The Relationship of Sleep Apnea and Other Disease Processes

 

Low SAO2 Levels and The Development of Diseases:

It has been know for some time that people who suffer from sleep apnea develop other diseases as a result of the sleep apnea. In the last few years there has been a sparked interest in this area, shedding light onto this relationship. The following is a system-by system review of the current knowledge.

The Cardiovascular System:

The cardiovascular system is comprised of the heart, the arteries, veins and about five litres of blood. This system is critical in many ways. Circulating blood transfers oxygen from the lungs to the blood and removes carbon dioxide from the cells of the body. It transfers nutrients to the cells. It transports the immune system cells to areas of infection and increases the number of blood vessels into an infected area. It caries sugar to the nervous system and muscles.

When someone has untreated sleep apnea, they experience recurrent drops in the level of dissolved oxygen in their blood, otherwise known as the saturated oxygen level or SAO2. Red blood cells are responsible for transporting oxygen as each cell has a molecule of iron in it. The iron binds reversibly to the oxygen allowing these cells to act as transporters until a cell in need removes the oxygen (interestingly, carbon monoxide, found in cigarettes and car exhaust etc. also binds to this iron in red blood cells. The difference is that the bond is irreversible and the cell can no longer carry oxygen. If enough cells are effected, you die). The heart, as it is constantly working throughout one’s lifetime, is very dependent upon oxygen and dissolved sugar in the blood. It has been found that SAO2 levels can affect the heath of the cardiac muscle. If SAO2 levels start to fall, the heart can adjust to this. There are CO2 (carbon dioxide) sensors on the aorta, the large curved artery that immediately leaves the heart). These sensors are particularly sensitive to increases in CO2 and increases in hydrogen ions (H+) in the blood. when H+ ions increase, the blood becomes more acidic. These sensors can also detect, less sensitively, falls in SAO2 levels. There are also chemoreceptors or sensors in muscle tissue, joint tissues, the aorta and in the brain itself.

The result of these sensors recognizing high CO2, high H+ and low SAO2 is that adrenaline is released from the adrenal glands. Adrenaline is the hormone that is involved in the “fight or flight” response. It causes the heart to increase in rate and in output volume. It pumps harder and faster. This is an attempt to circulate more oxygen around the body, and remove the CO2. Imagine this occurring 150-200 times each night. The heart, like any other muscle, will start to bulk up with exercise. The left ventricle is the main pump to the body and, in untreated OSA patients, they often develop enlargement of the heart (left ventricle). The valves inside the heart may start to leak as the ventricle is swollen in size. This allows low oxygen blood and high oxygen blood to mix, reducing further the SAO2 level in the blood. The heart is a living organ and has specific needs. It requires sugar for energy and the cardiac muscle requires oxygen like every other cell of the body. If the SAO2 levels in the blood fall below the level that the heart can adapt to, then the cardiac muscle begins to die. This is known as a heart attack and people wilth untreated OSA have a 30% higher chance of having a heart attack than people without  sleep apnea! The SAO2 level determined to place someone at this risk is around 80%. Many OSA patient drop below 80% for short periods each apnea event. During these times the heart is very stressed due to low oxygen. Add adrenaline and make it work much harder and you have a recipe for disaster. It is a well know fact that high blood pressure is associated with sleep apnea. It is often resistant to treatment until the sleep apnea has been treated. The kidneys are highly vascular and are key in regulating blood pressure. The kidneys can alter the amount of sodium and potassium in the blood. These two chemicals affect the volume of blood circulating. If sodium levels are higher, the blood becomes hypertonic or too salty. This results in fluids within the surrounding tissues to be drawn into the blood vessels until the blood resumes a normal level of sodium or salt (raising the blood pressure). The kidneys are highly vascular and increased blood pressure causes the finest blood vessels to rupture, rendering the kidneys less effective.

The renal medulla, or inner filtration network, is made up of billions of very tiny blood vessels (capillaries). The blood enters the kidneys on the outside and leaves it on the inside. If the blood pressure is elevated, these tiny blood vessels explode and filtration efficiency goes down. Now the kidneys can no longer regulate the sodium levels and blood sodium levels start to increase. This draws more fluid into the system from the surrounding tissues and increases the volume of circulating blood (and blood pressure). Blood pressure is measured with a sphygmomanometer. This is well known and very accurate cuff that the nurse inflates and then slowly releases while listening to your pulse. The number recorded is in the form of xx/xxx. The normal number is 120/80. What does this mean? Think of a garden hose. You connect it to the faucet and turn on the faucet. Assuming you have already attached a hand sprayer to it, nothing happens. In the hose, however, there is a pressure buildup. This is the lower number. It gives the doctor the pressure of the system and how likely you are to suffer an aneurysm (a bubble forms at a weak point in a blood vessel and expands until it bursts. The most common area for aneurysms are in the brain, the aorta, and the arteries supplying the stomach. Back to the hose analogy. You have the water turned on, and now you squeeze the handle on the sprayer and the water goes shooting out. This is the upper number. This is a direct measurement of the amount of force the heart must pump out each beat, in order to circulate the blood. These two numbers are codependent. If the low number goes up, the heart has more volume to deal with and the upper number generally goes up as well. Don’t forget that it is the left ventricle of the heart doing all the work. And this ties the kidney damage back to the heart and circulatory system. It is much more complicated than this, but this the general idea of it. As seen in the above animation, the end result of this is enlargement of the left ventricle of the heart, which leads to congestive heart failure. This process can and does occur at any age in OSA patients that are not treated.

In sleep apnea, there are repeated events of drops in SAO2, sometimes much lower than the threshold that can damage the heart and other tissues. This repeated drop of SAO2 is what likely causes the diseases that are seen to parallel sleep apnea.

The Pancreas:

The pancreas is a very important organ. it is made up of different types of cells, each with a different function. The Alpha Cells produce glucagon, the Beta Cells produce insulin, Delta Cells produce Somatostin (which regulates the alpha and beta cells) and the Gamma Cells produce pancreatic polypeptide which aids in digestion. The pancreas’ anatomy is of very tightly packed cells. The cells are so tightly packed that there are no actual blood vessels within the pancreas, blood passes through the pancreas  by a process called “perfusion”. This is where blood cells from the pancreatic artery, which is high is oxygen, leave the artery and enter freely into the pancreas. The blood cells move through the pancreatic cells distributing oxygen and nutrients to these cells. In normal perfusion, the oxygen carrying cells enter the pancreas and slowly filter through it, losing oxygen as they go. The cells closer to the artery receive good oxygenation. As the cells pass through the tissue they lose more oxygen until they reach the side with the vein where they are collected and taken back to the lungs to be replenished with oxygen. All of the tissue receives adequate oxygen and the cells carry on with their jobs. (red = higher oxygen, blue = lower)

In Sleep Apnea it is not uncommon for oxygen levels to fall drastically for short periods of time (2 minutes or less). During these times, perfusion in the pancreas is compromised as the cells entering it are already low in oxygen and deplete their oxygen rapidly. The result is that tissue further from the arterial supply becomes hypoxic, or low in oxygen, and can die. In the pancreas, cell death results in Type 2 Diabetes.

 Thyroid Disease:

The thyroid organ, located in the neck area, also has a tightly packed cellular form, similar to the pancreas. It too receives its internal blood supply through perfusion and can suffer the same fate as the pancreatic cells when the blood oxygen levels fall. Cell death in the thyroid gland results in Hypothyroidism or an under-active thyroid. The blood enters the thyroid by blood vessels and then enters into the follicular region by perfusion. Again, if the blood cells entering are already low in oxygen, the tissues deepest and farthest from the arterial supply will not receive oxygen and can die. The thyroid is very sensitive to drops in SAO2.

The Kidneys:

As already shown above, as the blood pressure rises due to increased heart rate and intensity, the fragile capillaries in the kidneys can be damaged from the increase in pressure. To compound this, the kidneys, even though they process an incredible amount of blood, have oxygen levels within the cells of the  kidneys that are quite low. This renders the nephritic cells very sensitive to falls in SAO2. The more damage to the kidneys, the poorer the control of blood pressure (due to poor sodium etc. regulation). The poorer the control of blood pressure, the more damage there is to the kidneys. A vicious circle indeed!

The cellular structure of kidneys is similar the other organs discussed: tight cellular formation relying upon perfusion from blood vessels on the surface to the inside of the kidney. Kidney disease is high in untreated OSA patients due to this affect.

The Liver:

The liver is a very important organ as it assists the pancreas in regulating blood sugar (through storage of sugar as glucogen which allows time release of blood sugar between meals) as well as well as accepting all of the waste collected from the lymphatic system. In a healthy person, 7% of the liver’s weight is glucogen. The liver cells receive blood through perfusion similar to the other organs discussed. When the liver is exposed to lower SAO2 levels a number of changes occur. Hypoxia (low oxygen) is a stresser, it stresses the body and liver. The liver is metabolically very active and uses a lot of energy (ATP at the cellular level). Like the heart and brain tissue, the liver is very susceptible to hypoxic injury. The liver is resilient to injury due to its structure. It is supplied by both an artery, rich in oxygen and a larger vein, which is lower but still contains some oxygen. Although the vein (the Hepatic vein) is much larger than the artery (the Hepatic artery), the artery carries much more oxygen to the liver. In total, they both supply the liver with about the same amount of oxygen, providing the liver with a dual blood supply. The two blood supplies mix inside the liver in the hepatic sinusoid, a sinus inside the liver.

The liver, like the heart and the brain, is vulnerable to hypoxic injury. The mixing of the two blood supplies however, offers the liver some protection. In the case untreated sleep apnea,which can lower the SAO2 level repeatedly and significantly, the liver is often damaged. As the oxygen levels vary between different lobes of the liver, the areas with lower oxygen levels are damaged first. Ischemia and perfusion injury are common and can lead to cellular changes. The first to been seen is the formation of plasma membrane protrusions called “Blebs” which occur with swelling of the cells by 30-50%! These blebs contain cytosol and endoplasmic reticulum, but no mitochondria or lysosomes. Irreversible injury occurs if these Blebs burst releasing intracellular enzymes and metabolites. In the image below, these blebs can be seen. These blebs accumulate in the liver regardless of body size and weight.

ATP is the basic molecule of energy at the cellular level. It is produced in mitochondria, small organelles within each cell, by the citric acid cycle (Krebs’s Cycle). This is called “Aerobic Respiration” which occurs constantly in normal cells in the presence of oxygen.

 

 

Mitochondria are very susceptible to hypoxia and ATP production falls significantly during hypoxic events as mitochondria are damaged. The glucogen contains some stored ATP and this must be used by the liver in hypoxia (anaerobic respiration). This is much less effective but still can prevent lethal damage to liver cells. This occurs through “glycolysis”, the process of breaking down glycogen, fructose (fruit sugar) and glucose (regular sugar) through anaerobic processes to produce ATP.

Glycolysis is not as efficient as the Citric Acid Cycle and uses up the stores of glucogen in the liver. Without ATP, cellular processes cease and the cell dies.

Another recent finding in multiple studies is the development of “fatty liver” that is seen with untreated sleep apnea. This is termed NAFLD or non-alcoholic fatty liver disease and can lead to permanent liver damage including enlargement of the liver and scar tissue replacement of the liver cells called cirrhosis. Up to 20% of adults have NAFLD and are not aware of it. Asian and Hispanic children are more prone to NAFLD genetically. Of interest, Asian and Hispanic populations are also at higher risk of OSA. NASH (uncomplicated hepatic steatosis to steatohepatitis) is an early form of NAFLD that is caused by obesity and insulin resistance. OSA has now been shown to also cause NASH and the severity of OSA has been shown to play a role in the development of NASH into NAFLD and hepatic steatosis. Several good studies have shown OSA to be linked to the severity and good predictor of the severity of NAFLD seen upon liver biopsies. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473309/figure/F1/ (Article Link)

The Brain:

Brain cells, like the heart and pancreas are very susceptible to hypoxia. If SAO2 levels fall too low, brain cells can die. The brain cannot survive long without oxygen (remember your CPR?).

The lymphatic system is a separate circulatory system that parallels our blood vessels. It is made up of the lymphatic vessels and the lymph nodes. Harmful bacteria and virus are collected and attacked in the lymph nodes (mumps is a good example) as well as waste products are collected from the cellular fluids. Blood vessels leak plasma or salty water and this would result in a drop over time in blood pressure and swelling of the tissues. The lymphatic system recovers this plasma which is ultimately returned to the blood stream. The termination of the lymphatic system is at the liver.

 The Glymphatic System of the Brain:

The brain also has a system like the lymphatic system called the Glymphatic System. This system is responsible for cleaning up metabolites and other debris from the brain. Two such waste products that have received much attention lately are Beta Amyloid and Tao protein. These are proteins that make up the axons or long filaments that connect the brain cells to each other or, as in the case of Beta Amyloid, occur normally in the space between the neurons. In this diagram it can be seen that the unwinding of the axons releases much debris, including Tao proteins.

Beta Amyloid is a solitary protein occurring in the brain. If it builds up too much however it can form into clumps, usually at the junction where cells communication with each other (the synapse). Loss of these connections means loss of brain function. Tao protein, when released due to breakdown of the axons, also forms into clumps. These two proteins have been shown to be present in high levels in Alzheimer’s disease. The characteristic Amyloid plaques are often described on MRI’s of these patients.

The Glymphatic System’s main purpose is to cleanse the brain including beta Amyloid and Tao protein. This works by the glial cells, a type of brain cell, that swell and release CSF (cerebrospinal fluid) into the spaces between the cells. The entire brain gets larger during this process as there are billions of glial cells in the brain. This diagram shows how waste products (Tao Protein and Beta Amyloid) are flushed from the brain by this system:

(The small dark particles being removed in the diagram below represent Beta Amyloid and Tao proteins)

The veins of the brain (Para-Venous Efflux)  carry the waste products (Beta Amyloid and Tao proteins) removed by this system to the liver for processing, just as the lymphatic system does.

Of interest, the Glymphatic System is only active during REM sleep (deep sleep). In OSA patients, REM sleep is very limited or absent completely. This is likely one of the major factors in the high incidence of OSA in Alzheimer’s disease (40% of Alzheimer’s patients have undiagnosed OSA!). The image below shows a typical Amyloid plaque seen in Alzheimer’s disease as the protein forms clumps around the cells killing them. Head traumas can also damage the Glymphatic system leading to dementia (i.e. boxers) through gross damage of the brain. Concussion injuries, and the associated “brown areas” of dead tissue likely have little or no Glymphatic system in place and buildup of toxins and proteins is likely.

 

 Low Oxygen (SAO2) and Cancer:

Cancer is a disease that can affect almost any tissue in the body. There is one commonality between the different types of tumors: when the tumor reaches a certain mass or size, the center is anaerobic (does not use oxygen). Conditions in the body that lower the SAO2 may favor tumor growth. There is conflicting research on this currently but the hypothesis is valid. It is known that tumors release chemicals that induce increased growth of blood vessels to the tumor, to feed its growth. The lack of blood vessels to the center of the tumor and hypoxic conditions at the center also make delivery of chemotherapeutic drugs to the center of tumors difficult and often surgical removal is needed. More research is needed in this area, to determine the effects of low SAO2 on tumorigenesis.

To Summarize…

The drops in SAO2 associated with sleep apnea / UARS can significantly damage the body. And, if left untreated over time, can result in serious diseases that affect quality of life as well as shorting the expected life span of those affected. The following table outlines the oxygen drops that are known to cause disease:

 

Organ	SAO2 Level Where Tissue Damage Occurs Below	Diseases Seen Clinically
Pancreas	84%	Type 2 Diabetes
Thyroid	84%	Hypothyroidism
Cardiac Muscle	80%	Heart Attack/Heart Disease

These oxygen levels are the minimal amounts of SAO2 that these tissue can tolerate before cell death occurs. This is one of the main reasons that people with untreated sleep apnea are highly prone to Type 2 diabetes, hypothyroidism and heart disease/heart attacks.

Snoring, a very common affliction in our population, is not generally thought of as serious (and often as comical). Recent studies have shown that just snoring lowers SAO2 levels by up to 10%. Normal SAO2 levels are around 98% and a drop of 10% takes a snorer down to 88%, only 4% above pancreas and thyroid damage! Snoring also increases ones’ risk of throat cancer, especially in those who smoke.

Treatment of snoring, sleep apnea and UARS are critical in the maintenance of health and prevention of many serious diseases. Research is only beginning to discover the relationships of OSA and systemic disease. The Luco Hybrid OSA Appliance is approved for the treatment of primary snoring and mild to moderate obstructive sleep apnea in the USA, Canada, and the European Union.