Connor A Howe

• PhD
• Post-Doctoral Fellow at University of Innsbruck

A number of indigenous populations have resided at high-altitude for generations, resulting in various phenotypical adaptations promoting successful high-altitude adaptation. While many of these adaptations have been investigated in adults, little is known regarding how children residing at high-altitudes adapt, particularly with regards to the cer...

Serotonin (5-HT) is integral to signalling in areas of the brainstem controlling ventilation and is involved in central chemoreception. Selective serotonin reuptake inhibitors (SSRIs), used to effectively increase 5-HT concentrations, are commonly prescribed for depression. The effects of SSRIs on the control of breathing and the potential influenc...

Background. Since vascular responses to hypoxia in both healthy high-altitude natives and chronic mountain sickness (a maladaptive high-altitude pathology characterised by excessive erythrocytosis and the presence of symptoms – CMS) remain unclear, the role of inflammation and oxidative/nitrosative stress on the endothelium-dependent and -independe...

Permanent residence at high-altitude and chronic mountain sickness (CMS) may alter the cerebrovascular homeostasis and orthostatic responses. Healthy male participants living at sea-level (LL; n = 15), 3800 m (HL3800m; n = 13) and 5100 m (HL5100m; n = 17), respectively, and CMS highlanders living at 5100 m (n = 31) were recruited. Middle cerebral a...

Aim How the cerebral metabolic rates of oxygen and glucose utilization (CMRO 2 and CMR Glc , respectively) are affected by alterations in arterial PCO 2 (PaCO 2 ) is equivocal and therefore was the primary question of this study. Methods This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 ma...

Pentoxifylline is a non-selective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo...

Permanent residence at high-altitude and chronic mountain sickness (CMS) may alter the cerebrovascular homeostasis and orthostatic responses. 15/13/17 healthy participants living at sea-level (LL), 3,800m (HL3800m) and 5,100m (HL5100m), respectively, and 31 additional highlanders with CMS living at 5,100m were recruited. Middle cerebral artery mean...

Introduction and Objectives: Chronic Mountain Sickness (CMS) syndrome, combining excessive erythrocytosis and clinical symptoms in highlanders, remains a public health concern in high-altitude areas, especially in the Andes, with limited therapeutic approaches. The objectives of this study were to assess in CMS-highlanders permanently living in La...

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite (NO2-) signaling in the regulation of cerebral hypoxic va...

Vizcardo-Galindo, Gustavo A., Connor A. Howe, Ryan L. Hoiland, Howard H. Carter, Christopher K. Willie, Philip N. Ainslie, and Joshua C. Tremblay. Impact of oxygen supplementation on brachial artery hemodynamics and vascular function during ascent to 5,050 m. High Alt Med Biol. 24:27-36, 2023.-High-altitude trekking alters upper limb hemodynamics a...

High‐altitude (HA) hypoxia may alter the structural–functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex‐, age‐ and body mass index‐matched healthy highlanders (n = 9) native to CdP...

We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function (cerebral shear-mediated dilation; cSMD) in the internal carotid artery (ICA) with and without systemic 1 -adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, while cSMD would remain unchanged, after Prazosin administration when...

This study investigated the influence of acute reductions in arterial O 2 content (CaO 2 ) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO 2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m ² ). Radial artery and internal jugular vein catheters provided measurement of blo...

New findings: What is the central question of this study? We assessed the contributions of shear stress to brachial artery vasodilation during hypercapnia, using a within-individual bilateral experimental design, with increases in shear stress in one artery prevented via manual arterial compression. We repeated this design with and without an α₁-a...

High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood t...

Introduction Chronic mountain sickness (CMS) is a condition characterized by excessive erythrocytosis in response to chronic hypobaric hypoxia. CMS frequently triggers cardiorespiratory diseases such as pulmonary hypertension and right or left heart failure. Ambient hypoxia might be further amplified night-time by intermittent hypoxia related to sl...

Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A. Howe, David MacLeod, James D. Anholm, Christopher Gasho, and Michael M. Tymko. Global REACH 2018: characterizing acid-base balance over 21 days at 4,300 m in lowlanders. High Alt Med Biol. 00:000-000, 2022. Introduction: High altitude exposure results in hy...

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH(a) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations - where the latter are thought to be fully adapted t...

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear‐mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)‐dependency of CVR and cSMD. Eleven volunteers underwent a steady‐state CVR t...

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO 3 ⁻ ]) and carbon dioxide tension (PCO 2 ) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO 2 (PaCO 2 ) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaus...

Background Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpa at high altitude. In contrast, the pulmonary vasculature of Andeans suffering with chronic mountain sickness is resistant to iron administration. While pulmonary vascular remodeling and hypertension are characteristic features of c...

Haemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signalling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: (i) at sea level, in normoxia and isocapnic hypoxia w...

Key points We investigated the influence of arterial PCO2 (PaCO2) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso‐oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3–]. The NVC response was not altered following NaHCO3 between...

New findings: What is the central question of this study? How does deep breath-hold diving impact cardiopulmonary function, both acutely and over the subsequent 2.5 hours post-dive? What is the main finding and its importance? Breath-hold diving to depths below residual volume are associated with acute impairments in pulmonary gas exchange, that t...

Key points We investigated the influence of arterial PCO2 (PaCO2) with and without acutely elevated arterial pH and bicarbonate ([HCO3–]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso‐oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. so...

Key points Brachial artery (BA) shear‐mediated dilatation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk. Cerebral vascular health is often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide. We show that endothelium‐dependent diameter (dil...

Key points Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular couplin...

New findings: What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia an...

Key points Changes in haematocrit influence nitric oxide signalling through alterations in shear stress stimuli and haemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously Isovolumic haemodilution led to a marked increase in brachial artery flow‐mediated dilatation in humans The increase in flow‐me...

We hypothesized that an expiratory resistance and dead space (ER/DS) mask, a version of which was previously shown to partially alleviate sleep-disordered breathing and headache severity during acute normobaric hypoxia (Patrician et al.), would exhibit similar results in conditions of hypobaric hypoxia. In a randomized, single-blinded, sham-control...

New findings: What is the central question of this study? Herein, a methodological overview of our research team's (Global REACH) latest high altitude research expedition to Peru is provided. What is the main finding and its importance? The experimental objectives, expedition organization, measurements, and key cohort data are discussed. The selec...

New findings: What is the central question of this study? Does chronic mountain sickness (CMS) alter sympathetic neural control and arterial baroreflex regulation of blood pressure in Andean (Quechua) highlanders? What is the main finding and its importance? Compared to healthy Andean highlanders, basal sympathetic vasomotor outflow is lower, baro...

Background Pulmonary gas exchange efficiency, determined by the alveolar-to-arterial PO2 difference (A-aDO2), progressively worsens during exercise at sea-level; this response is further elevated during exercise in hypoxia. Traditionally, pulmonary gas exchange efficiency is assessed through measurements of ventilation and end-tidal gases paired wi...

Purpose We examined the effects of hypoxaemia on dynamic cerebral autoregulation (dCA) in lowlanders and Sherpa highlanders. We hypothesized that dCA in lowlanders would be reduced to a greater extent in the common carotid artery (CCA) compared to the internal carotid artery (ICA) during acute hypoxia at sea level and at high altitude, whereas Sher...

New findings: What is the central question of this study? To determine if differing magnitudes of ventilation influence cerebrovascular CO2 reactivity and the cerebral blood flow response to increases in arterial carbon dioxide. What is the main finding and its importance? The main finding is that while a greater ventilation, through voluntary hyp...

Key points Aerobic exercise elicits increases in cerebral blood flow (CBF), as well as core body temperature; however, the isolated influence of temperature on CBF regulation during exercise has not been investigated The present study assessed CBF regulation and neurovascular coupling during submaximal cycling exercise and temperature‐matched passi...

Key points Thermal and hypoxic stress commonly coexist in environmental, occupational and clinical settings, yet how the brain tolerates these multi‐stressor environments is unknown Core cooling by 1.0°C reduced cerebral blood flow (CBF) by 20–30% and cerebral oxygen delivery (CDO2) by 12–19% at sea level and high altitude, whereas core heating by...

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g dl ⁻¹ in adult males) is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation; however, whether a similar impairment occurs in response to more commonly-encountered sustained increases in shear stres...

New findings: The central question of this study was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high-altitude. Through haemodilution, we determined that, following one-week of acclimatization, the primary mechanism contributing to the cerebral blood flow...

Key points Sherpa have lived in the Nepal Himalaya for 25–40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery...

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans wi...

Breath‐hold diving is a ubiquitous activity, with recreational, fishing, military and competitive divers. During a dive, immersion and the increasing hydrostatic pressure of descent facilitate cardiovascular adjustments that promote a blood volume shift into the heart and chest vasculature, further augmenting autonomic responses (i.e. diving bradyc...

We examined the hypothesis that an expiratory resistance mask containing a small amount of dead space (ER/DS) would reduce the apnea-hypopnea index (AHI) during sleep, attenuate the severity of acute mountain sickness (AMS), and offset decrements in cognitive function compared with a sham mask. In a double-blinded, randomized, sham-controlled, cros...

The study of conduit artery endothelial adaptation to hypoxia has been restricted to the brachial artery, and comparisons to highlanders have been confounded by differences in altitude exposure, exercise, and unknown levels of blood viscosity. To address these gaps, we tested the hypothesis that lowlanders, but not Sherpa, would demonstrate decreas...

Blood pressure regulation is widely recognised as being integral to the control of end-organ perfusion but it remains unclear whether end-organ perfusion also plays a role in driving changes in blood pressure (BP). A randomized and placebo controlled study design was followed to examine the feedback relationships between very-low-frequency fluctuat...

Shear stress (SS) regulates blood flow within the systemic and cerebral circulation. For example, in clinical populations (e.g. hemochromatosis), endothelium‐dependent flow‐mediated dilation (FMD) is improved and impaired by increases and decreases in whole blood viscosity (WBV), respectively. We tested the hypothesis that reductions in WBV would a...

Experimentally-induced oscillatory shear stress (OSS) and hypoxia reduce endothelial function in humans. Acute and sustained hypoxia may cause increases in resting OSS; however, whether this influences endothelial susceptibility to further increases in OSS is unknown. Healthy lowlanders (n=15, 30{plus minus}6 years [mean{plus minus}SD]) participate...

Ascent to high-altitude elicits compensatory physiological adaptations in order to improve oxygenation throughout the body. The brain is particularly vulnerable to the hypoxemia of terrestrial altitude exposure. Herein we review the ventilatory and cerebrovascular changes at altitude and how they are both implicated in the maintenance of oxygen del...

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high-altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g. shear...

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, placebo controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants t...

Key points: Our objective was to quantify endothelial function (via brachial artery flow-mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate-intensity cycling exercise with and without administration of an α1 -adrenergic blockade. Brachial endothelial function did...