Could oxygen gradient ektacytometry help to detect sickle cell trait carriers at risk for kidney disorders or exercise-related complications?

The study of Ellsworth et al. (Br J Haematol, 2024) demonstrated the usefulness of oxygen gradient ektacytometry technique to better identify the physiological parameters that could increase the risk of sickling of red blood cells (RBCs) from sickle cell trait (SCT) carriers. Oxygen gradient ektacytometry combined with pH and osmolality modulations could help in identifying SCT carriers at risk for kidney disorders or exercise-related complications. Other factors than the percentages of haemoglobin S are probably involved in the propensity of RBCs from SCT carriers to sickle during deoxygenation. Commentary on: Ellsworth et al. Hypertonicity and/or acidosis induce marked rheological changes under hypoxic conditions in sickle trait red blood cells. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19669.

Controversies in the pathophysiology of leg ulcers in sickle cell disease.

Patients with sickle cell disease (SCD) often experience painful vaso-occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso-occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.

Oxygen release from hemoglobin has limited effects on mitochondrial respiration measured from red blood cells. Reply to the Comment on "Increased retention of functional mitochondria in mature sickle red blood cells is associated with increased sickling tendency, hemolysis and oxidative stress".

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Plasma monomeric ApoA1 and high-density lipoprotein bound ApoA1 are markedly decreased and associated with low levels of lipophilic antioxidants in sickle cell disease: A potential new pathway for therapy.

Patients with sickle cell disease (SCD) exhibit high levels of reactive oxygen species and low plasma levels of lipophilic antioxidants, which may contribute to end-organ damage and disease sequelae. Apolipoprotein A1, the major apolipoprotein of high-density lipoprotein (HDL), is mainly secreted by the intestine and liver in the form of monomeric ApoA1 (mApoA1) present in plasma. Cholesterol and α-tocopherol are delivered to ApoA1 via the ATP-binding cassette transporter, subfamily A, member 1 (ABCA1). We measured cholesterol, mApoA1, ApoA1, and lipophilic antioxidants in the plasma of 17 patients with SCD and 40 healthy volunteers. Mean HDL cholesterol (-C) levels in SCD patients and healthy subjects were 59.3 and 48.1 mg/dL, respectively, and plasma lutein, zeaxanthin, and α-tocopherol were 64.0%, 68.7%, and 9.1% lower, respectively. To compare SCD to healthy subjects with similar HDL-C, we also performed subgroup analyses of healthy subjects with HDL-C above or below the mean. In SCD, the mApoA1 level was 30.4 µg/mL; 80% lower than 141 µg/mL measured in healthy volunteers with similar HDL-C (56.7 mg/dL). The mApoA1 level was also 38.4% greater in the higher versus lower HDL-C subgroups (p = .002). In the higher HDL-C subgroup, lutein and zeaxanthin transported by HDL were 48.9% (p = .01) and 41.9% (p = .02) higher, respectively, whereas α-tocopherol was 31.7% higher (p = .003), compared to the lower HDL-C subgroup. Plasma mApoA1 may be a marker of the capacity of HDL to capture and deliver liposoluble antioxidants, and treatments which raise HDL may benefit patients with high oxidative stress as exemplified by SCD.

Exercise and training in sickle cell disease: Safety, potential benefits, and recommendations.

Sickle cell disease (SCD) is a genetic disorder characterized by complex pathophysiological mechanisms leading to vaso-occlusive crisis, chronic pain, chronic hemolytic anemia, and vascular complications, which require considerations for exercise and physical activity. This review aims to elucidate the safety, potential benefits, and recommendations regarding exercise and training in individuals with SCD. SCD patients are characterized by decreased exercise capacity and tolerance. Acute intense exercise may be accompanied by biological changes (acidosis, increased oxidative stress, and dehydration) that could increase the risk of red blood cell sickling and acute clinical complications. However, recent findings suggest that controlled exercise training is safe and well tolerated by SCD patients and could confer benefits in disease management. Regular endurance exercises of submaximal intensity or exercise interventions incorporating resistance training have been shown to improve cardiorespiratory and muscle function in SCD, which may improve quality of life. Recommendations for exercise prescription in SCD should be based on accurate clinical and functional evaluations, taking into account disease phenotype and cardiorespiratory status at rest and in response to exercise. Exercise programs should include gradual progression, incorporating adequate warm-up, cool-down, and hydration strategies. Exercise training represents promising therapeutic strategy in the management of SCD. It is now time to move through the investigation of long-term biological, physiological, and clinical effects of regular physical activity in SCD patients.

Making a virtue out of an evil: Are red blood cells from chronic mountain sickness patients eligible for transfusions?

We investigated highlanders, permanently living at an altitude of 5100 m and compared Chronic Mountain Sickness (CMS) patients with control volunteers. While we found differences in systemic parameters such as blood oxygen content, hematocrit, hemoglobin concentration, and blood viscosity, the mechanical and rheological properties of single red blood cells did not differ between the two investigated groups.

Liver X receptor agonist upregulates LPCAT3 in human aortic endothelial cells.

Objective: Endothelial cells (ECs) play an important role in tissue homeostasis. Recently, EC lipid metabolism has emerged as a regulator of EC function. The liver X receptors (LXRs) are involved in the transcriptional regulation of genes involved in lipid metabolism and have been identified as a potential target in cardiovascular disease. We aimed to decipher the role of LXRs in the regulation of lipid metabolism in human aortic endothelial cells. Approach and Results: Lipid composition analysis of endothelial cells treated with the LXR agonist T0901317 revealed that LXR activation increased the proportion of polyunsaturated fatty acids (PUFAs) and decreased the proportion of saturated fatty acids. The LXR agonist decreased the uptake of fatty acids (FAs) by ECs. This effect was abolished by LXRα silencing. LXR activation increased the activity and the expression of lysophosphatidylcholine acyltransferase, LPCAT3, which is involved in the turnover of FAs at the sn-2 position of phospholipids. Transcriptomic analysis also revealed that LXRs increased the expression of key genes involved in the synthesis of PUFAs, including FA desaturase one and 2, FA elongase 5 and fatty acid synthase. Subsequently, the LXR agonist increased PUFA synthesis and enhanced arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid content in the EC phospholipids. Modification of the FA composition of ECs by LXRs led to a decrease of arachidonate and linoleate derived prostaglandins synthesis and release. No change on markers of inflammation induced by plasma from sickle cell patient were observed in presence of LXR agonist. Conclusion: These results identify LXR as a key regulator of lipid metabolism in human aortic endothelial cells and a direct effect of LXR agonist on lysophosphatidylacyl transferase (LPCAT3).

Nondepolarizing muscle relaxant improves direct laryngoscopy view with no effect on face mask ventilation / Relaxantes musculares não despolarizantes melhoram a visibilidade em laringoscopia direta sem efeito sobre a ventilação via máscara facial

Abstract Background: Difficult or impossible face mask ventilation complicated with difficult tracheal intubation during anesthesia induction occurs in 0.4% of adult anesthesia cases, possibly leading to life-threatening complications. Because of such catastrophes, muscle relaxants have been recommended to be administered after confirming adequate face mask ventilation without a solid scientific validation of this principal. Methods: In this observational study, the ease of ventilation and the scores of direct laryngoscopy views before and after administration of cisatracurium were assessed in ninety young healthy adults, without anesthetic risks and without foreseen difficult intubation and who were scheduled for general elective surgeries. Results: Before muscle relaxation, 43 patients (48%) were Cormack Grade I, while the remaining 47 patients (52%) were either Cormack Grade II (28 patients, 31%) or Cormack Grade II (19 patients, 21%). Following muscle relaxation with cisatracurium, the number of patients with Cormack Grade I significantly increased from 43 patients (48%) to 65 patients (72%) (p = 0.0013). Only 1 patient out of 19 patients (5%) improved his Cormack grade from Grade III to Grade I while 16 out 19 patients (84%) improved their Cormack grade from Grade III to Grade II after the use of cisatracurium. The quality of face mask ventilation did not differ with and without muscle relaxants in all patients. Conclusion: The use of cisatracurium in healthy young adults undergoing general elective surgeries with no anticipated difficult endotracheal intubation had no effect on the quality of face mask ventilation despite resulting in a quantifiable improvement in the laryngeal view.

Resumo Justificativa: A ventilação difícil ou impossível via máscara facial complicada pela intubação traqueal difícil durante a indução da anestesia ocorre em 0,4% dos casos de anestesia em adultos, possivelmente leva a complicações fatais. Devido a tais catástrofes, recomendou-se que a administração de relaxantes musculares seja feita após a confirmação de ventilação adequada via máscara facial, sem uma validação científica sólida dessa conduta. Métodos: Neste estudo observacional, a facilidade de ventilação e os escores de visibilidade em laringoscopia direta antes e após a administração de cisatracúrio foram avaliados em 90 adultos jovens e saudáveis, sem riscos anestésicos e sem intubação difícil prevista, agendados para cirurgias eletivas gerais. Resultados: Antes do relaxamento muscular, 43 pacientes (48%) eram Cormack Grau I, enquanto os 47 (52%) restantes eram ou Cormack Grau II (28, 31%) ou Cormack Grade III (19, 21%). Após o relaxamento muscular com cisatracúrio, o número de pacientes com Cormack Grau I aumentou significativamente de 43 (48%) para 65 (72%) (p = 0,0013). Apenas um paciente (5%) dos 19 melhorou sua classificação de Cormack do Grau III para o Grau I, enquanto 16 dos 19 (84%) melhoraram suas classificações de Cormack do Grau III para o grau II após o uso de cisatracúrio. A qualidade da ventilação via máscara facial não diferiu com ou sem relaxantes musculares em todos os pacientes. Conclusão: O uso de cisatracúrio em adultos jovens saudáveis submetidos a cirurgias eletivas gerais sem intubação traqueal difícil prevista não teve efeito sobre a qualidade da ventilação via máscara facial, mesmo resultando em melhora quantificável da visibilidade da laringe.