Goal: The pulmonary circulation is the only circulation that vasoconstricts when exposed to hypoxia, a phenomenon known as hypoxic pulmonary vasoconstriction (HPV). The goal of this work is to understand how healthy aging affects HPV. This is important because HPV is the major active mechanism ensuring efficient .. pulmonary gas exchange. HPV optimizes ventilation-perfusion (VA/Q ) matching by constricting arterioles in poorly ventilated (low PO2) regions, redistributing blood to well-ventilated lung, and defending PO2 Background: Ventilation heterogeneity is known to increases with age, but VA/Q mismatch also increases and arterial PO2 declines. Our prior studies found that healthy aging is associated with increased spatial heterogeneity in pulmonary blood flow, but also decreased arterial saturation. Together this suggests that some modulation by HPV is balancing a growing heterogeneity of ventilation, but that there is attenuation of HPV in some older subjects, affecting gas exchange efficiency and oxygenation. Hypothesis: We will test the hypotheses that the ability of HPV to modulate blood flow and thus compensate for ventilation heterogeneity is reduced in older compared to younger individuals. We propose recently developed proton MRI methods for quantitative measurement of the spatial distribution of perfusion, ventilation and VA/Q ratio to evaluate the pulmonary circulation. To test for the HPV activity in an individual, we use a 30% oxygen challenge: if local flow is reduced by HPV due to local hypoxia, breathing 30% O2 will release HPV, and increase flow in previously low flow regions. The result is overall flow heterogeneity decreases. Our preliminary data shows that 30% O2 decreases blood flow heterogeneity in subjects <30 y.o., as expected, but not in those aged >30 years.
Aims : 1. Directly test for the presence of HPV with inhalation of 30% O in older subjects (45-75+y) and controls (18-30y). 2. In these subjects, quantify the spatial distribution of ventilation, VA/Q ratio and alveolar O2 in the entire lung and compare to the HPV activity, to assess the effectiveness of HPV in maintaining gas exchange and 3. Evaluate the ability of HPV to actively respond to an acute stimulus .inducing regional hypoxia. We predict that healthy older populations will show an attenuation of HPV affecting VA/Qmatching. Impact: Although beneficial for gas exchange, HPV may also be detrimental: During exposure to hypoxia such as during in patients with obstructive sleep apnea (OSA), HPV raises pulmonary arterial pressure and may contribute to pulmonary hypertension in OSA. HPV increases right heart strain and may worsen the clinical picture, particularly if heart failure is present. Establishing the extent f changes with normal aging is essential to evaluate the potential role of HPV in disease. If loss of HPV is a normal part of healthy aging, then testing for retained HPV may become part of a standard clinical workup in lung disease and OSA, and an important predictor of morbidity and mortality.

Public Health Relevance

This proposal uses novel proton MRI techniques to evaluate how the activity of hypoxic pulmonary vasoconstriction (HPV), and thus compensation for heterogeneous ventilation, is altered by aging in healthy human subjects aged 18-75+. This is important because although beneficial for gas exchange, HPV may also be detrimental in patients where (if present) HPV will raise pulmonary arterial pressure, possibly contributing to pulmonary hypertension in obstructive sleep apnea (OSA) and lung disease. If loss of HPV is a normal part of healthy aging, then testing for retained HPV may become part of a standard clinical workup in lung disease and OSA, and an important predictor of morbidity and mortality.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Fessel, Joshua P
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Levin, David L; Schiebler, Mark L; Hopkins, Susan R (2017) Physiology for the pulmonary functional imager. Eur J Radiol 86:308-312
Hopkins, Susan R; Elliott, Ann R; Prisk, G Kim et al. (2017) Ventilation heterogeneity measured by multiple breath inert gas testing is not affected by inspired oxygen concentration in healthy humans. J Appl Physiol (1985) 122:1379-1387