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

Reduced blood flow through intrapulmonary arteriovenous anastomoses at rest and during exercise in lowlanders during acclimatization to high altitude

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) is elevated during exercise at sea level (SL) and at rest in acute normobaric hypoxia. Following high altitude (HA) acclimatization, resting QIPAVA is similar to SL, but it is unknown if this is true during exercise at HA. We reasoned that exercise at HA (5,050 m) would exacerbate QIPAVA due to heightened pulmonary arterial pressure. Using a supine cycle ergometer, seven healthy adults free from intracardiac shunts underwent an incremental exercise test at SL (25, 50, 75% of SL VO2peak ) and at HA (25, 50% of SL VO2peak ). Echocardiography was used to determine cardiac output (Q) and pulmonary artery systolic pressure (PASP) and agitated saline contrast was used to determine QIPAVA (bubble score; 0-5). The principal findings were: (1) Q was similar at SL-rest (3.9 +/- 0.47 l min-1 ) compared with HA-rest (4.5 +/- 0.49 l min-1 ; P = 0.382), but increased from rest during both SL and HA exercise (P < 0.001); (2) PASP increased from SL-rest (19.2 +/- 0.7 mmHg) to HA-rest (33.7 +/- 2.8 mmHg; P = 0.001) and, compared with SL, PASP was further elevated during HA exercise (P = 0.003); (3) QIPAVA was increased from SL-rest (0) to HA-rest (median = 1; P = 0.04) and increased from resting values during SL exercise (P < 0.05), but were unchanged during HA exercise (P = 0.91), despite significant increases in Q and PASP. Theoretical modeling of microbubble dissolution suggests that the lack of QIPAVA in response to exercise at HA is unlikely caused by saline contrast instability

Assessment of the stability and quantification of agitated saline contrast to assess blood flow through intrapulmonary arteriovenous anastomoses

Substantial research has been conducted on right-to-left shunts in healthy humans using transthoracic agitated saline contrast echocardiography (TTSCE), however, TTSCE is limited by an inherent instability and an imprecise method of quantification. The goal of this dissertation is twofold: (1) to assess the stability of TTSCE using an in vitro model of the pulmonary circulation under varying environmental conditions, and (2) to determine the feasibility of measuring shunt fraction by modelling ultrasound contrast data. Study 1 aims to determine if the stability of saline contrast microbubbles is altered under gas conditions that match mixed venous (5.9 % CO2, 4.9 % O2) blood and hyperoxic conditions (100% O2) at varying flow rates (1.8, 2.8, 4.3 & 6.8 l/min). At higher flow rates (4.3 & 6.8 l/min), less ultrasound contrast was lost in the hyperoxic vs mixed venous gas condition whereas no significant difference was observed at low flow rates (1.8 – 2.8 l/min). The purpose of study 2 was to determine if hypobaria (simulated altitude: 5050m) affects microbubble stability. Using the experimental design from study 1, it was determined that reduced barometric pressure did not significantly alter microbubble stability. Finally, study 3 was designed to determine if mathematical modelling can be applied to saline contrast data from TTSCE to quantify a simulated shunt fraction. Saline contrast was injected into an in vitro model of the pulmonary circulation that was adapted to include an adjustable shunt vessel. Results show a good agreement between shunt flow measured using modeled data and actual shunt flow at higher flow rates but was less reliable at low flow rates. In summary, we determined that the stability of saline contrast microbubbles generated using TTSCE is not affected by hypobaria and is only slightly increased in hyperoxic conditions compared to mixed venous conditions suggesting the technique can be employed in a wide variety of environmental conditions. Furthermore, this work demonstrates that mathematical modelling applied to saline contrast ultrasound data can be used to assess shunt fraction, however it loses some fidelity at low flow rates and with small shunt fractions.Health and Social Development, Faculty of (Okanagan)Graduat

Influence of methazolamide on the human control of breathing : a comparison to acetazolamide

Acetazolamide is used to prevent/treat acute mountain sickness and both central and obstructive sleep apnoea. Methazolamide, like acetazolamide reduces hypoxic pulmonary vasoconstriction, but has fewer side effects including less skeletal muscle function impairment. Since methazolamide’s effects on respiratory control in humans are unknown, we (1) compared the effects of oral methazolamide and acetazolamide on ventilatory control, and (2) determined the ventilation-log PO₂ relationship in humans. In a double blind, placebo-controlled, randomized cross-over design, we studied the effects of acetazolamide (250 mg tid), methazolamide (100 mg bid) and placebo in fourteen young male subjects who were exposed to 7 minutes of normoxic hypercapnia and to three levels of eucapnia and hypercapnic hypoxia. With placebo, methazolamide, and acetazolamide, the CO₂ sensitivities were 2.39 ± 1.29, 3.27 ± 1.82 and 2.62 ± 1.79 l/min/mmHg (NS) and estimated apnoeic thresholds were 32 ± 3, 28 ± 3 and 26 ± 3 mmHg, respectively (P < 0.001, placebo vs methazolamide and acetazolamide). The relationship between ventilation (V̇ I) and log PO₂ (using arterialized venous PO₂ in hypoxia) was linear, while neither agent influenced the relationship between hypoxic sensitivity (ΔV̇ I/Δlog PO₂) and arterial [H⁺]. Using ΔV̇ I/Δlog PO₂ rather than ΔV̇ I/ΔSaO₂ enables a more accurate estimation of oxygenation and ventilatory control in metabolic acidosis/alkalosis when right- or left-ward shifts of the oxyhaemoglobin saturation curve occur. Since acetazolamide and methazolamide has similar effects on ventilatory control, methazolamide may be preferred for indications requiring the use of a carbonic anhydrase inhibitor, avoiding some of the negative side-effects of acetazolamide.Health and Social Development, Faculty of (Okanagan)Medicine, Faculty ofOther UBCNon UBCHealth and Exercise Sciences, School of (Okanagan)Southern Medical Program (Okanagan)ReviewedFacult

Changes in left ventricular function and coronary blood flow velocity during isocapnic hypoxia: A cardiac magnetic resonance imaging study

Other UBCNon UBCReviewedFacult