Mrs. S, age 36, complains of progressive dyspnea on exertion that has been present for six months. Initially her dyspnea was mild, occurring only when walking up a flight of stairs.  Now it has progressed to the point that she is short of breath when carrying a gallon of milk from the car, and she reports increasing fatigue. On cardiac examination, you note a prominent pulmonic component to the second heart sound (P2) as well as a holosystolic murmur. There is mild lower-extremity edema as well. An echocardiogram reveals a normal left ventricle, but the septum is D-shaped and the right ventricle (RV) is enlarged. 

Exertional dyspnea, fatigue, and dizziness are commonly seen in the clinician’s office, but they are so nonspecific that the differential diagnoses can sometimes be elusive. Heart disease, asthma, obesity, and deconditioning, to name a few, often come up in the differential. This article will focus on pulmonary hypertension, or, more specifically, pulmonary arterial hypertension (PAH), and will review clinical findings associated with the disease as well as diagnostic testing necessary to confirm the diagnosis. A complete and thorough workup is needed to assure that correct therapy is initiated. If the clinician is not familiar with the disease and the medications used to treat it, referral should be made to a specialist in the field.   

Characteristics of PAH

PAH is a progressive disease characterized by alterations in the pulmonary vasculature. The pathophysiology involves intimal proliferation, medial hypertrophy, and development of plexiform lesions. Chemical imbalances, including decreases in vasodilators and antiproliferative factors (e.g., prostacyclin and a synthase of nitric oxide) and increases in vasoconstrictors and proliferative factors (e.g., endothelin-1, thromboxane, and 5-hydroxytryptamine), initiate the cascade of events that eventually leads to advanced disease. The high-flow, low-pressure system of the pulmonary vasculature is replaced by a high-pressure, low-flow system. As the disease progresses, symptoms that were somewhat vague initially become more pronounced and more severe. Eventually dizziness leads to syncope, an ominous sign of low cardiac output, and minimal exertion causes chest discomfort secondary to RV ischemia. As the pressure in the pulmonary arteries rises (due to greater pulmonary vascular resistance [PVR]), the strain placed on the RV increases. This is the result of RV dilation and eventually RV failure. PAH is present if the mean pulmonary artery pressure is >25 mm Hg at rest (or >30 mm Hg with exercise) with a PVR >3 Woods units AND a pulmonary capillary wedge pressure <15 mm Hg by cardiac catheterization.1,2

Patients with suspected PAH exhibit characteristic findings on evaluation. Initially there may only be an increased P2 component to the heart sounds, which later may include a gallop as the patient develops heart failure. Also present can be an RV heave, systolic murmur secondary to triscupid regurgitation, and perhaps even a diastolic murmur secondary to pulmonic insufficiency. Jugular venous distension and hepatomegaly occur with heart failure, sometimes causing a pulsatile liver later in the disease state. Edema and ascites are commonly seen in this patient population, prompting the use of diuretics.

In 2003 a panel of experts established the five categories of pulmonary hypertension,3 which are now recognized by the World Health Organization (WHO) (Table 1). Tests used to diagnose pulmonary hypertension fall into one of two categories: those used to identify possible causes and those that detect specific abnormalities.

Comorbid contributors

A number of conditions may be the underlying cause of pulmonary hypertension, and their presence can increase the likelihood of diagnosis.
Pulmonary embolism (PE) and pulmonary fibrosis (PF) are potential causes of pulmonary hypertension. A ventilation-perfusion (V/Q) scan is the most useful test for PE,4 and a contrast CT scan of the chest can reveal
the presence of acute or chronic PE as well as the parenchymal honeycombing seen in PF. The presence of a large PE in the proximal pulmonary artery requires pulmonary arteriography to determine the need for pulmonary endarterectomy.

Pulmonary function testing is used to assess patients for restrictive or obstructive pulmonary disease (PF or chronic obstructive pulmonary disease). If the patient has normal lung function, the diffusing capacity of the lung for carbon monoxide (DLCO) may be the only abnormality suggesting pulmonary hypertension. Patients with idiopathic PF having a DLCO <30% demonstrated a twofold increase in the prevalence of pulmonary hypertension when compared with those patients having a DLCO ³30% in a study conducted by Nathan et al.5 In a study by Escribano et al, the DLCO was abnormal in patients with PAH, while forced vital capacity, forced expiratory volume in one second, and total lung capacity were normal.6

Another condition that may cause pulmonary hypertension is obstructive sleep apnea (OSA). Patients meeting the screening criteria for OSA should have polysomnography. Chronic hypoxia has been shown to play a role in the development of pulmonary hypertension and is thought to be secondary to hypoxic vasoconstriction.7 As many as 12%-17% of patients with OSA may have pulmonary hypertension.8

In patients suspected of having pulmonary hypertension, autoantibody testing should be done to rule out connective tissue diseases, such as scleroderma (limited or diffuse) or systemic lupus erythematosus (SLE). Even rheumatoid arthritis can be the culprit in pulmonary hypertension, although that scenario is not as common. Interestingly, as many as 40% of patients with PAH will have serologic abnormalities. Measure liver enzymes to rule out liver disease (cirrhosis or hepatitis), and do HIV testing to rule out HIV infection.