The presence of a PFO is a potential cause of a person having hypoxemia. This article provides an overview of this syndrome and the role of PFO closure in its treatment.
To understand how hypoxemia can be caused by a PFO first requires an understanding of the concept of shunting, an abnormal flow of blood. In most people the wall, i.e. septum, between the right and left atria is intact and no flow can occur between these heart chambers. The wall is solid due to the fusion of two flaps, the septum secundum and septum primum, together shortly after birth. The presence of a persistent PFO allows shunting, abnormal blood flow to occur across the interatrial septum. The flow may be in either direction or intermittently in both directions, so called bidirectional shunting. When flow occurs in the direction of blood moving from the left to the right atrium, it is referred to as left-to-right shunting. When flow occurs in the direction of blood moving from the right to the left atrium, it is referred to as right-to-left shunting. Right-to-left shunting is the most common form of shunting when a PFO is present.
The PFO is often described as being a flap valve, a structure capable of intermittently opening and closing. The two components of the PFO flap valve are the septum primum and septum secundum which did not fuse together. The septum primum is typically a thin layer of tissue, i.e. a flap, and it is this structure that accounts for most of the motion that results in the PFO opening or closing. Relatively small forces can move the PFO into and out of its closed position by the septum primum moving away and back towards the septum secundum. Normally the left atrial pressure exceeds the right atrial pressure and this keeps the PFO in a closed position with no shunting. Under some normal conditions the right atrial pressure may transiently increase and the PFO can open. A good example is during normal breathing. When we inspire there is a negative pressure created in the chest that is cause by the downward movement of the diaphragm. Not only does this cause air to flow into the lungs but is also causes more blood to return to the heart from the venous drainage of both the upper and lower body. This rush of blood into the right atrium from the upper body (via the superior vena cava, SVC) and lower body (via the inferior vena cava, IVC) can transiently increase the right atrial pressure and push the septum primum into an open position with subsequent right to left shunting.
There are a variety of conditions that may promote right to left shunting. Most of these conditions abnormally increase the right atrial pressure. Some conditions result in a deformation of the PFO that puts it into an open position. In general the PFO is dynamic and depending on variations in day to day conditions as well as the acquisition of a variety of conditions, the PFO may be more or less open or closed.
The size of the PFO opening is thus dynamic and the absolute size of this opening varies from person to person. It is easiest to consider the maximum size of the PFO opening. Since the PFO opening is determined by the septum primum moving away from the septum secundum the shape of the opening is also best thought of as a slit. This makes sizing the PFO more difficult that if it was a simple tube. With advances in medical imaging we are increasingly able to describe the shape and size of the PFO in three dimensions but this is not routinely done at the present. Rather we usually describe the PFO in terms of one dimension, the distance between the septum secundum and the septum primum. The PFO tunnel is the part of the PFO where the septum secundum and septum primum overlap but are not fused together. When the PFO is open it is the smallest dimension of the tunnel that can be easily measured. It may be more difficult to estimate the maximum size of the PFO opening and during a cardiac catheterization we can perform balloon sizing of the PFO. A soft balloon tipped catheter is inserted thru the PFO, the balloon is inflated, and the waist on the balloon corresponds to the portion of the tunnel where a diameter measurement is taken. The size of the PFO varies from person to person and can be as small as 1 mm to over 25 mm, i.e. over an inch.
This discussion of PFO size and the dynamics of shunting are necessary because hypoxemia can only be produced when there is a substantial volume of blood that is shunting from the right atrium into the left atrium. To understand how the volume of shunting relates to the production of hypoxemia we must next understand the differential oxygen content of blood in the right versus the left heart.
The human cardiovascular system is a circulation of blood that has two major components, the system and the pulmonary circulations. The system circulation consists of any arterial side beginning with the left atrium, leading into the left ventricle, and then the aorta, the largest systemic artery of the body. Systemic circulatory blood carries the nutrients to all tissues and organs of the body other than the lungs. It is blood high in oxygen content which is quantified by the percentage of hemoglobin that has oxygen bound to it. Systemic arterial blood is fully saturated, i.e. in the 95-100% range. After blood passes thru the tissues and organs of the body, oxygen saturation falls because of the extraction of oxygen. Therefore systemic venous blood has a reduced oxygen saturation, often between 40 and 80% depending on blood from what vein is measured and how metabolically active that tissue is. Systemic venous blood returns to the right atrium from the IVC and SVC described above abut also the venous blood draining from the heart itself, from the coronary sinus. These three sources of blood mix together in the right atrium producing average oxygen saturation in the 65-75% range under normal inactive conditions.
The pulmonary circulation includes the structures that takes the blood to the lungs, the pulmonary arterial system and then drains it back to the left atrium, the pulmonary venous system. As blood flows thru the papillary system in the lungs it is oxygenated increasing its saturation from the 65-75% range to the 95-100% range.
Right to left shunting thru a PFO causes blood from the right atrium with this 65-75% oxygen saturation to mix with the highly saturated blood entering the left atrium from the pulmonary veins. Thus the blood in the left atrium may be reduced below the 95-100% range depending on how much blood flows across the PFO. Since the size of the PFO varies from person to person and the dynamics of the PFO opening and closing are constantly changing, the degree of hypoxemia, i.e. low oxygen saturation in systemic arterial blood may vary greatly. With a small amount of shunting the oxygen saturation will be normal but if the shunting is a large volume of blood that saturation is as low as 70% in some people.
Not unexpectedly the degree of hypoxemia often varies constantly and part of the challenge in the evaluation of people with possible PFO induced hypoxemia is measuring it under different conditions. On the other hand hypoxemia can be measured and the understanding of how a PFO causes hypoxemia in some people, what we call the pathophysiology of the condition, is based on well established science of the circulation.
Because of the dynamic nature of shunting it is often necessary to assess people under different states to understand if they intermittently have hypoxemia. For example some people only have hypoxemia when they stand-up, a condition called orthodeoxia platypnea. Some people have hypoxemia only when they exercise. The dynamics of shunting causing hypoxemia is an active area of research trying to understand the variations in pathophysiology of hypoxemia related to shunting thru a PFO.
An additional challenge to the study of PFO related hypoxemia is that many of these patients also have other conditions that can also result in hypoxemia. The most common cause of hypoxemia, in the vast majority of people with hypoxemia, is in fact not a PFO but the presence of lung disease. Must of the evaluation of hypoxemia thus rightly starts with an evaluation of lung function. People with severe chronic obstructive lung disease often have damaged lungs that cannot fully oxygenate blood passing thru the lung capillaries and when they walk their oxygen saturations may further fall. People with pneumonia may have hypoxemia from the transient inability of the infected lung tissue to oxygenate blood. Patients with congestive heart failure may have fluid accumulation in the lung tissue that impairs lung function and leads to hypoxemia.
The PFO is often not considered as a cause or contributing factor unless there appears to be little or limited lung disease for the amount of hypoxemia that has been found. These multiple causes for a person’s hypoxemia also adds the challenge of predicting how much they may improve by treating one of the causes, such as closing the person’s PFO.
Other people with PFO related hypoxemia only have it discovered when they are being evaluated following a stroke and have a “bubble study” that shows a large amount of right to left shunting.
Hypoxemia often causes symptoms but these are typically not at all specific for PFO related hypoxemia. People usually are abnormally short of breath. In some people they are short of breath a rest, others with variable degrees of exercise, and in others, like in trained athletes they notice a decline in their maximum performance which cannot be otherwise explained. The symptom of shortness of breath, what we call dyspnea, is common to many medical conditions and therefore PFO related hypoxemia is a relatively rare cause.
Fatigue is also a response of the body to hypoxemia. This is clearly an even more nonspecific symptom that dyspnea.
The human body is very sensitive to hypoxemia. Reduction of systemic oxygen saturation to 85% makes a normal person feel quite ill.
Therefore, the large degrees of shunting thru a PFO can produce hypoxemia and symptoms, what can be referred to as the PFO-hypoxemia syndrome. This is a unique PFO related condition to PFO-related strokes and PFO-associated migraines although we increasingly recognize that people may have several of these syndromes related to having a PFO. It is reasonable that those having PFO-related hypoxemia must have the large PFO’s capable of shunting enough blood to cause hypoxemia.
Closing a PFO to reduce or eliminate the degree of hypoxemia has a clear rationale. It is a simple mechanical action that immediately halts any ability to have severe right to left shunting. Closure devices that can be implanted during a non-surgical procedure can often completely eliminate if not significantly reduce the right to left shunting thru a PFO. PFO related hypoxemia has been considered fairly rare such that PFO closure has not been well studied for this indication. Specifically there is no large prospective trial to understand the disorder better and help define the role of PFO closure for this indication. There are scattered individual patient reports often illustrating unusual pathophysiological mechanisms producing severe tight to left shunting. We suspect that PFO-related hypoxemia may be found more often if it is searched for both in questioning people found to have a large PFO and in further developing tests to understand and quantify the degree of dynamic shunting. At the University of Colorado we have focused energy in attempting to identify and test people for PFO-related hypoxemia and discussing PFO closure. Approximately one half of the patients have been referred from National Jewish Medical Center, a nationally prominent research and clinical center for respiratory disease, in patients whose pulmonary evaluation has not adequately explained their symptoms and hypoxemia. This clinical practice experience is being gathered and with an IRB approved study will be published in the upcoming months.