Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial–mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal–endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.

Secretome of Stressed Peripheral Blood Mononuclear Cells Alters Transcriptome Signature in Heart, Liver, and Spleen after an Experimental Acute Myocardial Infarction: An In Silico Analysis

Acute myocardial infarction (AMI) is a result of cardiac non-perfusion and leads to cardiomyocyte necrosis, inflammation, and compromised cardiac performance. Here, we showed that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) improved heart function in a porcine AMI model and displayed beneficial long- and short-term effects. As an AMI is known to strongly affect gene regulation of the ischemia non-affected heart muscle and distal organs, we employed a transcriptomics approach to further study the immediate molecular events orchestrated using the PBMCsec in myocardium, liver, and spleen 24 h post ischemia. In the infarcted area, the PBMCsec mainly induced genes that were essential for cardiomyocyte function and simultaneously downregulated pro-inflammatory genes. Interestingly, genes associated with pro-inflammatory processes were activated in the transition zone, while being downregulated in the remote zone. In the liver, we observed a pronounced inhibition of immune responses using the PBMCsec, while genes involved in urea and tricarboxylic cycles were induced. The spleen displayed elevated lipid metabolism and reduced immunological processes. Together, our study suggested several types of pharmacodynamics by which the PBMCsec conferred immediate cardioprotection. Furthermore, our data supported the assumption that an AMI significantly affects distal organs, suggesting that a holistic treatment of an AMI, as achieved by PBMCsec, might be highly beneficial.

Exercise Rehabilitation Improves Heart Function and Quality of Life in Elderly Patients with Chronic Heart Failure

With the acceleration of the aging process, there are more and more elderly patients with chronic heart failure. Chronic heart failure has severely affected the heart function and quality of life of the elderly. This article aims to study the further improvement of the heart function and the quality of life of elderly patients with chronic heart failure through exercise rehabilitation. In this paper, experimental analysis and comparative analysis are adopted, the experimental group and the control group are designed, the adaptive heart rate and breathing rate algorithm is adopted, the heart failure symptom assessment scale and the quality of life assessment tool are selected, and the two groups of different rehabilitation forms are compared. Data collection, sorting, and analysis of the patient’s conditions are utilized. Through the use of exercise rehabilitation, the heart failure process will be slower and the recovery of heart strength will be faster than the control group. Before the experiment, the probability of shortness of breath in the two groups of patients with chronic heart failure symptoms was as high as 84.08%, and the symptom clusters were more serious; after the experiment, the SV and EF values after exercise rehabilitation were higher than those of the control group ( p < 0.05 ). The quality of life in the realm, emotional realm, and other realms has been significantly improved. For elderly patients with chronic heart failure, reasonable exercise rehabilitation training can provide them with effective preventive measures and protective measures, improve the patients’ heart function and quality of life, and play an important and key role.

Thyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes

Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3′,5-triiodo-l-Thyronine (T3) and 3,3′,5,5′-tetraiodo-l-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq analysis showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.

Impairment of μ-calpain activation by rhTNFR:Fc reduces severe burn-induced membrane disruption in the heart

Stress cardiomyopathy is a major clinical complication after severe burn. Multiple upstream initiators have been identified; however, the downstream targets are not fully understood. This study assessed the role of the plasma membrane in this process and its relationship with the protease μ-calpain and tumor necrosis factor-alpha (TNF-α). Here, third-degree burn injury of approximately 40% of the total body surface area was established in rats. Plasma levels of LDH and cTnI and cardiac cell apoptosis increased at 0.5 h post burn, reached a peak at 6 h, and gradually declined at 24 h. This effect correlated well with not only the disruption of cytoskeletal proteins, including dystrophin and ankyrin-B, but also with the activation of μ-calpain, as indicated by the cleaved fragments of α-spectrin and membrane recruitment of the catalytic subunit CAPN1. More importantly, these alterations were diminished by blocking calpain activity with MDL28170. Burn injury markedly increased the cellular uptake of Evans blue, indicating membrane integrity disruption, and this effect was also reversed by MDL28170. Compared with those in the control group, cardiac cells in the burn plasma-treated group were more prone to damage, as indicated by a marked decrease in cell viability and increases in LDH release and apoptosis. Of note, these alterations were mitigated by CAPN1 siRNA. Moreover, after neutralizing TNF-α with rhTNFR:Fc, calpain activity was blocked, and heart function was improved. In conclusion, we identified μ-calpain as a trigger for severe burn-induced membrane disruption in the heart and provided evidence for the application of rhTNFR:Fc to inhibit calpain for cardioprotection.

Decrease of Pdzrn3 is required for heart maturation and protects against heart failure

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

In vivo Antioxidant Related Effect of Orally Administered Aqueous Extract of Saliva triloba in Human Volunteers

Saliva triloba, belongs to the Lamiaceae family, is one in all the vital medicinal plant species. This work aims to study the antioxidant-related effects of trilobite saliva in the human body through in vivo studies and the effects on liver, kidney, and heart function tests. For five days, nine healthy participants consumed 250 mL of trilobite saliva extract orally. On the fifth day, blood samples were taken one hour before and after the first dosage of water extract (samples I and II, respectively), and again one day after the last dose (ie, day 6, sample III). Before the first dosage, the first blood sample was taken (ie sample I) was used as a control for the subsequent II and III samples. Subsequent determinations were performed: serum total antioxidant status (TAS), red blood cell reduced glutathione (GSH), red blood cell superoxide dismutation (SOD) A activity, malondialdehyde (MDA), and serum-selected biochemical tests. After 5 days of oral administration of trilobite saliva extract in healthy volunteers, serum TAS, erythrocyte GSH and erythrocyte SOD activity were significantly increased, and had no influence on serum biochemical examinations of kidney, liver, heart, pancreas, etc., contrasted with zero-time management. In Conclusion, salivary clover extract has effective anti-oxidation related effects in vivo. Because these findings were obtained in healthy people without oxidative stress, it means that clover saliva will enhance the bottom line of the defense system against probable oxidative stress while having no adverse effects, decreasing or avoiding pathological diseases associated with oxidative stress

Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Label-free Quantitative Proteomics Combined With Transcriptomics Revealed the Importance of Cardiac Development in Producing the High Metabolic Capacity of Yellowfin Tuna (Thunnus Albacares)

Tuna are commercially important fish throughout the world, and they are renowned for their endothermy, which allows them to maintain elevated temperatures in the oxidative locomotor muscles, viscera, brain, and eyes while occupying cold, productive, high-latitude waters. The endothermic mechanism is supported by a high heart rate and cardiac output, but the genes and proteins that participate in this cardiac function are poorly known. In this study, we combined label-free quantitative proteomics and transcriptomics to investigate the changes in the heart of yellowfin tuna (Thunnus albacares) before and after they developed endothermy. We identified 515,428 transcripts and 3355 protein groups in the hearts of two development stages of yellowfin tuna. Twenty-eight differentially expressed proteins were correlated with differentially expressed genes. The proteins that accelerate energy production were more highly expressed in the hearts of the large yellowfin tuna compared with the small specimens. Moreover, the proteins in the Z-disk, which protect against mechanical damage, were only detected in the hearts of large fish. These results indicate that as yellowfin tuna grow, the heart develops a self-protection strategy to cope with high metabolic rates and high mechanical forces. The differentially expressed proteins related to cardiac function, which are closely associated with striated muscle differentiation, glycosylation, and cardiac myocytes motility, were highly expressed in the larger (endothermic) tuna than that in the smaller (poikilothermic) tuna. Therefore, we suggest that the heart function of yellowfin tuna changes and improves during the transition from poikilothermic tuna (small size, 126 mm < fork length (FL) < 152 mm, 30 g < body weight < 46 g) to endothermic tuna (large size, 207 mm < FL < 235 mm, 170 g < body weight < 200 g). This is the first report of how gene and protein expression levels explain the strong heart function of yellowfin tuna.

Cardiac Function in Brain Death, Usage of Advanced Hemodynamic Monitoring

Background: This study used advanced hemodynamic monitoring along with simultaneous echocardiography to assess donated heart function of brain death patients using advanced hemodynamic monitoring and its efficacy in organ donation. Methods: Forty-eight brain death patients who were candidates of heart donation on the basis of primary standard investigations were selected with purposive and convenient sampling methods. They were investigated with advanced hemodynamic monitoring after echocardiography and primary assessments and the gleaned data were recorded. Results: Echocardiography showed that LVS (left ventricle size) and LVF (left ventricle function) were normal in %100 and %87.5 of patients, respectively. LVEF (left ventricle ejection fraction) was <%50 in %12.5 and >%50 in %87.5 of patients. SVR was smaller than 1200 at the beginning of the study that reached %54.4 at the end of the study. CI (cardiac index) was < 2.4 in %16.7 of the patients at the onset of the study that reached %25 at the end. Reduction of CI and SVR in patients with EF <%50 was significantly higher than that in patients with EF>%50. Conclusion: Given the extensive pathological changes in the cardiovascular system exerted by brain death, advanced hemodynamic monitoring, if performed continually, can greatly aid in managing inotropic drugs in these patients, decision-making for managing intravascular volume, creating hemodynamic stability, and finally, preventing deterioration of function of the donated heart and loss of a donated organ.