Update on Pulmonary Arterial Hypertension

WHILE HIGH BLOOD pressure is well understood as the single most prevalent cause of early mortality in the U.S. and Europe, a specific subset, pulmonary arterial hypertension (PAH), is a little-known yet deadly condition in which high blood pressure is confined to or focused on the lungs. It is chronic and progressive, and the eventual outcome is heart failure.

What Is PAH?

PAH is an incurable disease in which the arteries in the lungs become constricted (either through narrowing or internal blockages), causing increased pressure on the right side of the heart. It is one of five categories of the larger disease group known as pulmonary hypertension,¹ and it is subcategorized based on the likely cause of the disease. Most cases will fall into one of the first four categories, but there are even more rare cases as well:

• Associated PAH (APAH)
• Drug- and toxin-induced PAH
• Heritable PAH (HPAH)
• Idiopathic PAH (IPAH)
• Persistent pulmonary hypertension of the newborn (PPHN)
• Pulmonary veno-occlusive disease (PVOD)
• Pulmonary capillary haemangiomatosis (PCH)

While exact numbers of patients with PAH are not available,² estimates range from 15 to 50 cases per million in the U.S. for the larger pulmonary hypertension disease group known as APAH.³ Women are more likely than men to develop PAH, and it generally manifests between the ages of 20 years and 60 years. Being overweight is also correlated with developing PAH, as is a family history of the disease. Those living at high altitude are also at higher risk.²

Survival rates for those diagnosed with IPAH (the form in which no cause can be determined) range from 68 percent at one year down to a five-year rate of just 34 percent.⁴ (However, these numbers are not adjusted for patient age or how far the disease had progressed at time of diagnosis.)

Causes of PAH

More than half of PAH cases are thought to be caused by another condition that strains the body. These disparate conditions are grouped together as APAH, with underlying causes ranging from connective tissue diseases (lupus, scleroderma), liver disease (including cirrhosis and portal hypertension), HIV, sickle cell disease, lung disease (emphysema, chronic obstructive pulmonary disease [COPD]) and congenital heart disease. These connective tissue diseases are associated with roughly 30 percent of all PAH cases.⁵

Scleroderma (also known as systemic sclerosis, or SSc) and lupus can lead to APAH by scarring the blood vessels in the lungs.⁶ Up to 12 percent of all patients with SSc will develop PAH, with only a 50 percent three-year survival rate.⁷

Cirrhosis and other liver diseases, including portal hypertension, are thought to cause PAH through elevated sodium levels left in the bloodstream by a weakened liver, leading to higher blood pressure.⁸

The specific mechanisms by which HIV leads to PAH are not fully understood, but researchers believe the statistical correlation is too high to be coincidence.⁹

Sickle cell disease can lead to PAH through the general deterioration of tissue, including arterial walls, associated with the genetic disease.¹⁰

Researchers believe that the lung diseases emphysema and COPD can trigger PAH through the inflammation and hypoxia affecting the tissue in the arteries.¹¹

Congenital heart disease can trigger PAH through overcirculation, causing lesions to form on the arterial walls. Researchers believe other factors also come into play, but don’t fully understand the mechanisms that can trigger PAH.¹²

Another leading cause of PAH in developing areas of the world is schistosomiasis, a parasitic infection of the Trematoda freshwater flatworm.¹³ It is found in the Caribbean, and travelers who have been to tropical locations in other parts of the world may bring the infection home. About 4.6 percent of those with schistosomiasis will develop PAH.⁶

Drugs and poisons can also lead to the development of PAH. These are sometimes included with APAH, while other researchers and practitioners place them in their own category. Substances that have a high correlation with PAH and are thought to play a role include illegal street drugs such as cocaine and methamphetamine (which both constrict blood vessels and can cause scarring on the internal walls),¹⁴ as well as since removed prescription weight-loss drugs fenfluramine and dexfenfluramine (which had a high correlation between their use and later development of PAH).¹⁵

HPAH is sometimes referred to as familial PAH. It is tied to an inherited genetic mutation that is thought to either cause development of, or make it more likely to develop, PAH. The two genes thought to be associated with PAH are bone morphogenetic protein receptor type 2 and activin receptor-like kinase 1.⁶ There is a correlative tie with PAH, but the causative function that leads the mutation to bring about PAH is not yet understood. Some 15 percent to 20 percent of all PAH patients have HPAH.⁵

When doctors are unable to determine a likely cause of PAH, it is then diagnosed as IPAH. This is likely the second-largest group of cases, behind APAH.

Infants born with PAH are described as having PPHN. The specific trigger is not understood, but it is thought to be a failure of the normal circulation transition that occurs immediately after birth as infants begin processing their own oxygen via the lungs rather than via the placenta.

Lastly, two closely related diseases to PAH generally included in the PAH classification under the World Health Organization’s (WHO) pulmonary hypertension descriptions are PVOD and PCH. PVOD is a condition in which the small veins in the lungs become obstructed with new tissue growth. 16 PCH is considered a pretumorous growth of capillaries that typically manifests in children and young adults, and generally progresses to PAH.¹⁷ The causes of these are also unknown.

Symptoms and Progression of PAH

Patients with PAH can be asymptomatic in the earliest stages of disease.¹⁸ Initial symptoms of PAH are generally identical to those of other forms of hypertension:

• Shortness of breath (especially following physical activity)
• Excess fatigue
• Dizziness or fainting
• Racing pulse
• Chest pain or pressure

Depending on the progression of PAH, symptoms may also include:

• Swollen arms, legs or face due to edema
• Cough
• Hoarseness
• Low blood pressure

Late-stage PAH patients may exhibit blue coloration on lips or skin, particularly the extremities, due to low oxygen levels in the blood. Some patients may also develop Raynaud’s disease, which causes fingers and toes to feel cold or grow numb.⁵

WHO has created a functional status classification to assist physicians in treating patients with all forms of pulmonary hypertension, including PAH:¹⁹

• No limitation of usual physical activity; ordinary physical activity does not cause dyspnea, fatigue, chest pain or presyncope [lightheadedness, muscular weakness, blurred vision and feeling faint]
• Mild limitation of physical activity; no discomfort at rest, but normal activity causes increased dyspnea, fatigue, chest pain or presyncope
• Marked limitation of activity; no discomfort at rest, but less than normal physical activity causes increased dyspnea, fatigue, chest pain or presyncope
• Unable to perform physical activity at rest; may have signs of right ventricular failure; symptoms increased by almost any physical activity

Regardless of the initial cause or trigger (if known), once PAH has developed, disease progression will typically follow the same general path: increasing fatigue as the lungs struggle to oxygenate the blood, and then a gradual weakening of the heart as the right side tries to make up for resistance in the pulmonary arteries. The disease is progressive and, ultimately, fatal. Progression tends to be rapid — years rather than decades. There is some statistical evidence that the condition of patients with HPAH will deteriorate more rapidly than patients with other forms of PAH.²⁰

Diagnosing PAH

Given the similarity of PAH symptoms to other forms of hypertension, and that many cases of PAH are caused by a preexisting lung or heart condition that will also manifest the same symptoms, a specific diagnosis can be challenging. In fact, it is thought that it typically takes more than two years from a patient’s initial symptoms to disease diagnosis.²¹

Because of the lack of unique initial symptoms, a PAH diagnosis is usually one of exclusion.⁶ In 1999, a group of associations (American Heart Association, American College of Chest Physicians, American Thoracic Society and the Pulmonary Hypertension Association) developed a standardized sequence of tests and procedures to assist physicians in correctly diagnosing PAH and similar diseases.²² The sequence follows typical best practices: an initial physical examination and review of patient history (particularly noting any family history of PAH, as well as any conditions linked to APAH such as liver disease, connective tissue disease, HIV, etc.), followed by blood tests, chest X-ray, electrocardiogram, echocardiography and possible angiogram or polysomnography, with each step a process of elimination to help narrow the possibilities. Other tests included in the sequence include lung function, right heart catheterization and a lung ventilation/perfusion scan. ²³ Genetic testing may also be ordered if HPAH is suspected.

PPHN is diagnosed by measurement of right-to-left shunt coupled with a lack of congenital heart disease.²⁴

PVOD may result in a negative reaction to normal PAH treatment. It can be definitively identified by microscopic examination of the veins in a sample of lung tissue taken during a biopsy, although due to the risks involved and that the prognosis for both diseases is short-term, this is rarely done.²⁵

Because sudden death is a high risk for PCH patients, the risks of a biopsy may be warranted for a definitive diagnosis.²⁶

Treating PAH

There is presently no cure for PAH, PVOD or PCH, but treatments can be used to ease symptoms and prolong patient quality of life. A lung or heart-lung transplant is the only option to extend a patient’s life more than a few years. The one exception is PPHN, which can be successfully treated, usually with oxygen therapy (CPAP, hood or ventilator), medications to control blood pressure and, possibly, antibiotics if there is an associated infection.²⁷

There are two main approaches to treating all other cases of PAH, depending on the type. For APAH, the underlying cause (whether it’s liver disease, connective tissue disease or lung or heart disease) will be treated at the same time the symptoms of PAH are addressed. With SSc-PAH, the use of intravenous immune globulin has recently been shown to reduce fibrous scarring and overall inflammation.²⁸ And, with schistosomiasis, the parasite can be effectively treated with praziquantel.²⁹

In all other cases, whether drug-induced, hereditary or idiopathic, treatment is focused on maintaining as much quality of life as possible given the progression of disease. WHO recommends using its functional status classification to help devise the appropriate treatment and how much activity a patient can reasonably tolerate.

Calcium channel blocking drugs are one treatment option to control the symptoms of PAH. These can help smooth the interior of blood vessels to ease resistance from the heart. Some popular options include amlodipine (Norvasc), diltiazem (Cardizem, Tiazac), felodipine (Plendil) and isradipine (Dynacirc).³⁰

Endothelin receptor blockers such as bosentan (Tracleer) and ambrisentan (Letairis) are another treatment option that has been effective in addressing PAH symptoms. Endothelin is a natural substance produced by the body that causes blood vessels to tighten. Using an endothelin receptor blocker can help maintain higher blood flow.⁴

A third class of drug that has shown effectiveness in easing symptoms is synthetic prostacyclin. Prostacyclin is produced by the body and dilates blood vessels. Examples of this drug are epoprostenol (Flolan), administered via IV, treprostinil (Remodulin), administered subcutaneously, and iloprost (Ventavis), taken via inhaler.⁴

Phosphodiesterase type 5 inhibitors have been found effective in restoring some mobility, as well as in decreasing the pressure in the pulmonary artery.⁵ These drugs include sildenafil (Revatio) and tadalafil (Adcirca). A similar drug is riociguat (Adempas).

Finally, last year, the U.S. Food and Drug Administration approved the use of selexipag (Uptravi), which works by relaxing the muscles in blood vessels.⁵

Oxygen will often be called for as the disease progresses. And, most PAH patients will be prescribed diuretics to help reduce fluid buildup.¹⁸

Still, all of these treatments can, at best, ease symptoms and, perhaps, slow progression. The only way to extend a patient’s life beyond a few years is a single- or double-lung transplant, or a heart-lung transplant. Early referral to a nearby transplant center to begin analyzing a patient’s potential suitability is often recommended.³¹

For the two PAH-related diseases, PVOD and PCH, the only proven treatment is a lung transplant.^26,32 In fact, studies show these two conditions are generally worsened by the drugs used to treat PAH symptoms.

As with any end-of-life diagnosis, ensuring patients have appropriate emotional and family support is crucial to maintaining the highest quality of life for their remaining time.

Preventing PAH

There is no inoculation to prevent onset of PAH. However, for APAH, early diagnosis and treatment of the underlying causes can help prevent its onset. Avoiding the use of cocaine and methamphetamine will prevent drug-induced PAH. Other types of PAH have no prevention, as their cause is not known.

Maintaining positive general health and avoiding smoking and use of illegal or dangerous recreational drugs can help lower one’s risk of developing PAH. And, those with HPAH are encouraged to avoid living at altitude if possible.

Ongoing Research

Hundreds of studies are currently being conducted for PAH, as well as thousands more for the related conditions that can trigger or contribute to PAH (such as sickle cell disease, connective tissue disease, liver disease, etc.).

Because the underlying biochemical reactions that cause or trigger PAH are not yet fully understood, the National Heart, Lung and Blood Institute (a branch of the National Institutes of Health) is funding basic research designed to further knowledge of how this disease occurs.³³

On the practical side, much of the research currently listed at ClinicalTrials.gov (861 active and recent PAH-related trials as of this writing) is focused on whether existing drugs approved for other treatments will also work on easing symptoms of PAH. A successful example is the use of phosphodiesterase type 5 inhibitors, which were originally brought to market to treat erectile dysfunction. Now, those same active ingredients under different brand names are being used to treat symptoms of PAH.

Some of the more interesting studies include one looking at the presence of antibodies to endothelial cells in patients with SSc-PAH.³⁴ Others are exploring whether the kinase-inhibiting leukemia drug imatinib might relieve PAH symptoms. And a beta blocker already approved for use in treating congestive heart failure is being tested to see if it can provide relief for PAH patients.³⁵

The subjects of other studies include the role of regular exercise in slowing the progression of PAH and technological advances in angiogenic imaging to allow for more accurate diagnosis and treatment planning.³⁶ Another in France is recruiting test subjects to determine if denervation of the pulmonary arteries will provide relief.³⁷ And, yet another is testing whether specific biomarkers in the blood can be used for a quicker definitive diagnosis.³⁸

Looking Ahead

With disparate identified causes and triggers for PAH, including genetic predisposition, drug use and underlying medical causes ranging from sickle cell disease to SSc, and with many causes not yet understood, this deadly, incurable disease will continue to be a challenge for physicians for decades to come. Current research may bring to market new treatments that improve a patient’s prognosis within a few years, but for now, transplant surgery is the only hope for most patients.