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

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

Influence of myocardial oxygen demand on the coronary vascular response to arterial blood gas changes in humans

It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial PO2 and PCO2 or if coronary vascular responses are the result of concomitant increases in myocardial O2 consumption/demand (MVO2). We hypothesized that the coronary vascular response to PO2 and PCO2 would be attenuated in healthy men when MVO2 was attenuated with β1-adrenergic receptor blockade. Healthy men (n=11; age: 25 {plus minus} 1 years) received intravenous esmolol (β1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized, crossover study, and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and following 5-min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate and arterial blood pressure. LADV values at the end of each hypoxic condition were compared between esmolol and placebo. Rate pressure product (RPP) and left-ventricular mechanical energy (MELV) were calculated as indices of MVO2. All gas manipulations augmented RPP, MELV, and LADV but only RPP and MELV were attenuated (4-18%) following β1-adrenergic receptor blockade (P<0.05). Despite attenuated RPP and MELV responses, β1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response when compared to placebo during poikilocapnic hypoxia (29.4{plus minus}2.2 vs. 27.3{plus minus}1.6 cm/s) and isocapnic hypoxia (29.5{plus minus}1.5 vs. 30.3{plus minus}2.2 cm/s). Hypercapnic hypoxia elicited a feed-forward coronary dilation that was blocked by β1-adrenergic receptor blockade. These results indicate a direct influence of arterial PO2 on coronary vascular regulation that is independent of MVO2

The independent effects of hypovolemia and pulmonary vasoconstriction on ventricular function and exercise capacity during acclimatisation to 3800 m

We aimed to determine the isolated and combined contribution of hypovolemia and hypoxic pulmonary vasoconstriction in limiting left ventricular (LV) function and exercise capacity under chronic hypoxemia at high altitude. In a double‐blinded, randomized and placebo‐controlled design, twelve healthy participants underwent echocardiography at rest and during submaximal exercise before completing a maximal test to exhaustion at sea level (SL; 344 m) and after 5–10 days at 3800 m. Plasma volume was normalised to SL values, and hypoxic pulmonary vasoconstriction was reversed by administration of Sildenafil (50 mg) to create four unique experimental conditions that were compared with SL values; high altitude (HA), Plasma Volume Expansion (HA‐PVX), Sildenafil (HA‐SIL) and Plasma Volume Expansion with Sildenafil (HA‐PVX‐SIL). High altitude exposure reduced plasma volume by 11% (P < 0.01) and increased pulmonary artery systolic pressure (19.6 ± 4.3 vs. 26.0 ± 5.4, P < 0.001); these differences were abolished by PVX and SIL respectively. LV end‐diastolic volume (EDV) and stroke volume (SV) were decreased upon ascent to high altitude, but were comparable to sea level in the HA‐PVX. LV EDV and SV were also elevated in the HA‐SIL and HA‐PVX‐SIL trials compared to HA, but to a lesser extent. Neither PVX or SIL had a significant effect on the LV EDV and SV response to exercise, or the maximal oxygen consumption or peak power output. In summary, at 3800 m both hypovolemia and hypoxic pulmonary vasoconstriction contribute to the decrease in LV filling, however, restoring LV filling does not confer an improvement in maximal exercise performance

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

In contrast to Andean natives, high altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e. no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also elevated in Sherpa compared to lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and towards a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude