A New Classification of Pulmonary Hypertension

Because pulmonary hypertension can occur from diverse etiologies, a classification of the disease has been very helpful. The original classification, established at a World Health Organization (WHO) symposium in 1973, classified pulmonary hypertension into groups based on the known cause and defined primary pulmonary hypertension (PPH) as a separate entity of unknown cause. PPH was then classified into three histopathological patterns: (a) plexogenic arteriopathy, (b) recurrent thromboembolism, and (c) veno-occlusive disease. In 1998, a new classification for pulmonary hypertension was developed that focused on the biologic expression of the disease and etiologic factors in an attempt to group these illnesses on the basis of clinical similarities.1 This classification serves as a useful guide to the clinician in organizing the evaluation of a patient with pulmonary hypertension and developing a treatment plan. In addition, a functional classification (see Table) patterned after the New York Heart Association Functional Classification for heart disease was developed to allow comparisons of patients with respect to the clinical severity of the disease process.Recently, parameters for normal pulmonary arterial systolic pressure derived by echo Doppler studies have been published which suggest that the upper limit of normal of pulmonary arterial systolic pressure in the general population may be higher than previously appreciated.2 Importantly, however, the study characterized changes based on age and found a modest increase in pulmonary arterial pressure with age similar to what exists in the systemic circulation.There are patients whose resting hemodynamics are normal, but in whom marked elevations in pulmonary pressure occur with exercise. It has been presumed that this represents an early stage of pulmonary vascular disease. However, as patients may have a hypertensive response to exercise with respect to the systemic vasculature, a similar type of response can occur in the pulmonary vasculature. Thus, whether exercise induced pulmonary hypertension represents true pulmonary vascular disease or reduced compliance of an otherwise normal pulmonary circulation can be difficult to ascertain.Patients with pulmonary arterial hypertension characteristically present with effort dyspnea that can have a slowly progressive course.3 The onset of right ventricular failure, manifest by a reduction in cardiac output and/or elevation in right atrial pressure, is usually associated with a marked clinical deterioration and poor prognosis.4 The rapidity in which this occurs in highly variable and is often related to the age of onset and associated conditions. Thus, patients with pulmonary arterial hypertension associated with congenital heart defects will more commonly have a slow, insidious onset of symptoms and develop right heart failure after decades, whereas patients with the CREST syndrome* present later in life with a progressive downhill course.Patients with primary pulmonary hypertension (PPH) are subcategorized into sporadic and familial. The diagnosis of familial PPH is made through a patient's family history, as there are no clinical or pathologic features that separate these two entities. Although the prevalence of familial PPH had been published as being 12% at the time of the NIH Registry, this underestimates the true familial prevalence. Because of incomplete penetrance of the gene, it may skip several generations, which would not be uncovered unless the physician were to take an in-depth look at the patient's family medical histories. The PPH-1 gene, which has been recently described, has been reported to be present in approximately half the patients with familial PPH.5 Those without the PPH-1 gene may have other genetic mutations that have not yet been discovered or may have a gene that cannot be determined by current techniques. Patients with sporadic PPH have also been noted to test positive for the PPH-1 gene in about 25%. These patients actually may be familial but mischaracterized as sporadic because of the lack of a supporting family history, or may indeed represent point mutations.Patients with pulmonary arterial hypertension related to the collagen vascular diseases will have clinical features representing both entities. It is most common for the collagen vascular disease to manifest itself years before the onset of pulmonary hypertension, but on occasion the opposite has occurred. Many patients with PPH will have elevated titers of antinuclear antibodies.6 Whether this represents a form fruste of a collagen vascular disease, or is just a clinical feature of PPH, has been debated. The high incidence of pulmonary hypertension in patients with CREST and scleroderma has supported the recommendation that these patients be screened periodically with echocardiography.Congenital systemic to pulmonary shunts can cause pulmonary hypertension believed to be related to the increased blood flow and pressure transmitted to the pulmonary circulation. In most instances this entity is reversible if detected early and the shunt is corrected. In some instances, however, pulmonary hypertension develops very rapidly at the early stages of the disease and precludes any surgical correction. Some patients present with a remote history of a patent ductus arteriosis that was ligated, or an atrial septal defect that was relatively small with coexisting pulmonary vascular disease. Whether the shunt and the pulmonary hypertension are related or coincidental has been a matter of debate.7 Right-to left-shunting through a patent foramen ovale needs to be distinguished from congenital heart disease. It is uncommon for a patent foramen ovale to be associated with significant right-to-left shunting at rest, but it can contribute to exercise-induced hypoxemia. When uncertainty exists, transesophageal echocardiography should distinguish a foramen ovale from an atrial septal defect. If necessary the distinction can be made during catheterization by sizing the defect with the balloon from a pulmonary artery catheter.The association between liver disease and pulmonary hypertension appears to be related to portal hypertension, and not to liver disease itself.8 Why portal hypertension leads to pulmonary hypertension has never been fully understood. Making the diagnosis of portal hypertension in a patient with pulmonary hypertension can be problematic. The diagnosis of portal hypertension, an elevation in portal pressure, can be made by direct wedge pressure determination of the portal vein at the time of cardiac catheterization. An elevation of portal pressure above 10 mmHg from a normal right atrial pressure defines portal hypertension. It has never been determined, however, what gradient is necessary to make this diagnosis in a patient with an elevated right atrial pressure that is commonly found in patients with pulmonary hypertension. Thus, the clinical diagnosis of portal hypertension may have to be made by other indirect determinations such as the presence of esophageal varices or an abnormal flow pattern in the hepatic veins determined by Doppler.It is well established that the presence of the HIV virus can induce pulmonary hypertension, probably through activation of cytokine or growth factor pathways. There has been no association made between the viral load or the type of antiviral therapy and the severity of the pulmonary hypertension.9 As antiviral therapy against HIV improves over time, it will be of interest to note whether or not the coexisting pulmonary hypertension resolves with treatment.Although several drugs and toxins have been associated with the development of pulmonary hypertension, a causal relationship with many of these remains uncertain. The strongest association between drug ingestion and the development of pulmonary hypertension has been made with the fenfluramines. 10 Although the syndrome is indistinguishable from primary pulmonary hypertension, our experience suggests these patients tend to have a more aggressive disease with a poorer prognosis than similar patients with PPH. This may be a result of the fenfluramines triggering a unique molecular pathway that produces pulmonary vasculopathy.Persistent pulmonary hypertension of the newborn is to be distinguished from congenital abnormalities of the heart and pulmonary vasculature. It represents an entity similar to PPH and is typically somewhat more responsive to acute and chronic vasodilator therapies.11 Untreated, it can be rapidly fatal.Pulmonary venous hypertension represents a clinical entity that has a pathophysiology and clinical course that is markedly different from pulmonary arterial hypertension. Orthopnea and paroxysmal nocturnal dyspnea are characteristic features, which may precede effort dyspnea. These patients often have a history of chronic congestive heart failure and/or recurring pulmonary edema, which then becomes obscured when right ventricular failure ensues.Pulmonary venous hypertension is the most common cause of pulmonary hypertension in clinical practice. Because blood by necessity flows through the pulmonary vascular bed into the left heart, any elevation of the filling pressure of the left side of the heart will result in an increase in pulmonary artery pressure. Although often times this is quite apparent, there are some circumstances where the situation is confusing. For example, chronic pulmonary venous hypertension can lead to morphologic changes in the pulmonary arterial and venous bed resulting in further elevation of the pulmonary artery pressure beyond that which was initially a result of the elevated left-sided pressure, implying pulmonary vasoconstriction or a vasculopathy triggered by the elevation in pulmonary venous pressure. Often, the physician is confronted as to whether or not two processes are ongoing or the long-term result of a single process.Another scenario is the patient who has a longstanding history of left heart disease who develops pulmonary hypertension and severe right heart failure. At the time of cardiac catheterization these patients may have a normal pulmonary capillary wedge or left ventricular end diastolic pressure in the presence of a low cardiac output. Thus, they may have the hemodynamic profile of a patient with PPH because one is unable to determine what the left ventricular end diastolic pressure would be in the face of a normal cardiac output.The diagnosis of pulmonary veno-occlusive disease can be difficult, since the pulmonary wedge pressure may be normal or elevated depending on the segment of the lung that is measured. In our experience these patients often have a very abnormal perfusion lung scan without any evidence of pulmonary thromboembolic disease.12 Another common, but inconsistent, feature is an elevation in pulmonary capillary wedge pressure following the challenge of an infusion of adenosine or prostacyclin at the time of catheterization.Although hypoxemia may coexist in all forms of pulmonary hypertension, it is the hallmark of these conditions. These patients are often dyspneic at rest as well as with minimal activity, with only subtle clinical features of pulmonary hypertension. Supplemental oxygen will usually provide substantial clinical improvement.A subset of patients present with severe elevations in pulmonary artery pressure beyond those typically seen in these disease entities.13 Whether this represents an extreme manifestation of the underlying disease or a different disease process characteristic of pulmonary arterial hypertension that has been triggered by a common pathway is currently unknown. Clinically, it can be difficult to sort out the basis of a patient's complaint of dyspnea. In addition, even successful treatment of the pulmonary hypertensive component of the problem may not render the patient clinically improved if the hypoxemia persists. Of great concern is that some therapies directed toward the pulmonary hypertension can worsen gas exchange and make the hypoxemia even worse.These patients often present with clinical signs and symptoms that are indistinguishable from pulmonary arterial hypertension. Unless a thorough evaluation is conducted to exclude these diseases, patients may be misdiagnosed and inappropriately treated. Chronic proximal thromboembolic obstruction of the pulmonary arteries is a well characterized clinical entity that has been extensively studied.14 Because it is potentially reversible, it must be excluded in every patient who presents with pulmonary hypertension irrespective of the lack of an antecedent history of deep vein thrombosis or pulmonary thromboembolism.Obstruction of the distal pulmonary arteries can be either embolic or thrombotic. Recurrent microthromboembolism does not appear to be a clinical entity, since current evidence points to thrombosis in situ as being responsible for the thrombotic changes noted in the arteriolar bed in patients with pulmonary arterial hypertension. Thrombotic obstruction, however, can occur anywhere from the pulmonary capillary bed to the main pulmonary arteries and may reflect a continuum of a disease process. This makes it difficult to ascertain the cause of pulmonary hypertension in a patient with clear evidence of pulmonary thromboembolism involving a relatively few number of vessels. It appears that in some of these patients thrombotic obstruction of the pulmonary arteries leads to chronic pathologic changes in the uninvolved vasculature. Diffuse pulmonary embolism can occur on rare occasions from metastatic tumors, parasitic disease, or from foreign material through intravenous injection.These very rare entities require a high index of suspicion in order for a diagnosis to be made. Schistosomiasis, for example, is probably the most common cause of pulmonary hypertension worldwide, although it is virtually never seen in Westernized countries. It should be kept in mind when patients are referred from underdeveloped countries as a potential underlying etiology.Sarcoidosis can cause extensive destruction of the pulmonary parenchyma and pulmonary vascular bed and can cause pulmonary hypertension merely by lung destruction and resulting hypoxemia. In addition, these patients may develop pulmonary hypertension presumed to be on the basis of involvement of the pulmonary circulation from the sarcoid process. It is unlikely that this is due to local granuloma formation within the pulmonary vasculature and is more likely the result of growth factors triggering the same process that is seen in pulmonary arterial hypertension. Some of these patients may respond very favorably to long-term intravenous epoprostenol.15Pulmonary capillary hemangiomatosis is an extremely rare disorder involving the pulmonary capillary bed that can present in different stages. It is often associated with frequent hemoptysis, severe pulmonary hypertension, and a progressive fatal course in a short period of time. The diagnosis can be made with pulmonary angiography in the hands of an experienced radiologist. PH