George M. Balanos

The increase in pulmonary arterial pressure caused by hypoxia depends on iron status

Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia‐inducible factor (HIF) is central to this process. The oxygen‐sensing iron‐dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron‐replete volunteers undertook two separate protocols. The ‘Iron Protocol’ studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The ‘Desferrioxamine Protocol’ examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia (ΔPASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P= 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and ΔPASP (P= 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease.

Sex differences in carotid baroreflex control of arterial blood pressure in humans: relative contribution of cardiac output and total vascular conductance

It is presently unknown whether there are sex differences in the magnitude of blood pressure (BP) responses to baroreceptor perturbation or if the relative contribution of cardiac output (CO) and total vascular conductance (TVC) to baroreflex-mediated changes in BP differs in young women and men. Since sympathetic vasoconstrictor tone is attenuated in women, we hypothesized that carotid baroreflex-mediated BP responses would be attenuated in women by virtue of a blunted vascular response (i.e., an attenuated TVC response). BP, heart rate (HR), and stroke volume were continuously recorded during the application of 5-s pulses of neck pressure (NP; carotid hypotension) and neck suction (NS; carotid hypertension) ranging from +40 to -80 Torr in women (n = 20, 21 ± 0.5 yr) and men (n = 20, 21 ± 0.4 yr). CO and TVC were calculated on a beat-to-beat basis. Women demonstrated greater depressor responses to NS (e.g., -60 Torr, -17 ± 1%baseline in women vs. -11 ± 1%baseline in men, P < 0.05), which were driven by augmented decreases in HR that, in turn, contributed to larger reductions in CO (-60 Torr, -15 ± 2%baseline in women vs. -6 ± 2%baseline in men, P < 0.05). In contrast, pressor responses to NP were similar in women and men (e.g., +40 Torr, +14 ± 2%baseline in women vs. +10 ± 1%baseline in men, P > 0.05), with TVC being the primary mediating factor in both groups. Our findings indicate that sex differences in the baroreflex control of BP are evident during carotid hypertension but not carotid hypotension. Furthermore, in contrast to our hypothesis, young women exhibited greater BP responses to carotid hypertension by virtue of a greater cardiac responsiveness.

Metabolically exaggerated cardiac reactions to acute psychological stress revisited

The reactivity hypothesis postulates that large magnitude cardiovascular reactions to psychological stress contribute to the development of pathology. A key but little tested assumption is that such reactions are metabolically exaggerated. Cardiac activity, using Doppler echocardiography, and oxygen consumption, using mass spectrometry, were measured at rest and during and after a mental stress task and during graded submaximal cycling exercise. Cardiac activity and oxygen consumption showed the expected orderly association during exercise. However, during stress, large increases in cardiac activity were observed in the context of modest rises in energy expenditure; observed cardiac activity during stress substantially exceeded that predicted on the basis of contemporary levels of oxygen consumption. Thus, psychological stress can provoke increases in cardiac activity difficult to account for in terms of the metabolic demands of the stress task.

Metabolically exaggerated cardiac reactions to acute psychological stress:the effects of resting blood pressure status and possible underlying mechanisms

The study aimed to: confirm that acute stress elicits metabolically exaggerated increases in cardiac activity; test whether individuals with elevated resting blood pressure show more exaggerated cardiac reactions to stress than those who are clearly normotensive; and explore the underlying mechanisms. Cardiovascular activity and oxygen consumption were measured pre-, during, and post-mental stress, and during graded sub-maximal cycling exercise in 11 young men with moderately elevated resting blood pressure and 11 normotensives. Stress provoked increases in cardiac output that were much greater than would be expected from contemporary levels of oxygen consumption. Exaggerated cardiac reactions were larger in the relatively elevated blood pressure group. They also had greater reductions in total peripheral resistance, but not heart rate variability, implying that their more exaggerated cardiac reactions reflected greater beta-adrenergic activation.

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (ΔPmax), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6–24xa0h to measure spontaneous diurnal variations in ΔPmax and cardiac output. Cardiac output varied by up to ~2.5xa0l/min; ΔPmax varied little with cardiac output [0.61±0.74 (SD) mmHg minxa0l−1]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal

The pulmonary vascular response to the sustained activation of the muscle metaboreflex in man

P_{{rm O}_{2}} = 50,{text{mmHg}}

Extent to which pulmonary vascular responses to Pco2 and Po2 play a functional role within the healthy human lung

) for 8xa0h. In this group ΔPmax rose progressively from 21xa0mmHg to 37xa0mmHg over 8xa0h. By comparing diurnal variations in ΔPmax during air breathing with changes in ΔPmax during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in ΔPmax during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of ΔPmax to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.

Stability and intra-tester reliability of an in vivo measurement of thoracic axial rotation using an innovative methodology

Arterial spin labelling allows simultaneous measurement of both the blood-oxygenation-level-dependent (BOLD) and the cerebral blood flow (CBF) response to changes in neural activity. The addition of a hypercapnia or hyperoxia calibration allows additional quantification of changes in the cerebral metabolic rate of oxygen (CMRO(2)). In this study we test the reproducibility of measurements derived using the hyperoxia approach, during a cognitive Stroop task. A QUIPSSII sequence is used at 3 T to collect simultaneous CBF and BOLD signal during two 3 min periods of hyperoxia and an 8 min Stroop task. Hyperoxia was administered via an open system and end-tidal values were sampled via a nasal cannula; average end-tidal values of 60% were reached. This procedure is repeated to allow the reproducibility of the estimated parameters to be tested. The use of a cognitive Stroop task allows testing of the measurements in frontal and parietal regions as well as sensorimotor areas in which previous studies have been focussed. We find reduced reproducibility of the calculated parameters compared to the hypercapnia approach, thought to be attributable to lower absolute BOLD and CBF responses. In particular we do not find n to have improved reproducibility compared to other parameters, as has been found in previous work using the hypercapnia approach. Across all brain areas we report a value of DeltaCMRO(2) of 12% and neurovascular coupling constant n of 2.5. Interestingly we find n to be higher in parietal and frontal areas in comparison to the primary motor cortex.