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Ageing and Pulmonary Vascular Dysfunction in the General Population: contributing factors and potential interventions


Project Description

Chronological age is a primary facilitator of pulmonary vascular dysfunction, which is characterised by an increase in pulmonary vascular stiffness, pulmonary vascular pressures, and pulmonary vascular resistance along with a decrease in pulmonary vascular perfusion. Clinically-significant pulmonary hypertension (systolic pulmonary artery pressure, sPAP >40 mmHg via echocardiography) occurs in 3-8% of the general population and causes premature mortality. Importantly, even a modest elevation in sPAP (>28 mmHg via echocardiography), which occurs in ~35% of the general population, is associated with a 2- to 3-fold increase in all-cause mortality in middle-aged/older adults free from cardiorespiratory or metabolic disease. Accordingly, even small increases in lung blood pressure represent a novel cardiovascular risk factor and an attractive target for therapeutic intervention in the elderly.

Project rationale:
Potential causes: There is variation in the development and severity of elevated pulmonary vascular pressures among older individuals. This is presumably due to inherent (e.g., genetics) and acquired factors (e.g., lifestyle). Genetic variations (e.g., polymorphisms in the nitric oxide-cyclic GMP system) contribute to arterial stiffness and increased risk of cardiovascular disease. In addition, regular aerobic exercise and better maintenance of cardiorespiratory fitness protects against the development of large elastic artery stiffness and endothelial dysfunction in the systemic circulation with advancing age. However, the role of specific gene polymorphisms and regular physical activity in the development of pulmonary vascular dysfunction with ageing are unknown.

Potential interventions: In the systemic circulation, aerobic exercise interventions reduce arterial stiffness and restore vascular endothelial function in previously sedentary middle-aged/older adults. Similarly, dietary inorganic nitrate (NO3−) supplementation (increases the bioavailability of nitric oxide) lowers blood pressure and improves systemic vascular health. However, the effect of an aerobic exercise intervention and/or dietary NO3− supplementation on pulmonary vascular function in healthy older adults is unknown.

The project aims are:
Aim 1. To determine the contributions of: a) polymorphisms in specific target genes related to vascular function; and b) habitual physical activity and cardiorespiratory fitness to age-related pulmonary vascular dysfunction and elevated pulmonary vascular pressures.

Aim 2. To determine the independent and combined effect of interval exercise training and dietary inorganic NO3- supplementation on pulmonary vascular function and pulmonary vascular pressures in older adults.

Project plan:
The project will use a multidisciplinary experimental approach, and will be conducted at the state-of-the-art laboratories within the Integrative Exercise Medicine Research Facility at the University of Leeds. Aim 1: Pulmonary vascular function and pressures, polymorphisms in specific target genes related to vascular function, habitual physical activity, vascular endothelial function, and peak oxygen uptake will be assessed/identified. The factors associated with elevated pulmonary vascular pressures in older adults will be identified. Aim 2: Four groups will be studied; Group 1: short-interval exercise training (Short-IT); Group 2: inorganic NO3- supplementation; Group 3: combined Short-IT and inorganic NO3- supplementation; Group 4: normal daily activity and inorganic NO3- depleted supplement. Pulmonary vascular function, peak oxygen uptake, and vascular endothelial function will be measured before and after each intervention.

Project impact:
The proposed project will shed light on the inherent and acquired factors that contribute to pulmonary vascular dysfunction with ageing, and may provide a ‘first-step’ in the development of effective and low-cost strategies to ‘slow-down’ or ‘resist-against’ ageing of the lung blood vessels. This could have important implications for quality-of-life in older people.

Funding Notes

Project is eligible for funding under the FBS Faculty Studentships scheme. Successful candidates will receive a PhD studentship for 4 years, covering fees at UK/EU level and stipend at research council level (£14,777 for 2018-19).
Candidates should have, or be expecting, a 2.1 or above at undergraduate level in a relevant field. If English is not your first language, you will also be required to meet our language entry requirements. The PhD is to start in Oct 2018.
Please apply online here View Website Include project title and supervisor name, and upload a CV and transcripts.

References

Coffman KE, Curry TB, Dietz NM, Chase SC, Carlson AR, Ziegler BL, Johnson BD. The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging. Physiol Rep, 2018; 6(2).

Coffman KE, Carlson AR, Miller AD, Johnson BD, Taylor BJ. The effect of aging and cardiorespiratory fitness on the lung diffusing capacity response to exercise in healthy humans. J Appl Physiol, 2017; 122(6): 1425-1434.

Rakobowchuk M, Harris E, Taylor A, Cubbon RM, Birch KM. Moderate and heavy metabolic stress interval training improves arterial stiffness and heart rate dynamics in humans. Eur J Appl Physiol, 2013; 113(4): 839-849.

Taylor BJ, Johnson BD. The pulmonary circulation and exercise responses in the elderly. Semin Respir Crit Care Med, 2010; 31(5): 528-538.

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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