Publications

BACKGROUND

Studies of occupational acute mountain sickness (AMS) have not focused on the more severe end of the spectrum to date.

AIMS

To examine risk factors associated with the development of occupational AMS severe enough to receive treatment in a compression chamber.

METHODS

A nested case referent study in a cohort of high-altitude (4000 m) mine workers, comparing cases of severe, chamber-treated AMS to matched referents. Using logistic regression, we tested potential risk factors based on premorbid surveillance examinations, including cigarette smoking (current smoking, smoking intensity and exhaled carbon monoxide [CO]).

RESULTS

There were 15 cases and 30 controls. In multivariate analysis including age, sex and place of residence, current smoking was associated with increased risk of severe AMS (odds ratio [OR] 10.0; 95% confidence interval [CI] 1.5-67.4), taking into account any prior, less severe AMS event, which was also a potent risk factor (OR 33.3; 95% CI 2.8-390). Smoking intensity (cigarettes per day) and exhaled CO were also statistically significantly associated with severe AMS.

CONCLUSIONS

Cigarette smoking is a strong, previously under-appreciated risk factor for severe AMS. Because this is a modifiable factor, these findings suggest that workplace-based smoking cessation should be tested as an intervention to prevent such morbidity.

Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca(2+)]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca(2+)]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca(2+). Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca(2+)]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na(+)-Ca(2+) exchange. These results suggest that LQTS mutations act partly on cytosolic Ca(2+) cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site.