Pulmonary Hypertension

Pulmonary Hypertension

It is defined as a mean pulmonary arterial pressure ≥ 25 mmHg measured by right cardiac catheterization.  The normal limits of the mean pulmonary arterial pressure are 11-20 mmHg. A borderline level between 20 and 24 is of unknown clinical significance. These patients should be carefully followed especially when they have conditions predisposing to the development of PH (eg connective tissue disease).
 By echocardiography, an indication of pulmonary hypertension (PH) is a peak velocity of the jet of tricuspid regurgitation > 2.8 m/s (in the absence of pulmonary valve stenosis), or an estimated pulmonary artery systolic pressure  40 mmHg.
Although pulmonary hypertension is often first suspected or discovered by echocardiography, for confirming the diagnosis a right heart catheterization (RHC) demonstrating mean pulmonary arterial pressure ≥ 25 mm Hg is required.
 Another information from the RHC that is central to the diagnosis is the pulmonary arterial occlusion or pulmonary capillary wedge pressure (PCWP).
A hemodynamic classification of pulmonary hypertension (PH) includes
- Precapillary PH, where the pulmonary capillary wedge pressure PCWP is normal ( ≤ 15 mmHg). This applies to PH due to lung disease or chronic thromboembolic lung disease or pulmonary arterial hypertension (PAH) and 
-Postcapillary PH, where the PCWP is elevated (>15 mmHg). This is the case in the most common group of PH, classified under WHO group II ( in this group, PH is due to pulmonary venous hypertension as a result of left heart disease).
PH is a disorder that may develop in multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases (especially diseases at a severe stage).

 Classification of severity of pulmonary hypertension.

Mild pulmonary hypertension (PH) is characterized by systolic pulmonary arterial (PA) pressure 35–50 mmHg and mean PA pressure 25–35 mmHg. 
Moderate PH is characterized by systolic PA pressure 50–70 mmHg and mean PA pressure 35–45 mmHg.
Severe PH is characterized by systolic PA pressure >70 mmHg and mean PA pressure >45 mmHg, or pulmonary vascular resistance (PVR) >6-7 Wood units.

In chronic severe PH, although the PA pressure initially is severely elevated, later it may start declining into the moderate to mild range as right ventricular failure progressively worsens. When there is a severe right ventricular failure, the right ventricle cannot generate a high PA pressure. On the other hand, PVR remains severely elevated.

Pathophysiology of pulmonary hypertension

The pulmonary and systemic circulations are in series with each other and normally the total pulmonary and systemic blood flows are virtually identical.
 Despite the same rate of blood flow, the anatomic, hemodynamic, and physiological characteristics of these two sections of the cardiovascular system have substantial differences. The main difference is in vascular resistance: The pulmonary circulation is a low-resistance network of highly distensible vessels.
An elevated pulmonary arterial pressure can be caused by:
An elevated pulmonary arterial resistance (normally pulmonary arterial resistance is about 10 times less than systemic vascular resistance)
An increased blood flow in the pulmonary circulation
An increased pulmonary venous pressure 
Pulmonary hypertension can lead to right ventricular failure. The ability of the right ventricle to adapt to pulmonary hypertension depends not only on the level of pulmonary arterial pressure, but also on the rapidity of the development of PH and on other factors such as the age of the patient, hypoxemia due to a pulmonary disease or concomitant coronary artery disease (these factors can impair the ability of the right ventricle to compensate). The onset of clinical symptoms and signs of right ventricular failure indicates a poor prognosis.

Symptoms of pulmonary hypertension 

The most common symptom is exertional dyspnea, which may progressively worsen. Other manifestations include fatigue (also a very common manifestation), angina (right ventricular hypertrophy and the increased workload of the right ventricle due to the elevated pulmonary arterial pressure can cause right ventricular ischemia), presyncope or syncope, peripheral edema (due to right ventricular failure) and in some cases hemoptysis (in cases of mitral stenosis, or pulmonary thromboembolic disease).

Physical examination in pulmonary hypertension (PH)

An accentuated pulmonic component of the second heart sound (P2) is common. There may be evidence of right ventricular failure with elevated jugular venous pressure (a common finding), a right-sided S3 or S4  and a holosystolic murmur of secondary tricuspid regurgitation, lower extremity edema (this is common), hepatomegaly (enlargement of the liver) and/or ascites. 
Symptoms and signs of the disease that has caused the PH are often present, e.g. paroxysmal nocturnal dyspnea, hypertension, or crackles at the lung bases can be clues to left-sided systolic or diastolic heart failure, a murmur can be a clue to left sided valvular heart disease, rhonchi indicate obstruction of medium sized airways of the bronchial tree, as in chronic obstructive pulmonary disease, clubbing may be seen in some chronic lung diseases, sclerodactyly and telangiectasia can be present in scleroderma, etc.

The ECG in pulmonary hypertension

An electrocardiogram (ECG) may show evidence supportive of PH, but a normal ECG does not exclude the diagnosis. ECG abnormalities can be suggestive of the diagnosis but they are neither specific nor sensitive. ECG abnormalities in cases of moderate to severe PH may include right ventricular strain (inverted T waves in the right precordial leads-this is a relatively sensitive, but not specific sign), P pulmonale, right axis deviation, right ventricular hypertrophy, right bundle branch block, and QTc prolongation. In cases of PH due to a left heart disease, the ECG usually shows evidence consistent with this disease, e.g a P mitrale in mitral valve disease, evidence of a previous myocardial infarction in cases of ischemic cardiomyopathy, left ventricular hypertrophy in hypertensive heart disease or in aortic valve stenosis, etc.

Chest radiography in pulmonary hypertension (PH)

Chest X-ray in pulmonary arterial hypertension (PAH) shows enlarged central pulmonary arteries with rapid tapering of vessels toward the periphery of the lungs (a “pruned tree” appearance) and it may also show enlargement of the right heart chambers.
In other causes of PH, findings depend on the causative disease.
In PH caused by parenchymal lung disease, the chest X-ray may show hyperinflation and bullous disease (suggestive of COPD), or increased interstitial lung markings (suggestive of interstitial lung disease).
In PH caused by left heart disease, the chest X ray may show dilated left heart chambers and signs of pulmonary venous congestion.

Echocardiography in the evaluation of pulmonary hypertension

It can demonstrate enlargement of the right heart chambers (right ventricle and right atrium), signs of right ventricular pressure overload, including paradoxical bulging of the septum into the left ventricle during systole and hypertrophy of the right ventricular free wall.
(Watch this video from 123sonography, which demonstrates these echocardiographic findings Link: 123sonography

Estimation of pulmonary arterial systolic pressure based on the peak velocity of tricuspid regurgitation (TR) by using the continuous wave Doppler signal of TR,  can suggest the presence of pulmonary hypertension. This is a good method to suspect, or suggest PH, but not to accurately measure  PA pressure (Accurate measurement requires right heart catheterization). The peak systolic pressure gradient (pressure difference) between the right ventricle and the right atrium, according to the modified Bernoulli equation is 4V2 , where V= the peak velocity of the TR jet. Thus the peak right ventricular systolic pressure (RVSP) is  4V2+ RAP (where RAP=right atrial pressure). When there is no pulmonary stenosis, RVSP=PASP (PASP: pulmonary artery systolic pressure). Thus, if there is no pulmonary stenosis,  PASP=4V2+ RAP. 
Right atrial pressure (RAP) can be estimated by echocardiography based on the maximum diameter and respiratory variation in the diameter of the inferior vena cava (IVC): 
An IVC diameter < 2.1 cm that collapses > 50% with a sniff suggests a normal RAP of 3 mmHg (range 0–5 mmHg). 
An IVC diameter >2.1 cm that collapses < 50% with a sniff or < 20% on quiet inspiration suggests a high RA pressure of 15 mmHg (range 10–20 mmHg).
 In cases in which the IVC diameter and collapse do not fit this description, an intermediate value of 8 mmHg (range 5–10 mmHg) may be used. Such an approach is more accurate than using for RAP a fixed value of 5 or 10 mmHg. 
However, given the inaccuracies of RAP estimation, it is better to use the continuous wave Doppler measurement of peak TR velocity (and not the estimated PASP) as the main variable for assigning the echocardiographic probability of PH. The echocardiographic probability of pulmonary hypertension (PH) in symptomatic patients with a suspicion of PH can be estimated from the  peak tricuspid regurgitation velocity TRV (expressed in m/s):
 When the peak tricuspid regurgitation velocity, TRV ≤2.8, or is not measurable and other echocardiographic signs suggestive of PH are absent, then the probability of PH is low (for the other suggestive echocardiographic signs of PH see below). 
When TRV ≤2.8, or not measurable and other echocardiographic signs suggestive of PH are present, then the probability of PH is intermediate.
When TRV 2.9–3.4, then the probability of PH is intermediate if other echocardiographic signs suggestive of PH are absent, but the probability is high if other suggestive echocardiographic signs are present.
When TRV >3.4 there is a high probability of PH, regardless of the presence or absence of other echocardiographic signs.
For a good measurement to be obtained the entire Doppler envelope of tricuspid regurgitation (TR) should be visualized with the characteristic bullet-shaped form. Do not measure peak velocity if the jet is not fully formed. Every Doppler velocity measurement should be performed with the Doppler beam as parallel to blood flow as possible. (This rule applies to every Doppler velocity measurement and not only to the measurement of TRV).
Doppler derived right ventricular systolic pressure estimation can be inaccurate in patients with severe tricuspid regurgitation (TR), where TRV may significantly underestimate the pulmonary artery systolic pressure. Thus in patients with severe TR, peak TR velocity should not be used to exclude PH.

Other echocardiographic signs suggestive of pulmonary hypertension (PH) besides TRV

There are several echocardiographic signs suggesting pulmonary hypertension. These signs are used to assess the probability of pulmonary hypertension in addition to tricuspid regurgitation velocity measurement and include: 
An enlarged right ventricle (RV) with RV/ LV basal diameter ratio >1 (LV=left ventricle). 
An enlarged right atrium: Right atrial area (at end-systole) >18 cm2 measured in the apical 4 chamber view.
A dilated pulmonary artery with a diameter >25 mm (measured in the parasternal basal short axis view).
Flattening of the interventricular septum (left ventricular eccentricity index >1.1 in systole and/or diastole). LV eccentricity index is the ratio of the anterior-inferior and septal-posterolateral cavity dimensions at the mid-ventricular level in the parasternal short axis view.
Right ventricular outflow tract(RVOT) acceleration time (AT) <105 msec and/or midsystolic notching of the Doppler signal. AT is the time from the onset to the peak velocity of flow. These two signs are assessed with the pulse wave Doppler immediately proximal to the pulmonary valve in the parasternal basal short axis view.
The RVOT or pulmonary arterial AT (measured with the pulse wave Doppler) can also be used to calculate mean pulmonary arterial (PA) with the following formula
Mean PA pressure = 79 - 0.45(AT)  
  From the same view with continuous wave Doppler interrogation of the flow through the pulmonic valve, an early diastolic pulmonary regurgitation velocity >2.2 m/sec, is also suggestive of PH.
Inferior cava diameter >21 mm with decreased inspiratory collapse (<50 % with a sniff, or <20 % with quiet inspiration).Echocardiography can also show evidence of some etiologies of PH such as left heart disease, or congenital heart disease with a left to right shunt.

General diagnostic workup of patients with suspected PH:

Echocardiography is recommended as a first-line test in case of suspicion of PH.
Lung function test with DLCO (diffusing capacity of the lung for carbon monoxide ) is recommended in the initial evaluation of patients with PH and a high-resolution CT should be considered in all patients with PH, to search for pulmonary disease.
In patients with a working diagnosis of PAH right heart catheterization is needed to measure mean pulmonary arterial pressure, PVR, and PCWP.
When measurement of PCWP is unreliable, left heart catheterization should be considered to measure left ventricular end diastolic pressure (LVEDP). Diagnosis of PAH and specific treatment decisions always require prior diagnostic confirmation with right heart catheterization.
In all patients with PAH routine biochemistry, hematology, immunology, HIV testing and thyroid function tests are recommended to search for a specific associated condition.
Abdominal ultrasound is recommended to screen for portal hypertension.
In patients with unexplained PH a ventilation /perfusion lung scan is recommended to exclude chronic thromboembolic PH (CTEPH). 
 A contrast CT angiography of the pulmonary artery is recommended in the workup of patients with CTEPH.
Patients with CTEPH should undergo screening for thrombophilia, including antiphospholipid antibodies, anticardiolipin antibodies, and lupus anticoagulant.

Note: lung biopsy (open or thoracoscopic)  is not recommended in patients with PAH, according to the recent ESC guidelines.

Clinical classification of pulmonary hypertension (PH) according to the etiology and pathophysiology: 

PH is classified into 5 groups: 


It contains 3 subgroups: 
Pulmonary arterial hypertension (PAH),  
Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis,  and
 Persistent pulmonary hypertension of the newborn.

Pulmonary arterial hypertension (PAH, group 1)

 It is characterized by the presence of pre-capillary PH ( mean pulmonary arterial pressure  ≥ 25 mmHg and  PCWP is normal ≤ 15 mmHgand pulmonary vascular resistance >3 Wood units, in the absence of other causes of pre-capillary PH such as lung disease or chronic thromboembolic disease or other rare diseases such as pulmonary capillary haemangiomatosis.  Pulmonary arterial hypertension (PAH) includes several different etiologies of PH that share a similar clinical picture and virtually identical pathological changes of the lung microcirculation.  These changes of the lung microcirculation include vasoconstriction, intimal proliferation and fibrosis, medial hyper­trophy and in situ thrombosis. These changes cause a progressive increase in pulmonic vascular resistance (PVR) and thus in right ventricular afterload and right ventricular work.
Etiologically pulmonary arterial hypertension (PAH) is classified as 
Heritable (BMPR2 mutation /Other mutations )
 Induced by drugs and toxins 
PAH associated with: 
Connective tissue disease
 Human immunodeficiency virus (HIV) infection
Portal hypertension 
 Congenital heart disease

PAH is a relatively rare form of pulmonary hypertension. The characteristic symptoms of PAH are dyspnea, chest pain, and syncope and if left untreated, PAH carries a high mortality rate, with the most common cause of death being decompensated right heart failure. There is often a considerable delay in the diagnosis of PAH because the symptoms are insidious and overlap with many common diseases including asthma, chronic obstructive lung disease, and other lung disease and cardiac disease (such as congestive heart failure of many etiologies, or coronary artery disease).
Early diagnosis is important, so that specific treatment for PAH can be initiated because new drugs have been recently developed resulting in a change in the management of this disease, with significant improvement in the quality of life and mortality.The current treatment for PAH can be divided into three main steps: The initial approach includes General measures such as counseling on physical activity and supervised rehabilitation, pregnancy, birth control,  psychosocial support, etc.  PAH patients should avoid pregnancy because it is associated with significant mortality. Immunization of PAH patients against influenza and pneumococcal infection is recommended. Supervised exercise training should be considered in physically deconditioned PAH patients under medical therapy. PAH patients should be encouraged to be active within symptom limits, avoiding excessive physical activity that leads to distressing symptoms.
Supportive therapy such as oral anticoagulants, diuretics, oxygen, digoxin, is important.
Referral to expert centers for PAH treatment and right heart catheterization is indicated in every patient with clinical suspicion of PAH. During right heart catheterization of patients with PAH acute vasoreactivity testing is indicated. 
The second step of PAH treatment includes initial therapy with high-dose with calcium channel blockers only in vasoreactive patients or with drugs approved for PAH in non-vasoreactive patients. These drugs include prostacyclin, an endothelin receptor antagonist, or a phosphodiesterase-5 inhibitor.
Prostacyclin (epoprostenol in continuous intravenous infusion) and prostacyclin analogues ( treprostinil, iloprost) are direct pulmonary vasodilators. 
Endothelin receptor antagonists (e.g., bosentan,
ambrisentan) inhibit the vasoconstricting
effects of endothelin-1.
Phosphodiesterase-5 inhibitors (e.g., sildenafil,
tadalafil) enhance nitric oxide-mediated vasodilation.
The third part of the treatment strategy is related to the response to the initial treatment. In case of an inadequate response,  combinations of the above drugs for PAH, or lung transplantation are considered.

 Pulmonary hypertension due to pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis,

 etiologically is classified as: 
Heritable (EIF2AK4 mutation/other mutations)
Induced by drugs, toxins and radiation, and 
 Associated with: 
Connective tissue disease
HIV infection

Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis,

 These are uncommon causes of PH. These two conditions have similarities in pathologic features and clinical characteristics. Another feature, that they have in common is the risk of drug-induced pulmonary edema with PAH. Thus, there is evidence that these two conditions overlap. They also share some important clinical similarities with PAH. 
Pulmonary veno‐occlusive disease is characterized by abnormalities of the pulmonary venules similar to the arteriolar abnormalities seen in idiopathic PAH. and may be idiopathic or associated with scleroderma. Similar to PAH, true pulmonary arterial wedging is difficult during catheterization, but, if successful, the truly wedged PCWP is approximately the same as the left atrial pressure and has normal value. Although the PCWP i.e. the  LA pressure, is normal, the pulmonary capillary pressure is increased due to the obstructive disease of the pulmonary venules. Thus, pulmonary edema can develop.

Group 2 of diseases causing pulmonary hypertension (PH) is PH due to left heart disease 

PH secondary to left heart disease is also called pulmonary venous hypertension or postcapillary PH, because the initial pathophysiologic and etiologic event is the elevated pulmonary venous pressure. This is the most common group of disorders causing PH.
Left heart ventricular or valvular diseases may produce an increase in left atrial pressure. This results in passive backward transmission of pressure to the pulmonary circulation. As a result, the first event is a rise in pulmonary capillary wedge pressure(PCWP) and then also the pulmonary arterial pressure rises. The hemodynamic features are: 
PCWP is elevated (>15 mmHg).
 Diastolic PA pressure is passively increased 
 Pulmonary vascular resistance (PVR) is <3 Wood units. 
The transpulmonary gradient, which is the pressure difference that produces flow in the pulmonary circulation, i.e., mean PA pressure minus PCWP, is <12 mmHg
The transpulmonary gradient is the numerator in pulmonary vascular resistance (PVR) calculation: PVR = transpulmonary gradient/cardiac output.
Causes are classified as :
 Left ventricular systolic dysfunction 
Left ventricular diastolic dysfunction 
Valvular disease, obstruction, and congenital cardiomyopathies 
 Congenital or acquired stenosis of the pulmonary veins 
In PH of the group 2 treatment is of the underlying cause, e.g. treatment for congestive heart failure, or surgery for severe disease of the left heart valves.

Group 3 of the causes of pulmonary hypertension (PH) : Pulmonary hypertension due to lung diseases and/or hypoxia 

These causes of PH are classified as:
 Chronic obstructive pulmonary disease (COPD)
 Interstitial lung disease 
Other pulmonary diseases with mixed restrictive and obstructive pattern 
Sleep-disordered breathing (sleep apnea)
 Alveolar hypoventilation disorders 
Chronic exposure to high altitude 
Developmental lung diseases 
In patients with COPD, mild pH is common, but  moderate PH is only seen in about 5-10% of cases
and severe PH is quite uncommon ( in 2% of cases). respectively. 
Sleep apnea also usually causes mild PH. 
Conversely, severe interstitial lung disease, especially advanced‐stage fibrotic lung disease that obliterates the pulmonary capillaries can cause severe PH.
Severe PH may also be seen with interstitial lung disease due to sarcoidosis and with obesity-hypoventilation syndrome.

In group 3 PH, treatment is of the underlying lung disease or cause. Usually, in case of a lung disease bronchodilators and oxygen are used.

Group 4 of PH:  Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions 

This etiologic group includes
Chronic thromboembolic pulmonary hypertension 4 Other pulmonary artery obstructions 
Other intravascular tumors 
Congenital pulmonary arteries stenoses 
Parasites (hydatidosis)
 In thromboembolic PH with proximal thromboembolic disease, the treatment is surgical: pulmonary thromboendarterectomy.

Group 5 of pulmonary hypertension: PH with unclear and/or multifactorial mechanisms

 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 
 Others: pulmonary tumoral thrombotic microangiopathy, osing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension
In these patients, there is no specific treatment for PH. Treatment is for the underlying disease. Drugs for PAH are not used in the treatment of group 5 disorders, since there are no randomized trials.

Bibliography and links 

LINK:  2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension 
Galie N, et al. Eur Heart J 2016; 37: 67-119.

Hoeper MM,et al. Treatment of pulmonary hypertension. The  Lancet Respiratory Medicine 2016; 4, 323–336. 


Kiely DG, et al. Pulmonary hypertension: diagnosis and management. BMJ 2013;346:f2028