Pulmonary Hypertension

Many conditions and drugs cause pulmonary hypertension. The most common overall causes of pulmonary hypertension are

• Left heart failure, including diastolic dysfunction

• Parenchymal lung disease with hypoxia

Several other causes of pulmonary hypertension include sleep apnea, connective tissue disorders, and recurrent pulmonary embolism.

Pulmonary hypertension is currently classified into 5 groups (see table Classification of Pulmonary Hypertension) based on a number of pathologic, physiologic, and clinical factors. In the first group (pulmonary arterial hypertension [PAH]), the primary disorder affects the small pulmonary arterioles.

A small number of cases of AH occur sporadically, unrelated to any identifiable disorder; these cases are termed idiopathic PAH.

Hereditary forms of PAH (autosomal dominant with incomplete penetrance) have been identified; mutations of the following genes have been found:

• Activin-like kinase type 1 receptor (ALK-1)

• Bone morphogenetic protein receptor type 2 (BMPR2)

• Caveolin 1 (CAV1)

• Endoglin (ENG)

• Growth differentiation factor 2 (GDF2)

• Potassium channel subfamily K member 3 (KCNK3)

• Mothers against decapentaplegic homologue 9 (SMAD9)

• T-box transcription factor 4 (TBX4)

Mutations in BMPR2 cause 75% of cases. The other mutations are much less common, occurring in about 1% of cases.

In about 20% of cases of hereditary PAH, the causative mutations are unidentified.

A mutation in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) has been linked to pulmonary veno-occlusive disease, a form of PAH Group 1' (1, 2).

Certain drugs and toxins3). Selective serotonin reuptake inhibitors taken by pregnant women are a risk for development of persistent pulmonary hypertension of the newborn4).

Patients with hereditary causes of hemolytic anemia, such as sickle cell disease, are at high risk of developing pulmonary hypertension (10% of cases based on right heart catheterization criteria). The mechanism is related to intravascular hemolysis and release of cell-free hemoglobin into the plasma, which scavenges nitric oxide, generates reactive oxygen species, and activates the hemostatic system. Other risk factors for pulmonary hypertension in sickle cell disease include iron overload, liver dysfunction, thrombotic disorders, and chronic kidney disease.

Pathophysiologic mechanisms that cause pulmonary hypertension include

• Increased pulmonary vascular resistance

• Increased pulmonary venous pressure

• Increased pulmonary venous flow due to congenital heart diseases

Increased pulmonary vascular resistanceBMPR2 gene account for most cases of hereditary PAH and also occurs in idiopathic PAH. Aberrant BMPR2 signaling disturbs the TGF-β/BMP balance, favoring a pro-proliferative and anti-apoptotic response in pulmonary artery smooth muscle and endothelial cells. BMPR2 signaling, therefore, has become an increasingly studied drug target for pulmonary hypertension.

Increased pulmonary venous pressure is typically caused by disorders that affect the left side of the heart and raise left chamber pressures, which ultimately lead to elevated pressure in the pulmonary veins. Elevated pulmonary venous pressures can cause acute damage to the alveolar-capillary wall and subsequent edema. Persistently high pressures may eventually lead to irreversible thickening of the walls of the alveolar-capillary membrane, decreasing lung diffusion capacity. The most common setting for pulmonary venous hypertension is in left heart failure with preserved ejection fraction (HFpEF), typically in older women who have hypertension and metabolic syndrome.

In pulmonary hypertension secondary to HFpEF, certain hemodynamic parameters predict an increased risk of death. These parameters include

• Transpulmonary gradient (TPG, defined as the mean pulmonary artery pressure to pulmonary artery occlusion pressure gradient) > 12 mm Hg

• Pulmonary vascular resistance (PVR, defined as the TPG divided by the cardiac output) ≥ 3 Woods units

• Diastolic pulmonary gradient (DPG, defined as the pulmonary artery diastolic pressure to pulmonary artery occlusion pressure gradient) ≥ 7 mm Hg

In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure. Right ventricular failure limits cardiac output during exertion.

Increased pulmonary venous blood flow due to congenital heart disease can cause pulmonary hypertension. This can occur in conditions such as atrial septal defects, ventricular septal defects, and patent ductus arteriosus, presumably through the development of characteristic pulmonary vascular lesions. However, the true effect of increased pulmonary blood flow is poorly defined and increased flow may lead to vascular obstruction only with concomitant pulmonary vascular resistance or a second stimulus.

Progressive exertional dyspnea and easy fatigability occur in almost all patients. Atypical chest discomfort and exertional light-headedness or presyncope may accompany dyspnea and indicate more severe disease. These symptoms are due primarily to insufficient cardiac output caused by right heart failure. Raynaud syndrome occurs in about 10% of patients with idiopathic pulmonary arterial hypertension; the majority are women. Hemoptysis is rare but may be fatal. Hoarseness due to recurrent laryngeal nerve compression by an enlarged pulmonary artery (ie, Ortner syndrome) also occurs rarely.

In advanced disease, signs of right heart failure may include right ventricular heave, widely split 2nd heart sound (S2), an accentuated pulmonic component (P2) of S2, a pulmonary ejection click, a right ventricular 3rd heart sound (S3), tricuspid regurgitation murmur, and jugular vein distention, possibly with v-waves. Liver congestion and peripheral edema are common late manifestations. Pulmonary auscultation is usually normal. Patients also may have manifestations of causative or associated disorders.

• Exertional dyspnea

• Initial confirmation: Chest x-ray, ECG, and echocardiography

• Identification of underlying disorder: Spirometry, ventilation/perfusion scanning or CT angiography, high-resolution CT (HRCT) of the chest, pulmonary function testing, polysomnography, HIV testing, complete blood count, liver tests, and autoantibody testing

• Confirmation of the diagnosis and gauging severity: Pulmonary artery (right heart) catheterization

• Additional studies to determine severity: 6-minute walk distance and plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) or BNP

Pulmonary hypertension is suspected in patients with significant exertional dyspnea who are otherwise relatively healthy and have no history or signs of other disorders known to cause pulmonary symptoms.

Patients initially undergo chest x-ray, spirometry, and ECG to identify more common causes of dyspnea, followed by transthoracic Doppler echocardiography to assess right ventricular function and pulmonary artery systolic pressures as well as to detect structural left heart disease that might be causing pulmonary hypertension. Complete blood count is obtained to document the presence or absence of erythrocytosis, anemia, and thrombocytopenia.

The most common x-ray finding in pulmonary hypertension is enlarged hilar vessels that rapidly prune into the periphery and a right ventricle that fills the anterior airspace on lateral view. Spirometry and lung volumes may be normal or show mild restriction, and diffusing capacity for carbon monoxide (DLCO) is usually reduced. Other ECG findings include right axis deviation, R > S in V1, S1Q3T3 (suggesting right ventricular hypertrophy), and peaked P waves (suggesting right atrial dilation) in lead II.

Additional tests are obtained as indicated to diagnose secondary causes that are not apparent clinically. These tests can include

• Ventilation/perfusion scanning or CT angiography to detect thromboembolic disease

• HRCT for detailed information about lung parenchymal disorders in patients in whom CT angiography is not done

• Pulmonary function tests to identify obstructive or restrictive lung disease

• Serum autoantibody tests (eg, antinuclear antibodies [ANA], rheumatoid factor [RF], Scl-70 [topoisomerase I], anti-Ro (anti-SSA), anti-ribonucleoprotein [anti-RNP], and anticentromere antibodies) to gather evidence for or against associated autoimmune disorders

Chronic thromboembolic pulmonary hypertension is suggested by CT angiography or ventilation/perfusion (VQ) scan findings and is confirmed by arteriography. CT angiography is useful to evaluate proximal clot and fibrotic encroachment of the vascular lumen. Other tests, such as HIV testing, liver tests, and polysomnography, are done in the appropriate clinical context.

When the initial evaluation suggests a diagnosis of pulmonary hypertension, pulmonary artery catheterization is necessary to measure the following:

• Right atrial pressure

• Right ventricular pressure

• Pulmonary artery pressure

• Pulmonary artery occlusion pressure

• Cardiac output

• Left ventricular diastolic pressure

Right-sided oxygen saturation should be measured to exclude left-to-right shunt through atrial septal defect. Although finding a mean pulmonary arterial pressure of > 20 mm Hg and a pulmonary artery occlusion pressure ≤ 15 mm Hg in the absence of an underlying disorder identifies pulmonary arterial hypertension (PAH), most patients with PAH present with substantially higher pressure (eg, mean of 60 mm Hg).

adenosine, are often given during catheterization. Decreasing right-sided pressures in response to these drugs may help in the choice of drugs for treatment. Lung biopsy, once widely done, is neither needed nor recommended because of its associated high morbidity and mortality.

Echocardiography findings of right heart systolic dysfunction (eg, tricuspid annular plane systolic excursion) and certain right heart catheterization results (eg, low cardiac output, very high mean pulmonary artery pressures, and high right atrial pressures) indicate that pulmonary hypertension is severe.

Other indicators of severity in pulmonary hypertension are assessed to evaluate prognosis and to help monitor responses to therapy. They include a low 6-minute walk distance and high plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) or brain natriuretic peptide (BNP).

Once pulmonary hypertension is diagnosed, the patient's family history should be reviewed to detect possible genetic transmission (eg, premature deaths in otherwise healthy members of the extended family). In familial PAH, genetic counseling is needed to advise mutation carriers of the risk of disease (about 20%) and to advocate serial screening with echocardiography. Testing for mutations in the BMPR2 gene in idiopathic PAH can help identify family members at risk. If patients are negative for BMPR2, gene testing for SMAD9, KCN3, and CAV1 can further help identify family members at risk.

Five-year survival for treated patients is about 50%. However, some patient registries suggest lower mortality (eg, 20 to 30% at 3 to 5 years in the French registry and 10 to 30% at 1 to 3 years in the REVEAL registry), presumably because currently available treatments are superior. Indicators of a poorer prognosis include

• Lack of response to vasodilators

• Hypoxemia

• Reduced overall physical functioning

• Low 6-minute walk distance

• High plasma levels of NT-pro-BNP or BNP

• Echocardiographic indicators of right heart systolic dysfunction (eg, a tricuspid annular plane systolic excursion of < 1.6 cm, dilated right ventricle, flattened interventricular septum with paradoxical septal motion, and pericardial effusion)

• Right heart catheterization showing low cardiac output, very high mean pulmonary artery pressures, and/or high right atrial pressures

Patients with systemic sclerosis, sickle cell disease, or HIV infection with pulmonary arterial hypertension (PAH) have a worse prognosis than those without PAH. For example, patients with sickle cell disease and PAH have a 40% 4-year mortality rate.

• Avoidance of activities that may exacerbate the condition (eg, cigarette smoking, high altitude, pregnancy, use of sympathomimetics)

• Secondary pulmonary arterial hypertension: Treatment of the underlying disorder

• Lung transplantation

• Adjunctive therapy: Supplemental oxygen, diuretics, and/or anticoagulants