Idiopathic pulmonary arterial hypertension (formerly referred to as primary pulmonary hypertension) is an uncommon yet progressively fatal disease defined by the presence of mean pulmonary artery pressure greater than 25mmHg at rest or greater than 30mmHg with exercise as tested by right heart catheterization in the absence of other etiologies for pulmonary hypertension. Across several studied populations, the diagnosis takes an average of 2.0-2.9 years to make,1-4 because its initial symptoms are minimized by patients and are characteristic of other, more common disorders. Diseases such as connective tissue diseases, chronic thromboembolic disease, congenital heart defects, chronic hypoxia, left ventricular dysfunction, portal hypertension, and HIV, as well as exposures to anorexigens, methamphetamines, and cocaine, have also been found to have disease- and toxin-associated pulmonary arterial hypertension (PAH). Physical exam and first-line diagnostic studies such as electrocardiograms (ECGs) and chest radiographs often show only subtle (if any) differences compared with normal patients. Patients are stratified according to symptoms based upon the modified New York Heart Association (NYHA) classification, also referred to as the World Health Organization (WHO) functional classification, as these strata have mortality implications. Untreated patients in class I and II have a median survival of nearly six years compared with untreated patients in class III, who have a median survival of 2.5 years, and untreated patients in class IV, who have a median survival of six months.5 Note that according to the WHO classification, the presence of syncope independently places pulmonary hypertension patients into class IV, unlike patients who have congestive heart failure. Patients' clinical course can be followed invasively with routine right heart catheterizations or non-invasively through six-minute walk testing, or newer modalities such as cardiac computed tomography (CT) or cardiac magnetic resonance imaging (MRI). An expert panel from the American College of Chest Physicians (ACCP) has developed an algorithm from their 2004 guidelines (see Figure 1) to help clinicians navigate through the myriad diagnostic tests to make the correct diagnosis.6
Delays in diagnosis may have clinical implications as data suggest that instituting therapy in the setting of less advanced disease results in greater survival benefits.7,8 Additionally, with the availability of oral agents, such as endothelin receptor antagonists and phosphodiesterase inhibitors, early institution of therapy is more acceptable to patients. Calcium channel blockers were previously thought to be the first-line treatment for many patients, but only 6.8% will have durable response to oral calcium channel blockers when properly stratified during acute vasodilator testing.9 Early recognition of symptoms, diagnosis, and close monitoring of affected patients through appropriate steps is critical to improving patient morbidity and mortality.
Initial Clinical Assessment
Pulmonary hypertension should be considered in any patient who has progressive dyspnea or fatigue that cannot otherwise be explained; these were the two most common presenting symptoms in the National Institutes of Health (NIH) registry on PPH from 1981 to 1987.1 Other symptoms include angina due to right ventricular myocardial oxygen demand, lower extremity edema secondary to right ventricular failure, or syncope caused by depressed cardiac output. Particular attention should be paid to those patients who fall into 'at risk' categories, namely: women and men in their third and fourth decade, respectively; patients with a family history of pulmonary hypertension; and patients who have connective tissue disease, chronic thromboembolic disease, congenital heart defects, chronic hypoxia, portal hypertension, HIV, or previous exposure to anorexigens, methamphetamines, or cocaine.
Physical examination can reveal increased jugular venous distention with elevated A waves, a right ventricular heave, a tricuspid regurgitant holosystolic murmur, and a loud P2, all suggestive of elevated right-sided pressures. Occasionally, a right-sided S4 can be heard, representing reduced compliance of the hypertrophied right ventricular myocardium. Thin patients also have a palpable pulmonary artery located along the left upper sternal border. Special attention should be given to abnormal heart sounds suggestive of congenital heart defects, such a pansystolic murmur associated with ventricular septal defects and a fixed split S2 associated with atrial septal defects. Cyanosis may also be present in patients with congenital heart defects.
ECG testing may provide some evidence of right heart dysfunction through the presence of right ventricular hypertrophy and right axis deviation, which may be seen in 87% and 79% of patients, respectively.1 Right atrial enlargement (P wave >2.5mm in leads II, III, aVF with frontal P axis >75┬║) has been associated with a 2.8-fold increased risk of mortality over six years of observation in patients diagnosed with pulmonary hypertension.10 These findings in patients with suspected PAH merit further testing.
Chest radiography provides even fewer specific clues to help in the diagnosis of pulmonary hypertension, but can offer insight into the severity of lung parenchymal disease from chronic hypoxia, pulmonary edema secondary to left ventricular dysfunction, and, rarely, chronic thrombo-embolic disease. No associations have been made regarding radiographic changes and severity of disease,1 but classic changes such as enlarged main pulmonary arteries with marked peripheral tapering or pruning can be seen.
All patients with suspected or documented pulmonary hypertension should undergo serological testing for connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease, as well as serological testing for HIV, as these diagnoses will have significant impact on therapy.
Transthoracic Doppler echocardiography currently serves as the most widely used non-invasive tool to evaluate pulmonary hypertension; its sensitivity and specificity range from 0.79 to 1.0 and 0.6 to 0.98, respectively.6,11-14 Echocardiography receives an 'A' recommendation from the ACCP guidelines for initial testing of pulmonary hypertension; furthermore, high-risk patients (family history of pulmonary hypertension, personal history of congenital heart disease or connective tissues diseases, and exposure to anorexigens, for example) should be screened for pulmonary hypertension using echocardiography based on expert opinion. Echocardiography also offers an advantage in the early detection of pulmonary hypertension, as it can be used to demonstrate exercise-induced pulmonary hypertension. Quantification of the maximal tricuspid regurgitant (TR) jet velocity allows for estimation of right ventricular systolic pressure (RVSP) via the modified Bernoulli equation. Pulmonary artery systolic pressure (PASP) can be estimated in 59-72% of patients using this method,11,14 although PASP may be overestimated in patients with significant lung disease.15 Similarly, pulmonary arterial diastolic pressure can also be estimated with pulmonic regurgitant jet velocities. Other echocardiographic findings include right atrial and inferior vena caval dilation, which may not collapse with respiration if the right atrial pressure exceeds 20mmHg. Right ventricular hypertrophy, defined by a right ventricular wall thickness >5mm on parasternal and subcostal views, can eventually lead to left ventricular diastolic dysfunction due to abnormal interventricular septal relaxation.
Pericardial effusions can also be present and are poor prognostic indicators.16,17 Intracardiac shunts should be ruled out through the use of an agitated saline contrast ('bubble') study. Lastly, ECGs can evaluate the degree of left ventricular diastolic and systolic dysfunction and left atrial enlargement as possible causes of elevated right-sided pressures, which is important as the absence of elevated left-sided pressures is a prerequisite for the diagnosis of idiopathic pulmonary artery hypertension.
Ventilation/perfusion scans are often used to rule out other causes of dyspnea or used to determine the potential degree of involvement clot burden; if central and large, these chronic pulmonary emboli may be surgically resected, resolving the dyspnea associated with pulmonary hypertension. Normal ventilation and quantification (V/Q) scans rule out chronic thromboembolic disease.
CT is typically used to evaluate for the presence of pulmonary emboli suggestive of chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable cause of pulmonary hypertension. If CTEPH is suspected, pulmonary angiography is essential for diagnosis and characterization of the extent of the clot burden for possible surgical thrombo-endar-terectomy. The primary CT and MRI findings of pulmonary hypertension include enlargement of central pulmonary arteries, particularly when the diameters are >29mm.16 High-resolution CT scans can evaluate lung parenchyma for the causes of chronic hypoxia, which may lead to pulmonary hypertension. CT (or MRI) may also lead to alternate diagnoses.
Pulmonar y Function Testing
The role of pulmonary function testing is to rule out parenchymal or obstructive lung disease as the cause of the patient's symptoms. Pulmonary function testing often reveals normal lung physiology, but hyper-reactivity can be seen, incorrectly pointing the clinician to diagnose the patient with reactive airway disease. Patients with IPAH can have a mild decline in their total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO), but the severity of these declines do not correlate with disease severity.5 Nearly 20% of patients with systemic sclerosis will have an isolated fall in their DLCO (<55% predicted),9,19 which portends development of pulmonary hypertension in 35% of those patients, independent of their development of interstitial lung disease.20 Note that lung biopsies have no role in the diagnosis of pulmonary hypertension.
Right Heart Catheterization
Right-heart catheterization verifies the suspected diagnosis of pulmonary hypertension, presuming the pulmonary capillary wedge pressure is not elevated, and receives an 'A' recommendation from the ACCP guidelines.6 The goals of right heart catheterization, in addition to making the diagnosis, are to measure right atrial and ventricular pressures, pulmonary vascular resistance, and cardiac output/index (end organ function), to evaluate for the presence of left-to-right shunts, and to test the patient's response to acute vasodilators such as adenosine, prostacyclin, or nitric oxide.21 On occasion, exercise is used in conjunction with right heart catheterization. Responders to acute vasodilator testing have a favorable clinical response and course when treated with calcium channel blockers, but calcium channel blockers should be strictly avoided in non-responders. According to the European Society of Cardiology and the ACCP, a response to acute vasodilator testing includes a >20% and >10mmHg reduction in mean pulmonary artery pressure, to a mean pulmonary artery pressure of <35-40mmHg. Although previous reports have listed 20% of patients with IPAH as responders, this number is generally accepted to be between 5 and 6%; the rate of response is even lower in patients with pulmonary hypertension from other causes. There are no absolute contraindications to right heart catheterization and complications are rare, although present. In advanced disease, the technical execution of the right heart catheterization can be difficult, particularly in the setting of dilated right heart chambers. Measurements of cardiac output can have wide variations, particularly when the thermodilution method is used; the Fick method is preferred in the setting of depressed cardiac output and is required in the setting of intracardiac shunts. Attention must be paid to proper acquisition of these data, as they affect prognosis and management. For example, the ionotropic effects of adenosine during acute vasodilator testing may increase cardiac output without changes to pulmonary vascular resistance, which can be misinterpreted as adequate vasodilator response. Nitric oxide has little effect on cardiac output and is used more widely as a result; it is typically delivered via facemask at 10-40 parts per million (ppm). At select centers, pulmonary angioscopy will accompany right heart catheterization (and/or pulmonary angiography) to evaluate the lumen of the pulmonary arterial tree to the subsegmental level using a 3mm angioscope, usually to determine whether the patient is a candidate for surgical embolectomy.
Due to the fact that patients with pulmonary hypertension have limited capacity to increase their cardiac output, exercise testing may reveal early disease activity. In clinical practice, exercise testing is used to monitor disease activity and response to treatment, because cardiopulmonary exercise testing (CPET) and six-minute walk testing (6MWT) are correlated with WHO classification and predict survival and treatment response. 22,23 Full CPET may reveal changes in peak oxygen consumption (VO2max), rate of increase in VO2, anaerobic threshold, blood pressure, pulse, and ventilatory efficiency in a reproducible and safe manner without complications or deaths in severely decompensated patients. 6MWT is a simpler, accepted substitute for full CPET, as distance walked correlates with VO2max,24 and frequently serves as a primary or secondary end-point in many clinical trials associated with pulmonary hypertension. In addition to prognostic implications at the time of diagnosis, distance achieved during a 6MWT while on therapy may allow for further risk stratification. Sitbon and colleagues demonstrated that a 6MWT distance of >380m after three months of epoprostenol therapy confers a better prognosis than <80m.8
Pulmonary hypertension is a rare, lethal disease that occurs in isolation or in association with myriad diseases; it often eludes diagnosis unless the clinician has a high initial suspicion. Clinical history and exam reveal subtle clues, as do initial testing with electrocardiography and chest radiography. Transthoracic echocardiography may provide initial data supporting a diagnosis of pulmonary hypertension but right heart catheterization is the gold standard for demonstrating mean pulmonary artery pressures >25mmHg at rest in the setting of a normal pulmonary capillary wedge pressure. The algorithm developed by the ACCP should be used as a guide for diagnostic strategy for the initial evaluation. Exercise testing, either through full cardiopulmonary exercise testing or 6MWT, predicts clinically relevant end-points, including mortality, and helps to monitor treatment response and progression of disease.