Idiopathic Pulmonary Artery Hypertension

Etiology

Although the cause of idiopathic pulmonary hypertension is unknown, some cases are known to be familial secondary to a gene defect with autosomal dominant inheritance. A mutation in the gene that makes these blood vessels more susceptible to vasoconstrictors may cause the condition. Environmental factors also play a role. Acute hypoxia can cause vasodilation of the systemic arteries and vasoconstriction of pulmonary arteries.[4]

Epidemiology

IPAH is a rare disease with a very low incidence of about 4 to 6 cases per million people worldwide and four million people in the United States. There are nearly 140 deaths per year in the United States from IPAH.  The condition is more common in females, with most cases present in the fourth decade of life.[5]

Pathophysiology

IPAH results in narrowing of the blood vessels going to or within the lungs, restricting the pulmonary circulation and making it difficult for the heart to pump blood. Pulmonary artery resistance is increased due to vasoconstriction, vascular remodeling, and thrombosis. As the disease progresses, the constant increase in pressure and remodeling of pulmonary vasculature promotes further pulmonary hypertension. To maintain cardiac output, the right ventricular systolic pressure is elevated to overcome the increased pulmonary vascular resistance.[6]

The compensation of the heart to balance the effects of IPAH can be explained with Ohm’s law. There is a relationship between the resistance (R), pressure (V), and flow through a vessel (I), in this case, pulmonary vasculature.

• Ohm’s law: V = RI or I = V/R

According to Ohm's law, the pressure increases, and the flow decreases when there is increased resistance. Decrease flow results in the backup of blood into the right ventricle and less blood flowing forward through the pulmonary vasculature. Progression of the condition can lead to right heart failure and decreased cardiac output.

Genetic susceptibility (BMRP2 mutation and other genetic factors) leads to endothelium dysfunction, leading to an altered synthesis of endothelium-derived vasoactive substances that affect many intracellular pathways. The major intracellular pathways involved are nitric oxide, endothelin, and prostacyclin pathway, which leads to the changes in the vasculature in PAH. The decrease in the production of vasodilators and overexpression of vasoconstrictors leads to vasoconstriction due to an imbalance between vasodilators and vasoconstrictors.

There is an imbalance between prostacyclin (vasodilator and inhibit platelet activation) and thromboxane A2 (vasoconstrictor and platelet agonist). Prostacyclin synthase production and nitric oxide decrease in idiopathic pulmonary artery hypertension. The overexpression of endothelin-1 not only causes vasoconstriction but also promotes the proliferation of smooth muscle cells of the pulmonary artery and vascular remodeling. Serotonin levels are increased in plasma, which promotes vasoconstriction and endothelial cell proliferation. Serotonin transporter mutation in lung tissues and platelets also plays a role in pathogenesis. Decreased levels of vasoactive intestinal peptide, which is a vasodilator and inhibits platelets. All these alterations in vasoactive substances lead to vasoconstriction, vascular remodeling, and thrombosis, which causes an increase in pulmonary vascular resistance.

Histopathology

Pulmonary arterial hypertension, irrespective of the cause, has the same histopathology. Vasculopathy with features of hypertrophy of the media, intimal hyperplasia and fibrosis, recanalized thrombi, plexiform, and thrombotic lesions are seen.

History and Physical

Exertional dyspnea is the most common symptom. Nonspecific presentation leads to a delay in diagnosis. As the disease advances, other symptoms such as fatigue, near syncope, syncope, palpitations, chest pain or angina (due to right ventricle ischemia), and peripheral edema occur. More severe symptoms are due to a failing right heart.

The physical exam includes findings related to back pressure due to pulmonary vasculature resistance. There is jugular venous distention, increased second heart sound due to the pulmonic component. There may be a right-sided fourth heart sound and tricuspid regurgitation murmur.

Evaluation

Physicians can suspect PAH based on clinical grounds. However, it is difficult to diagnose primary pulmonary hypertension based on history and exam alone because of the nonspecific presentation, and the signs and symptoms overlap with many heart and lung diseases. It is, therefore, important to exclude other possible causes of pulmonary hypertension.[7][8][9]

Chest x-ray shows large central pulmonary arteries, right ventricular hypertrophy, clear lung fields. On ECG, there may be right ventricular hypertrophy with right atrial enlargement, right axis deviation, increased the amplitude of P wave due to right atrial enlargement (lead II). Echocardiography is the most sensitive test which helps assess the right ventricular size and pressure-volume overload. It also gives an estimate of pulmonary artery pressure. There is right atrial and ventricular enlargement, tricuspid regurgitation.

Arterial blood gas may reveal increased A-a gradient, low pO2. On pulmonary function test (PFT), impaired DLCO is seen. Perfusion lung scan (V/Q scan) to rule out pulmonary thromboembolism. Liver function tests, autoimmune tests, and HIV testing (in high-risk patients) exclude other possible causes.

Cardiac catheterization of the right heart to measure accurate pressures (at end-expiration) is the gold standard test. It measures pulmonary artery pressure, left ventricular filling pressure, and cardiac output. IPAH patients have high mean pulmonary artery pressures (greater than 25 mmHg at rest and greater than 30 mmHg with exercise) with normal pulmonary capillary wedge pressure (18 and below). Pericardial effusion confers poor prognosis.

The patients with pulmonary artery hypertension on cardiac catheterization should undergo vasoreactivity testing with short-acting pulmonary vasodilatory medications at the same time as cardiac catheterization. A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output. This is important as the patients who respond to these drugs can be treated with calcium channel blockers and have a more favorable prognosis.

Treatment / Management

No definite drug can cure the disease. The management is based on NYHA Classification (i.e., patient symptoms and functional status) with the goal of positive impact on the quality of life by improving symptoms and functional status. Calcium channel blockers and the vasoactive substance are mainly used for IPAH. Many new agents have been introduced, and their effectiveness can be measured by a “6-minute walk test."[10][11][12](A1)

Oral, high-dose calcium channel blockers (diltiazem, nifedipine) are the first-line treatment but used only in those with vasoreactivity testing positive for acute vasodilator response with short-acting pulmonary vasodilators such as adenosine, nitric oxide, or epoprostenol. The criteria for testing positive is a fall in pulmonary artery pressure to more than 10 mmHg with an increase or no change in cardiac output. Although first-line useful only in 5% of patients with IPAH and should not be used in non-responders to vasoreactivity test due to the risk of harm rather than any improvement.

Vasoactive substances such as endothelin receptor antagonists, phosphodiesterase inhibitors, and prostanoids alter the mechanisms causing pulmonary artery smooth muscle proliferation and contraction.

For class II NYHA:

• Oral endothelin receptor antagonists (ambrisentan, bosentan, macitentan), macitentan, and modified bosentan have been shown to reduce morbidity and mortality in some studies.
• Phosphodiesterase type-5 inhibitors, PDE5 inhibitors (sildenafil, tadalafil) relax arterial smooth muscles and pulmonary artery vasodilation while inhibiting vascular remodeling.
• Non-parenteral prostanoids can be added.

For class III, class IV, and those unresponsive to previous therapies:

Prostanoid agents (epoprostenol, treprostinil, iloprost): Continuous long-term intravenous epoprostenol infusion for which a semi-permanent central venous catheter is required is considered the most effective therapy. It has been shown to improve mortality, but a short half-life and high cost are the limitations. For those who cannot tolerate intravenous infusion, inhaled or subcutaneous prostanoids can be considered. Treprostinil can be used by various routes such as intravenous, subcutaneous, and inhalation. Oral prostanoids are still under clinical trials. Benefits include vasodilation, platelet inhibition, antiproliferative, and inotropic effects.[13](B3)

Soluble guanylate cyclase stimulators (riociguat, cinaciguat) are under clinical trials and are beneficial in pulmonary artery hypertension as they have a dual mode of action. They stimulate the receptor to mimic nitric oxide action and increase the sensitivity of guanylyl cyclase to endogenous nitric oxide. Riociguat has been shown to improve exercise capacity and decrease pulmonary vascular resistance in the studies.

Selexipag, a newer drug, is a selective IP prostacyclin receptor agonist.

Monotherapy does relieve symptoms in patients with PAH but has not been shown to improve the prognosis and survival, and this has led to a shift to combination therapy which has shown improvement in survival (especially combination therapy including prostaglandins). Combination therapy is being used now with the goal of targeting different mechanisms involved in the pathogenesis of PAH simultaneously (prostacyclin, endothelin, and nitric oxide pathways). A combination is considered better than increasing the dose of a single drug used and has better outcomes. Although the most common combination used is ERAs and PDE5 inhibitors, which have also been shown to reduce hospitalization in a study, but with newer drugs available now, other combinations can also be used.

Some observational studies suggest an improvement in survival in primary pulmonary hypertension with long-term anticoagulation. Also, based on the symptoms and with progression to heart failure, certain other drugs like diuretics, digoxin, and oxygen can be added.

Idiopathic pulmonary hypertension patients should be admitted to specialized centers to initiate advanced therapies (e.g., intravenous prostacyclins). Sometimes they are admitted for aggressive diuresis if they present with severe symptoms, and there is evidence for decompensated heart failure with volume overload.

When medical therapy is no longer effective, surgical options such as atrial septostomy and lung or heart-lung transplantation are considered.[14]

Differential Diagnosis

The differential diagnosis is broad since the symptoms are non-specific.

• Chronic obstructive asthma
• Anemia
• Heart failure
• Chronic obstructive pulmonary disease (COPD)
• Cor pulmonale
• Dilated cardiomyopathy
• Mitral stenosis
• Connective tissue diseases
• Portal hypertension
• Obstructive sleep apnea

Prognosis

The prognosis of idiopathic pulmonary hypertension is poor. The mean survival of untreated IPAH is 2 to 3 years from the diagnosis. The NYHA functional class is an important predictor of survival, with class 4 mean survival of less than 6 months.

The most important prognostic factor is right ventricular function which is also the cause of death in advanced IPAH. Increased mortality is seen in pregnant patients with advanced IPAH.

Complications

• Right heart failure
• Pleural effusions
• Dyspnea at rest
• Ascites
• Death