Asthma Exacerbations and Vascular Function
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

Summary: 
      Although asthma is a disease of the airways, research is now showing that asthmatics are more
      likely to develop cardiovascular disease (CVD) compared to non-asthmatics. Vascular
      dysfunction is seen in people at high risk of CVD and has been linked to inflammation. During
      an asthma attack, levels of inflammation in the whole body increase, which could potentially
      explain why asthmatics are at increased risk of CVD. By exercising, people can change the
      amount of inflammation in their bodies, improve vascular function, and thereby reduce the
      risk of CVD. In the proposed study the investigators will assess if asthma attacks lead to
      increased risk of CVD by evaluating inflammatory levels and vascular function before and
      after asthma attacks. The investigators will also evaluate if exercise reduces the
      cardiovascular risk following asthma attacks. The results from this study will help in
      understanding why asthmatics are at increased risk of CVD.
    

Detailed description: 
      BACKGROUND & SCOPE: While asthma is generally considered to be a disease of the airways,
      there are important systemic consequences which have predisposed people with asthma to become
      more likely to die from cardiovascular (CV) disease compared to non-asthmatics. Additional CV
      risks have been reported in people with severe asthma, and there is a relationship between
      reductions in lung function and cardiac death. To date, little is known in regards to the
      interaction between asthma exacerbations and CV risk.

      Brachial flow-mediated dilation (FMD) is used as a non-invasive tool to evaluate endothelial
      function. Brachial FMD is impaired in people with coronary dysfunction, and has been shown to
      predict future CV events better than traditional CV risk factors. People with asthma have
      previously been shown to have impaired endothelial function compared to non-asthmatics, but
      the underlying mechanism(s) are unclear.

      Chronic systemic inflammation is an established risk factor and predictor of future CV
      events, and levels of systemic inflammation has been shown to be increased in asthma and to
      be are related to disease severity. While systemic inflammation can directly impair vascular
      function, it is unknown how an asthma attack may affect vascular function and CV risk. Thus,
      to gain better understanding of the increased CV risks associated with asthma exacerbations,
      the first aim of this study is to evaluate how acutely increased pulmonary inflammation
      affects vascular function in people with asthma.

      Physical inactivity has previously been associated with increased systemic inflammation,
      while higher levels of physical activity can reduce inflammation and vascular dysfunction.
      Acute exercise has been shown to modulate the systemic responses to inflammatory insults, and
      being more physically active is associated with better asthma symptoms but whether acute
      exercise influences the systemic responses to asthma exacerbations is unknown. The second aim
      is to assess the influence of acute exercise on the systemic and vascular responses to acute
      pulmonary inflammation in asthma.

      OBJECTIVE 1: To examine the acute impact of pulmonary inflammation and bronchoconstriction on
      systemic inflammation and vascular function in asthma.

      METHODS & PROCEDURES, objective 1: Outline: Asthmatics will undergo a screening and three
      trials for which they will report to the laboratory in the morning of two consecutive days
      (Day 1 and Day 2) per trial. The screening day is to establish presence/absence of asthma and
      and will consist of pulmonary function testing before and after inhalation of a
      bronchodilator (Salbutamol), and an exercise challenge and cardiopulmonary fitness test. On
      Day 1, baseline pulmonary function and vascular function will be evaluated, and venous blood
      samples and exhaled breath condensate will also be obtained for evaluation of baseline
      systemic and pulmonary inflammation, respectively. The participants will then undergo either
      a mannitol challenge (Trial 1), a methacholine challenge (Trial 2), or a placebo (saline)
      challenge (Trial 3). At 1 hour post-challenge, another set of vascular function measurements,
      and systemic and pulmonary inflammation measurements will be done. The participants will be
      asked to come back 24 hours after each trial (Day 2) for a follow-up evaluation of vascular
      function and systemic inflammation. The order of the trials will be randomized and they will
      be separated by 1 week to allow for washout between tests.

      Pulmonary function: A standard pulmonary function test will be performed by all participants
      as per established clinical guidelines.

      Pulmonary inflammation: Exhaled breath condensate will be collected using RTube™ and analyzed
      for levels of CRP and markers of oxidative stress.

      Systemic inflammation: The analysis of serum CRP, IL-6, TNFα, and nitrates and nitrites
      levels will be outsourced to Eve Technologies, Calgary.

      Vascular function: Flow-mediated dilation (FMD) of the brachial artery following 5 minutes of
      forearm occlusion will be measured ultrasound imaging using our ultrasound machine. FMD will
      be determined using Doppler ultrasound immediately after the release of the occlusion. The
      secondary outcome is arterial stiffness, which will be determined using carotid -
      femoral/brachial pulse wave velocity, and PWV will be calculated from measurements of pulse
      transit time and the distance traveled by the pulse between recording sites.

      Mannitol, methacholine and placebo challenge: Mannitol challenges have been shown to induce
      pulmonary inflammation in addition to bronchoconstriction in asthmatics and will be performed
      until either a cumulative dose of 635 mg has been obtained or until there is a reduction in
      the forced expiratory volume in the first second (FEV1) of ≥10% of baseline values. If
      bronchoconstriction occurs, the FEV1 will be monitored every 10 minutes until spontaneous
      recovery to within 5% of baseline FEV1, or reversed using 4 puffs (100 mg/puff) Salbutamol.
      Peripheral oxygen saturation will be monitored throughout the test. A methacholine challenge
      causes bronchoconstriction without an increase in pulmonary inflammation in asthmatics and
      will be used to separate between the effects of bronchoconstriction and pulmonary
      inflammation on vascular function. Except for the inhalation of methacholine, which will be
      performed according to established guidelines (in incremental concentrations until either 16
      mg/ml methacholine has been inhaled, or there is a 20% reduction in FEV1), the same protocol
      will be used for the methacholine challenge and the placebo challenges. The participants will
      be blinded to the order of the tests.

      OBJECTIVE 2: To evaluate the influence of acute exercise on systemic inflammatory and
      vascular responses to acute pulmonary inflammation.

      METHODS & PROCEDURES, objective 2: Outline: The design of Objective 2 will be similar to the
      Mannitol challenge day in Objective 1 except the participants will in random order either a)
      exercise and inhale mannitol, b) exercise and placebo (saline), c) rest and inhale mannitol,
      or d) rest and placebo (saline). In addition to the inflammatory markers measured in
      Objective 1, the anti-inflammatory cytokine IL-10 will be measured in serum at each time
      point (baseline, 1 hour post-challenge, and 1 day post-challenge).

      The exercise work load on the challenge day will correspond to 25 watts below achieved
      workload at anaerobic threshold during the screening day cardiopulmonary fitness test and
      will be held for 30 minutes. For the inactive day, the participants will be asked to withhold
      any exercise and/or moderate to heavy physical activity for 48 hours prior to the test. On
      the resting trial day, the participant will report to the lab at the same time of day as for
      exercise and instead rest quietly during for the same duration as the exercise period.
    

Intervention name(s): Mannitol; Methacholine; Placebo; Rest; Exercise
Intervention type(s): Drug; Drug; Drug; Other; Other
Intervention description(s): Mannitol consists of inhaling 0 (empty capsule acting as a placebo), 5, 10, 20, 40, 80, 160, 160, and 160 mg mannitol, resulting in a maximum cumulative dose of 635 mg; Methacholine consists of inhaling 0.0625 mg/mL, 0.25 mg/mL, 1 mg/mL, 4 mg/mL, and 16 mg/mL; Placebo consists of inhaling humidified air
Other intervention name(s): Mannitol Challenge Test; Methacholine Challenge Test; Placebo Challenge Test
Intervention MeSH terms: Mannitol; Methacholine Chloride
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized double-blind cross over design
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science