Pulmonary hypertension, also known as idiopathic pulmonary artery hypertension (IPAH), is a progressive disease that affects the precapillary pulmonary vasculature. The exact underlying risk factors for IPAH are still unknown. The pulmonary artery pressure is persistently more than 25 mm Hg at rest and more than 30 mm Hg during exercise. IPAH is a rare but fatal disease with a high mortality rate. If left untreated, it may result in increasing back pressures and ultimately right heart failure and death.
Primary pulmonary hypertension is classified in the World Health Organizations's (WHO) classification system as part of group 1. The WHO classification of pulmonary hypertension is based on the mechanism or underlying 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 be one cause for the condition. Environmental factors also play a role. Acute hypoxia can cause vasodilation of the systemic arteries and vasoconstriction of pulmonary arteries.
IPAH is a rare disease with a very low incidence of about 4 to 6 cases per million people worldwide and four cases per 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. 
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.
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.
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) lead to endothelium dysfunction that leads to an altered synthesis of endothelium-derived vasoactive substances that affects 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 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 it 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.
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.
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 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 right-sided fourth heart sound and tricuspid regurgitation murmur.
Physicians can suspect PAH based on the 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.
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. LFT, Autoimmune tests and HIV testing (in high-risk patients) to 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 mm Hg at rest and greater than 30 mm Hg 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 mm Hg 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.
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 effectivity can be measured by “6-minute walk test."
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 fall in pulmonary artery pressure to more than 10 mm Hg with an increase or no change in cardiac output. Although first line but useful only in 5% 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:
For class III, class IV and those unresponsive to previous therapies:
Prostanoid agents (epoprostenol, treprostinil, iloprost): Continuous long-term intravenous epoprostenol infusion for which semi-permanent central venous catheter is required is considered the most effective therapy. It has 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 an intravenous, subcutaneous and inhalation. Oral prostanoids are still under clinical trials. Benefits include vasodilation, platelet inhibition, antiproliferative, and inotropic effects.
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 shown to improve exercise capacity and decrease in pulmonary vascular resistance in the studies done so far.
Selexipag, a newer drug, is a selective IP prostacyclin receptor agonist.
Monotherapy does relieve symptoms in PAH patients but has not 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 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 is considered.
The differential diagnosis is broad since the symptoms are non-specific.
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 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.
IPAH is a fatal disease with or without treatment. Medications to prolong survival but only for a few years. However, medications do improve the quality of life. A dietitian should educate the patient on the importance of low salt and low fluid diet since they often develop volume overload from right heart failure. Patients on anticoagulants like warfarin should avoid green leafy vegetables which can counter the effects of warfarin. A physical therapy consult should be sought as some patients may benefit from cardiac rehabilitation. It is important that these patients do not lead a sedentary lifestyle. Finally, the patient should be seen by a transplant nurse in case the patient becomes a candidate for a heart-lung transplant. Finally, the pharmacist should encourage compliance with the prescribed medications as they can improve the quality of life. (Level V)
Despite 4 decades of intense research, there is no cure for IPAH. The development of phosphodiesterase-5-inhibitors and prostacyclin analogs has led to an improvement in symptoms, but life expectancy still remains guarded. Untreated patients have a very poor survival but with medical treatment, some can survive into the 5th decade of life. Patients who fail to respond to medications usually have the worst prognosis. Patients with persistently elevated pulmonary pressures and right heart failure usually are dead within 5 years. (Level V)
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