In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2

Effects of a persistent sodium current through mutated hnav1.5 sodium channels on intracellular ionic homeostasis in a ventricular cell model

International audienceIn LQT3 patients, SCN5A mutations were found that lead to a small fraction of persistent hNav1.5 current. We explored the effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell. At steady-state under 1 Hz stimulation, the presence of a persistent Na+ current (INap) with gNap 0.02 ms/cm 2 led to a prolongation of the action potential from 153 ms (control) to 223 ms and an increase of [Na+]i , diastolic and systolic [Ca2+]i and [Ca2+]SRup by 10 %, 30 %, 40 % and 43 %, respectively. These changes were larger at 3 Hz. Such intracellular Na+ and Ca2+ overload was not found when the action potential prolongation (to 222 ms at 1 Hz) was due to decreased IKr and IKs currents. The model with INap became arrhythmogenic when [K+] e was lowered from 5.4 to 5.0 mM, whereas control and low K+ current models did not produce arrhythmias even when [K+] e was 2.5 mM

Radiation on Earth or in Space: What Does It Change?

After having been an instrument of the Cold War, space exploration has become a major technological, scientific and societal challenge for a number of countries. With new projects to return to the Moon and go to Mars, radiobiologists have been called upon to better assess the risks linked to exposure to radiation emitted from space (IRS), one of the major hazards for astronauts. To this aim, a major task is to identify the specificities of the different sources of IRS that concern astronauts. By considering the probabilities of the impact of IRS against spacecraft shielding, three conclusions can be drawn: (1) The impacts of heavy ions are rare and their contribution to radiation dose may be low during low Earth orbit; (2) secondary particles, including neutrons emitted at low energy from the spacecraft shielding, may be common in deep space and may preferentially target surface tissues such as the eyes and skin; (3) a “bath of radiation” composed of residual rays and fast neutrons inside the spacecraft may present a concern for deep tissues such as bones and the cardiovascular system. Hence, skin melanoma, cataracts, loss of bone mass, and aging of the cardiovascular system are possible, dependent on the dose, dose-rate, and individual factors. This suggests that both radiosusceptibility and radiodegeneration may be concerns related to space exploration. In addition, in the particular case of extreme solar events, radiosensitivity reactions—such as those observed in acute radiation syndrome—may occur and affect blood composition, gastrointestinal and neurologic systems. This review summarizes the specificities of space radiobiology and opens the debate as regards refinements of current radiation protection concepts that will be useful for the better estimation of risks.</jats:p

Undernourished patients do not have increased risk of severe COVID-19 outcomes

International audienceBackground: Undernutrition has been previously identified as a deleterious factor in acute infections. In covid-19 infection, obesity is a risk-factor of severe evolution, but initial undernutrition has not been evaluated yet.Methods: We retrospectively analyzed correlation between nutritional status at admission and severe outcomes (intensive care unit admission, invasive mechanical ventilation requirement and death) of patients hospitalized for confirmed covid-19 infection.Results: Risk of intensive care unit admission and invasive mechanical ventilation requirement was not significantly different between undernutrition and normoweight sub-groups, but increased in excessive weight sub-group (ODDR (IC 95%) 1.048 (1.011-1.086), p = 0.011). Risk of death was the same in all sub-groups.Conclusion: Undernutrition didn't appear as a factor of severe outcomes in covid-19 infection