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CLASSIFICATION OF PULMONARY HYPERTENSION

Pulmonary hypertension (PH) is defined as an elevation in the mean pulmonary artery pressure (mPAP) of at least 25 mm Hg.¹ The World Health Organization (WHO) clinical classification of PH according to the Fifth World Symposium on Pulmonary Hypertension (WSPH) is summarized in Table 1.¹ The WHO organizes groups of PH on the basis of shared pathologic features, similarities in hemodynamics, and management strategies.¹ 

Pulmonary arterial hypertension

Group 1 PH, also referred to as pulmonary arterial hypertension (PAH), is an orphan disease state with an overall incidence of 15 cases per 1 million people.² It predominantly affects younger female patients: recent United States (U.S.) registry data revealed a PAH population that is 80% female with a mean age of 50 ± 14 years.³ Median survival was found to be 7 years for patients enrolled between 2006 and 2007 into the U.S. Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).⁴ This represents a marked improvement compared to the median survival of only 2.8 years reported from registry data collected by the U.S. National Heart, Lung, and Blood Institute in the 1980s.⁵ This change parallels the increased availability of effective treatment options over the past 2 decades. 

Nitric oxide (NO) is a potent vasodilator and inhibits platelet activation and vascular smooth muscle cell proliferation. A deficiency of NO is a result of impaired synthesis and signaling via the NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway. NO activates its molecular target, sGC, which, in turn, leads to increases in cGMP production. The degradation of cGMP is regulated by the enzyme phosphodiesterase type 5 (PDE5).^6,7 Prostacyclin (prostaglandin I₂ [PGI2 or IP]) and thromboxane A₂ are major metabolites of arachidonic acid metabolism and they have significant effects on pulmonary arterial vascular smooth muscle: prostacyclin is a potent vasodilator and an inhibitor of platelet activation, and it has antiproliferative properties; thromboxane A₂ exhibits the opposite effects (i.e., vasoconstriction, stimulation of platelet activation, and promotion of cell proliferation). In PAH, there is an excess of thromboxane A₂ and a deficiency of prostacyclin.^6,7 Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen that exerts its effects in the pulmonary vascular smooth muscle via endothelin type A (ET_A) and endothelin type B (ET_B) receptors. In PAH, ET-1 concentrations are elevated and its clearance is impaired.^6,7 

Risk factors for PAH

The presence of connective tissue disorders (i.e., scleroderma, systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, mixed connective tissue disease) greatly increases the risk for developing PAH. Genetics may also play a role in the development of PAH: in familial PAH, genetic mutations are detectable in 80% of families with the disease. Exposures to certain drugs and toxins, such as anorexigens with serotonergic properties and amphetamines and related derivatives, also increase the risk for developing PAH.¹

Pathophysiology of PAH

The pathogenesis of PAH is complex and multifactorial. However, the central features of the disease pathophysiology include vasoconstriction, vascular wall remodeling, and in situ thrombosis. The culmination of each of these leads to an increase in vascular resistance. PAH is characterized by vasculopathy, which mainly affects small pulmonary arteries.⁷ Excessive vasoconstriction also plays a role in the pathogenesis. A dysregulation and imbalance of vasodilators (i.e., NO, prostacyclins) and vasoconstrictors (i.e., thromboxane A₂, ET-1) within the vascular endothelium and smooth muscle provide a construct for the major pathways of PAH and associated therapeutic targets.^6,7

Symptoms of PAH

The onset of PAH may be insidious and its presentation can be very nonspecific. For these reasons, the time from symptom onset to diagnosis has been reported to be as long as 27 months.⁸ Symptoms may include dyspnea, fatigue, exercise intolerance, chest pain, fluid retention, and, less commonly, syncope. Clinical evidence of right ventricular (RV) dysfunction, such as increased jugular venous pressure, lower extremity edema, hepatomegaly, and tricuspid regurgitation, may indicate advanced disease.

The severity of patient symptoms is described by the WHO functional classification: class I, symptoms elicited at levels of exertion that would limit normal individuals; class II, symptoms on ordinary exertion; class III, symptoms on less-than-ordinary exertion; and class IV, symptoms at rest.⁶ 

Diagnosis of PAH

To correctly diagnose PH, careful patient assessment is warranted and should include comprehensive testing using echocardiography, pulmonary function tests, sleep studies, serologies, ventilation-perfusion (V/Q) scanning, and computed tomography scans of the chest to evaluate for possible underlying causes of symptoms. When PH is suspected, a right heart catheterization is required to confirm the diagnosis. Specific hemodynamic criteria must also be met for diagnosis: an mPAP of at least 25 mm Hg accompanied by a pulmonary capillary wedge pressure (PCWP) of  15 mm Hg or less.⁹ The latter is necessary to exclude the presence of passive increases in pulmonary pressures on the basis of increased preload due to left-sided heart disease. Diastolic pressure gradient (i.e., diastolic pulmonary artery pressure minus the mean PCWP) along with pulmonary vascular resistance may be useful in identifying different phenotypes of PH related to left-sided heart disease.⁹    

Classification of PAH

In the U.S. REVEAL registry, patients with Group 1 disease were classified into 3 major subtypes: associated PAH (50.7%), idiopathic PAH (46.2%), and familial PAH (2.7%). Patients with the associated PAH subtype were further divided into subgroups on the basis of cause, which included connective tissue disease (49.9%), congenital heart disease (19.5%), portal hypertension (10.6%), drug/toxin-induced (10.5%), HIV associated (4%), and other (5.5%).⁴

Connective tissue diseases represent the most common cause of PAH. Half of these disorders are attributed to scleroderma, which is also referred to as systemic sclerosis and formerly known as Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasias (CREST) syndrome. The prevalence of PAH among people with scleroderma is between 7% and 12% and it is a major cause of mortality.^10,11 Other types of connective tissue disorders associated with PAH include systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, and mixed connective tissue disease.

Idiopathic PAH, formerly known as primary PH, is the second most common subset of Group 1 disease.⁴ In familial PAH, genetic mutations can be detected in 80% of families with multiple cases of PAH. The most common mutation is located in the bone morphogenetic protein type II receptor (BMPR2), which is part of the transforming growth factor-β superfamily.¹ Other less common genetic mutations have also been described. No detectable changes in disease-associated genes can be identified in 20% of patients.¹ The pathology of idiopathic disease and PAH associated with connective tissue disorders is similar. Therefore, the treatments are generally similar but the relative benefits in patients with connective tissue disease are less.⁹

A summary of drugs and toxins that can induce PAH and the likelihood of each association are outlined in Table 2.¹ Historically, anorexigens such as fenfluramine and dexfenfluramine were found to be associated with an increased risk for developing PAH due to their ability to increase serotonin release and block serotonin reuptake. Selective serotonin reuptake inhibitors (SSRIs) have similarly been implicated in the development of persistent PH in newborn infants whose mothers were exposed to these medications in the later stages of pregnancy. However, an association between SSRI exposure and PH in adults remains unclear. Amphetamines have also been shown to be associated with PAH and caution is, therefore, warranted with the use of related derivatives, such as phentermine, topiramate, methylphenidate, and ropinirole. Another novel class of medications known as the tyrosine kinase inhibitors (TKIs) have recently been investigated for their potential association with PAH. At this time, dasatinib appears to have the highest association with the development of PAH compared to other TKIs.¹