The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment. In developing a COVID-19 vaccine, we applied technology previously used for ...MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein, S-2P. To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of neutralizing antibodies in sera of immunized mice against pseudotyped lentivirus reporter or live wild-type SARS-CoV-2. In addition, the antibodies elicited were able to cross-neutralize pseudovirus containing the spike protein of the D614G variant, indicating the potential for broad spectrum protection. A marked Th1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens of S-2P combined with CpG 1018 alone or CpG 1018 with alum. These data support continued development of CHO-derived S-2P formulated with CpG 1018 and alum as a candidate vaccine to prevent COVID-19 disease.
Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca
) and sodium (Na⁺) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however ...the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca
/Na⁺ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca
contents, intracellular Ca
transients, L-type Ca
, reverse mode Na⁺-Ca
exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca
sparks, cytosolic and mitochondrial reactive oxygen species, and late Na⁺ current and Na⁺/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca
regulation, late Na⁺ and Na⁺/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.
Testosterone deficiency is associated with poor prognosis among patients with chronic heart failure (HF). Physiological testosterone improves the exercise capacity of patients with HF. In this study, ...we evaluated whether treatment with physiological testosterone contributes to anti-fibrogenesis by modifying calcium homeostasis in cardiac fibroblasts and we studied the underlying mechanisms. Nitric oxide (NO) analyses, calcium (Ca2+) fluorescence, and Western blotting were performed in primary isolated rat cardiac fibroblasts with or without (control cells) testosterone (10, 100, 1,000 nmol/L) treatment for 48 hours. Physiological testosterone (10 nmol/L) increased NO production and phosphorylation at the inhibitory site of the inositol trisphosphate (IP3) receptor, thereby reducing Ca2+ entry, phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) expression, type I and type III pro-collagen production. Non-physiological testosterone-treated fibroblasts exhibited similar NO and collagen production capabilities as compared to control (testosterone deficient) fibroblasts. These effects were blocked by co-treatment with NO inhibitor (L-NG-nitro arginine methyl ester L-NAME, 100 μmol/L). In the presence of the IP3 receptor inhibitor (2-aminoethyl diphenylborinate 2-APB, 50 μmol/L), testosterone-deficient and physiological testosterone-treated fibroblasts exhibited similar phosphorylated CaMKII expression. When treated with 2-APB or CaMKII inhibitor (KN93, 10 μmol/L), testosterone-deficient and physiological testosterone-treated fibroblasts exhibited similar type I, and type III collagen production. In conclusion, physiological testosterone activates NO production, and attenuates the IP3 receptor/Ca2+ entry/CaMKII signaling pathway, thereby inhibiting the collagen production capability of cardiac fibroblasts.
This is a retrospective cohort study by analyzing a multi‐institutional electronic medical records database in Taiwan to compare long‐term effectiveness and risk of major adverse cardiac events ...(MACE) in chemotherapy‐naïve metastatic castration‐resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate‐specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63‐1.17) and OS (0.68: 0.41‐1.14) between the use of ENZ and AA in chemotherapy‐naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07‐0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy‐naïve mCRPC patients with high CV risk profile.
What's new?
While second generation androgen receptor (AR)‐targeted therapies are promising for the treatment of chemotherapy‐naïve metastatic castration‐resistant prostate cancer (mCRPC), data on survival benefit and cardiovascular safety are lacking. Here, using a multi‐institutional electronic health records database, the authors investigated the effectiveness, long‐term outcome, and cardiovascular safety of the AR‐targeted mCRPC therapies enzalutamide and abiraterone. Compared to abiraterone, enzalutamide is more efficacious in terms of prostate‐specific antigen response and carries a lower risk of major adverse cardiac events. The findings are relevant for treatment decisions regarding AR‐targeted therapies for chemotherapy‐naïve mCRPC patients with high risk of adverse cardiovascular events.
The novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF ...and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms.
Migration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca
fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca
leakage, Ca
entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na
-H
exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca
leakage, Ca
entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats.
By inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca
release, extracellular Ca
entry and the profibrotic activities of atrial fibroblasts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Atrial fibrillation (AF) is the most common sustained atrial arrhythmia. Accurate detection of the timing and possibility of AF termination is vital for optimizing rhythm and rate control ...strategies. The present study evaluated whether the ventricular response (VR) in AF offers a distinctive electrocardiographic indicator for predicting AF termination.
Methods
Patients experiencing sustained paroxysmal AF for more than 3 h were observed using 24‐h ambulatory Holter monitoring. VR within 5 min before AF termination (VR 0–5 min, BAFT) was compared with VR observed during the 60th to 65th min (VR 60–65 min, BAFT) and the 120th to 125th min (VR 120–125 min, BAFT) before AF termination. Maximum and minimum VRs were calculated on the basis of the average of the highest and lowest VRs across 10 consecutive heartbeats.
Results
Data from 37 episodes of paroxysmal AF revealed that the minimum VR0–5 min, BAFT (64 ± 20 bpm) was significantly faster than both the minimum VR120–125 min, BAFT (56 ± 15 bpm) and the minimum VR60–65 min, BAFT (57 ± 16 bpm, p < .05). Similarly, the maximum VR0–5 min, BAFT (158 ± 49 bpm) was significantly faster than the maximum VR120–125 min, BAFT (148 ± 45 bpm, p < .05). In the daytime, the minimum VR0–5 min, BAFT (66 ± 20 bpm) was significantly faster than both the minimum VR60–65 min, BAFT (58 ± 17 bpm) and minimum VR120–125 min, BAFT (57 ± 15 bpm, p < .05). However, the mean and maximum VR0–5 min, BAFT in the daytime were similar to the mean and maximum VR120–125 min in the daytime, respectively. At night, the minimum, mean, and maximum VR0–5 min, BAFT were similar to the minimum, mean, and maximum VR120–125 min, respectively.
Conclusions
Elevated VR rates during AF episodes may be predictors for the termination of AF, especially during the daytime and in patients with nondilated left atria. These findings may guide the development of clinical approaches to rhythm control in AF.
Aging plays a critical role in the genesis of atrial fibrillation (AF) and also increases the risks of cardiac dysfunction and stroke in AF patients. AF is caused by increased AF triggering from ...abnormalities of the thoracic vein and/or modulated substrate (atrial) with enhancement of AF maintenance. Clinical and laboratory evidence indicates that aging is significant in the creation of atrial electrical and structural remodeling that leads to increased susceptibility to AF occurrence. Aging is commonly associated with cardiovascular comorbidities, oxidative stress, calcium dysregulation, atrial myopathy with apoptosis, and fibrosis, which all contribute to the genesis of AF. This review updates the current understanding of the effects of aging on the pathophysiology of AF.
Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist ...directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.
The right ventricular outflow tract (RVOT) is the major origin of ventricular arrhythmias, including premature ventricular contractions, idiopathic ventricular arrhythmias, Brugada syndrome, torsade ...de pointes, long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy. The RVOT has distinct developmental origins and cellular characteristics and a complex myocardial architecture with high shear wall stress, which may lead to its high vulnerability to arrhythmogenesis. RVOT myocytes are vulnerable to intracellular sodium and calcium overload due to calcium handling protein modulation, enhanced CaMKII activity, ryanodine receptor phosphorylation, and a higher cAMP level activated by predisposing factors or pathological conditions. A reduction in
and
expression may lead to electrical uncoupling in RVOT. The purpose of this review is to update the current understanding of the cellular and molecular mechanisms of RVOT arrhythmogenesis.
The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the ...current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 μg or 5 μg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.
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