The document discusses pulmonary hypertension (PH) due to lung disorders. It defines PH and classifies it based on its underlying causes. PH due to lung diseases and hypoxia (group 3 PH) is associated with obstructive lung diseases like COPD, restrictive lung diseases, mixed lung diseases, and hypoxia without lung disease. Symptoms include dyspnea, fatigue, and signs of right heart failure as PH progresses. Imaging like echocardiogram and right heart catheterization are used to diagnose and assess severity of PH. Treatment involves managing the underlying lung condition, supportive therapies, and in severe cases, pulmonary arterial hypertension therapies may be considered though data is limited in group 3 PH. Prognosis is typically progressive with increased mortality

1. Pulmonary hypertension (PH)
due to lung disorder

2. 1.Definition
• PH is defined as a mean pulmonary artery pressure (mPAP) >20 mmHg at rest,
measured by right heart catheterization ( in the past >25).
PH is considered severe if mPAP is ≥35 mmHg or the mPAP is >20 mmHg with an
elevated right atrial pressure (>14 mmHg) and/or the cardiac index is <2 L/min/m2 .
• Cor pulmonale refers to PH-induced altered structure (eg, hypertrophy or
dilatation) and/or impaired function of the RV that is associated with chronic
lung disease and/or hypoxemia (ie, group 3 PH).

3. 2.Classification
1. Pulmonary arterial hypertension ( PAH ).
Idiopathic.
Heritable.
Drug-induced and toxin-induced .
Associated with the following:
Connective tissue disease.
Portal hypertension.
Congenital heart disease.
Schistosomiasis.
PAH long-term responders to calcium channel blockers .
PAH with overt features of pulmonary veno-occlusive disease/or
pulmonary capillary hemangiomatosis .
Persistent PH of the newborn syndrome.
2. Pulmonary hypertension due to left heart disease.
A. PH due to HFpEF.
B. PH due to HFrEF
C. Valvular heart disease.
D. Congenital/acquired cardiovascular conditions leading to
postcapillary PH.
3. Pulmonary hypertension due to lung disease and/or
hypoxia.
A. Obstructive pulmonary diseases.
B. Restrictive pulmonary diseases.
C. Other lung disease with mixed restrictive/obstructive pattern.
D. Hypoxia without lung disease.
4. Pulmonary hypertension due to pulmonary artery
obstruction.
A. Chronic thromboembolic PH.
B. Other pulmonary artery obstructions.
Sarcoma (high or intermediate grade) or angiosarcoma.
Other malignant tumors (renal, uterine, germ cell tumor of the
testis, other tumors).
Non-malignant tumors (uterine leiomyoma).
Arteritis without connective tissue disease.
Congenital pulmonary arteries stenoses.
Parasites (hydatidosis).
5. Pulmonary hypertension with unclear and/or multifactorial
mechanisms.
A. Hematological disorders: chronic hemolytic anemia and
myeloproliferative disorders.
B. Systemic and metabolic disorders: pulmonary Langerhans cell
histiocytosis, Gaucher disease, glycogen storage disease,
neurofibromatosis and sarcoidosis.
C. Others: fibrosing mediastinitis, chronic renal failure
(with/without dialysis), pulmonary tumorous thrombotic
microangiopathy and HIV.

4. Group 3 PH due to lung disease and/or hypoxia.:
1. Obstructive lung disease (eg, COPD or bronchiectasis).
2. Restrictive lung disease (eg, ILD , kyphoscoliosis).
3. Other lung disease with mixed obstruction and restriction (eg, pulmonary fibrosis
with emphysema).
4. Hypoxia without lung disease (eg, high altitude, sleep-disordered breathing,
obesity hypoventilation).
5. Developmental lung disorders (eg, bronchopulmonary dysplasia, congenital lobar
emphysema).

5. 1. Dyspnea and fatigue
 The most common initial symptoms of PH are exertional dyspnea, lethargy, and fatigue and are due to
an inadequate increase in cardiac output during exercise.
2. Symptoms of RV failure– Symptoms of RV failure develop as PH progresses and include the following:
A. Exertional chest pain – (Angina) is usually due to subendocardial hypoperfusion caused by increased RV
wall stress and myocardial oxygen demand. However, it is occasionally caused by compression of the left
main coronary artery by an enlarged pulmonary artery.
B. Exertional syncope – An unusual symptom that is due to insufficient increase in cardiac output during activity
or reflex bradycardia from mechanoreceptor activation in the RV.
C. Weight gain from edema – Peripheral edema.
D. Anorexia and/or abdominal pain and swelling – Anorexia and/or abdominal pain in the RUQ is due to
passive hepatic congestion. The patient may also complain of increase in abdominal girth from ascites.
3. Symptoms

6. 3. Uncommon symptoms include cough, hemoptysis, and hoarseness.
A. The hoarseness is caused by compression of the left recurrent laryngeal nerve by
a dilated main pulmonary artery (Ortner’s syndrome) resulting in unilateral vocal
cord paralysis.
B. Palpitations from arrhythmias (eg, atrial fibrillation or flutter) is a rare presenting
feature of PH.

7. 4.Examination
Initial findings:
Increased intensity of the pulmonic component of the second heart sound, which
may become palpable as PH progresses.
The second heart sound is narrowly split or single (ie, normal) in patients
with preserved RV function.

8. • Signs of RV failure – As PH progresses the following signs of RV failure may be evident
:
JVP abnormalities – The JVP is typically elevated. Initially, a prominent a wave is seen, while
a prominent v wave indicates significant tricuspid regurgitation and often severe RV failure.
Right-sided auscultatory findings that are augmented with inspiration may be heard
including:
-A right-sided third or fourth heart sound (ie, a gallop)
-Wide splitting of the second heart sound.
-A holosystolic murmur of tricuspid regurgitation.
-And in more severe disease, a diastolic pulmonic regurgitation murmur.
Hepatomegaly, a pulsatile or tender liver, peripheral edema, ascites, and pleural effusion
(ie, signs of severe decompensated RV failure).
Splenomegaly is rare but may be seen in PAH due to schistosomiasis or portopulmonary
hypertension.

9. 5.Laboratories
• PH in itself is not associated with specific diagnostic laboratory abnormalities,
although the BNP values may be elevated due to RV wall stretch.
• Elevated BNP, however, can also be found in left ventricular failure and in
chronic renal insufficiency

10. 6.Imaging
A. Chest radiograph may be normal in a few patients, it classically shows enlargement
of the central pulmonary arteries with attenuation of the peripheral vessels,
resulting in oligemic lung fields .
RV enlargement (diminished retrosternal space), right atrial dilatation (prominent right heart border)
and pleural effusions may also be seen as PH progresses.
Evidence of underlying chronic lung disease or heart failure may also be present.
B. Chest CT may have findings similar to those seen on chest radiography but greater
detail on CT.
The main pulmonary artery/ascending aorta diameter ratio ≥1 is also suggestive of PH on CT.
C. Ventilation Perfusion (V/Q) imaging is usually normal or has reduced peripheral
perfusion, Unless PH is due to venous thromboembolism.

11. D. Electrocardiogram (ECG)
An ECG may provide supportive evidence of PH, but a normal ECG does not
exclude the diagnosis.
An abnormal ECG is more likely in severe rather than mild PH.
ECG abnormalities may include P pulmonale, right axis deviation, RV
hypertrophy, RV strain, right bundle branch block, and QTc prolongation.
 Prolongation of the QRS complex and QTc suggests severe disease.
Supraventricular arrhythmias may occur in advanced disease, in particular atrial
flutter, but also atrial fibrillation, with a cumulative incidence of 25% in patients
after 5 years.
Ventricular arrhythmias are rare.
 ECG changes do not correlate with disease severity or prognosis.

12. E.Echocardiography
 Once PH is suspected, the initial test of choice, which then determines the
sequence of subsequent testing.
 TTE evaluates the following:
A. The probability of PH using the tricuspid Regurgitant jet Velocity (TRV).
 TRV can also be used to estimate the pulmonary artery systolic pressure (ePASP).
B. The assessment of RV size, wall thickness, and function.
C. The potential contribution of left-sided heart disease to PH (if PH is identified on
TTE).
The ESC/ERS and the Sixth World Symposium do not recommend using estimated systolic PAP anymore given inaccuracies
of right atrial pressure (RAP) estimation and the amplification of measurement errors using derived variables; thus,
continuous-wave Doppler measurement of peak Tricuspid Regurgitation Velocity (TRV) is the main variable for assigning
echocardiographic probability of PH

13. A. Tricuspid Regurgitant jet Velocity (TRV)
 TR is commonly encountered in patients with PH.
The ePASP can be calculated with Doppler Echo. using the formula: ePASP = (4 x [TRV]2) + RAP.
Newer guidelines issued by the ESC/ERS in 2015 , which are place greater
emphasis on using the peak TRV rather than ePASP on echocardiography to
report the echocardiographic probability of PH:
Peak tricuspid regurgitation velocity (m/s) Presence of other Echo. signs of PH Echo. probability of PH
 <2.8 or not measurable No Low
 <2.8 or not measurable Yes Intermediate
 2.9–3.4 No
 2.9–3.4 Yes High
 >3.4 Not required

15. B. Other signs of pulmonary hypertension
The ventricles – RV/LV basal diameter ratio >1.0; flattening of the interventricular
septum (ie, left ventricular eccentricity index >1.1 in systole and/or diastole).
The pulmonary artery – RV outflow Doppler acceleration time <105 ms and/or mid
systolic notching; early diastolic pulmonary regurgitation velocity >2.2 m.s-1;
pulmonary artery diameter ≥25 mm.
The inferior vena cava and right atrium – Inferior vena cava diameter >21 mm with
decreased inspiratory collapse (<50 % with a deep inspiration or <20 percent with
quiet inspiration); right atrial area (end-systole) >18 cm2.

16. Pulmonary Hypertension (PH)
1. If Echo is supportive of Mild PH (eg, ePASP 20 to 39 mmHg) in the absence of any other
etiology for PH, then most clinicians do not proceed with right heart catheterization
(RHC), but rather observe patients for progressive symptoms over time.
2. If PH is Moderate (eg, ePASP ≥40 and <60 mmHg) or Severe (ePASP ≥60 mmHg, tricuspid
regurgitant jet >3 meters/second, RV dilatation or dysfunction), then most experts refer
to a center with expertise in PH to proceed with RHC to confirm the diagnosis.
3. If echocardiography does not reveal PH (eg, PASP <20 mmHg), no RHC is generally done,
unless the suspicion for PH is high (eg, unexplained symptoms or hypoxemia).
 Similarly, for those with an inadequate study in whom the suspicion is high, then many experts proceed with RHC.

17. 8.Treatment
A. GENERAL MEASURES
B. SPECIFIC THERAPY

18. A.GENERAL MEASURES
1. Treatment of associated condition — Treatment of the underlying condition (eg,
COPD,ILD, sleep-disordered breathing [SDB])
2. Conventional and supportive therapies —all patients with group 3 PH should
exercise as tolerated, receive routine vaccinations , be counselled against
smoking, and be treated with supportive measures including oxygen and diuretics,
when indicated.
3. Supplemental oxygen, has been documented to improve survival and pulmonary
vascular resistance in patients with COPD-associated PH who also have documented
hypoxemia (ie, a partial arterial pressure of oxygen [PaO2] below 60 mmHg)
4. Inotropic agents – Digoxin has symptomatic benefit to patients with left ventricle
(LV) systolic dysfunction; however, it is not typically indicated for the treatment of
group 3 PH in the absence of coexisting atrial fibrillation or LV dysfunction; as may
have adverse effects: induce pulmonary vasoconstriction and worsening pulmonary
hypertension.

19. UP-TODATE Approach
1. Mild to Moderate pulmonary hypertension — estimated systolic pulmonary
artery pressure [sPAP] between 20 and 60 mmHg), or mean pulmonary artery
pressure (mPAP) on right heart catheterization (RHC) between 25 and 34
mmHg .
Observation — Closely monitored every 6 to 12 months for the signs and symptoms of
progressive PH.

20. 2. Severe pulmonary hypertension — estimated by echocardiography (eg,
estimated sPAP ≥60 mmHg), or by RHC (eg, mPAP ≥35 mmHg or mPAP ≥25
mmHg with elevated right atrial pressure and/or low cardiac index <2
liters/minute/meter2)
Most patients in this category are treated with general measures and, unlike patients
with group 1 PAH, they are not typically treated with PAH-directed therapy, although
rare exceptions exist.
These patients should be referred to a specialized center for further evaluation
and management and for potential inclusion in clinical trials.

21. • Pulmonary arterial hypertension-directed therapy :
1. Prostacyclin pathway agonists (eg, epoprostenol, treprostinil, iloprost, selexipag)
2. Phosphodiesterase-5 (PDE5) inhibitors (eg, sildenafil, tadalafil, )
3. Nitric oxide-cyclic guanosine monophosphate enhancers including soluble guanylate
cyclase stimulators (riociguat)
4. Pndothelin receptor antagonists (ERA; eg, bosentan, ambrisentan, macitentan).
While many of these agents have efficacy in the treatment of patients with group 1 PAH,
their efficacy in group 3 PH is limited, and in some cases may be harmful .
With the exception of Inhaled Treprostinil, none of these agents have been approved for use in group
3 PH.
• Patients who fail therapy — Patients with severe group 3 PH who fail therapy should be
considered for Lung Transplantation.
B. SPECIFIC THERAPY

22. 9.Prognosis
• PH from underlying lung disease and/or hypoxemia is typically progressive
and is generally associated with increased morbidity and mortality.

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