Apnea, hypoventilation and pulmonary hypertension: Pathology review

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Case Study0:00–1:00

Joseph, a 42 year old man comes to the clinic because he’s been waking up many times at night, which makes him very sleepy during the day.
His partner also complains that Joseph has always snored but recently it’s louder than ever. On physical examination he has a BMI of 35 kilograms per square meter, and has a blood pressure of 140 over 90 millimeters of mercury.
You decide to conduct a sleep study, which reveals a very low partial pressure of oxygen. Later, a 35 year old woman called Robin also comes to the clinic.
She tells you that, lately, she’s been experiencing shortness of breath and fatigue. Robin is quite worried, and mentions that she has a congenital heart defect.
On physical examination, she has a mean pulmonary arterial pressure of 28 millimeters of mercury. You decide to perform an electrocardiogram or ECG test, and a chest X-ray, which show that Robin has right ventricular hypertrophy.Based on the presentation, both cases seem to have some respiratory disease, associated with some cardiovascular issues.

Pathology1:00–1:19

Now, for your exams, some important conditions include sleep apnea, obesity hypoventilation syndrome, and pulmonary hypertension.

Sleep Apnea1:19–4:09

So, let’s begin with sleep apnea! This is when a person, during their sleep, experiences recurrent and intermittent episodes in which they stop breathing for more than 10 seconds.
In addition, since fresh air is not getting into the lungs, individuals with sleep apnea will have nocturnal hypoxia. This puts the body under stress, which in turn responds by releasing epinephrine.
Now, the recurrent epinephrine surges have several effects. Firstly, this wakes up the person so that they can breathe again.
This causes disrupted sleep, which in turn leads to somnolence or sleepiness during the day or while awake. Secondly, the body tries to compensate for the hypoxia by increasing the amount of red blood cells, or erythrocytes, available to carry the oxygen in blood to our tissues.
To do so, our kidneys produce a hormone called erythropoietin, or EPO, which stimulates the bone marrow to produce more red blood cells, and this process is known as erythropoiesis.
The problem with sleep apnea though is that, even if we increase the number of red blood cells, the amount of oxygen that’s entering the body is not enough, so there’s still hypoxia.
Third, having high epinephrine levels can cause vasoconstriction, increasing the vascular resistance. Over time, this can result in vascular remodeling, which can lead to the development of both pulmonary and systemic hypertension.
Pulmonary hypertension is when the blood pressure in the lung arteries is increased, while systemic hypertension involves the arteries of the rest of the body.
Over time, this can put too much strain on the heart, and ultimately cause abnormal heart rhythms, like atrial fibrillation or atrial flutter, heart failure, and even sudden death.
Diagnosis of sleep apnea involves a sleep study, also known as polysomnography, which counts the number of apnea episodes, and monitors several parameters like heart rhythm and oxygen saturation.
Another important diagnostic value is partial pressure of oxygen in the arteries, since it helps us understand if the tissues are receiving adequate oxygen supply.
This value can be easily and indirectly obtained with a pulse oximeter, or directly obtained via blood gas sampling. For your exams, remember that people with sleep apnea have low oxygen saturation levels, and thus low partial arterial pressure of oxygen during sleep, but bear in mind that this partial pressure is typically normal when they’re awake.Now, when the cause of sleep apnea originates in the central nervous system, it’s called central sleep apnea.
Most often though, sleep apnea is caused by an obstruction of airflow in the airways, which is known as obstructive sleep apnea.
And when a person experiences both obstructive and central sleep apnea, it’s called complex or mixed sleep apnea. Okay, let’s start with central sleep apnea or CSA for short.

Central sleep apnea (CSA)4:09–6:25

Central sleep apnea is caused by an imbalance in the respiratory center of the brain, so during sleep it fails to activate the muscles that control breathing.
The main causes of central sleep apnea include central nervous system injury involving the respiratory center, as well as central nervous system toxicity, often due to use of opioid medications.
Another major risk factor for central sleep apnea is congestive heart failure. What’s important for your exams is that congestive heart failure leads to increased chemosensitivity, which is how the body senses and responds to changes in the partial pressures of oxygen and carbon dioxide.
So when there’s an apnea episode, oxygen levels decrease while carbon dioxide levels rise. Now, keep in mind that carbon dioxide is the main stimulus for the respiratory center, so when there are high levels of carbon dioxide, the respiratory center responds by increasing our respiratory rate.
Now, when there’s increased chemosensitivity, the increased CO2 triggers an exaggerated response in the form of hyperventilation, and ends up decreasing the carbon dioxide too much.
So now the CO2 level is too low, and this ultimately causes depression of the respiratory center and thus another apnea episode.
As a result, there’s a vicious cycle that leads to central sleep apnea. Now, when central sleep apnea is associated with congestive heart failure, it often manifests as an abnormal breathing pattern called Cheyne-Stokes respiration, also known as cyclic respiration.
This is a periodic breathing characterized by oscillation between periods of apnea alternated with deep breaths or hyperpnea.So, for your exams, remember that the three main things you need to know all start with a ‘C’ for central sleep apnea!
The first is central nervous system injury or toxicity, the second ‘c’ is congestive heart failure, and the third ‘c’ is for- Cheyne-Stokes respiration.
Treatment of central sleep apnea mainly involves positive airway pressure therapy, as well as taking care of the underlying cause.And then we have obstructive sleep apnea, or OSA for short.

Obstructive sleep apnea (OSA)6:25–8:08

As the name suggests, it is caused by a narrowing or obstruction of the airways. Now, normally, the airway muscles relax while sleepingIn healthy people though, the airway muscle tone is strong enough to counteract factors that would cause the airway to collapse, such as gravity while lying down, and the negative pressure in the airway during inspiration.
In obstructive sleep apnea, the airway muscle tone is not strong enough to counteract these factors, and so the airway collapses.
In adults, the most common cause is an excess of parapharyngeal tissue, which basically means that there’s excess fat in the neck region.
That’s why obstructive sleep apnea is most common in obese individuals, so those with a BMI over 30 kilograms per square meter.
On a test question, the most important clue suggesting obstructive sleep apnea is loud snoring in an obese individual, like they’re trying to gasp for air until they wake up.
This leads to disrupted sleep, which in turn causes excessive sleepiness during the day or while awake. Sometimes though, obstructive sleep apnea may affect children; in this case, the most common cause is adenotonsillar hypertrophy, meaning an enlargement of the pharyngeal and palatine tonsils.
Treatment of obstructive sleep apnea involves continuous positive airway pressure, or CPAP therapy, which delivers a steady stream of pressure, in order to keep the airway open.
In addition, weight loss is highly recommended for overweight people. Finally, one last option is surgery to remove the excess parapharyngeal tissue.Now, another important respiratory disease that’s very often related to obstructive sleep apnea is obesity hypoventilation syndrome, or OHS for short.

Obesity hypoventilation syndrome (OHS)8:08–9:25

Obesity hypoventilation syndrome is also named Pickwickian syndrome after Charles Dickens’ novel “The Pickwick Papers”, in which there is an overweight character who’s constantly falling asleep at any time of the day.
As the name suggests, obesity hypoventilation syndrome only affects obese individuals. That’s because the excess weight can restrict the movement of the diaphragm and chest wall, which impairs lung expansion.
As a result, affected individuals develop hypoventilation, meaning slow or shallow breathing. In most cases, obesity hypoventilation syndrome also causes obstructive sleep apnea and hypoventilation during sleep, but bear in mind that these individuals also experience hypoventilation while awake.
And that’s a high yield fact!Because of that, diagnosis of obesity hypoventilation syndrome includes an increased partial pressure of carbon dioxide while awake, and while sleeping, they’ll also have a decreased partial pressure of oxygen.
Treatment is mainly focused on weight loss, and some cases can also get positive airway pressure during sleep.Okay, let’s switch gears to pulmonary hypertension, or PH for short, which is defined as a mean pulmonary pressure at rest that’s greater than 25 millimeters of mercury.

Pulmonary hypertension (PH)9:25–16:32

And this often results in four hallmark pathological changes to the pulmonary arteries. Now, to remember these four pathological changes, think of the mnemonic “Ants In My Pants”.
The first change is arteriosclerosis, in which the arterial walls become thicker, harder, and lose elasticity. Another change is intimal fibrosis, which is similar to arteriosclerosis, but only involves the tunica intima, which is the innermost layer of the arteries.
Then there’s medial hypertrophy, meaning a thickening of the tunica media, which is the middle layer of the arteries. Now, these three changes can lead to a narrowing or even closing of the pulmonary arteries, which compensate by forming new networks of vascular channels between the arterial branches.
These channels are known as plexiform lesions, and are the fourth pathological change. Over time, pulmonary hypertension can progress to severe respiratory distress, and individuals may present cyanosis or bluish skin discoloration due to poor blood oxygenation.
In addition, since the lung arteries are narrowed, the pressure inside increases. And since the afterload of the right ventricle is proportional to the pulmonary pressure, it becomes harder for the heart to pump blood, so it backs up, leading to an overload in the right heart.
In response, the heart muscle will try to compensate by progressively remodelling its shape and size and becoming thicker.
This is called right ventricular hypertrophy or RVH. Ultimately, the heart isn’t able to compensate anymore, which leads to cor pulmonale, meaning right-sided heart failure that’s caused by a lung condition.
If not treated, decompensated cor pulmonale is fatal.Now, pulmonary hypertension can be classified based on the underlying cause into five groups.
Group 1 is pulmonary arterial hypertension, or PAH for short. Now, pulmonary arterial hypertension refers specifically to pulmonary hypertension that’s caused by a progressive stiffening and constriction or narrowing of the arteries in the lungs.
This is often associated with endothelial dysfunction, meaning that the endothelial cells start producing more vasoconstrictors, such as endothelin, but less vasodilators like nitric oxide and prostacyclins.Now, the reason why this happens is most often idiopathic, meaning its cause is unknown.
However, there are some well understood causes that you must know for your exams. These causes include congenital heart disease associated with left-to-right shunts, which is when an anatomical defect of the heart’s septum causes blood to leak from the left side into the right side; as well as portal hypertension, which refers to increased pressure in the portal vein, that drains blood from the gastrointestinal tract into the liver.
Other causes include connective tissue diseases, such as lupus or scleroderma, as well as some infectious diseases like HIV infection, or schistosomiasis, which is caused by the parasitic flatworm Schistosoma.
Pulmonary arterial hypertension can also be caused by some abuse drugs like cocaine and amphetamines. In addition, some cases of pulmonary arterial hypertension can be inherited.
Now, heritable pulmonary arterial hypertension is caused by an inactivating mutation in the BMPR2 gene. Normally, the BMPR2 gene codes for a protein that inhibits the proliferation of smooth muscle cells, and this is particularly important in blood vessels.
What’s important for you to know is that the inactivation of BMPR2 leads to medial hypertrophy of the lung arteries, and this generally has a poor prognosis.
All right, now let’s go back to the causes of pulmonary hypertension. Group 2 is left sided heart disease, which can be due to congenital heart defects, systolic or diastolic dysfunctions, or a valvular disease.
Remember that the left side of the heart receives oxygenated blood coming from the lungs, and then pumps this blood to the rest of the body.
So when the heart’s ability to pump blood is compromised, the backflow of blood leads to increased pressure in the pulmonary circulation.
Group 3 is pulmonary hypertension caused by chronic lung diseases like chronic obstructive pulmonary disease or COPD, in which the lung parenchyma is destroyed; as well as interstitial lung disease, in which there’s inflammation and fibrosis of the lungs.Group 3 also includes any condition that causes hypoxia, such as living at high altitudes or having sleep apnea.
To compensate for the hypoxia, the lungs try to divert blood into lung segments with better oxygenation by constricting the small pulmonary arteries of poorly oxygenated alveoli.
This mechanism is known as hypoxic pulmonary vasoconstriction. Group 4 is for chronic thromboembolic pulmonary hypertension, which is when there’s recurrent or chronic formation of thrombi or blood clots that may block or damage the pulmonary arteries.
As a result, blood cannot flow properly through the affected arteries, ultimately causing an increased pressure in the pulmonary arterial tree.
Chronic thromboembolic pulmonary hypertension can be associated with clotting disorders, chronic inflammatory diseases, or systemic diseases like cancer.The fifth and last group is multifactorial, meaning multiple causes, and mainly refers to less common causes of pulmonary hypertension that don’t fit into the other groups.
Multifactorial causes include metabolic disorders like thyroid disorders, blood disorders like anemia, systemic disorders like sarcoidosis, and tumors that compress the pulmonary vessels.Okay!
We’re near the end! Diagnosis of pulmonary hypertension is usually made with right heart catheterization, where a catheter is inserted through the right heart to measure the pulmonary pressure.
Pulmonary hypertension is diagnosed when the mean arterial pressure is greater than or equal to 25 millimeters of mercury.
Follow up tests can be done to identify the underlying cause, and can include an ECG and imaging, among others. Finally, treatment of pulmonary hypertension generally involves giving supplemental oxygen, and further treatment options will depend on the underlying cause.
So for instance, if the cause is pulmonary arterial hypertension, medications like endothelin receptor antagonists and prostacyclins can be given.
If the cause is left heart disease, treatment can involve medications aimed at boosting the heart’s performance or lowering the blood pressure.And if the cause is chronic thromboembolic pulmonary hypertension, treatment can involve long-term anticoagulants, as well as surgery to remove the thrombi when possible.

Review16:32–18:21

All right, as a quick recap… Sleep apnea is when an individual intermittently stops breathing for at least 10 seconds during sleep, and it’s typically associated with snoring, disruptive sleep, and daytime sleepiness, as well as nocturnal hypoxia, that over time can lead to hypertension, arrhythmias, and sudden death.
Sleep apnea could be central, due to an imbalance of the respiratory center in the brain during sleep, and is associated with central nervous system toxicity or injury, congestive heart failure, and Cheyne-Stokes respiration; whereas obstructive sleep apnea most often occurs in obese individuals and is associated with airway obstruction and loud snoring.
A potentially related disease is obesity hypoventilation syndrome, also known as Pickwickian syndrome, which affects obese individuals, presenting shallow or slow breathing, and increased partial pressure of carbon dioxide both during sleep and while awake.
Treatment of sleep apnea can include weight loss, positive airway pressure, or surgery. Lastly, pulmonary hypertension is characterized by a mean pulmonary pressure at rest that’s greater than 25 millimeters of mercury.
Its four hallmark pathological changes include arteriosclerosis, intimal fibrosis, medial hypertrophy, and plexiform lesions.
Eventually there’s a severe respiratory distress leading to cyanosis, right ventricular hypertrophy, decompensated cor pulmonale, and death.
The causes of pulmonary hypertension are classified into 5 groups, including pulmonary arterial hypertension, left heart disease, chronic lung diseases or hypoxia, chronic thromboembolic pulmonary hypertension, and multifactorial causes.Okay, back to our cases.

Summary18:21–19:21

Joseph is a 42 year old man who experiences sleeping problems associated with loud snoring and sleepiness during the day.
This is already pretty suggestive of obstructive sleep apnea. This is further supported by the fact that Joseph is obese and has systemic hypertension.
The final clue is given by the sleep study, which reveals nocturnal hypoxia. And since Joseph has none of the three main ‘Cs’, you can rule out central sleep apnea.
Next, Robin is a 35 year old woman complaining of shortness of breath and fatigue that may be related to her congenital heart disease.
This, combined with her high mean pulmonary arterial pressure, should make you think of group 2, or left sided heart disease causing pulmonary hypertension.
In addition, Robin’s ECG and chest X-ray show right ventricular hypertrophy, which is a common compensation mechanism to pulmonary hypertension.
If Robin doesn’t get treatment, she might eventually develop cor