a. Pulmonary hypertension occurs when the mean pulmonary artery pressure is >25 mm Hg at rest. A feature of many diseases, the presence of pulmonary hypertension portends a poor prognosis, especially if it is severe. While signs, symptoms, and tests such as an echocardiogram can provide strong evidence for pulmonary hypertension, the best test to differentiate among different causes of pulmonary hypertension is pulmonary arterial catheterization.
b. Untreated pulmonary hypertension carries a high mortality. It is important to identify and treat the underlying condition leading to pulmonary hypertension in addition to treating the pressure itself.
B. Causes of Pulmonary Hypertension. Pulmonary hypertension is classified into five groups based on pathobiologic features, natural history, and response to treatment.
a. Group 1: Pulmonary arterial hypertension (PAH) is characterized by remodeling of all three layers of the vessel wall: adventitia, media, and intima. This is caused by an imbalance between pulmonary vasoconstrictors and vasodilators, abnormal endothelial cell and smooth muscle proliferation, and in situ thrombosis. The plexiform lesion, a diagnostic feature of PAH, is characterized by proangiogenic factors causing proliferation of endothelial cells and disordered multichannel, obstructive vessel beds. PAH is categorized as shown below. A handy mnemonic is an angry patient saying, “I Hate Drug CHIPS!” (Table 22.1).
Table 22.1 Causes of Pulmonary Arterial Hypertension: “I Hate Drug CHIPS”
BMPR2, ALK1 gene mutations
Cocaine, amphetamine, anorexigenic drugs
Connective tissue disease
Scleroderma, systemic lupus erythematosus, mixed connective tissue disease
Heart disease, congenital
Patent ductus arteriosus, atrial septal defect, ventricular septal defect
Infection with HIV
Screen for this, in any cause of cirrhosis
Prevalent in developing countries
i. Idiopathic and familial PAH. Most often seen in women, this represents a subgroup with a historical survival rate of about 50% at 5 years from diagnosis. This population has benefited tremendously from new pharmacologic therapies, with improved survival and quality of life.
ii. Drug toxicity. Includes drugs such as cocaine and methamphetamine.
iii. Diseases associated with PAH. Connective tissue disorders (scleroderma, lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, polymyositis, Sjögren’s syndrome), congenital heart disease (atrial or ventricular septal defect, patent ductus arteriosus), portopulmonary hypertension, human immunodeficiency virus (HIV) infection, and schistosomiasis. Outcomes are variable depending on severity of PAH, comorbidities, and ability to treat the underlying cause. These groups of patients may benefit from pharmacologic therapy for PAH in addition to treatment of underlying disease.
b. Group 2: Postcapillary pulmonary hypertension is caused by left heart disease, including left-sided heart failure and/or valvular disease.
c. Group 3: Respiratory diseases and/or chronic hypoxemia are most commonly obstructive and restrictive lung diseases, such as chronic obstructive pulmonary disease (COPD) and interstitial lung disease, respectively. Untreated obstructive sleep apnea and obesity hypoventilation syndrome can cause severe pulmonary hypertension but are most commonly associated with mild to moderate disease. Other hypoxemic states (e.g., high altitude) may cause pulmonary hypertension.
d. Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by chronic pulmonary emboli and/or in situ thrombosis. CTEPH should be distinguished from acute pulmonary embolism. CTEPH occurs when acute pulmonary embolism is untreated or in patients who do not respond to anticoagulation therapy.
e. Group 5: Unclear or multiple mechanisms. This group of disorders can lead to pulmonary hypertension through multiple mechanisms and includes:
i. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, and splenectomy.
ii. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis.
iii. Metabolic disorders: glycogen storage disease, Gaucher’s disease, and thyroid disease.
iv. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, and segmental pulmonary hypertension.
C. Clinical Manifestations of Pulmonary Hypertension
a. Symptoms include:
i. Progressive dyspnea
ii. Chest pain (can be a result of right ventricular ischemia)
iv. Peripheral edema (from right ventricular failure)
v. Presyncope and/or syncope
b. Signs. Pulmonary hypertension can present with physical examination findings that reflect right ventricular failure:
i. Increased jugular venous pressure
ii. A right-sided third or fourth heart sound (S3 or S4)
iii. A right ventricular lift
iv. Pulmonic component of the second heart sound (P2) is prominent, louder than the aortic component of the second heart sound (A2)
v. Murmurs of tricuspid and pulmonary regurgitation
vi. Presence of hepatojugular reflux
vii. Right upper quadrant fullness, abdominal distention, and peripheral edema
D. Approach to the Patient. Because so many diseases cause pulmonary hypertension, it is important to elicit an accurate history and physical examination. In particular, for group 1 disease, ask about and look for rheumatologic signs and symptoms (e.g., Raynaud’s phenomenon in scleroderma, malar rash in lupus), symptoms of liver disease, or risk for HIV infection.
a. Preliminary evaluation
i. Physical examination findings
1. Carefully compare the components of the second heart sound at the upper sternal border. A P2 (pulmonic component) that is louder than the A2 (aortic component) suggests pulmonary artery hypertension (PAH).
2. A left-sided S3 or S4 may indicate left ventricular dysfunction. Also, listen for diastolic murmurs indicating mitral stenosis, a variable S1, and intermittent “plop” that may indicate a left atrial myxoma.
3. Elevated jugular venous pressure (JVP), prominent V waves, hepatojugular reflux, and lower extremity edema suggest right-sided heart failure.
4. Look for systemic manifestations of connective tissue diseases and liver disease. Heart and lung examination will give you clues that point toward group 2 or 3 diseases, respectively.
ii. Laboratory findings. Chronic hypoxemia may be present. Elevated brain natriuretic peptide (BNP) is suggestive of right heart failure.
iii. Radiographic findings
1. Pulmonary hypertension will result in enlarged central pulmonary arteries visible on the chest radiograph. Right ventricular and atrial enlargement may also be seen in severe, chronic cases.
2. Evidence of the underlying cause (group 2 or 3) may also be visible radiographically. For example:
a. In emphysema, apical blebs, “pruning” of distal vessels, or hyperinflation indicated by flat diaphragms is seen.
b. In left ventricular dysfunction, left ventricular or atrial enlargement or evidence of pulmonary edema occurs.
iv. Electrocardiogram (EKG) findings. The EKG typically shows right axis deviation. Right ventricular hypertrophy and right atrial enlargement are also common findings (see Chapter 5).
b. Confirmation. Several invasive and noninvasive diagnostic tests can be used to confirm the nature and severity of pulmonary hypertension. A systematic approach is necessary.
1. Doppler echocardiography. Measurement of pulmonary pressures can support or dispute the initial clinical diagnosis. Doppler is used to measure the velocity of the tricuspid valve regurgitant jet. A small amount of tricuspid regurgitation may be present in healthy patients.
a. Right ventricular hypertrophy or enlargement, paradoxical motion of the interventricular septum or D-shaped septum on the short axis view on echo, and right atrial enlargement indicate right ventricular pressure and volume overload due to pulmonary hypertension.
b. The presence of left ventricular dysfunction, mitral stenosis, or left atrial myxoma confirms a diagnosis of left heart disease and left-sided (i.e., postcapillary) group 2 pulmonary hypertension. No additional workup is necessary, and appropriate treatment can be instituted.
2. Bubble study. A bubble study allows detection of a right-to-left intracardiac shunt and provides evidence of congenital heart disease (atrial and ventricular septal defects).
ii. Laboratory tests. Some tests can help support associated causes of group 1 PAH. For example, consider serologic testing for connective tissue diseases (e.g., antinuclear antibody [ANA], Scl-70, anticentromere, rheumatoid factor [RF]), HIV testing if high-risk features are present, and liver function tests if liver disease is suspected.
iii. Pulmonary function tests (PFTs)
1. Obstructive ventilatory defect. This provides evidence of COPD as a cause of group 3 pulmonary hypertension.
2. Restrictive ventilatory defect. This can signify the presence of interstitial lung disease a cause of group 3 pulmonary hypertension.
3. Impaired gas exchange (low Dlco) is nonspecific and can suggest heart or lung disease. An isolated low Dlco in the presence of normal PFTs should raise suspicion for pulmonary hypertension as a possible cause.
iv. Sleep studies are indicated in patients with risk factors for sleep apnea or obesity hypoventilation (i.e., hypercarbia, obesity, and a history of snoring). Sleep studies correlate poorly with degree of pulmonary hypertension.
v. Ventilation-perfusion (V/Q) lung scanning can detect perfusion defects in the large and small pulmonary arteries and is the preferred test to evaluate for pulmonary hypertension due to CTEPH (Group 4). Computed tomographic angiography may be used to rule out proximal occlusion but may miss emboli or thrombosis in the smaller blood vessels.
vi. Right heart catheterization becomes necessary if group 1 PAH is suspected and studies do not reveal a diagnosis. This invasive study can confirm the diagnosis, assess severity, and test for a vasodilator response to determine benefit of pharmacologic treatment.
a. General therapeutic principles
i. Avoid further exacerbation of vasoconstrictor/vasodilator imbalance.
1. Ensure oxygen saturation ≥90% (hypoxemia causes pulmonary arteriolar vasoconstriction).
ii. Avoid right ventricular failure: avoid increased wall stress (volume overload, increased pulmonary arterial pressures) and/or drop in diastolic blood pressure (causes right ventricular ischemia and leads to failure especially if wall stress is increased). Diuretics reduce wall stress and relieve symptoms of congestion. Remember to avoid overdiuresis because the right ventricle is dependent on preload.
iii. Prevent in situ thrombosis: long-term anticoagulation is required in CTEPH and, with weaker evidence, in patients with group 1 PAH.
b. Pharmacologic therapy. Referral to an expert in the treatment of pulmonary hypertension is necessary because decisions regarding which therapy to initiate are complex and require close outpatient monitoring, titration, and clinical support. During cardiac catheterization, a vasoreactivity test should be performed to determine vasodilator responsiveness. Inhaled nitric oxide is the most common vasodilator used. A positive response is defined by a pulmonary arterial pressure decrease of >10 mm Hg and a mean pulmonary artery pressure of <40 mm Hg with stable or increased cardiac output. About 10% of patients with PAH have a positive vasoreactivity test. These patients are eligible for calcium channel blocker treatment (diltiazem or nifedipine) and have an excellent overall prognosis. Approximately 50% (about 5% of all patients with PAH) will have a continued long-term positive response to calcium channel blockers. Oral, inhaled, and intravenous pulmonary vasodilator regimens can be initiated in patients with a negative vasoreactivity test. Vasodilator selection is dependent upon severity of disease on presentation and patient tolerance to the particular regimen that is chosen.
c. Patients with groups 2 through 5 pulmonary hypertension require treatment of the underlying disorder. Vasodilator therapy in patients with heart or lung disease has not yielded positive results in studies. Riociguat has been shown to improve function in patients with CTEPH. The following three causes of pulmonary hypertension are encountered frequently:
i. Systolic/diastolic heart failure: treat underlying causes, often with combinations of antihypertensives, diuretics, and fluid/salt restriction (see Chapter 12).
ii. COPD: treat with smoking cessation, bronchodilators, and oxygen therapy.
iii. Sleep apnea: treat with weight reduction, avoidance of alcohol and sedatives, and nocturnal oxygen with or without continuous positive airway pressure (CPAP).
Suggested Further Readings
Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37:67–119.Find this resource:
Ghofrani H-A, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–29.Find this resource:
McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol 2015;65:1976–97.Find this resource: