Journal of the Practice of Cardiovascular Sciences

: 2021  |  Volume : 7  |  Issue : 1  |  Page : 8--15

Pulmonary artery hypertension: A bedside review

Mohit Bhagwati1, Rahul Mehrotra2,  
1 Associate Consultant, Department of Cardiology, PSRI Heart Institute, New Delhi, India
2 Non Invasive Cardiology, Max Super Specialty Hospital, New Delhi, India

Correspondence Address:
Rahul Mehrotra
Max Super Specialty Hospital, 2, Press Enclave Road, Saket, New Delhi - 110 017


Pulmonary artery hypertension (PAH) is a rare progressive disease affecting pulmonary arterial vasculature and the right side of the heart. The disease is notorious for its ominous course and high accelerated rates of mortality. Due to its varied etiology, it requires stepwise evaluation to differentiate various causes of PAH. With the advent of new drugs and improved registry-based data, there has been a global effort to reduce the morbidity and mortality of this disease. Therefore, all efforts should be made for quick diagnosis and uniform workup to reach the etiologic and hemodynamic diagnosis. There is a need of specialized PAH clinics and PAH specialists to cater to the needs of these patients who require multidisciplinary clinical care. This review aims to discuss the important aspects of the disease and its management in a ward round scenario as a case-based discussion format to put emphasis on the recent guidelines and classification.

How to cite this article:
Bhagwati M, Mehrotra R. Pulmonary artery hypertension: A bedside review.J Pract Cardiovasc Sci 2021;7:8-15

How to cite this URL:
Bhagwati M, Mehrotra R. Pulmonary artery hypertension: A bedside review. J Pract Cardiovasc Sci [serial online] 2021 [cited 2021 May 18 ];7:8-15
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In the field of cardiovascular (CVS) sciences, almost all diseases have much better-modified history, when compared to their natural history due to advances in medical and surgical management. However, pulmonary artery hypertension (PAH) is one such disease which has been despair for the patients and challenge for the physicians now for many decades. After an epidemic of pulmonary hypertension (PH) in some European countries in the decade of 1960s, in 1973, the first world symposium on pulmonary hypertension (WSPH) was conducted in Geneva by the World Health Organization (WHO). Since then, there has been a dedicated worldwide research and regular symposium of disease experts under the able leadership of the WHO. The latest edition, 6th WSPH was organized in 2018 in Nice, France.[1] With the better understanding of pathophysiology and recent developments in therapeutics of PAH, many changes in definition, classification, and management algorithms were suggested in this symposium. Recent advances including new drugs such as macitentan and selexipag were discussed upon in detail and upfront combination therapy in advanced disease was advocated. As PAH requires a dedicated PAH specialist clinic with multidisciplinary management, this review aims to enlighten the physician community with the simplified explanation of the syndrome and the approach to the patient. The main objective is to generate awareness in the physician community so that quick referral to PAH specialized clinic can be done. The review also discusses, how to manage critically ill patients and when to offer surgical/intervention therapy. To keep the flow as simple as possible, the review is designed as a discussion between a student and professor in an evergreen classical case discussion format.


A literature search has been conducted across PubMed, Scopus, and other electronic databases along with commentaries on world symposiums. Relevant articles amounting to clinical and diagnosis and management were selected and reviewed for the purpose of writing this article. The design of the review is in accordance with a classical bedside clinical case discussion so as to increase the understanding of the readers and give them a practical overview to approach to diagnose and manage pulmonary arterial hypertension.

 Case Discussion

Q. Present your case?

Answer: My patient is a 26-year-old lady, resident of Haryana, school teacher by profession, presented with complaint of:

Shortness of breath on exertion since 6 months which was the gradual onset and progressive from NYHA class II to now NYHA class IIIFatigue, NYHA class II since 3 months.

There was no history of syncope/palpitation/wheeze/blood loss. She has no history suggestive of rheumatic fever or a shunt physiology in past. She is married for 2 years, is nulliparous, and is not using any contraception.

On examination, she is conscious, oriented. There is mild pallor, no icterus, cyanosis, clubbing, or lymphadenopathy. Pulse is 84 per min, regular, all pulses palpable. Blood pressure (BP) is 110/80, comparable in all limbs. Respiratory rate is 14/min with thoracoabdominal respiration, SpO2 is 97% on room air. Jugular venous pressure is raised with large a wave and v-y descent.

CVS examination showed right ventricular (RV) type apex, Grade 3 left parasternal lift, loud and palpable P2, RV S4+, Grade 3 pansystolic murmur at the left lower sternal border, and Grade 2 ejection systolic murmur at the pulmonary area. Other systems are within normal limit.

Electrocardiogram (ECG) shows sinus rhythm, right axis deviation, right atrial enlargement, and RV hypertrophy with strain pattern.

Chest X-ray posteroanterior (PA) and lateral view shows dilated main pulmonary artery and right descending pulmonary artery with peripheral pruning, Lateral view shows RV enlargement with obliteration of retrosternal space.

Echocardiography showed-

No Regional wall motion abnormality, left ventricular (LV) ejection fraction 55%

Dilated RA and RV, dilated main pulmonary artery, D shaped LV cavity, LV eccentricity index >1.1

RVOT Doppler Acceleration Time (AT) 53 ms with mid systolic notching

Moderate TR, TR velocity (TRV) max 3.4 m/s

RV systolic function normal, TAPSE 2.0 cm

IVC dilated and noncompressible with inspiration (RA pressure 15 mmHg)

These findings are suggestive of a high probability of PH.

Q. Why do you say high probability of pulmonary hypertension, what else is left to commit to the diagnosis?

Answer: Echo is not a diagnostic modality of choice or confirmation regarding the diagnosis of PH. By using echo, we can only stratify the probability of PH in patients.[2],[3]

Q. How do you decide on probability of pulmonary hypertension on echocardiography?

Answer: We calculate TR Vmax using continuous-wave Doppler across the tricuspid regurgitation jet. In addition to TR jet, we evaluate echo parameters of the right heart, i.e., right ventricle, right atrium, and pulmonary artery. We use these readings to calculate the probability of PH as outlined here [Table 1] and [Figure 1]. Among various echo parameters, RV outflow Doppler acceleration time (AT) can be to define the severity of PAH. As PAH worsens, AT decreases, AT <80 ms is usually PAH and AT <60 ms is seen in severe PAH.{Figure 1}{Table 1}

Q. Did you do some other tests as well?

Answer: Yes, we did a battery of investigations which are required to make the etiological diagnosis of PH.

ECG:[4] Right axis deviation, right atrial enlargement, RV hypertrophy with strainPulmonary function test with Diffusion capacity of lungs for carbon Monoxide (DLCO):[5] Within Normal Limits (WNL)V/Q scan:[6] No probability of V/Q mismatchHIV and ANA:[7],[8] NegativeLFT:[9] WNLUSG abdomen:[10] WNL6-min walk distance:[11] 400 mNT-proBNP:[12] 1200 ng/lHemoglobin:[13] 11 g/dl (microcytic hypochromic).

Q. What is the proposed line of workup for pulmonary hypertension?

Answer: There has been a new proposed line of workup for PH[14] [Figure 2] and [Figure 3].{Figure 2}{Figure 3}

Q. What is your next step?

Answer: As I have effectively ruled out other common causes of PH, I would like to do a right heart catheterization (RHC) to make a final hemodynamic diagnosis.[15]

Q. Is the right heart catheterization required to make a diagnosis? A high probability ECHO with a battery of negative tests is much suggestive of only one diagnosis?

Answer: Yes, cardiac catheterization is the gold standard and still required to make a hemodynamic diagnosis of precapillary PH versus postcapillary PH and we also need to do acute vasoreactivity testing to check for vasodilator response. It has both diagnostic and therapeutic implications.

Q. What is your catheterization data?

My RHC data was as follows [Table 2].{Table 2}

Q. How do you interpret this data?

Answer: My data is consistent with the diagnosis of precapillary PH without any vasodilator response. The previous definition of PH was mean pulmonary artery pressure (mPAP) >25 mmHg. There are few proposed changes in this definition on the recommendation of the 6th World PH symposium, Nice 2018, which recommends the definition of PH being mPAP >20 mmHg.[16] [Table 3].{Table 3}

Q. What is transpulmonary gradient and how is it different from diastolic pulmonary gradient?

Answer: Transpulmonary gradient (TPG) is the difference between mPAP and mean wedge pressure. Greater TPG (>12 mmHg) is suggestive of elevated right-sided pressures without rise in left-sided pressures. However, TPG is dependent on loading conditions including flow and filling pressures. A novel and better marker is the diastolic pulmonary gradient (DPG), that is calculated as the difference between pulmonary artery diastolic pressure (PADP) and mean pulmonary capillary wedge pressure. A DPG value ≥7 mmHg signals pulmonary artery remodeling and presence of combined precapillary and postcapillary PH in patients with elevated mean PA pressures and elevated pulmonary artery wedge pressures (PAWP >15 mmHg). IPAH is associated with PAWP ≤15 mmHg and DPG value ≥7 mmHg. Among patients with heart failure with preserved ejection fraction and systemic hypotension, one can get a DPG value <7 mmHg and lower PAWP, and one must consider fluid challenge to reassess hemodynamics in such patients.[15]

Q. What is your final diagnosis?

Answer: My final diagnosis is:

PAH-WHO Group 1-IPAHWHO Functional Class IIIIntermediate riskNormal sinus rhythm.

Q. Why do you say intermediate risk? Is it important to risk stratify pulmonary artery hypertension patients?

Answer: All PAH patients need to be risk stratified before starting PAH-specific therapy. This helps to prognosticate the patients. The choice of therapy also depends on the risk group.

Q. How do you risk stratify pulmonary artery hypertension patients

Answer: We risk stratify PAH patients into three groups according to their expected 1-year mortality risk as per the REVEAL registry.[17] The expected 1-year mortality of low-, intermediate-, and high-risk groups is <5%, 5%–10%, and >10%, respectively. We use the following scheme [Table 4].{Table 4}

Q. Why do you call it Group 1 pulmonary hypertension?

Answer: The WHO has classified PH in five groups according to the recommendation of the 6th WSPH as follows [Table 5].{Table 5}

Q: What do you mean by the World Health Organization functional class?

Answer: The WHO has recommended to use a WHO functional classification for all patients which is similar to commonly used NYHA classification for other CVS diseases except the use of syncope/presyncope in place of palpitations[18] [Table 6].{Table 6}

Q. How did you perform acute vasodilator testing? What is a positive test? What all agents can be used?

Answer: We used inhaled nitric oxide (NO) at the dose of 40 ppm through noninvasive ventilation mask. The recommended agent to perform acute vasodilator testing is inhaled NO. However, IV adenosine, IV sildenafil, and IV epoprostenol can also be used.

A positive vasodilator response is defined as a reduction in the mPAP of at least 10 mmHg to an absolute mean PA pressure of <40 mmHg with a stable or improved cardiac output.[19] We do not use IV adenosine in children.

Q. How will you manage your patient?

I will manage my patient on the following plan:

Gener [Figure 1]: How to calculate the echocardiographic probability of pulmonary hypertension. al measures and supportive therapy:

Counseling against pregnancy[20]Immunization – annual influenza and pneumococcal[21]Psychosocial support – Add to our PAH clinic patients smartphone messenger group for self-helpCounseling against strenuous exercise, however graded aerobic exercise (walking) recommendedPharmacological therapyCombination therapy of ambrisentan 5 mg once daily and tadalafil 20 mg once dailyTablet torsemide 5 mg once dailyTablet ferrous sulfate 200 mg once daily.

Q. What is the recommended treatment algorithm for pulmonary artery hypertension?

Answer: We approach the PAH patient as per the following scheme [Figure 4].{Figure 4}

Q. Will you give your patient oxygen therapy?

Answer: No, oxygen therapy is only recommended in arterial pO2 <60 mmHg on room air and in flight administration of O2 is recommended in WHO FC III or IV patients whose paO2 <60 mmHg.[3] The surrogate SpO2 <92% can also be used in place of paO2.

Q. Will you give anticoagulation to your patient?

Answer: No, the evidence regarding the use of anticoagulation in IPAH is ambiguous. Both ACC and ESC recommend anticoagulation in IPAH with a weak IIB recommendation.[3] The results from the COMPERA registry showed improved 3-year survival with warfarin. However, REVEAL registry data showed no improvement in survival; it, in fact, showed increased mortality in one subgroup. So, I would refrain using warfarin for primary prophylaxis.

Q. Will you give digoxin to your patient?

Answer: No, the use of digoxin is not recommended in PAH by any guidelines. It has a role in the prevention and treatment of supraventricular arrhythmias in patients with PAH and who have and left ventricular dysfunction causing low cardiac output. Digoxin is not useful in the treatment of right-sided ventricular failure.

Q. What pulmonary artery hypertension-specific drugs do you know? How do you use them?

Answer: PAH-specific drugs are the drugs approved for use in Group 1 PH which are pulmonary vasodilators. These drugs belong to three broad groups [Table 7]:{Table 7}

NO pathway: Oral PDE5 inhibitors like sildenafil and tadalafil and soluble guanylate cyclase (sGC) stimulators like riociguat work through this pathway by increasing NO and thus causing vasodilatationProstacyclin pathway: Prostanoids such as IV epoprostenol, IV/SC/intranasal treprostinil, inhaled iloprost, and prostacyclin receptor agonist like oral selexipag work through this pathway and are potent vasodilators

Endothelin pathway: Oral endothelin receptor blockers like bosentan, ambrisentan, and macitentan work through this pathway and cause pulmonary vasodilatation.

Q. Why did you use a upfront combination therapy? Is there an evidence?

Answer: Our patient was in WHO FC III. We used a guideline-recommended upfront combination therapy of ambrisentan and tadalafil on the basis of the results of the AMBITION trial.[22] Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) Trial showed that patients who were treated upfront with a combination of tadalafil and ambrisentan had a 50% lower risk of clinical failure event and lower rate of hospitalization.

Q. Does any drug have morbidity and mortality benefit in pulmonary artery hypertension patients?

Answer: Yes, as shown in a study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial with macitentan is the first clinical trial showing improvement in morbidity and mortality in PAH patients.[23] So, macitentan reduces morbidity and mortality in PAH patients.

Q. What should be the goals of your treatment?

Answer: Ideally, the goals of treatment are as follows:[24]

atient should be in WHO-FC: I or IIEchocardiography/CMR should show normal or near-normal RV size and functionHemodynamics should show normal RV function (right atrial pressure <8 mmHg and cardiac index >2.5–3.0 l/min/m26-min walk distance should be more than 380–440 mCardiopulmonary exercise testing should show peak VO2 higher than 15 mL/min/kg and VE/VCO2 (minute ventilation–carbon dioxide production slope; EqCO2) lower than 45 l/minBNP level should be “normal.”

Q. How often will you follow-up the patient and what all tests will you do?

Answer: I will follow patients of PAH as per the following scheme[25] [Table 8].{Table 8}

Q. If your patient wants to undergo some noncardiac surgery, what shall be your advice?

Answer: I would recommend to use regional anesthesia preferably and avoid general anesthesia (GA). All patients of PH are high-risk patients for GA.[26] If GA is required, I would advise invasive hemodynamic monitoring and continuation of all PAH-specific drugs. Inhaled NO should be kept standby by in case the patient goes in PH crisis.

Q. What is the status of balloon atrial septostomy in pulmonary artery hypertension patients?

Answer: Balloon atrial septostomy gets a very weak recommendation (IIb) after maximal drug therapy. The procedural mortality rate is high, in the range of 9% to 22% (More PH, more mortality). It should not be performed in patients with impending death and severe RV failure.[27]

Contraindications to BAS in PAH are:

Mean RA pressure >20 mmHgResting SpO2 <90% on room airLVEDP >18 mmHg.

Therefore, BAS stands as a therapy for sick patients who are not very sick.

Q. Is there any other intervention therapy you know of in pulmonary artery hypertension patients?

Answer: Yes, Pott's shunt and atrial flow regulator are other potential intervention therapy in PAH patients.

Q. If your patient is critically ill in the intensive care unit, what will be your advice?

Answer: I would take care of the following points:[28]

Invasive hemodynamic monitoringIncrease the systolic BP (SBP) with drugs such as dobutamine and/or phenylephrine to achieve SBP >90 mmHgOptimize the CVP to 8–10 mmHgTransfuse packed red blood cell to maintain the hemoglobin >10 g/dL in case of anemiaContinue pulmonary vasodilator drugs that the patient was taking previously as an outpatient; andConsider prescribing inhaled NO (typical dosage, 20 ppm), especially if the patient is on a ventilator, will add an inotropic agent to increase the RV contractilityWould keep mechanical circulatory assist device like tandem heart (inflow cannula in the right atrium and outflow cannula in the pulmonary artery), RV impella, VA ECMO as a bail out optionBilateral lung transplant if inadequate clinical response to therapy.

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Conflicts of interest

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