elevation of both superoxide production and nitrate reductase activity and resulted in strong lipid peroxidation. Ecdysterone and enalapril differently affected RNS metabolism. Ecdysterone moderately restored cNOS but strongly suppressed iNOS, which resulted in the reduction of NO3−, but full restoration of NO2− production. Enalapril better restored cNOS but less effectively suppressed iNOS, which promoted NO3− formation. Both drugs similarly inhibited XOR, which equally alleviated oxidative stress and lipid peroxidation. The synergistic action of iNOS and XOR was a plausible explanation for strong lipid peroxidation, abolished by the inhibition of iNOS and XOR by ecdysterone or enalapril. Complementary effects of ecdysterone and enalapril on cNOS, iNOS, and RNS are a promising basis for their combined use in the treatment of cardiovascular disorders caused by cNOS dysfunction in diabetes. [ABSTRACT FROM AUTHOR]

As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction. [ABSTRACT FROM AUTHOR]

Objective: To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE−/− mice. Methods: Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE−/− mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe2+ in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively. Results: BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (P<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe2+ in BBR group was significantly lower than that in the model group (P<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (P<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (P<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (P<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe2+, MDA and ROS levels increased (P<0.05 or P<0.01), and the activity of SOD decreased (P<0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (P<0.01). Conclusion: Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Ethanol is still one of the most frequently consumed drugs worldwide and is a strong risk factor for more than 60 illnesses including alcoholic cardiomyopathy which is a specific heart muscle disease caused by long-term excessive alcohol consumption. The review aims to gather available data and summarize it to give better understanding of the disease, to help select patients with the condition to implement proper treatment, and to present possible future directions as the incidence of the disease is projected to persist in the future. Brief description of the state of knowledge: Alcoholic cardiomyopathy (ACM) is characterized by dilation, increased mass of the left ventricle, and reduced ejection fraction leading to end-stage heart failure. It is caused by ethanol's direct toxicity on myocytes disturbing many different metabolic pathways. The result is a decrease in both systolic and diastolic function of the heart. The ACM development depends on factors such as genetics, gender, dietary factors and the dosage of ethanol consumption. The goal of the treatment is total alcohol abstinence, but the reduction of ethanol intake may also be beneficial. Patients should obtain a complete pharmacological treatment for heart failure. Summary: Ethanol overconsumption remains an unresolved problem, with the incidence of ACM projected to persist in the future, especially among patients with alcohol use disorder (AUD). Efforts for prevention, early detection, and effective treatment of ACM need to be established. A primary focus should be on treating AUD because it is the most effective way to halt the progression of the disease. Further research should focus on both asymptomatic and symptomatic patients with AUD to better define clinical manifestations, diagnostic approaches, and the most effective treatments for ACM. [ABSTRACT FROM AUTHOR]

We sought to evaluate the acceptability and feasibility of a culturally tailored food box intervention for improving blood pressure (BP), food security and Body Mass Index (BMI) among Chickasaw Nation adults with uncontrolled hypertension. As part of the Chickasaw Healthy Eating Environments Research Study (CHEERS), we administered a group randomized pilot study in four tribal communities (two intervention, two control). Participants in the intervention communities received six heart-healthy food boxes, culturally tailored to traditional Chickasaw diet and current food context. Outcomes were measured over 6 months. We enrolled 262 participants, and 204 with complete data on key variables were included in the analysis. The food boxes were very popular, and we achieved high retention for follow-up data collection. Intervention community participants had 2.6 mmHg lower mean systolic BP and improved diet quality and BMI compared with control participants, although, as expected for a pilot study, the differences were not statistically significant. The culturally tailored diet intervention and randomized trial study design were acceptable and feasible for Chickasaw Nation adults with uncontrolled hypertension. Our findings support the value of tribal-food bank partnerships as a potential approach for reducing food insecurity and hypertension-related disparities in Native American communities. [ABSTRACT FROM AUTHOR]

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Environmental stressors such as micro‐ and nanosized plastic particles (MNPs) or crude oil have a detrimental effect on aquatic animals; however, the impact upon the cardiovascular system of fish remains relatively under‐researched. This study presents a novel approach for investigating the effect of crude oil and MNPs on the cardiac system of fish. We used salmonid larvae and cardiac cell cultures derived from hearts of salmonid fish and exposed them to environmental stressors. Following exposure to plastic particles or crude oil, the larvae exhibited some variation in contraction rate. In contrast, significant alterations in the contraction rate were observed in all cardiac cell cultures. The greatest differences between the control and treatment groups were observed in cardiac cell cultures derived from older brown trout. Following 7 days of exposure to MNPs or crude oil in Atlantic salmon larval hearts or cardiac cell cultures, there were only minor responses noted in mRNA expression of the selected marker genes. These findings show the use of a novel in vitro technique contributing to the existing body of knowledge on the impact of MNPs and crude oil on the cardiovascular system of salmonids and the associated risk. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. Methods: The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Results: We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45–50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). Conclusion: Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research. [ABSTRACT FROM AUTHOR]

Benign cardiac neoplasms are relatively uncommon. Cardiac leiomyomas are usually diagnosed as a benign metastasizing leiomyoma or as a part of intravenous leiomyomatosis spectrum. Primary cardiac leiomyomas are extremely rare and should be diagnosed after ruling out the involvement of systemic leiomyomas. Only nine cases were found in the literature that described De novo occurrence of primary intra-cardiac leiomyoma. In this study, we present a case of 60-year-old female patient with a large pedunculated mass located in the left ventricle. Histopathology examination and immunohistochemistry aid confirmed the diagnosis of benign leiomyoma. No evidence of extra cardiac lesions was detected in the patient. The patient remained healthy with no signs of recurrence four years after the surgical resection. Benign cardiac tumors are not often seen, but when they do occur, they can present a serious risk to life. This is particularly significant because these tumors can detach and cause embolization, leading to the development of strokes. Moreover, these individuals do not show any clinical symptoms, making their detection quite challenging. When there is a suspicion, it is advised to utilize echocardiography and other imaging techniques to verify the presence of a tumor. In this report, we present a rare case and provide differential diagnoses, along with a review of the literature. [ABSTRACT FROM AUTHOR]

The 2-oxoglutarate dehydrogenase complex (OGDHc) orchestrates a critical reaction regulating the TCA cycle. Although the structure of each OGDHc subunit has been solved, the architecture of the intact complex and inter-subunit interactions still remain unknown. Here we report the assembly of native, intact OGDHc from Sus scrofa heart tissue using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and subtomogram averaging (STA) to discern native structures of the whole complex and each subunit. Our cryo-EM analyses revealed the E2o cubic core structure comprising eight homotrimers at 3.3-Å resolution. More importantly, the numbers, positions and orientations of each OGDHc subunit were determined by cryo-ET and the STA structures of the core were resolved at 7.9-Å with the peripheral subunits reaching nanometer resolution. Although the distribution of the peripheral subunits E1o and E3 vary among complexes, they demonstrate a certain regularity within the position and orientation. Moreover, we analyzed and validated the interactions between each subunit, and determined the flexible binding mode for E1o, E2o and E3, resulting in a proposed model of Sus scrofa OGDHc. Together, our results reveal distinctive factors driving the architecture of the intact, native OGDHc. The 2-oxoglutarate dehydrogenase complex (OGDHc) is a rate-limiting enzyme complex regulating the TCA cycle. Here, the authors use cryo-EM and cryo-ET to discern native structures of the whole complex and reveal its assembly mechanism. [ABSTRACT FROM AUTHOR]

Georges Bataille is remarkably absent from Gilles Deleuze’s oeuvre, even though early commentators like Michel Foucault, in his ‘Theatrum Philosophicum’, recognised an obvious affinity between the two thinkers. Direct references to Bataille in Deleuze’s published works are few and far between, and most of them are barely more than offhand remarks. In these few comments, Deleuze’s treatment of Bataille seems to oscillate between contempt and admiration. In an astonishing footnote within the Anti-Oedipus, Bataille’s concept of ‘sumptuary, non-productive expenditure’ is equated with Deleuze’s and Guattari’s concept of the ‘production of consumption’. Taking this passing remark seriously would mean finding Bataille at the very heart of Deleuze’s thought. This paper, therefore, seeks to investigate the traces of Bataille in Deleuze’s work, in order to evaluate the footnote in question. I will show that the equivocation of ‘sumptuary, non-productive expenditure’ and ‘production of consumption’ is indeed warranted and that Deleuze’s thought is far closer to Bataille’s than Deleuze ever cared to admit. Bataille emerges as a great precursor to the thought of immanence, difference, and the event. [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]

The heart's intricate myocardial architecture has been called the Gordian knot of anatomy, an impossible tangle of intricate muscle fibers. This complexity dictates equally complex cardiac motions that are difficult to mimic in physical systems. If these motions could be generated by a robotic system, then cardiac device testing, cardiovascular disease studies, and surgical procedure training could reduce their reliance on animal models, saving time, costs, and lives. This work introduces a bioinspired soft robotic left ventricle simulator capable of reproducing the minutiae of cardiac motion while providing physiological pressures. This device uses thin-filament artificial muscles to mimic the multilayered myocardial architecture. To demonstrate the device's ability to follow the cardiac motions observed in the literature, we used canine myocardial strain data as input signals that were subsequently applied to each artificial myocardial layer. The device's ability to reproduce physiological volume and pressure under healthy and heart failure conditions, as well as effective simulation of a cardiac support device, were experimentally demonstrated in a left-sided mock circulation loop. This work also has the potential to deliver faithful simulated cardiac motion for preclinical device and surgical procedure testing, with the potential to simulate patient-specific myocardial architecture and motion. Editor's summary: Cardiac devices and interventions are often dependent on the use of animal models and ex vivo tissue for testing and development. Moreover, surgical training for procedure-specific skills also relies on animal tissue. Davies et al. have developed a soft robotic device that can mimic the left ventricle of the heart and reproduce cardiac motion as well as physiological hemodynamic conditions. They demonstrated the ability to simulate conditions of healthy and diseased heart states, with the potential to counter the need for animal models to develop cardiac devices. —Amos Matsiko [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]

Simple Summary: One male adult crested porcupine was found moribund in the province of Siena (Tuscany, Central Italy), and died soon after being recovered by a wildlife rescue service. At necropsy, a rounded nodule was noted on the surface of the heart. Differential diagnoses included abscess, systemic tuberculosis, parasitic cyst, and neoplasia. Histology was performed on the lesion, revealing a cystic formation in the epicardium. The cyst was lined by stratified squamous epithelium and was filled with lamellar keratin without hair shafts. The lesion was diagnosed as an epicardial epidermoid cyst (EC). EC are most commonly found in the skin, both in human and animal patients, although rarely they can occur in various internal organs. However, cardiac EC has not been reported before in animals. To the best of our knowledge, this is the first report of EC in a wild animal species. The crested porcupine (Hystrix cristata) is present in central Italy with an estimated population of 1800 individuals. Despite the local abundance, little data are available on the diseases affecting free-ranging individuals. We describe a case of an epidermoid cyst (EC) in a male adult porcupine found in the municipality of Sovicille, province of Siena (Tuscany). At necropsy, a firm rounded nodule was noted on the left ventricle wall. Histological examination revealed a cystic formation lined by stratified squamous epithelium. The cyst was filled with lamellar keratin, while hair shafts were not present. The adjacent epicardium was infiltrated by lymphoplasmacytic cells in reaction to the rupture of the cyst with the spilling of keratinaceous debris. The lesion was diagnosed as a ruptured epicardial epidermoid cyst. EC are most commonly found in the skin, both in human and animal patients, though infrequently, they can occur in any internal organ. Cardiac EC has not been reported in domestic animals, and this is the first report of EC in a wild animal species. Clinical veterinarians should consider the possibility of similar cardiac lesions in captive subjects since the long lifespan of these rodents could allow the growth of the cyst with the compression of the adjacent tissues. [ABSTRACT FROM AUTHOR]

Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal‐synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in‐vivo and in‐vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy‐related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD. [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]

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]