An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis. Mouse and rabbit models have been mostly used, followed by pigs and non-human primates. Each of these models has its advantages and limitations. The mouse has become the predominant species to study experimental atherosclerosis because of its rapid reproduction, ease of genetic manipulation and its ability to monitor atherogenesis in a reasonable time frame. Both Apolipoprotein E deficient (ApoE) and LDL-receptor (LDLr) knockout mice have been frequently used, but also ApoE/LDLr double-knockout, ApoE3-Leiden and PCSK9-AAV mice are valuable tools in atherosclerosis research. However, a great challenge was the development of a model in which intra-plaque microvessels, haemorrhages, spontaneous atherosclerotic plaque ruptures, myocardial infarction and sudden death occur consistently. These features are present in ApoEFbn1 mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.

Background Flow-controlled ventilation (FCV), a novel mode of mechanical ventilation characterised by constant flow during active expiration, may result in more efficient alveolar gas exchange, better lung recruitment and might be useful in limiting ventilator-induced lung injury. However, data regarding FCV in mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome (ARDS) are scarce. Objectives We hypothesised that the use of FCV is feasible and would improve oxygenation in moderate COVID-19 ARDS compared to conventional ventilation. Design Open-label repeated-measures controlled trial. Setting From February to April 2021, patients with moderate COVID-19 ARDS were recruited in a tertiary referral intensive care unit. Patients Patients with moderate ARDS (PaO2/FIO2 ratio 100–200 mmHg, SpO2 88–94% and PaO2 60–80 mmHg) were considered eligible. Exclusion criteria were: extremes of age (< 18 years, > 80 years), obesity (body mass index > 40 kg/m2), prone positioning at the time of intervention, mechanical ventilation for more than 10 days and extracorporeal membrane oxygenation. Eleven patients were recruited. Intervention Participants were ventilated in FCV mode for 30 min, and subsequently in volume-control mode (VCV) for 30 min. Main outcome measures Feasibility of FCV to maintain oxygenation was assessed by the PaO2/FiO2 ratio (mmHg) as a primary outcome parameter. Secondary outcomes included ventilator parameters, PaCO2 and haemodynamic data. All adverse events were recorded. Results FCV was feasible in all patients and no adverse events were observed. There was no difference in the PaO2/FIO2 ratio after 30 min of ventilation in FCV mode (169 mmHg) compared to 30 min of ventilation in VCV mode subsequently (168 mmHg, 95% CI of pseudo-medians (− 10.5, 3.6), p = 0.56). The tidal volumes (p < 0.01) and minute ventilation were lower during FCV (p = 0.01) while PaCO2 was similar at the end of the 30-min ventilation periods (p = 0.31). Mean arterial pressure during FCV was comparable to baseline. Conclusions Thirty minutes of FCV in patients with moderate COVID-19 ARDS receiving neuromuscular blocking agents resulted in similar oxygenation, compared to VCV. FCV was feasible and did not result in adverse events. Trial registration: Clinicaltrials.gov identifier: NCT04894214.

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