Is Blood Flow Through IPAVA and PFO Related to Breath-hold and SCUBA Diving-induced Pulmonary Hypertension?
Condition: Patent Foramen Ovale; Intrapulmonary Arteriovenous Anastamosis
MeSH terms: Hypertension, Pulmonary; Hypertension; Foramen Ovale, Patent
Study type: Interventional
Phase: Early Phase 1

Summary: 
      In summary, the investigators propose to study elite Croatian breath-hold and SCUBA divers.
      The investigators will quantify breath-hold hypoxia- and SCUBA diving-induced pulmonary
      hypertension and right heart function to investigate the relationships between PFO and IPAVA
      blood flow. The investigators will use a placebo-controlled intervention (sildenafil) to
      reduce pulmonary arterial pressure in these subjects to examine the impact of the change in
      pressure (or absence of change) on the relationships determined above.
    

Detailed description: 
      Pulmonary arterial hypertension (increased lung blood pressure) is a multifactorial disease
      without a cure. Investigating reversible forms of pulmonary hypertension induced under
      extreme conditions such as a prolonged breath-hold and/or SCUBA diving may help to better
      understand why some individuals develop this devastating disease, and others do not.

      Pulmonary arterial pressure is typically very low in healthy humans. Low oxygen levels
      (hypoxia) cause a constriction of the lung blood vessels resulting in smaller diameters, but
      lung blood flow stays constant or increases. Having constant flow with smaller vessel
      diameters causes pulmonary arterial pressure to increase but it will return to normal once
      normal oxygen levels are restored. Moreover, there is an association with patent foramen
      ovale (PFO, small hole between the atria in the heart) and excessive pulmonary arterial
      pressures in low oxygen conditions. However, the reasons for the exacerbated increase in
      pulmonary arterial pressure in these subjects with a PFO (PFO+) is unknown, but may be due to
      an exaggerated constriction response to low oxygen.

      During a breath-hold, the oxygen in the lung decreases and in elite breath-hold divers, it
      decreases to very low levels. Compared to subjects without a PFO (PFO-), the oxygen may drop
      even lower in those PFO+ subjects because deoxygenated blood travels through the small hole
      to mix with oxygenated blood, exacerbating the level to which blood oxygen decreases. Thus,
      using a breath-hold model of lung hypoxia is one approach to examining a hypoxia-induced
      increase in pulmonary arterial pressure - a method critically dependent upon the elite
      breath-hold diver's ability to hold their breath for significant durations.

      Intrapulmonary arteriovenous anastomoses (IPAVA) are vessels within the lung that bypass
      capillaries. The investigator's group has investigated the possible roles these unique
      vessels may have in physiological and pathophysiological conditions. The investigators have
      found that IPAVA blood flow occurs when healthy subjects breathe low oxygen gas. The
      investigators have also found that IPAVA blood flow is inversely related to pulmonary
      arterial pressure. Specifically, individuals with high pulmonary arterial pressures have low
      IPAVA blood flow and vice versa.

      The right ventricle of the heart pumps blood through the pulmonary artery to the lungs. Under
      resting conditions the right heart performs a minimal amount of work because the pressure in
      the lung blood vessels is low. When pulmonary arterial pressure increases, the work of the
      right side of the heart has to increase substantially to keep blood pumping through the lung.
      Thus, high pulmonary arterial pressures will increase the work of the right heart and may
      lead to right heart dysfunction thereby limiting the amount of blood the heart can pump. If
      the pressure is high enough to limit the amount of blood flowing through the lung then this
      can be detected by a reduction in pulmonary blood flow and/or changes in the function of the
      heart during contraction (systole) and relaxation (diastole). Accordingly, an intervention
      that reduces pulmonary arterial pressures during a breath-hold may have a beneficial effect
      on right heart function.

      Taken together, during an elite breath-hold dive, where the level of oxygen decreases, the
      investigators expect that pulmonary arterial pressures will increase as lung oxygen levels
      decrease, and the reduction in oxygen may be even lower in PFO+ subjects. Furthermore, as
      blood oxygen levels decrease, IPAVA blood flow will increase in some PFO- subjects thereby
      keeping pulmonary arterial pressures low in those individuals. Conversely, PFO+ subjects and
      those PFO- subjects with low levels of IPAVA blood flow would be expected to have the
      greatest pulmonary pressures. Whether or not this is true is unknown. Therefore, Objective #1
      will quantify pulmonary arterial pressure and right heart function and investigate their
      relationships with PFO and IPAVA blood flow in elite breath-hold divers while breathing
      concentrations of oxygen and carbon dioxide that mimic breath-hold-induced hypoxia [NOTE: it
      is not possible to image the heart during a breath hold because the fully inflated lung
      obstructs the ultrasound view of the heart]. Objective #2 will use sildenafil, a drug that
      increases nitric oxide bioavailability to dilate lung blood vessels, to decrease pulmonary
      arterial pressure while breathing concentrations of oxygen and carbon dioxide that mimic
      breath-hold-induced hypoxia. Investigators will quantify the effect of sildenafil on
      pulmonary arterial pressure and right heart function and will determine if it alters the
      relationship with IPAVA and PFO blood flow. As mentioned above, because those PFO+ subjects
      may have an exaggerated pulmonary vasoconstrictor response to hypoxia, sildenafil may be
      either less effective or ineffective in reducing the pulmonary arterial pressure in these
      subjects. Objective #3 will compare the elite breath hold diver study data to data obtained
      in age, sex and PFO matched subjects who do not have extensive experience with breath hold
      diving. To do this control subjects will undergo the same procedures in Objectives #1 & 2
      above. These studies will also allow investigators to determine if there are differences in
      pulmonary vascular responses to hypoxia between those with and without breath hold diving
      experience.

      In addition to the heart and lung alterations that occur in breath hold divers outlined
      above, it is also known that pulmonary arterial pressure increases after SCUBA diving, but
      returns to normal within a few hours. The mechanisms responsible for the increase in
      pulmonary arterial pressure are unknown, but are independent of hypoxia. Thus, investigating
      the relationship between IPAVA, PFO and SCUBA diving-induced increases in pulmonary arterial
      pressures offers an additional avenue for understanding pulmonary arterial hypertension
      susceptibility. Although it is unknown why pulmonary arterial pressure increases with SCUBA
      diving, it is known that pulmonary hypertension may contribute to right heart dysfunction and
      pulmonary edema (lung water accumulation) that can occur in subjects who are swimming and/or
      SCUBA diving. Prevention of increased pulmonary arterial pressures during and/or after a dive
      may help to prevent excessive right heart dysfunction and pulmonary edema. Thus, Objective #4
      will quantify pulmonary arterial pressure and right heart function and investigate their
      relationships with PFO and IPAVA blood flow, pre- and post-SCUBA diving. Objective #5 will
      quantify the effect of sildenafil (post dive) on pulmonary arterial pressure and right heart
      function and will determine if it alters the relationship with IPAVA and PFO blood flow, pre-
      and post-SCUBA diving.

      In summary, the investigators propose to study elite Croatian breath-hold and SCUBA divers.
      Investigators will quantify breath-hold hypoxia- and SCUBA diving-induced pulmonary
      hypertension and right heart function to investigate the relationships between PFO and IPAVA
      blood flow. Investigators will use a placebo-controlled intervention (sildenafil) to reduce
      pulmonary arterial pressure in these subjects to examine the impact of the change in pressure
      (or absence of change) on the relationships determined above.
    

Intervention name(s): Sildenafil; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 50mg administration of sildenafil, one time, one hour prior to measurements.; 50mg administration in gel-encapsulated microcrystalline cellulose one time, one hour prior to measurements.
Intervention MeSH terms: Sildenafil Citrate
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Breath hold divers will be administered sildenafil and placebo. Age-matched controls will be administered sildenafil and placebo.
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science