Joshua C. Tremblay

Hypoxia, not pulmonary vascular pressure, induces blood flow through intrapulmonary arteriovenous anastomoses

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased by acute hypoxia during rest by unknown mechanisms. Oral administration of acetazolamide blunts the pulmonary vascular pressure response to acute hypoxia, thus permitting the observation of IPAVA blood flow with minimal pulmonary pressure change. Hypoxic pulmonary vasoconstriction was attenuated in humans following acetazolamide administration and partially restored with bicarbonate infusion, indicating that the effects of acetazolamide on hypoxic pulmonary vasoconstriction may involve an interaction between arterial pH and PCO2 . We observed that IPAVA blood flow during hypoxia was similar before and after acetazolamide administration, even after acid–base status correction, indicating that pulmonary pressure, pH and PCO2 are unlikely regulators of IPAVA blood flow.

Measuring the human ventilatory and cerebral blood flow response to CO2: a technical consideration for the end-tidal-to-arterial gas gradient.

Our aim was to quantify the end-tidal-to-arterial gas gradients for O2 (PET-PaO2) and CO2 (Pa-PETCO2) during a CO2 reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO-, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-PETCO2 would be greater in hypoxia compared with normoxia, 2) the Pa-PETCO2 would be similar, whereas the PET-PaO2 gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against PETCO2 compared with PaCO2, and 4) previously derived prediction algorithms will accurately target PaCO2. PETCO2 was controlled by dynamic end-tidal forcing in steady-state steps of -8, -4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇E), internal carotid artery blood flow (Q̇ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇E and relative changes in Q̇ICA, and MCAv against PETCO2, predicted PaCO2, and measured PaCO2. The Pa-PETCO2 was similar between hypoxia and normoxia and PFO+ and PFO-. The PET-PaO2 was greater in PFO+ by 2.1 mmHg during normoxia (P = 0.003). HCVR and CVR plotted against PETCO2 underestimated HCVR and CVR indexed against PaCO2 in normoxia and hypoxia. Our PaCO2 prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to PETCO2 compared with PaCO2.

Intermittent hypoxia and arterial blood pressure control in humans: role of the peripheral vasculature and carotid baroreflex

Intermittent hypoxia (IH) occurs in association with obstructive sleep apnea and likely contributes to the pathogenesis of hypertension. The purpose of this study was to examine the putative early adaptations at the level of the peripheral vasculature and carotid baroreflex (CBR) that may promote the development of hypertension. Ten healthy male participants (26 ± 1 yr, BMI = 24 ± 1 kg/m(2)) were exposed to 6 h of IH (1-min cycles of normoxia and hypoxia) and SHAM in a single-blinded, counterbalanced crossover study design. Ambulatory blood pressure was measured during each condition and the following night. Vascular strain of the carotid and femoral artery, a measure of localized arterial stiffness, and hemodynamic shear patterns in the brachial and femoral arteries were measured during each condition. Brachial artery reactive hyperemia flow-mediated vasodilation was assessed before and after each condition as a measure of endothelial function. CBR function and its control over leg vascular conductance (LVC) were measured after each condition with a variable-pressure neck chamber. Intermittent hypoxia 1) increased nighttime pulse pressure by 3.2 ± 1.3 mmHg, 2) altered femoral but not brachial artery hemodynamics, 3) did not affect brachial artery endothelial function, 4) reduced vascular strain in the carotid and possibly femoral artery, and 5) shifted CBR mean arterial pressure (MAP) to higher MAP while blunting LVC responses to CBR loading. These results suggest limb-specific vascular impairments, reduced vascular strain, and CBR resetting combined with blunted LVC responses are factors in the early pathogenesis of IH-induced development of hypertension.

The effect of α1 -adrenergic blockade on post-exercise brachial artery flow-mediated dilatation at sea level and high altitude.

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 not differ between sea level and high altitude at rest, nor following maximal exercise. At sea level, endothelial function decreased following 30 min of moderate‐intensity exercise, and this decrease was abolished with α1‐adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate‐intensity exercise, and administration of α1‐adrenergic blockade resulted in an increase in flow‐mediated dilatation. Our data indicate that post‐exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high‐altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function.

Pulmonary Mechanics and Gas Exchange during Exercise in Kenyan Distance Runners.

PURPOSE The purpose of this study was to determine arterial blood gases, the mechanical limits for generating expiratory flow and the work performed by the respiratory muscles during treadmill exercise in Kenyan runners. METHODS Kenyan runners (10 men and 4 women; mean ± SD age = 25.2 ± 1.3 yr) were instrumented with a radial artery catheter, an esophageal balloon-tipped catheter, and an esophageal temperature probe for the determination of blood gases, the work of breathing and core temperature, respectively. Testing occurred at 1545 m above sea level. RESULTS There were significant decreases in the arterial partial pressure of O2 and oxyhemoglobin saturation and a widening of the alveolar-to-arterial difference in O2 from rest to peak exercise. The mechanical work of breathing increased with increasing minute ventilation and was commensurate with values expected for treadmill running in elite athletes. During heavy exercise, significant expiratory flow limitation was present in half of the subjects while the remaining subjects demonstrated impending flow limitation. CONCLUSIONS Pulmonary system limitations were present in Kenyan runners in the form of exercise-induced arterial hypoxemia, expiratory flow limitation, and high levels of respiratory muscle work. It appears that Kenyan runners do not possess a pulmonary system that confers a physiological advantage.

Disturbed blood flow worsens endothelial dysfunction in moderate-severe chronic obstructive pulmonary disease

The aims of this study were: (1) to test whether oscillatory shear stress further exacerbates endothelial dysfunction in patients with moderate-severe COPD, and (2) to test whether low flow oxygen administration improves endothelial function and is protective against oscillatory shear stress-induced endothelial dysfunction in patients with moderate-severe COPD. In 17 patients and 10 age-matched non-smoking control subjects we examined brachial artery flow-mediated dilation (FMD) and circulating microparticles before and after 20 minutes of experimentally-induced oscillatory shear stress. COPD patients performed this intervention a second time following a 20-minute wash in period of low flow supplemental oxygen to normalize arterial oxygen saturation. COPD patients had ~six-fold greater baseline retrograde shear rate (P < 0.05) and lower FMD (P < 0.05). The oscillatory shear stress intervention induced significant decreases in brachial artery FMD of all groups (P < 0.05). Oscillatory shear stress elevated circulating markers of endothelial cell apoptosis (CD31+/CD41b− microparticles) in COPD patients, but not age-matched controls. Supplemental oxygen administration abrogated the oscillatory shear stress-induced increase in CD31+/CD41b− microparticles, and improved FMD after accounting for the shear stress stimulus. We have demonstrated that acutely disturbed blood flow with increased retrograde shear stress further deteriorates the already impaired endothelial function with attendant endothelial apoptosis in patients with moderate-severe COPD.

The effects of graded changes in oxygen and carbon dioxide tension on coronary blood velocity independent of myocardial energy demand

In humans, coronary blood flow is tightly regulated by microvessels within the myocardium to match myocardial energy demand. However, evidence regarding inherent sensitivity of the microvessels to changes in arterial partial pressure of carbon dioxide and oxygen is conflicting because of the accompanied changes in myocardial energy requirements. This study aimed to investigate the changes in coronary blood velocity while manipulating partial pressures of end-tidal CO2 (Petco2) and O2 (Peto2). It was hypothesized that an increase in Petco2 (hypercapnia) or decrease in Peto2 (hypoxia) would result in a significant increase in mean blood velocity in the left anterior descending artery (LADVmean) due to an increase in both blood gases and energy demand associated with the concomitant cardiovascular response. Cardiac energy demand was assessed through noninvasive measurement of the total left ventricular mechanical energy. Healthy subjects (n = 13) underwent a euoxic CO2 test (Petco2 = -8, -4, 0, +4, and +8 mmHg from baseline) and an isocapnic hypoxia test (Peto2 = 64, 52, and 45 mmHg). LADVmean was assessed using transthoracic Doppler echocardiography. Hypercapnia evoked a 34.6 ± 8.5% (mean ± SE; P < 0.01) increase in mean LADVmean, whereas hypoxia increased LADVmean by 51.4 ± 8.8% (P < 0.05). Multiple stepwise regressions revealed that both mechanical energy and changes in arterial blood gases are important contributors to the observed changes in LADVmean (P < 0.01). In summary, regulation of the coronary vasculature in humans is mediated by metabolic changes within the heart and an inherent sensitivity to arterial blood gases.

One session of remote ischemic preconditioning does not improve vascular function in acute normobaric and chronic hypobaric hypoxia

What is the central question of this study? It is suggested that remote ischemic preconditioning (RIPC) might offer protection against ischaemia–reperfusion injuries, but the utility of RIPC in high‐altitude settings remains unclear. What is the main finding and its importance? We found that RIPC offers no vascular protection relative to pulmonary artery pressure or peripheral endothelial function during acute, normobaric hypoxia and at high altitude in young, healthy adults. However, peripheral chemosensitivity was heightened 24 h after RIPC at high altitude.

Flow-mediated dilation stimulated by sustained increases in shear stress: a useful tool for assessing endothelial function in humans?

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress after the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress [sustained stimulus (SS)-FMD], most often created with limb heating or exercise. Exercise in particular creates a physiologically relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH-FMD versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and, as such, SS-FMD and RH-FMD appear to offer unique insights regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding 1) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and 2) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and that further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes. NEW & NOTEWORTHY Sustained increases in peripheral conduit artery shear stress, created via distal skin heating or exercise, provide a physiologically relevant stimulus for flow-mediated dilation (FMD). Sustained stimulus FMD and FMD stimulated by transient, reactive hyperemia-induced increases in shear stress provide distinct assessments of conduit artery endothelial function.

NIRS: Can it measure endothelial function?

The quest for a simple, inexpensive and non-invasive measure of endothelial function has long eluded physiologists. In a recent article published in Experimental Physiology, McLay et al. (2016) propose that the rate of oxyhaemoglobin resaturation in the tibialis anterior (slope 2), detected via near-infrared spectroscopy (NIRS) during the 10 s immediately following 5 min of ischaemia, can be a means of estimating vascular endothelial function. The authors established this conclusion based on a positive correlation (r = 0.63, P = 0.003) between slope 2 and simultaneously measured popliteal artery reactive hyperaemia flow-mediated dilatation (FMD) in a group of young, healthy men. We are enthusiastic about the idea of NIRS as a simple measure for endothelial function and commend the authors for the identification of a strong relationship between NIRS and FMD. However, whilst the NIRS-derived slope 2 certainly provides insight on microvascular reperfusion, we advise caution in the use of any measure of microvascular function as a surrogate for conduit artery endothelial function. Instead, we contend that the slope 2 might reflect reactive hyperaemia, the surge in blood flow responsible for the shear rate stimulus in the conduit artery, which ultimately evokes FMD. Our initial concern with suggesting that slope 2 provides similar physiological information to conduit artery FMD is that microvascular and macrovascular function are different entities (Dhindsa et al. 2008), and the correlation is likely to indicate that this measurement reflects the stimulus. Muscle reoxygenation occurs in concert with capillary perfusion, the rate of which is indicative of microvascular reactivity. Postischaemic measurements of microand macrovascular reactivity are not often correlated; in fact, Dhindsa et al. (2008) reported that only two (reactive hyperaemia index and finger temperature rebound) of seven measures of microvascular reactivity are modestly correlated with brachial artery FMD. The lack of association within trial may be attributable to disparate mechanisms of vasodilatation at different levels of the arterial tree. The administration of pharmacological blockade of endothelium-derived vasodilatory autocoids has been extensively investigated over the past two decades, confirming the endothelium dependence of conduit artery FMD and revealing that it is largely nitric oxide mediated (Green et al. 2014). In contrast, postischaemic blood flow responses (i.e. reactive hyperaemia) have been shown to be unaffected by inhibition of nitric oxide synthase, despite a decreased FMD (Mullen et al. 2001). Collectively, the mechanisms responsible for microvascular and macrovascular reactivity are heterogeneous, and the measurement of one should not be used to infer the other, but they can be used in combination to establish stimulus–response relationships. Although we argue that slope 2 is not a direct reflection of FMD, we contend that it provides useful information regarding the stimulus for FMD, rather than the response. To elaborate, the rate of reperfusion (slope 2) is dependent on microvascular reactivity, which serves as the downstream resistance for conduit artery flow and, consequently, shear rate. Although slope 2 provides insight on reactive hyperaemia, the downstream surge in flow, it may be a stronger reflection of the shear rate experienced in the conduit artery. However, shear rate should not be relied on to indicate FMD because the nature of the stimulus–response slope differs between healthy and at-risk populations. For example, the stimulus–response slope is blunted in individuals at moderate cardiovascular risk compared with young, healthy adults (Padilla et al. 2009). In other words, endothelial dysfunction would be characterized by a smaller FMD response to a given shear rate stimulus, thus measuring only the stimulus may not adequately characterize endothelial function. With that knowledge, it is unfortunate that McLay et al. (2016) did not publish measurements of blood velocity, a requisite for determination of shear rate (blood velocity/diameter), and correlate this with slope 2. Therefore, we contend that slope 2 is likely to provide a snapshot of the initial stimulus responsible for FMD. The potential for the use of NIRS to indicate endothelial function is promising, yet the first step on the quest to establish novel measures of endothelial function is to identify which path you tread: micro or macro. A follow-up investigation should incorporate simultaneous measures of shear rate, FMD and slope 2, in which case we would hypothesize that slope 2 correlates better with the postischaemic shear rate response than with FMD. Despite a correlation between slope 2 and FMD, we recommend establishing firmly whether the rate of oxyhaemoglobin resaturation reflects the stimulus for, or response of conduit artery FMD.