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Identify and treat pulmonary arterial hypertension

An article from the e-journal of the ESC Council for Cardiology Practice

Pulmonary arterial hypertension is a cardiopulmonary disease that is a form of pulmonary hypertension which has its own diagnosis and specific medications, distinct from the four other forms of pulmonary hypertension that are pulmonary hypertension with left heart disease, chronic lung disease, chronic thromboembolism or with unclear mechanisms. 
Review the latest considerations and therapy specific to pulmonary arterial hypertension in this article.

Valvular, Myocardial, Pericardial, Pulmonary, Congenital Heart Disease
Pulmonary Hypertension


Pulmonary hypertension is defined as a mean pulmonary artery pressure of ≥25 mmHg at right heart catherisation. The continuous update provided by five world symposia on pulmonary hypertension since 1973 up until 2013 have classified pulmonary hypertension into 5 clinical groups:

  • Pulmonary arterial hypertension: Group 1 - endothelin receptor antagonists, agents that act on nitric oxide pathway, and prostanoids. 

Pulmonary arterial hypertension is defined as mean pulmonary artery pressure of ≥ 25 mmHg at right heart catheterisation, pulmonary artery wedge pressure ≤ 15 mmHg and pulmonary vascular resistance of > 3 Wood units or mmHg·min/l. Pulmonary arterial hypertension is a rare disease that can be fatal. 

The other four groups are pulmonary hypertension with:

  • Left heart disease: Group 2 - no specific medication
  • Chronic lung disease: Group 3 - no specific medication and possible transpantation
  • Chronic thromboembolism: Group 4 - pulmonary endarterectomy and cautious iv epoprostenol infusion, possible transplantation. Riociguat, a soluble guanilat cyclase stimulator, is approved for when a patient is inoperable or with recurrent pulmonary hypertension after endarterectomy.
  • Unclear multifactorial mechanisms: Group 5.

Groups 1,3,4 and 5 can be labelled as “precapillary pulmonary hypertension” (1-5).

Idiopathic or associated with other conditions

Idiopathic pulmonary hypertension accounts for half of all cases of pulmonary arterial hypertension in our centers. 
The other half is due to conditions associated, of which connective tissue disease, HIV infection, portal hypertension, congenital heart disease or schistosomiasis. 
Pulmonary arterial hypertension is a rare disease - reported at 15 per million in a French registry. Distal pulmonary arterioles have an imbalanced vasoconstrictor/vasodilator and proliferation/apoptosis (proliferation dominant) milieu leading to increased pulmonary vascular resistance and right heart failure. Prognosis is poor with a 15% mortality within 1 year on modern therapy (6,7).

General considerations

  • Symptoms with no overt explanation: If a patient presents with symptoms, signs or history suggestive of pulmonary hypertension such as exertional dyspnea and easy fatigability, atypical chest discomfort and exertional light-headedness or presyncope - yet with no overt clinical explanation within cardiopulmonary disease states, pulmonary arterial hypertension can be considered for differential diagnosis. 
  • Associated conditions such as (hemolytic anemia is now considered group 5) or drugs and toxins that could induce it such as appetite suppressants-fenfluramine, dexfenfluramine, toxic rapeseed oil are to be checked for.
  • Diagnosis from echocardiographic screening
    - unlikely: An estimated pressure at echocardiographic screening of ≤ 36 mmHg with no right atrium/right ventricle dilatation nor interventricular septum flattening for example makes the diagnosis unlikely. 
    - likely: An estimated pressure at echocardiographic screening < 36mmHg with secondary signs, or 37-50 mHg with/without secondary signs, or > 50 mmHg warrants further study.
  • Classification: Further study, best carried out by experts, is group identification potentially with electrocardiography, chest X-ray, pulmonary function tests, arterial blood gas analysis, high resolution computed tomography of the thorax, transesophageal echography for congenital heart disease, cardiac heart disease or associated pulmonary arterial hypertension, immunological markers (anti-nuclear antibody, anti double strand DNA, connective tissue disease/scleroderma-associated pulmonary arterial hypertension), liver function tests, hepatitis markers, abdominal ultrasonography (portopulmonary hypertension-associated pulmonary arterial hypertension), HIV testing, cardiac magnetic resonance (congenital heart disease/associated pulmonary arterial hypertension), ventilation perfusion scan - V/Q scan - chronic thromboembolic pulmonary hypertension, right heart catheterisation sometimes coupled with vasoreactivity testing depending on the clinical circumstances.    
  • V/Q scan study: A ventilation/perfusion scan is necessary. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension may coincide insidiously and absence of history of pulmonary embolism should not rule out chronic thromboembolic pulmonary hypertension.
  • Vasoreactivity testing: Right heart catherisation, if necessary, coupled with vasoreactivity testing will confirm or exclude a diagnosis. 
  • Right heart catherisation will estimate prognosis and confirm response to treatment or deterioration during follow-up. From a hemodynamic perspective, a carefully obtained pulmonary arterial wedge pressure or, if in doubt, left ventricular end diastolic pressure of > 15 mmHg would direct the patient to pulmonary hypertension with left heart disease (Group 2).

Distinction from heart failure with preserved ejection fraction

It might be difficult to differentiate pulmonary arterial hypertension from pulmonary hypertension in case of heart failure with preserved ejection fraction. Means to do so are:

  • Volume or exercise challenge: A normal pulmonary arterial wedge pressure may not rule out heart failure with preserved ejection fraction, however a volume or exercise challenge during right heart catherisation may unmask it. 
  • Clinical and echocardiographic parameters favouring pulmonary hypertension and heart failure with preserved ejection fractions are: patients above the age of 65, with hypertension, elevated pulse pressure, obesity, metabolic syndrome, coronary artery disease, diabetes mellitus, atrial fibrillation, on echocardiography, left atrial enlargement, left ventricular hypertrophy, increased left ventricular filling pressures. 
  • Right heart catherisation: During right heart catherisation, a detailed study of oximetry, cardiac output, calculations for pulmonary vascular resistance and, if necessary, a pulmonary angiography (CTEPH-operability) and vasoreactivity testing (IPAH / anorexigen induced PAH) should be performed.
  • Vasoreactivity testing is to be done with short acting selective pulmonary vasodilator agents (inhaled nitric oxide, iv epoprostenol, iv adenosine): A reduction of mean pulmonary artery pressure ≥ 10 mmHg to reach an absolute value of ≤ 40 mmHg with an increased or unchanged cardiac output is a positive test result that constitutes 5-10 % of patients and indicates a dominant vasoconstrictive component of the pathophysiology, with good prognosis. 
  • Postcapillary pulmonary hypertension: A pulmonary arterial wedge pressure of >15 mmHg would indicate pulmonary hypertension with left heart disease, of which, in some cases, there will be a pulmonary hypertension component. Previously, termed “out of proportion”, and now called “postcapillary pulmonary hypertension with a precapillary component” (7-8), this diagnosis requires a right heart catherisation value of pulse aterial wedge pressure > 15 mmHg and a diastolic pulmonary artery pressure and pulse arterial wedge pressure difference of ≥ 7 mmHg.
  • Isolated post capillary pulmonary hypertension: This diagnosis requires a pulmonary arterial wedge pressure > 15 mmHg and a diastolic pulmonary artery pressure < 7mmHg). 


  • Supportive therapy consists of diuretics, digoxin, coumadine and nasal oxygen where necessary. 
  • Vasoreactive idiopathic pulmonary hypertension patients should be treated with relatively high doses of calcium channel blockers namely nifedipine, diltiazem, amlodipine. If patient is unresponsive on calcium channel blocker therapy, transition to pulmonary arterial hypertension specific treatment is mandatory. 
  • Specific agents come in 3 lines. 
    1. Prostanoids (iv epoprostenol, inhaled/iv iloprost, inhaled/iv/sc treprostinil, oral beraprost)
    2. Endothelin receptor antagonists-ERA (ambrisentan, bosentan, macitentan), 
    3. Nitric oxide pathway (sildenafil, tadalafil, riociguat). 
  • Sequential add on, a specific form of combination, is possible and quite frequently necessary as the disease progresses. “Sequential add on” is today’s accepted clinical rationale which prones initiating treatment with monotherapy and adding on other drugs as the patient deteriorates or when there is insufficient clinical response. Initial (upfront) combination, meaning directly initiating with combination therapy is now being questioned in clinical trials (9).
  • Balloon atrial septostomy: Graded balloon atrial septostomy is a palliative procedure reserved for right heart failure patients with symptoms of syncope. It should be avoided in patients with a right atrium pressure > 20 mmHg and room oxygen saturation < 85 %. It can also be used as a bridge to lung transplantation.


Whereas pulmonary hypertension with left heart disease or with lung disease have no specific medication pulmonary arterial hypertension does. 
We gain to be aware of the latest clinical classification of pulmonary hypertension brought to you and best performed in expert centers. Pulmonary arterial hypertension is a distinguishable form treatable with its own dedicated medication.


1 - Updated clinical classification of pulmonary hypertension  
Simonneau G, Gatzoulis MA, Adatia I et al. J Am Coll Cardiol 2013;62:D34-41

2 - Updated treatment algorithm of pulmonary arterial hypertension.
Galie N, Corris PA, Frost A et al J Am Coll Cardiol 2013;62:D60-72

3 - Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. 

Ghofrani HA, D’armini AM, Grimminger F et al. N Engl J Med 2013;369:319-29.

4 - Definitions and diagnosis of pulmonary hypertension  
Hoeper MM, Bogaard HJ, Condliffe R et al. J Am Coll Cardiol 2013;62: D42-50.

5 - A USA-based registry for pulmonary arterial hypertension:1982-2006. 
Thenappan T, Shah SJ, Rich S et al. Eur Respir J. 2007;30:1103-10.

6 - Pulmonary arterial hypertension in France: results from a national registry 
Humbert M, Sitbon O, Chaouat A et al. Am J Respir Crit Care Med. 2006;173:1023-30.

7 - ACCF/AHA expert consensus document on pulmonary hypertension. 
McLaughlin VV, Archer SL, Badesch DB et al. J Am Coll Cardiol 2009;53:1573-619.

8 - Guidelines for the diagnosis and treatment of pulmonary hypertension  
Galie N, Hoeper MM, Humbert M et al. Eur Heart J. 2009;30:2493-537.

9 - Pulmonary hypertension due to left heart diseases.  
Vachiery JL, Adir Y, Barbera JA et al. J Am Coll Cardiol 2013;62:D100-8.

Notes to editor

Prof. Dr.Tamer Sayın, Prof. Dr. Çetin Erol
Ankara University, Faculty of Medicine
Department of Cardiology, Ankara-Turkey

Authors' disclosures: none declared.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.