Background— Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results— We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P <0.001) and flow-mediated dilation was 30% smaller (6.3±1.2% versus 8.3±1.4%; P <0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure ( r =−0.61, P <0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. Conclusions— Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities.

The Swiss staging model for hypothermia uses clinical indicators to stage hypothermia and guide the management of hypothermic patients. The proposed temperature range for clinical stage 1 is < 35–32 °C, for stage 2 is < 32–28 °C, for stage 3 is < 28–24 °C, and for stage 4 is below 24 °C. Our previous study using 183 case reports from the literature showed that the measured temperature only corresponded to the clinical stage in the Swiss staging model in approximately 50% of cases. This study, however, included few patients with moderate hypothermia. We aimed to expand this database by adding cases of hypothermic patients admitted to hospital to perform a more comprehensive evaluation of the staging model. We retrospectively included patients aged ≥18 y admitted to hospital between 1.1.1994 and 15.7.2016 with a core temperature below 35 °C. We added the cases identified through our previously published literature review to estimate the percentage of those patients who were correctly classified and compare the theoretical with the observed temperature ranges for each clinical stage. We included 305 cases (122 patients from the hospital sampling and the 183 previously published). Using the theoretically derived temperature ranges for clinical stages resulted in 185/305 (61%) patients being assigned to the correct temperature range. Temperature was overestimated using the clinical stage in 55/305 cases (18%) and underestimated in 65/305 cases (21%); important overlaps in temperature existed among the four stage groups. The optimal temperature thresholds for discriminating between the four stages (32.1 °C, 27.5 °C, and 24.1 °C) were close to those proposed historically (32 °C, 28 °C, and 24 °C). Our results provide further evidence of the relationship between the clinical state of patients and their temperature. The historical proposed temperature thresholds were almost optimal for discriminating between the different stages. Adding overlapping temperature ranges for each clinical stage might help clinicians to make appropriate decisions when using clinical signs to infer temperature. An update of the Swiss staging model for hypothermia including our methodology and findings could positively impact clinical care and future research.