Pulmonary Hypertension

Pulmonary Hypertension

In simple terms having high blood pressure (>20 mm Hg) in the arteries carrying blood from the right ventricle to the lngs (Pulmonary arteries) is called pulmonary hypertension. The increase in the lung artery pressure can be measured by an echocardiogram or more accurately by cardiac catheterization. (detail below). Presence of high pressure in the lung arteries causes increase in pressure of the right side of the heart first causing the right side of the heart to increase in size followed by decrease in pumping function of the heart (heart failure). PH is a very complex and often misunderstood disease even amongst medical professionals. It is very important for a newly diagnosed patient with PH to find a PH specialist who can accurately find the cause of PH. Every patient with PH is different and unique hence it is extremely important to accurately access the cause of PH and tailor therapy according to need of individual patient. With appropriate therapy and tailormade management plan; patients with PH can live for many years.

Normally human heart has four chambers. Two receiving chambers also call atria and two pumping chambers also call ventricles. Vessels which bring blood to the heart are call veins and vessels which take away blood from the heart are called arteries. Impure blood (blood with low oxygen and high carbon dioxide) is brought to the right sided receiving chamber (Right atrium) from upper and lower part of the body via superior and inferior venacava respectively. This blood is then pumped to the right and left lung via the pulmonary artery by the right sided ventricle. This blood undergoes purification in the lung (Oxygen is added and carbon dioxide is removed) and transported to the left sided receiving chamber (left atrium) via 4 pulmonary veins (2 each from right and left lung). This blood is then pumped by the left sided ventricle to the entire body through the main artery of the body (Aorta). Normally the pressure in the left sided chambers is three times that of the right sided chanbers. Normal pressure in the right atrium is around 3 mm Hg (range 2-8 mm Hg), in the right ventricle systolic pressure is 15-20 mm Hg and diastolic pressure is 0-8 mm Hg. Mean pulmonary artery pressure is 12-19 mm Hg, Left atrial pressure is usually 8 mm Hg (6-12 mm Hg). Right side of the heart is usually weaker as compared to the left side of the heart as it has to pump blood only to the lungs and that too at a much lower pressure.

Pulmonary hypertension means increase in the blood pressure in the pulmonary arteries. However it is a very complex disease which is often misunderstood even by medical professionals. Depending on the cause of PH, the disease in divided into five groups by the World Health Organization (WHO).

In this type of pulmonary hypertension the increase in the pressure of the pulmonary artery is secondary to narrowing and increase in stiffness of the pulmonary artery. The right ventricle then has to work hard to push the blood across the thickened and stiff pulmonary artery. This extra pressure on the right side of the heart results in the increase in the size of the heart and if not addressed in time can lead to failure of the right heart. There can be various causes of PAH like congenital heart disease, liver disease, autoimmune diseases, HIV, drug abuse and medications used to decrease weight. While there are medications available to treat PAH, there is no cure.

In this type of PH, the increase in the pressure of pulmonary artery is secondary to problems in the left side of the heart. These problems could be in the squeezing or relaxation of the left ventricle or due to disease of the heart valves on the left side (mitral or aortic valve). These lead to back pressure changes in the pulmonary veins and consequently there is increase in pressure in pulmonary artery as the right side of the heart tries to push the blood across to the left side. This is the most common form of PH. Patients in this subgroup require medications to alter the pressure and mechanics in the left sided heart chambers rather than medications to decrease the pressure in the lung arteries.

This type of PH is secondary to chronic lung disease. These lung disease could be obstruction in the airways (COPD or emphysema) or restriction of the expansion of the lung during inhalation (restrictive lung disease like interstitial lung disease or pulmonary fibrosis), obstructive sleep apnea (obstruction of the airways during sleep) and staying at high altitude for long period of time. The main issue in all these lung disease is decrease in the oxygen content and increase in carbon dioxide of the blood which causes narrowing of the pulmonary arteries with increase in their pressure. Pulmonary vasodilators are usually not useful in this type of PH and treatment includes treating the underlying cause or oxygen inhalation.

Presence of long standing clots in the lung arteries can cause narrowing of these vessels and increase in the pulmonary artery pressure. This type of PH is unique as it can be potentially be cured by removing the clots from the lung artery (pulmonary endartectomy). Medications to decrease pulmonary artery pressures (Pulmonary vasodilators) in CTEPH are to be used only in the following conditions

In this group the exact cause of PH is not known. Various diseases like long standing kidney failure, sickle cell disease and some metabolic syndromes are included in this group. No matter what the group; PH is a severe disease. The pulmonary vasodilators can improve quality of life and slow down progress of disease in group 1 PH. They have limited role in treatment of patients with group 2 and 3 who benefit the most by treating the underlying cause. Patients with group 4 PH benefit most by surgery and role of pulmonary vasodilators is limited in this group (as mentioned above).

Pulmonary hypertension is a chronic depilating and progressive disease. With increase in the lung artery pressure the heart has to pump harder to move the blood across from the lungs back to the left side of the heart. The early symptoms of PH are non-specific and include

Since these symptoms are common with other diseases which are way more common than PH, there is an average diagnosis of 2-3 years between the onset of symptoms and the diagnosis of the disease. With progressive deterioration in the function of the right sided heart, the patient develops

Some patients with associated hole in the heart might have bluish discoloration of lips and fingers. In addition to these patients might have symptoms of associated diseases like Renaud’s phenomenon, rash over face and photosensitivity.

PH can be difficult to diagnose in routine clinical exam due to the symptoms which it shares with other more common diseases. If your doctor suspects that you have pulmonary hypertension he/she will order a battery of test to confirm the presence of the disease and once confirmed to find the cause of PH as well as determine the severity of the disease.

Tests done to confirm the presence of PH:

  • Chest Xray: A chest Xray might be one of the first tests done by your doctor. It might show enlargement of the right side of the heart as well as the pulmonary arteries.
  • Electrocardiogram (ECG): An ECG is a non invasive test which records the impulse of the heart. It might show enlargement of the right atrium and ventricle. However ECG by itself is not diagnostic and PH will require other supplementary test to confirm the diagnosis.
  • Echocardiogram (ECHO): Echo or ultrasound of the heart is a non invasive and safe test if often the first one which can confirm the presence of PH as well as throw some light on the etiology of PH. During an echo an experienced doctor can measure the lung artery pressures as well as assess the function of the right ventricle. In addition certain causes of PH like PH secondary to left heart disease (group 2 PH) and congenital heart disease can be diagnosed by an echocardiogram. An echo is also often used as monitoring tool to assess the response of the patient to therapy.
  • Cardiac catheterization with vasodilator study: If the initial results of the non invasive test point towards pulmonary hypertension, your doctor will schedule a cardiac catheterization test to confirm the diagnosis as well as plan the therapy. It is the only test which can accurately measure the pressure in the lung artery should be done atleast once to confirm the diagnosis of PH. During this test the doctor will pass a catheter (soft rubber/plastic tube) from the patients groin or neck, enter the right sided heart and the pulmonary artery to measure the pressures there. This is the “Gold standard” for diagnosis of PH.

Once the baseline pressures are measured the doctor will administer medications which can dilate the lung artery (nitric oxide, epoprostenol, iloprost etc) and remeasure the pressures. This is done to determine how much the lung artery can relax over a brief period of time. If positive the patient can be started on calcium channel blockers, a form of oral medication which is cheap and easily available in India. Patients with a positive vasodilator test fair much better that those with a negative test. According to the current guidelines (NICE 2018), a cardiac catheterization test with acute vasodilator study is strongly recommended in all patients with PH.

Once a diagnosis of PH is confirmed it is essential to try and find an accurate cause of PH. For the same your doctor will advise you to get a number of test done. This includes the following :

  • Blood Test: Certain blood test like an arterial blood gas, complete hemogram, tests to rule out HIV, Hepatitis B and C, tests to rule out collagen vascular disease like ANA by immunofluorescence assay, liver and kidney function tests and thyroid function test should be performed to find out the cause of PH.
  • Pulmonary function test with DLCO: With this test the doctor will be able to diagnose patients with group 3 PH. It determines how much air your lungs can hold, how much air moves in and out of the lungs as well as ability of the lungs to exchange oxygen and carbon dioxide.
  • CT Pulmonary Angiogram : This is a very useful test to determine presence of blood clots in the lung arteries (group 4 PH) as well as assess the presence of lung disease as a cause of PH (Group 3 PH)
  • Ultrasound abdomen with Portal Venous Doppler : This is another useful test to diagnose certain causes of PH like liver disease or presence of abnormal communication between the blood vessels in the abdomen.
  • Nuclear Scan/ VQ Scan : This test might be performed to rule out clots in the small lung arteries which might be rarely missed on CT pulmonary angiogram.
  • Sleep Study : Some patients especially obese can have transient stopping of breathing as well as drop in the oxygen levels during sleep.
  • Generic Test : If all other tests come out negative your doctor might advise a genetic test to determine a genetic cause of PH.

It is important to understand that despite best of efforts some times cause of PH cannot be determined and this is then labelled as “Idiopathic Pulmonary hypertension”

Once the diagnosis of PH and its cause is confirmed; it is extremely essential for the patient to follow up regularly with the PH specialist. Usually we recommend follow up every 3-6 months depending on the patients condition. The following investigations are done at baseline and at every follow up to risk stratify the patient and modify his/her medications accordingly:

  • Clinical Assessment: A through clinical assessment is essential at each visit. This includes determining the patients functional class and assessing for presence of symptoms of right heart failure.
  • Echocardiogram : A detailed echocardiogram is essential at each follow up. The goal of this echocardiogram is assessing the function of the right heart. Absolute pulmonary artery pressures is not important at this stage as they may vary from time to time. Also echocardiogram is only an indirect way to assess the PA pressures.
  • Exercise Test : Usually a 6 minute walk test is performed at each visit. The distance covered by the patient in minutes gives an insight into patients ability to perform day to day activities.
  • Blood Test : A special blood test known as the NT Pro BNP or BNP test should be done once in 6 months. This test gives an insight into the function of the right heart.

It is extremely important to risk stratify the patient at each visit. It is important to recognize progression of the disease early and escalate medications accordingly.

Pulmonary hypertension is a chronic, progressive and depilating disease. Early diagnosis, regular follow up and individual patient centric therapy is key to therapy. Prior to availability of current day medications the prognosis of PH was poor with a 10 year survival rate of only 10%. With the current medications the 10 year survival has significantly has improved to 80-90%.However we should realize that unlike the other parts of the world, most of the medications especially the prostacyclin analogues are currently not marketed in India. They need to be imported for individual patients and only a very few centers have experience in using these medications.

Whenever a patient is diagnosed with PH the risk stratification needs to be done. Depending on his or her clinical status and various lab test the patient is characterized as high, medium or low risk categories. The goal of therapy in PH is to get the patient in the low risk group as soon as possible and keep him in low risk group as long as possible.

Various online tools are available to assess the risk and determine one year survival in patients with PH. The reveal calculator is one such calculator which can assess one year survival in patients with PH. Calculate your own risk using the link below.
https://www.mdcalc.com/reveal-registry-risk-score-pulmonary-arterial-hypertension-pah#use-cases

Once the diagnosis of PH and its cause is confirmed; it is extremely essential for the patient to follow up regularly, the treatment plan needs to be charted out and followed. Since PH is a very complex disease with various etiologies, the treatment may vary from patient to patient. It is very important to understand that there is a lot of difference between pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). All the current available medications are useful in patients with PAH and might not be beneficial or even harm patients of other forms of PH. Hence it is extremely important for a PH specialist to determine if the patient had PH or PAH. Although an experienced PH specialist may be able to determine what type of PH the patient has, the only definitive way to differentiate between PAH and other forms of PH is by doing a right heart catheterization.

Here we will discuss treatment options for Group 1 pulmonary hypertension (pulmonary arterial hypertension). Although there is no cure for PAH a tailor made management plan makes it easier to control and ensures better quality of life. Treatment includes conventional medical therapies, pulmonary vasodilators and finally surgical and cardiac cath procedures.

Although prostanoids (one of the mainstay for managing PH) are not available in India, they can be imported for individual patients.

Specific pulmonary vasodilators include the following :

Conventional medical medical therapies include the following:Which medications come under this category and which are the ones available in India?
This group includes medications like Sildenafil and Tadalafil. Both of them are available in India. They are available in generic forms also.

How do they work?
Phosphodiesterase is an enzyme found in the blood vessels supplying the lungs and the penis. It inhibits degradation of endogenous nitric oxide, thus increasing its availability in the body. Nitric oxide in turn stimulates and enzyme guanylate cyclase to make cyclic GMP. Cyclic GMP relaxes the blood vessels thus decreasing the pressure and allowing more blood to flow in the blood vessels.

How long will they work? Will I develop tolerance?
Usually no. But PH by itself is a progressive disease and hence the symptoms of the patient might increase inspite of being on medications.

What are the side effects?
Most common side effects are nose bleed, nose stuffiness, headache, heart burn, flushing, jaw pain, leg pain, diarrhea and nausea. Most of these are temporary, lasting for 1-2 weeks and most patients tolerate these side effects very well.
There have been rare case reports of blurring of vision and blindness associated with taking sildenafil and tadalafil. This is secondary to a rare condition called non-atretic anterior ischemic optic neuropathy or NAION. However the incidence of NAION is higher in male patients with diabetes, hypertension and high cholesterol. Therefore it is believed that the incidence of NAION for patients taking sildenafil or tadalafil might not be higher than in general population. (reference)
Please consult your PH specialist if you develop any of the above side effects.

What precautions should I take?
These medications interact and should not be used with certain medications like nitrates (Isosorbide, Imdur, Ismo etc). Please inform your doctor if you are taking any of these medications. If you have chest pain and have to visit emergency department of any hospital please inform your attending doctor that you are taking these sildenafil/tadalafil. Nitrates are the most common medication given for chest pain.
Adjustment of dose might be required if you are taking anti tuberculous medication (Rifampicin), antifungal (ketoconazole) or some antiviral medications. Please inform your PH specialist if you are taking any of the above medications.

If I am already on Sildenafil will it benefit if I change over to Tadalafil?
Usually no. However tadalafil has an advantage over sildenafil in being long acting. Tadalafil can be taken only once a day. Sildenafil has to be taken atleast 3 – 4 times daily.

What is the approximate cost/month?
Both Sildenafil and Tadalafil are made in India by various companies. Generic forms of the medication are also available. Hence the cost might vary. However the approximate cost of therapy in appropriate doses comes to approximately Rs 1800- 2400/month

Which medications come under this category and which are the ones available in India?
Medications like Bosentan, Ambresentan and Macitentan come under this category. All three of them are available in India.

How do they work?
Endothelins (ET) are peptides which are normally present in the body. ET when comes in contact with its receptors cause them to constrict thus increasing the pressure inside these vessels. Normally ET are kept in check by safety mechanisms of the body. In patients with PAH there is increase in number of these endothelins which adhere to their receptors on lung vessels. This results in increase in blood pressure of the lungs. ERA antagonist prevent the ET from binding to its receptors. Subsequently the blood vessels dilate and the growth and proliferation inside the blood vessel is slowed. Patients taking these medications may not show immediate improvement and it take a month or so for the benefits to show.

What are the side effects?
ERA are usually tolerated well. The common side effects are liver toxicity (Bosentan), swelling of feet (Ambresentan and Bosentan) and anemia (Macitentan). Patients who are on Bosentan require monitoring of their liver function test once a month. Deterioration of liver function could also be due to right heart failure and it would be important to work with your treating PH specialist to understand what is the cause of PH and how best to resolve it. If there is significant deterioration of liver function, Bosentan might have to be stopped and some other medication from the same group (Ambresentan or Macitentan) will have to be started.

If I am already on one ERA will it benefit if I change over to another?
As mentioned above your doctor might have to change from bosentan to either ambresentan or macitentan if you have side effects with it. However if a patient is tolerating one medication well it might not be advantageous to change the medication.

What is the approximate cost/month?
The approximate cost of therapy in appropriate doses comes to approximately Rs 4500- 6000/month

Prostanoids are manmade versions of a substance which occurs naturally in our bodies (Prostacyclin I22). Prostacyclin works by dilating the blood vessels, keeping platelets from clumping together, improving the cardiac output and slowing the growth of the smooth muscles in the blood vessels. Most patients with PAH respond to prostanoids in a favorable manner with some even able to resume near normal lifestyle.

Which medications come under this category and which are the ones available in India?
Prostanoids were one of the first medications to show mortality benefit in patients with PAH. Epoprostenol was the first medication which was approved by US FDA for the use in PAH. Prostanoids can be administered in intravenous, subcutaneous, inhaled or even oral forms.
The following are few examples prostanoids are available in the world:

  • Injectable form:
    • Intravenous, inside one of the body veins: Epoprstenolol, Trepostinil),
    • Subcutaneous, given below the skin like a continuous infusion : trepostinil
  • Inhaled form: taken in as nebulizer eg. Iloprost, Trepostinil
  • Oral: Beraprost.

In addition to the above recently a medicine which stimulates the prostracyclin receptor is available to be given orally (Selexipag). Unfortunately, none of the prostanoids are marketed in India. However they can be imported for personal use by a patient. There are several limitations of the use of prostanoids in India, Along with the availability, the other most important limitations are the cost and difficulty in maintaining a continuous IV/subcutaneous line. Considering the entire clinical scenario, it is my personal opinion that iloprost is most feasible, affordable and effective in managing PAH in India. Currently we have 13 patients who are taking prostanoids (12 on iloprost and 1 on subcutaneous trepostinil). All of them have experienced significant improvement in their symptoms of PAH once started on this medications. The current cost of administering inhaled prostacyclin is approx.Rs. 20000/- month.

How long will they work? Will I develop tolerance?
Yes sometimes some patients develop tolerance to prostanoids and may require progressive increase in the doses of prostanoids or may have to consider other strategies of management like Potts shunt or Lung transplant.

What are the side effects?
Common side effects include, nasal stuffiness, jaw pain, muscle pain, headache, flushing, diarrhea, nausea and vomiting. Most of these are temporary and wean off as the patient continues to use these medications.

What is the approximate cost/month?
Approximate monthly cost of acquiring iloprost and using that in India is approximately Rs.20000/-. It has to be noted that this is a significant reduction from a couple of years back. Most of this reduction has been achieved as more patients have started to use these medications.

Which medications come under this category and which are the ones available in India?
Riociguat is the medicine which comes under this category. This medicine acts on the same pathway as PDE5 inhibitors (Sildenafil and tadalafil). But as oppsed to PDE5 inhibitors who inhibit the degradation of nitric oxide; Riociguat stimulates the nitric oxide receptor directly. Riociguat is currently available in India.

What are the side effects?
Side effects of Riociguat are similar to other PAH medications. However they sometimes can lower the pressure of the body leading to dizziness and hence have to be given only under strict medical guidance. Also if the patient is already on Sildenafil or tadalafil they have to be stopped for 48-72 hours prior to starting Riociguat.

  • Calcium channel blockers are medications which can be used only in patients who have demonstrated a positive vasodilator test on right heart catheterization. (Please see the section on right heart catheterization)
  • CCB work by relaxing the smooth muscle of the blood vessels supplying the lungs. When CCB work the change is almost immediate and the patient starts feeling better in a very short period of time.
  • CCBs are easily available in India and are much cheaper than other PH medications. Hence it is extremely important to perform a right heart catheterization with vasodilator study to determine if a patient is suitable for initiation of CCB.

Can CCB be used without right heart catheterization?
No CCB should never be used in PAH patients without right heart catheterization. Patients who are donot show positive response on vasodilator study might actually be harmed by CCB.

How long can they be used?
Some patients develop resistance to CCB over a period of time. If the patient develops tolerance, the PH specialist might have to change the medications to the conventional pulmonary vasodilators mentioned above.

Atrial Septostomy

Creating a hole in the upper wall separating upper chambers of the heart is called atrial septectomy. This can be done during a cardiac catheterization procedure when a balloon can be used to create and serially increase the size of the hole. Video describing how a balloon atrial septostomy is performed.

  • Rationale: Patients with PAH sometimes have a sudden surge in the pulmonary artery pressure usually during exercise or stress. This sudden increase in the lung artery pressures puts the right sided heart under undue stress resulting in decrease in pumping of blood from the right side to the left side across the lungs. This results in decrease in blood flow from the left sided heart to the body parts most importantly the brain. This sudden decrease in blood supply to the brain causes “black out” also called syncope in medical terms. Presence of hole in between upper chambers of the heart decompresses the right sided heart, the blood flows directly from the upper right chamber to the upper left chamber thus maintaining the blood flow to the body especially the brain. However since the blood bypasses the lung, the patient becomes blue. Patients with hole in the upper chambers of the heart fair better as compared to those without.
  • Advantages: Feasible, symptom relief.
  • Disadvantages: Time consuming, High procedural risks, the hole has the tendency towards decreasing in size and even closing down over a period of time. Does not improve right heart function, results are not consistent and needs to be done in an experienced center.
Potts Shunt

What is Potts Shunt?
Creation of communication between the artery supplying blood to the left lung and the part of the body artery supplying blood to the lower part of the body. It was initially done for patients in whom there was restricted flow to the lung artery. However a novel use of Potts shunt in PAH was first described by Barteau et al.

How does the Potts Shunt help in PAH?
In Potts shunt a large communication is created between the lung artery and body artery. Potts shunt may help patients in whom the pressure in the lung artery is more than that of the body artery (Suprasytemic lung artery pressure) by decompressing the lung artery into the part of the body artery supplying the lower part of the body. This eventually decreases the pressure on the right heart and improves its functioning.

When is Potts Shunt performed?
It is extremely important to perform Potts shunt at the earliest sign of clinical, biochemical or echocardiographic deterioration on a patient with PAH who is on maximal medical therapy. For optimal results it should be performed before irreversible damage occurs in the right heart.

Where can Potts Shunt be performed?
Very few centers in India offer Potts shunt as a palliation in patients with PAH. The center with maximal experience in India and mostly the world in Kokilaben Dhirubai Ambani Hospital In Mumbai.

What are the risks associated with Potts Shunt?
As with any procedure in a patient with PAH, Potts shunt is also a high risk procedure. The immediate success ratio is between 85-90%. However it has been noticed at our center as well as in the western world, that the patients who survive the surgery do relatively well in the long term. It might be even possible to reduce PAH specific medication in these patients.

What is the approximate cost of performing Potts Shunt?
The overall cost of performing the surgery and post operative management is close to 3.5 Lacs. However in order to decrease the risk further, the team performing Potts shunt might request the patient to procure prostacyclin analogues prior to surgery. The cost of which is mentioned in the section on prostanoid therapy.

Lung Transplant

Transplant is an option for patients who have exhausted all the above treatments for PH and still continue to have symptoms. The first successful lung transplant in humans was done by Joel Cooper in 1983. First successful heart transplant in India was done by Dr. P Venugopal in All India institute of medical science in 1994 and first heart lung transplant was done by Dr. KM Cherian at Madras medical Mission Hospital in 1999. There are a very few hospitals offering a successful Lung transplant program, most of which are concentrated in South of India esp. Chennai.

If lung transplant is the final operation why not do it at the first instance of diagnosis of PAH?
Although a lot of progress has been achieved over the last few years, lung transplant is still a very challenging process and is not as successful as liver, kidney or even heart transplant. Any patient undergoing any transplant has to take medications to decrease his immunity (Power to fight infection). This is necessary so that the new organ is accepted by the body. Lung is the only organ which is open to air and is exposed to various pathogens (Bacteria, virus, fungus etc.) with each breath. This is addition to the medications to decrease ones immunity makes one prone to infections.

What is the appropriate time to undergo transplant?
The following questions need to be asked before a particular patient is subjected to transplant :

What are the Various transplant options available?

What is the approximate cost of transplant?
The one time cost of double lung and heart and lung transplant in India is approximately Rs35 lacs. The cost for medicines in the first year is approx. Rs 10-12 lacs followed by Rs80,000-1,00,000 per year life long.

What is the current success rate for Lung transplant in India vs the Western World?
The current survival after lung transplant in the western world, is 80% at one year, 65% at 3 years and approx. 50 % at 5 years (In short, approximately 50% of patients who receive lung transplantation are able to live beyond 5 years). Although the exact figures of success rates in India are not available in scientific literature, they are most likely to be lower than the western world.

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