A Insight Into Recent Advances in Targeted Therapy for Pulmonary Veno-Occlusive Disease

Introduction:

The heart and lungs are the two most important organs of the human body. The heart acts as a pump and circulates blood in the body. Lungs receive deoxygenated blood from the heart and supply oxygenated blood to the heart. Pulmonary circulation is a bridge between them. In certain pathological conditions, the pressure of the pulmonary circulation is increased. As a result, the normal functioning of the heart is affected. Venous occlusion is one of the key causes of pulmonary hypertension.

What Is Pulmonary Hypertension?

The role of pulmonary circulation is to carry out deoxygenated blood from the right ventricle to the lungs and take back the oxygenated blood to the left atrium. Any blockage in this circulatory system disrupts the blood flow and increases the blood pressure inside the lumen. Such conditions cause pulmonary hypertension. The condition is known as pulmonary hypertension when the mean pulmonary arterial pressure is more than 25 millimeters of mercury. Patients suffering from pulmonary hypertension usually complain of:

1. Heaviness on the chest.

2. Chest pain.

3. Fatigue and frequent fainting.

4. Swelling of the body, specifically the legs, ankles, and tummy.

5. Irregular or racing heartbeat.

6. Bluish discoloration of the skin.

What Are the Causes of Pulmonary Hypertension?

The cause of pulmonary hypertension can vary on the basis of various factors. According to World Health Organization, the causes of pulmonary hypertension can be categorized into five groups:

1. Pulmonary Arterial Hypertension: The main cause of pulmonary hypertension is dimensional changes in the pulmonary artery. In this condition, the pulmonary artery becomes narrow and thickened. As a result, the required force for the heart to pump the blood becomes high. Several conditions, like familial history and mutation of the BMPR2 gene, are responsible for such factors. Durg toxicity or connective tissue disorders can be responsible for such conditions. Conditions like portal vein disorders, congenital heart diseases, and HIV (human immunodeficiency virus) infections are also responsible for such conditions.

2. Pulmonary Hypertension Due to Left Heart Disease: The blood from the pulmonary circulation reaches the left atrium, and from there, it reaches the left ventricle. The left ventricle pumps the blood throughout the body. Any morphological deformity of the left ventricle or left atrium leads to improper filling of the heart. This causes backflow of the blood and increases the blood pressure inside the pulmonary lumen. Congenital stenosis (narrowing of blood vessels) of the pulmonary vein and defects of the valves are responsible for such problems.

3. Pulmonary Hypertension Due to Lung Disease: In this type of disorder, chronic lung diseases are responsible for pulmonary hypertension. One of the main effects of chronic lung disease is a lack of oxygen supply. This leads to chemoreceptors' activation, which causes dilation of the peripheral blood vessels. But pulmonary blood vessels are constricted. This pulmonary vasoconstriction helps to maintain ventilation and perfusion in the alveoli. This causes an increase in pulmonary artery pressure. This is associated with diseases like chronic obstructive pulmonary disorders, interstitial lung diseases, and developmental lung diseases.

4. Pulmonary Hypertension Due to Chronic Blood Clots in the Lungs: Formation of the chronic blood clots or disorders of the blood vessels causes stenosis, which is responsible for such conditions. Intravascular tumors are also related to these conditions.

5. Pulmonary Hypertension Due to Unknown Causes: This type of pulmonary hypertension is caused by blood disorders like hemolytic anemia or metabolic disorders like glycogen storage disease. Systemic disorders like sarcoidosis (collection of granulation tissues and inflammatory cells in various organs) and pulmonary histiocytosis (a type of diffuse lung disorder) are also linked to pulmonary hypertension.

The blockage of the pulmonary circulation characterizes pulmonary veno-occlusive disorders. In veno-occlusive pulmonary hypertension, pulmonary venous components are mainly involved. The first description of pulmonary veno-occlusive disorders was given by German physician J. Hora around eighty years back. In 1966, Heath et al. coined the term pulmonary veno-occlusive disease and described it as a distinct entity.

What Is Pulmonary Veno-Occlusive Disorder?

The pulmonary veno-occlusive disorder is a pathological condition belonging to pulmonary arterial hypertension. The exact cause of the involvement of the venous component has not been identified. The potential risk factors for these conditions are:

1. Mutation of the EIF2AK4 gene is one of the most common causes of this type of pathology.

2. Environmental or occupational exposure to various substances, like trichloroethylene, is linked to veno-occlusive diseases.

3. Tobacco exposure is considered a risk factor for veno-occlusive diseases.

4. Different auto-immune or inflammatory conditions increase the risk of such conditions. Conditions like sarcoidosis, Langerhans cell granulomatosis (an uncommon condition characterized by the presence of abnormal cells), and Hashimoto’s thyroiditis (a type of chronic auto-immune thyroid disorder) are regarded as potential risk factors.

5. Different drugs like chemotherapeutic agents for cancer therapy and alkylating agents are responsible for such conditions.

All these factors are responsible for the over-expression of various factors like platelet-derived growth factor. Such factors are responsible for the proliferation of cells inside the lumen. Also, lesions in the blood vessels reduced nitric oxide synthesis, and the functioning of the T-lymphocytes are associated factors in the development of veno-occlusive disorders. The occurrence of “colander-like” lesions and hemorrhage leads to obstruction of pulmonary veins. This causes the accumulation of fluid around the lumen and raises the pressure. Besides this, the reduced diameter of the lumen increases the pulmonary pressure.

What Are the Targeted Therapy for Pulmonary Veno-Occlusive Disorders?

In traditional therapy for pulmonary hypertension, the oxygenation of the patient can be improved by oxygen therapy. Diuretics can be used to remove accumulated fluid from the body. Anticoagulants can be prescribed to reduce the chance of blood clot formation. ACE (Angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers can be used to improve the functionality of the heart. Calcium channel blockers can also be used, which act on the arterial smooth muscles and reduce pulmonary pressure.

But, all these therapies are not specific to the factors associated with pulmonary veno-occlusive disorders. As a result, the outcome of the treatment provided by such agents is limited. That is why the following drugs are used to target specific factors associated with veno-occlusive disorders:

1. Therapies Targeting Nitric Oxide (NO) Pathway: As discussed, the amount of nitric oxide produced in pulmonary hypertension is less, which is associated with the constriction of the blood vessels. Increased nitric oxide production is associated with dilatation of the blood vessels and reduced pulmonary blood pressure. Sildenafil can be used for 20 milligrams thrice daily to improve pulmonary circulation's hemodynamics. Similarly, Tadalafil 40 milligrams given once daily can improve nitric oxide production.

2. Endothelin Receptor Antagonists: Endothelin 1 acts as a vasoconstrictor associated with the constriction of the pulmonary blood vessels. The action of this mediator is controlled by the action of endothelin A (ETA) and endothelin B (ETB) receptors. Drugs like Bosentan, Ambrisentan, and Macitentan act on these receptors and prevent the action of Endothelin 1. This causes dilation of the blood vessels.

3. Prostacyclin Analogues: Endothelium-derived prostaglandin I₂ is a potential vasodilator. Also, it has antithrombotic, antiproliferative, and immunomodulatory activity. In pulmonary hypertension, prostacyclin synthase and prostacyclin metabolites are markedly reduced. The prostanoids belong to stable prostacyclin analogous that increase the level of prostaglandin in the pulmonary blood vessels. Epoprostenol, Treprostinil, and Beraprost are examples of drugs that belong to this group.

4. Prostacyclin (IP) Receptor Agonist: One of the drawbacks of prostacyclin analogs is the activation of other prostaglandin receptors. Prostacyclin receptor agonist selectively activates prostaglandin receptors. Selexipag, a drug belonging to this group, helps to delay the disease progression.

5. Soluble Guanylate Cyclase Stimulators: Nitric oxide produced by the blood vessels acts on the second messenger, cyclic guanosine monophosphate (cGMP), and causes dilation of blood vessels. Soluble guanylate cyclase stimulators act on the cyclic guanosine monophosphate (cGMP) receptors and increase its production without the presence of nitric oxide. The therapeutic effect of these drugs is better than phosphodiesterase type 5 (PDE5) inhibitors.

Conclusions:

Pulmonary hypertension is a serious complication. If not treated, this may lead to right-sided heart disease and, ultimately, heart failure. Venous constrictions are one of the main reasons for pulmonary hypertension. The goal of the targeted treatment is to improve the venous circulation. Dilatation of the venous and production of various chemical mediators are the role of targeted therapy in veno-occlusive pulmonary disorders.