Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m

Upon ascent to high altitude, cerebral blood flow (CBF) rises substantially before returning to sea-level values. The underlying mechanisms for these changes are unclear. We examined three hypotheses: (1) the balance of arterial blood gases upon arrival at and across 2 weeks of living at 5050 m will closely relate to changes in CBF; (2) CBF reactivity to steady-state changes in CO2 will be reduced following this 2 week acclimatisation period, and (3) reductions in CBF reactivity to CO2 will be reflected in an augmented ventilatory sensitivity to CO2. We measured arterial blood gases, middle cerebral artery blood flow velocity (MCAv, index of CBF) and ventilation () at rest and during steady-state hyperoxic hypercapnia (7% CO2) and voluntary hyperventilation (hypocapnia) at sea level and then again following 2–4, 7–9 and 12–15 days of living at 5050 m. Upon arrival at high altitude, resting MCAv was elevated (up 31 ± 31%; P < 0.01; vs. sea level), but returned to sea-level values within 7–9 days. Elevations in MCAv were strongly correlated (R2= 0.40) with the change in ratio (i.e. the collective tendency of arterial blood gases to cause CBF vasodilatation or constriction). Upon initial arrival and after 2 weeks at high altitude, cerebrovascular reactivity to hypercapnia was reduced (P < 0.05), whereas hypocapnic reactivity was enhanced (P < 0.05 vs. sea level). Ventilatory response to hypercapnia was elevated at days 2–4 (P < 0.05 vs. sea level, 4.01 ± 2.98 vs. 2.09 ± 1.32 l min−1 mmHg−1). These findings indicate that: (1) the balance of arterial blood gases accounts for a large part of the observed variability (∼40%) leading to changes in CBF at high altitude; (2) cerebrovascular reactivity to hypercapnia and hypocapnia is differentially affected by high-altitude exposure and remains distorted during partial acclimatisation, and (3) alterations in cerebrovascular reactivity to CO2 may also affect ventilatory sensitivity

Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. exposure to high altitude (HA) challenges the cardiovascular system to meet the metabolic demand for oxygen (O2) in an environment where arterial O2 content is markedly reduced. The drop in arterial O2 has both direct and indirect consequences for the heart, including depressed inotropy of cardiac muscle (40, 44), changes in blood volume and viscosity, and vasoconstriction of the pulmonary arteries (33). Despite these broad physiological changes, which have been reviewed previously (28, 49), there is evidence that the heart copes relatively well at HA (29, 34). Short-term HA exposure in lowland natives is characterized by a decreased plasma volume (PV), an increased sympathetic nerve activity, and pulmonary vasoconstriction (17, 30, 37), all of which have considerable impact on cardiac function and in time, could stimulate cardiac remodeling. Himalayan native Sherpa, who are of Tibetan lineage and have resided at HA for ∼25,000 yr (2), are well adapted to life at HA, demonstrating greater lung-diffusing capacity (11) and an absence of polycythemia compared with acclimatized lowlanders (4). Previous studies have also reported Sherpa to have higher maximal heart rates (HRs) and only moderate pulmonary hypertension compared with lowlanders at HA (11, 25). Due to their longevity at HA, Sherpa provide an excellent model to investigate the effects of chronic hypoxic exposure. Despite this, neither the acute nor lifelong effects of HA on right- and left-ventricular (RV and LV, respectively) structure and function have been fully assessed in lowlanders or the unique Sherpa population. Due to the unique arrangement of myofibers, cardiac form and function are intrinsically linked, as reflected in the cardiac mechanics (LV twist and rotation and ventricular strain) that underpin ventricular function. In response to altered physiological demand, ventricular mechanics acutely change (16, 41) and chronically remodel (31, 42) to reduce myofiber stress and achieve efficient ejection (5, 47). Therefore, concomitant examination of myocardial mechanics and ventricular structure in both the acute and chronic HA setting will provide novel insight into human adaptation to hypoxia. To investigate the effects of chronic hypoxic exposure, we compared ventricular volumes and mechanics in Sherpa at 5,050 m with lowlanders at sea level (SL). In addition, to reveal potential stimuli for remodeling and to examine the time course of adaptation, we compared Sherpa with lowlanders after short-term HA exposure. We hypothesized that: 1) Sherpa would exhibit smaller LV volumes and a higher RV/LV ratio than lowlanders at SL, 2) LV mechanics in Sherpa will closely resemble those of lowlanders at SL, and 3) following partial acclimatization to HA, LV volumes would be reduced in lowlanders and LV mechanics acutely increased

Influence of indomethacin on the ventilatory and cerebrovascular responsiveness to hypoxia

Indomethacin (INDO) has the potential to be a useful tool to explore the influence of cerebral blood flow and its responses to CO2 on ventilatory control. However, the effect of INDO on the cerebrovascular and ventilatory response to hypoxia remains unclear; therefore, we examined the effect of INDO on ventilatory and cerebrovascular sensitivity to hypoxia and hypercapnia. We measured end-tidal gases, ventilation $$(\dot{V}_{\text{E}} ),$$ and middle cerebral artery velocity (MCAv) before and 90min following INDO (100mg) in 12 healthy participants at rest and during hyperoxic hypercapnia and isocapnic hypoxia. Following INDO, resting $$\dot{V}_{\text{E}}$$ and end-tidal gases were unaltered (P>0.05), whilst MCAv was lowered by 25±19% (P0.05). These findings indicate that INDO does not alter cerebrovascular and ventilatory responsiveness to hypoxia, indicating a preserved peripheral chemoreflex in response to this pharmacological agen

Cardiac structure and function in adolescent Sherpa; effect of habitual altitude and developmental stage

The purpose of this study was to examine ventricular structure and function in Sherpa adolescents to determine whether age-specific differences in oxygen saturation (S

Cerebral haemodynamics during experimental intracranial hypertension.

Intracranial hypertension is a common final pathway in many acute neurological conditions. However, the cerebral haemodynamic response to acute intracranial hypertension is poorly understood. We assessed cerebral haemodynamics (arterial blood pressure, intracranial pressure, laser Doppler flowmetry, basilar artery Doppler flow velocity, and vascular wall tension) in 27 basilar artery-dependent rabbits during experimental (artificial CSF infusion) intracranial hypertension. From baseline (∼9 mmHg; SE 1.5) to moderate intracranial pressure (∼41 mmHg; SE 2.2), mean flow velocity remained unchanged (47 to 45 cm/s; p = 0.38), arterial blood pressure increased (88.8 to 94.2 mmHg; p < 0.01), whereas laser Doppler flowmetry and wall tension decreased (laser Doppler flowmetry 100 to 39.1% p < 0.001; wall tension 19.3 to 9.8 mmHg, p < 0.001). From moderate to high intracranial pressure (∼75 mmHg; SE 3.7), both mean flow velocity and laser Doppler flowmetry decreased (45 to 31.3 cm/s p < 0.001, laser Doppler flowmetry 39.1 to 13.3%, p < 0.001), arterial blood pressure increased still further (94.2 to 114.5 mmHg; p < 0.001), while wall tension was unchanged (9.7 to 9.6 mmHg; p = 0.35).This animal model of acute intracranial hypertension demonstrated two intracranial pressure-dependent cerebroprotective mechanisms: with moderate increases in intracranial pressure, wall tension decreased, and arterial blood pressure increased, while with severe increases in intracranial pressure, an arterial blood pressure increase predominated. Clinical monitoring of such phenomena could help individualise the management of neurocritical patients.The authors would acknowledge Dr Hugh Richards and Dr Stefan Piechnik who contributed to data collection. JD is supported by a Woolf Fisher scholarship. GVV is supported by an A.G. Leventis Foundation Scholarship, and a Charter Studentship from St Edmund’s College, Cambridge. XYL is supported by Bill Gates Scholarship, and DC is supported by a Cambridge Commonwealth, European & International Trust Scholarship (University of Cambridge).This is the author accepted manuscript. The final version is available from SAGE via https://doi.org/10.1177/0271678X1663906