Matthew C. Frise

Clinical iron deficiency disturbs normal human responses to hypoxia

BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01847352). FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.

Non-contact measurement of oxygen saturation with an RGB camera.

A novel method (Sophia) is presented to track oxygen saturation changes in a controlled environment using an RGB camera placed approximately 1.5 m away from the subject. The method is evaluated on five healthy volunteers (Fitzpatrick skin phenotypes II, III, and IV) whose oxygen saturations were varied between 80% and 100% in a purpose-built chamber over 40 minutes each. The method carefully selects regions of interest (ROI) in the camera image by calculating signal-to-noise ratios for each ROI. This allows it to track changes in oxygen saturation accurately with respect to a conventional pulse oximeter (median coefficient of determination, 0.85).

A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease.

Objectives Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Iron deficiency, with or without anaemia, is associated with other chronic conditions, such as congestive heart failure, where it predicts a worse outcome. However, the prevalence of iron deficiency in COPD is unknown. This observational study aimed to determine the prevalence of iron deficiency in COPD and associations with differences in clinical phenotype. Setting University hospital outpatient clinic. Participants 113 adult patients (65% male) with COPD diagnosed according to GOLD criteria (forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio <0·70 and FEV1 <80% predicted); with age-matched and sex-matched control group consisting of 57 healthy individuals. Main outcome measures Prevalence of iron deficiency, defined as: any one or more of (1) soluble transferrin receptor >28.1 nmol/L; (2) transferrin saturation <16% and (3) ferritin <12 µg/L. Severity of hypoxaemia, including resting peripheral arterial oxygen saturation (SpO2) and nocturnal oximetry; C reactive protein (CRP); FEV1; self-reported exacerbation rate and Shuttle Walk Test performance. Results Iron deficiency was more common in patients with COPD (18%) compared with controls (5%). In the COPD cohort, CRP was higher in patients with iron deficiency (median 10.5 vs 4.0 mg/L, p<0.001), who were also more hypoxaemic than their iron-replete counterparts (median resting SpO2 92% vs 95%, p<0.001), but haemoglobin concentration did not differ. Patients with iron deficiency had more self-reported exacerbations and a trend towards worse exercise tolerance. Conclusions Non-anaemic iron deficiency is common in COPD and appears to be driven by inflammation. Iron deficiency associates with hypoxaemia, an excess of exacerbations and, possibly, worse exercise tolerance, all markers of poor prognosis. Given that it has been shown to be beneficial in other chronic diseases, intravenous iron therapy should be explored as a novel therapeutic option in COPD.

How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure

Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca++-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.

The pulmonary vasculature - lessons from Tibetans and from rare diseases of oxygen sensing.

What is the topic of this review? This review is principally concerned with results from studies of the pulmonary vasculature in humans, particularly in relation to hypoxia and rare diseases that affect oxygen sensing. What advances does it highlight? This review highlights the degree to which the hypoxia‐inducible factor (HIF) transcription system influences human pulmonary vascular responses to hypoxia. Upregulation of the HIF pathway augments hypoxic pulmonary vasoconstriction, while alterations to the pathway found in Tibetans are associated with suppression of the progressive increase in pulmonary artery pressure with sustained hypoxia. It also highlights the potential importance of iron, which modulates the HIF pathway, in modifying the pulmonary vascular response to hypoxia.

Exaggerated pulmonary vascular response to acute hypoxia in older men

What is the central question of this study? Pulmonary arterial pressure is higher in older than younger humans and predicts mortality. It is also increased by acute hypoxia, which causes constriction of the pulmonary vasculature. We asked whether this pulmonary vascular response to hypoxia is greater in older humans. What is the main finding and its importance? Using Doppler echocardiography in 12 younger (∼20 years old) and nine older men (∼55 years old) exposed to 20 min of moderate isocapnic hypoxia, we demonstrated that older men showed a significantly greater rise in pulmonary arterial pressure during alveolar hypoxia than younger men. Future studies should examine the pathophysiological importance of increased hypoxic pulmonary vasoconstriction with age.

Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia

Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end‐tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end‐tidal PO2 = 420 mmHg) or euoxia (end‐tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.

Age, sex and arterial pressure: the kidney is essential

Joyner and colleagues recently reviewed ‘sex differences and blood pressure regulation in humans’ in an attempt to form ‘a coherent picture of why blood pressure rises more with age in women than men’ (Joyner et al. 2015). We are concerned that their analysis of the long-term changes in blood pressure with age, and how the processes underlying these changes differ between the sexes, is flawed. We take this view because their analysis makes no mention of the kidney, and the mechanisms that regulate blood pressure over prolonged periods of time are inextricably related to renal physiology (Hall, 1999; Keener & Sneyd, 2009; Ivy & Bailey, 2014). The review sees ‘an integrative physiology story’ as summarized in the equation MAP = CO × TPR, relating mean arterial pressure, cardiac output and total peripheral resistance. It explores the relationship between sympathetic nerve activity, TPR and CO, and views these as ‘determining’ arterial pressure. For short-term changes in a circulation of constant volume, over periods of minutes or hours, it is certainly informative to view TPR and CO as independent determinants of MAP; both of these factors are clearly under the influence of sympathetic efferent activity. In the longer term, over periods of days to years, the only level of MAP that can be sustained is that at which an individual is in sodium and water balance (Firth et al. 1990). The kidney is the primary route of elimination of sodium and water from a circulation of changeable volume. At equilibrium, MAP equals the pressure at which the kidney is set to eliminate the ongoing intake of salt and water, regulated by hormonal, neural and pharmacological influences. Away from this equilibrium, circulating volume continues to change slowly until sodium and water balance is achieved. Short-term fluctuations of pressure about this equilibrium MAP should not be allowed to distract from the renal origins of long-term blood pressure control. One of the problems in understanding the relationship between the variables involved in the regulation of blood pressure arises from the manner in which the equation MAP = CO × TPR is arranged. This construction implies that CO and TPR are somehow independent variables determining the dependent variable MAP. As already stated, this is helpful when considering short-term changes in blood pressure. However, in exploring changes in the circulation with age in relation to global vascular tone, it may be more informative to think of CO as the dependent variable and to write CO = MAP/TPR. (More strictly, CO = (MAP − CVP)/TRP, where CVP is central venous pressure, but this is hardly material here.) Mean arterial pressure is renally determined in the long term, as we have discussed, and TPR is a function of sympathetic outflow. Joyner et al. (2015) illustrate this relationship with the physiological data in Fig. 2 of their review, using two males with markedly differing sympathetic outflow, TPR and CO. They cannot, though, provide an integrative physiological account of why MAP is the same in the two cases, because the kidney is not considered. We agree with the authors that age and sex differences are pertinent to understanding the mechanisms underlying hypertension. However, we suggest that these mechanisms will be found by examining renal function, including renal sympathetic innervation (Nishi et al. 2015); they will not be found by ignoring the kidney.