By Alaa Ateya Mohammed

Pulmonary hypertension (PH) is a hemodynamic state defined by a resting mean pulmonary artery pressure (PAP) at or above 25 mmHg

Haemodynamic definitions ofpulmonary hypertension

This differentiation in pre- and post-capillary PH is important as it narrows the differential diagnosis and also has treatment implications.

Updated Clinical Classification of Pulmonary Hypertension

1. Pulmonary arterial hypertension (PAH) Idiopathic PAH

Heritable (Genetic mutations)BMPR2 (bone morphogenetic protein receptor type II)

ALK1(activin-like kinase type 1), endoglin (with or without hereditary hemorrhagic telangiectasia)

Drug- and toxin-induced (Fenfluramine, Aminorex, Cocaine, Amphitamine)

Associated withConnective tissue diseasesHIV infectionPortal hypertensionCongenital heart diseasesSchistosomiasisChronic hemolytic anemia

2. Pulmonary hypertension owing to left heart disease

Systolic dysfunction

Diastolic dysfunction

Valvular disease

3. Pulmonary hypertension owing to lung diseases and/or hypoxia

COPD

Interstitial lung disease

pulmonary diseases with mixed restrictive and obstructive pattern(CF, Broncheictasis)

OSA

Alveolar hypoventilation disorders

High altitude

Developmental abnormalities

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms

Hematologic disorders: myeloproliferative disorders, splenectomy

Systemic disorders: sarcoidosis, pulmonary Langerhanscell histiocytosis: lymph-angio-leiomyomatosis,

neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease,

Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis,

chronic renal failure on dialysis.

1- Pulmonary arterial hypertension (PAH) PAH is a rare disease

Aeitiology: idiopathic, heritable , associated forms

Pathophysiology:

Proliferative vasculopathy which is histologicallycharacterized by endothelial and smooth muscle cellproliferation, medial hypertrophy, fibrosis and in-situthrombi of the small pulmonary arteries andarterioles.

Pathobiologic basis of therapy

Imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling

Three major pathobiologic pathways (nitric oxide, endothelin, and prostacyclin) play important roles in the development and progression of PAH.

The endothelium-derived relaxing factor Nitric Oxide (N.O)

Potent pulmonary vasodilator

Produced in high levels in the upper and lower airways by nitric oxide synthase II (NOSII)

NO causes smooth muscle relaxation and maintaining the normal pulmonary vascular tone

Patients with IPAH have low levels of NO in their exhaled breath, and the severity of the disease inversely correlates with NO reaction products in bronchoalveolar lavage fluid.

Endothelin-1 A peptide produced by the vascular endothelium

Potent vasoconstrictive and proliferative paracrineactions on the vascular smooth muscle cells

The pulmonary circulation plays an important role in the production and clearance of endothelin-1, and this physiologic balance is reflected in the circulating levels of endothelin-1.

Prostacyclin The endothelium also produces prostacyclin (PGI2) by

cyclooxygenase metabolism of arachidonic acid

Prostacyclin causes vasodilation throughout the human circulation

Inhibitor of platelet aggregation by

Remodeling Pulmonary vascular smooth muscle cells that normally have

a low rate of multiplication undergo proliferation and hypertrophy leading to intimal narrowing and increased resistance to blood flow

Loss of the antimitogenic endothelial substances (e.g.PGI2 and NO)

Increased mitogenic substances (e.g.endothelin-1)

Other stimuli arise from locally activated platelets, which release thromboxane A2 and serotonin

Act as growthpromoting substances on the vascular smooth muscle cells, Both are vasoconstrictors

An abnormal proliferation of endothelial cells occurs in the irreversible plexogenic lesion.

are glomeruloid structures forming channels in branches of the pulmonary artery

may result from a deregulated growth of endothelial cells

represent a unique form of active angiogenesis

Vascular endothelial cell factor (VEGF) promotes endothelial cell proliferation

Thrombosis

Blood thrombin activity is increased, indicating activation of intravascular coagulation,

whereas soluble thrombomodulin, a cell membrane protein that acts as an important site of thrombin binding and coagulation inactivation, is decreased.

In addition, PGI2 and NO, both inhibitors of platelet aggregation, are decreased at the level of the injured endothelial cell.

Circulating platelets in patients with PAH seem to be in a continuous state of activation and contribute to the prothrombotic milieu by aggregating at the level of the injured endothelial cells

Signs and symptoms Nonspecific Dyspnea, weakness and recurrent syncope. Other symptoms include fatigue, angina, and abdominal

distention Symptoms at rest are reported only in very advanced cases

The physical signs include:left parasternal lift, loud pulmonary component of the second heart sound (P2), pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency, and right ventricular S3. Jugular vein distention, hepatomegaly, peripheral edema, ascites, central cyanosis and cool extremities may be seen

The lung examination is usually normal.

Investigations: Electrocardiography

RAA, RAD, RVH,

ST depression and T-wave inversions in anterior leads

However, a normal ECG does not exclude diagnosis

Chest radiography

cardiomegaly or prominent central pulmonary arteries

chest CT scanning Exclude interstitial lung disease and thromboembolic

disease.

main pulmonary artery diameter (MPAD) is > 29 mm and/or the ratio of the main pulmonary artery to ascending aorta diameter is >1

The most specific CT findings for the presence of PH were both a MPAD > 29 mm and segmental artery-to-bronchus ratio of >1:1 in three or four lobes

Rapid tapering or “pruning” of the distal pulmonary vessels.

Echocardiography

Extremely useful for:

assessing right and left ventricular function

estimating pulmonary systolic arterial pressure, and evaluating for congenital anomalies and valvulardisease

Systolic pulmonary artery pressure is estimated using tricuspid insufficiency jet velocity based on the simplified Bernoulli's equation

Right heart catheterization

FOR

right atrial pressure

mean PAP

pulmonary artery occlusion pressure (PAOP)

cardiac output (CO)

pulmonary vascular resistance (mPAP-PAOP)/CO

Transpulmonary gradient (mPAP-PAOP)

Evaluates pulmonary vasoreactivity

Treatment There is no cure for pulmonary hypertension.

The goals of treatment are:

to treat the underlying cause

to reduce symptoms

improve quality of life

to slow the growth of the smooth muscle cells and the development of blood clots

to increase the supply of blood and oxygen to the heart, while reducing its workload

General measures

Oral anticoagulation improves survival

Supplemental oxygen should be used to maintain oxygen saturation greater than 90%,especially because hypoxemia is a major cause of pulmonary vasoconstriction.

Diuretics are indicated for right ventricular volume overload

Digoxin is reserved for patients with refractory right ventricular failure and for rate control in atrial flutter or fibrillation.

Pulmonary vascular reactivity testing and vasodilator therapy Only patients with an acute vasodilator response to an

intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, epoprostenol, nitric oxide) derive any long-term benefit from CCBs.

Such patients constitute less than 15% of patients with IPAH and probably less than 3% of patients with other associated forms of PAH

Patients who do not have an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy

Calcium Channel Blocker therapy (CCB)

These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure.

The use of CCBs should be limited to patients without overt evidence of right-sided heart failure as they may worsen right ventricular failure

Specific vasodilator therapy

These drugs in general work by dilating the pulmonary arteries and, therefore, by reducing the pressure in these blood vessels and some help prevent the excessive overgrowth of tissue in the blood vessels (that decrease remodeling of the vessels).

Prostacyclins

dilates systemic and pulmonary arterial vascular beds.

Short acting drugs

include epoprostenol (Flolan), treprostinil (Remodulin), iloprost (Ventavis), Treprostinil (Tyvaso).

Phosphodiesterase type 5 Inhibitors (PDE5i)

Sildenafil (Viagra)

is an orally active pulmonary vasodilators.

promote selective smooth muscle relaxation in lung vasculature by inhibiting PDE5 thereby stabilizing cyclic guanosine monophosphate (cGMP, the second messenger of nitric oxide), allowing a more sustained effect of endogenous nitric oxide,

an indirect but effective and practical way of using the NO-cGMP pathway.

Endothelin Receptor Antagonists (ERAs)

Bosentan

Sitaxentan, a selective endothelin (ET)-A receptor antagonist, has negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation.

In clinical trials, the efficacy of sitaxentan has been much the same as bosentan with reduced hepatotoxicity.Dosing is once daily

Ambrisentan :

A-selective endothelin receptor antagonist

once-daily dosing.

improvements in 6-minute walk distance in patients

low risk of aminotransferase abnormalities.

The most frequent side effect of ambrisentan isfluid retention

ACCP guidelines recommend using the patient’s New York Heart Association (NYHA) functional class to guide the choice of vasodilator therapy

• Functional class II – Sildenafil

• Functional class III - Endothelin-receptor antagonists (bosentan), sildenafil, IV epoprostenol, or inhaled iloprost

• Functional class IV - Intravenous epoprostenol.

Surgery Atrial septostomy:

palliative procedure

in the setting of severe disease with recurrent syncope or right heart failure (or both) despite maximal medical therapy.

The procedure can also be used as a bridge to lung transplantation.

Lung transplantation

Pulmonary Hypertension in Chronic Lung Diseases and/or Hypoxia Pulmonary hypertension is a common complication in

lung disease.

In the most recent revised classification of pulmonary hypertension (PH), chronic lung diseases or conditions with alveolar hypoxia are included in WHO Group III of PH-related diseases

As both the primary respiratory condition and PH may be associated with dyspnoea, the latter often goes unrecognised

Pulmonary hypertension due to lung diseases and/or hypoxia Chronic obstructive pulmonary disease

Interstitial lung disease

Other pulmonary diseases with mixed restrictive and obstructive pattern

Sleep-disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Developmental abnormalities

Pathophysiology Alveolar hypoxia is a potent stimulus for pulmonary

vasoconstriction.

It operates at the endothelial level and is one of the most important pathways leading to PH development in chronic lung diseases.

Alveolar hypoventilation precipitates acute pulmonary vasoconstriction in some regions of the lungs, and vasodilation in others, causing physiological shunt.

Studies of the vasculature in hypoxic PH have demonstrated changes including intimal thickening, medial hypertrophy and muscularization of the small arterioles

chronic hypoxia triggers endothelial cell proliferation

Inflammatory cells have been detected in local vascular

structures in COPD patients, in addition to the evidence of systemic inflammation with raised inflammatory markers, such as CRP and TNF–α

The impact of PH on mortality in COPD is independent of age, lung function and blood gas derangements

In patients with parenchymal lung disease PH is generally modest (mean PAP 25-35 mmHg).

it increases significantly during exercise, sleep and acute infective exacerbations

Treatment of PH in COPD No clear guidelines and no medications currently

registered for the treatment of PH secondary to COPD.

The primary focus of treatment, therefore involves

standard therapy with smoking cessation, bronchodilators, inhaled steroids, long-term oxygen therapy (LTOT) and pulmonary rehabilitation

Long-term home oxygen therapy((LTOT

The only therapy that has demonstrated a survival advantage in people with COPD and coexistentPH is LTOT.

Indications for LTOT include patients with severe hypoxemia or those with moderate hypoxemia and corpulmonale

physically reliant on a machine, expensive

Prostanoids/ Endothelin receptor antagonists (ERA)/ Phosphodiesterase-5 (PDE-5) inhibitors

current practice does not favour routine use of these medications.

The primary concern in using pulmonary vasodilators is related to worsening gas exchange due to ventilation/ perfusion (V/Q) inequality

Calcium channel blockers Their use is largely limited to patients who

demonstrate acute vasoreactivity testing

Use the dihydropyridine group

An important practice point is that alternative causes of PH in patients with COPD, such as concomitant sleep disordered breathing or chronic thromboembolic disease should be actively investigated, as there are important treatment alternatives in these patients.

Sleep disordered breathing and PH True prevalence of PH in OSA is unknown and ranges

from 17 - 52%

Three main mechanisms have been proposed including hypoxia, mechanical factors and reflex mechanisms

with CPAP : decrease in the mean PAP observed

and associated with improved pulmonary endothelial function due to the elimination of intermittent hypoxemia

PH in interstitial lung diseases The prevalence of PH in IPF is high and varies between 32 -

85%. PH is mostly of moderate severity Adenosine has been associated with progression of

fibrotic lung disease and PH through the adenosine receptor

The prevalence of PH in systemic sclerosis is as high as 45%

The development of PH in ILD is associated with high mortality

However, most guidelines do not recommend use of PAH-specific treatments in patients with ILD

High altitude PH prevalence is between 5 and 18% in those living at ≥3000 metres

Migration to a lower altitude reverses HAPH. However, as an alternative, sildenafil maybe used