Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations

The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current

Caffeic acid phenethyl amide ameliorates ischemia/reperfusion injury and cardiac dysfunction in streptozotocin-induced diabetic rats

BACKGROUND: Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. METHODS: Type 1 diabetes mellitus was induced in Sprague–Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats. RESULTS: Compared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (l-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals. CONCLUSIONS: CAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals

Caffeic Acid Phenylethyl Amide Protects against the Metabolic Consequences in Diabetes Mellitus Induced by Diet and Streptozocin

Caffeic acid phenyl ester is distributed wildly in nature and has antidiabetic and cardiovascular protective effects. However, rapid decomposition by esterase leads to its low bioavailability in vivo. In this study, chronic metabolic and cardiovascular effects of oral caffeic acid phenylethyl amide, whose structure is similar to caffeic acid phenyl ester and resveratrol, were investigated in ICR mice. We found that caffeic acid phenylethyl amide protected against diet or streptozocin-induced metabolic changes increased coronary flow and decreased infarct size after global ischemia-reperfusion in Langendorff perfused heart. Further study indicated that at least two pathways might be involved in such beneficial effects: the induction of the antioxidant protein MnSOD and the decrease of the proinflammatory cytokine TNFα and NFκB in the liver. However, the detailed mechanisms of caffeic acid phenylethyl amide need further studies. In summary, this study demonstrated the protective potential of chronic treatment of caffeic acid phenylethyl amide against the metabolic consequences in diabetes mellitus

Cardiac Glycosides from Antiaris toxicaria with Potent Cardiotonic Activity

An ethanolic extract of Antiaris toxicaria trunk bark showed potent in vitro cardiotonic effect on isolated guinea pig atria. Bioassay-guided fractionation of the extract led to identification of 9 new cardiac glycosides (1–9, named antiarosides A-I), antiarotoxinin A (10), and 18 known compounds. Their structures were established using MS and NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The ability of these cardiotonic compounds to produce positive inotropic action and their safety indexes were examined in comparison with those of ouabain, a classical inhibitor of Na+/K+-ATPase. Malayoside (23) was nearly equipotent and had a similar safety index to ouabain in guinea pig atria. However, the maximal positive inotropic effect and safety index of 23 in papillary muscle were better than those of ouabain. An electrophysiological recording showed that 23 inhibited sodium pump current in a concentration-dependent manner

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men