AbstractIntroduction: Chronic Mountain Sickness (CMS), a syndrome that occurs after long-term exposure to high-altitude (> 2,500 m), is a public health problem experienced primarily by Andean countries. Although the cause of CMS is not understood and likely multifaceted, clinical symptoms of the disease disappear by descending to a lower altitude. CMS is characterized by exaggerated chronic arterial hypoxaemia, excessive erythrocytosis(EE) that can lead to myocardial failure and stroke, both recognised as the most common causes of death for CMS patients.Studies have identified that impaired systemic vascular endothelial function, subsequent to a free radical-mediated reduction in nitric oxide (NO) bioavailability [oxidative-nitrosative stress(OXNOS)], may contribute to the increased cardiovascular and potentially cerebrovascular risk. The observation that antioxidant defences are depressed in CMS patients tentatively suggests that inadequate dietary intake may predispose to vascular dysfunction. To that end, dietary intake of antioxidant nutrients in CMS sufferers and well-adapted (non-CMS) highlanders has not previously been assessed.
Aim: The aim of the study was to explore the potential relationships between dietary antioxidant nutrient intake, systemic vascular endothelial function and clinical outcomes(cognition and depression) in patients with(CMS+) and without(CMS-) CMS and compare to normoxicage-matched lowlander controls.
Hypotheses: It was hypothesised that: i) CMS+ would be characterised by impaired systemic vascular endothelial function, cognitive function and depression compared to CMS-and normoxic aged-matched lowlander controls, subsequent to ii) low intake of dietary antioxidants and corresponding elevation in systemic OXNOS.
Methodology: Thirty-three male highlanders were recruited from La Paz, Bolivia (3,600m). Twenty were diagnosed with CMS (CMS+; aged 58 ± 8 years; CMS score 9 ± 6points)and thirteen were free of CMS (CMS-; aged54 ± 7 years; CMS score 2 ± 2points). We also recruited thirteen British participants born and bred close to sea level (approximate altitude 80 m) (controls; aged 60 ±
37 years). Overnight fasted venous blood samples were obtained for the direct detection of plasma ascorbate free radical (A•-, electron paramagnetic resonance spectroscopy) and nitrite (NO2−, reductive ozone-based chemiluminescence) for the collective assessment of systemic OXNOS. Systemic vascular function was assessed using flow-mediated dilation (FMD, duplex ultrasound), arterial stiffness (applanation tonometry), the latter defined by carotid-femoral pulse wave velocity (c-f PWV), augmentation index normalised for a heart rate of 75 beats/minute(AIx@75) and carotid intima-media thickness (cIMT). Montreal Cognitive Assessment (MoCA) was used to clinically assess cognition and Beck Depression Inventory-II (BDI-II) to assess depression. Participants were also interviewed to collect 48-hourstructured dietary recall with data analysed using NetWISP dietary analysis software (Version4.0, Tinuviel Software; Anglesey, UK). Data were tested for normality using Shapiro-Wilk W tests and analysed using one-way ANOVAs and post hoc Bonferroni-adjusted independent samples t-tests.
Results: CMS+ patients reported lower intake of vitamin C (P= 0.003 vs. CMS-; P= <0.000 vs. controls) and carotene (P = 0.050 vs. CMS-; P= 0.058 vs. controls) due to inadequate consumption of fruit and vegetables. CMS+ exhibited a marked and persistent elevation in systemic OXNOS(P= <0.000 vs. controls), impaired FMD (P= <0.001 vs. controls)and greater c-f PWV(P= <0.001vs. controls) and AIx@75(P= 0.022 vs. controls) compared to lowlander controls and increased cIMT (P= 0.027 vs. CMS-) compared to CMS-. CMS+ patients also exhibited more pronounced cognitive impairment (P= 0.044 vs. CMS-; P= 0.001 vs. controls) and depression (P= 0.044 vs. CMS-; P= 0.014 vs. controls).
Discussion: Consistent with the hypothesis, CMS+ patients were characterised by an inadequate intake of dietary antioxidant vitamins, the likely consequence of inadequate fruit and vegetable consumption. This may have led to a chronic state of imbalance between the production of oxidants and antioxidant defence capacity, contributing to the persistent elevation in systemic OXNOS confirmed by a free radical-mediated reduction in vascular NO bioavailability. This may have contributed, at least in part, to the observed reduction in systemic vascular function, cognitive impairment and depression. While CMS-intake of vitamin C along with fruit and vegetable consumption were within the recommended amount, it may be argued that a higher intake of uncooked fruit and vegetables should be recommended for the highlander dwellers given the consistent elevation in systemic OXNOS and reduction in vascular function also observed in this subgroup.
Conclusions: Collectively, these findings demonstrate for the first time, that CMS+ are characterised by inadequate consumption of fruit and vegetables. A corresponding reduction in dietary antioxidant vitamin intake may contribute to systemic OXNOS-mediated impairments in vascular/cognitive function and depression.Public health programmes need to consider targeted dietary interventions, including nutrition education and dietary modification, that may help improve clinical outcomes in the highlander population.
|Date of Award||2022|
|Supervisor||Damian Bailey (Supervisor) & Christopher Marley (Supervisor)|