2 Classification of Pulmonary Hypertension
C. William Hargett and Victor F. Tapson
2. PULMONARY ARTERIAL HYPERTENSION Pulmonary arterial hypertension (PAH), the first major category in
2.3. Conditions Associated with Pulmonary Arterial Hypertension (APAH)
PAH occurring in the presence of a known cause or risk factor is termed “associated PAH” (APAH). This is the predominant category within the PAH grouping and includes PH associated with conditions such as connective tissue disease, drugs, HIV, and portal hypertension.
Since the likelihood of developing PAH in the company of these known risk factors is relatively low, individual susceptibility and/or genetics must be important factors in the development of APAH.
2.3.1. PAH Associated with Connective Tissue Disease PAH has been associated with every known type of connective tissue disease (CTD) (16). Most commonly, it complicates the sclero-derma spectrum of diseases, systemic lupus erythematosus, and mixed connective tissue disease, but it can also rarely be seen in rheumatoid arthritis, dermatomyositis/polymyositis, and primary Sjogren’s syndrome. PAH associated with connective tissue disease may occur as isolated pulmonary vascular disease or in association with parenchymal lung disease. While the term “collagen vascular disease” has been utilized, “connective tissue disease” (CTD) is most commonly used to describe this category of patients.
The pulmonary vascular disease associated with CTD is often indistinguishable from IPAH (16). Both conditions share presenting symptomatology, a female predominance, the presence of Raynaud’s phenomenon, and abnormal serologies (elevated antinuclear antibody titers and rheumatoid factor). The histopathologies of APAH due to CTD and IPAH also overlap. Although they often show similar acute hemodynamic and exercise improvements with medical therapy, patients with PAH associated with CTD tend to have a worse prognosis when compared to IPAH, whether treated or not (17,18).
2.3.2. PAH Associated with Congenital Systemic-to-Pulmonary Shunts
Pulmonary hypertension is a common manifestation of congenital heart disease (CHD). The Venice classification for congenital systemic-to-pulmonary shunts is outlined in Table 2. The initial association
Table 2
Guidelines for Classification of Congenital Systemic-to-Pulmonary Shunts∗
1. Type Simple
Atrial septal defect (ASD) Ventricular septal defect (VSD) Patent ductus arteriosus
Total or partial unobstructed anomalous pulmonary venous return Combined
Describe combination and define prevalent defect, if any Complex
Truncus arteriosus
Single ventricle with unobstructed pulmonary blood flow Atrioventricular septal defects
2. Dimensions
Small (ASD < 2.0 cm and VSD < 1.0 cm) Large (ASD > 2.0 cm and VSD > 1.0 cm) 3. Associated extracardiac abnormalities 4. Correction status
Noncorrected
Partially corrected (age)
Corrected: spontaneously or surgically (age)
∗Simonneau G, et al (2); reproduced with permission.
was reported by Eisenmenger in 1897, when he described a 32-year-old man with cyanosis and exercise intolerance who died of massive hemoptysis and in whom a ventricular septal defect and severe pulmonary vascular disease were discovered postmortem (19). This case characterizes the physiology and symptoms now referred to as
“Eisenmenger syndrome,” which includes all systemic to pulmonary arterial connections leading to PH and a right-to-left or bidirectional shunt. This abnormality begins as a left-to-right shunt that chroni-cally increases blood flow through the pulmonary vascular bed. For reasons not entirely understood, this increased blood flow leads to morphological and histological changes similar to those found in IPAH (20).
The clinical manifestations of PAH associated with CHD, however, have some important differences when compared to IPAH. Cyanosis and exercise oxygen desaturation are common and usually more severe than those of IPAH consistent with the right-to-left shunting. Hemop-tysis occurs more frequently in these patients, and stroke is more
common due to paradoxical embolization. The vascular disease of PAH associated with CHD progresses more slowly to right ventricular failure, which accounts at least partly for the better survival compared to IPAH (18,21).
The risk of developing Eisenmenger syndrome depends in large part on the size and location of the anatomical defect. Of the simple cardiac anomalies, ventricular septal defects most frequently lead to PH, especially in patients with large defects (>1.5 cm in diameter) (20,22). Early detection of the CHD defect is key, as surgical repair prior to the development of severe pulmonary hypertension halts the progression of pulmonary vascular disease. When the disease is advanced, patients with CHD and severe PH may not benefit or even worsen with surgical correction, and so medical therapy is preferred.
At such a severe stage, the differentiation between CHD and IPAPH becomes moot, because differentiating between a small atrial septal defect and a patent foramen ovale (PFO) may be impossible short of autopsy, and therapy will be the same for both.
2.3.3. PAH Associated with Portal Hypertension
Portopulmonary hypertension (PPHTN) is diagnosed when PAH occurs in association with portal hypertension without other risk factors. PPHTN seems to be related to the elevated portal pressure itself and can occur in the presence or absence of underlying liver parenchymal disease. The diagnosis is often indirect, based on the signs and symptoms of portal disease, as the direct measurement and definition of portal hypertension are unclear in the context of an elevated right atrial pressure.
A large autopsy series suggests that PH occurs in patients with cirrhosis at greater than five times the expected frequency and, even after excluding known cases of PPHTN, PH was found to complicate portal hypertension in 2% of over 500 patients studied (23,24). Whether the severity of portal hypertension influences the development of PAH is controversial, but the prevalence of PPHTN appears to be highest in patients with end-stage liver disease undergoing evaluation for liver transplantation (25). It is also possible that PAH is simply more often sought and identified in this group.
PPHTN is histologically and clinically similar to IPAH with a few important differences (24,26,27). PPHTN has no gender predilection and patients tend to be older. Hemodynamically, patients tend to have higher cardiac outputs than patients with other causes of PAH. The prognosis of untreated PPHTN is poor, but patients may respond to
intravenous epoprostenol, and liver transplantation may reverse the pulmonary vascular disease (28,29).
2.3.4. PAH Associated with HIV Infection
When present, PH increases the mortality of HIV-infected patients, in whom the incidence of HIV-associated PH may be between 0.1%
and 0.5% (30,31). PAH probably develops through the activation of cytokine or growth factor pathways, but the exact mechanism is unknown. IPAH and HIV-associated PAH appear clinically and histologically alike, and survival is also similar with comparable therapy (30,31). Improved survival has been associated with a higher CD4 count and combination highly active anti-retroviral therapy (HAART) (32,33).
2.3.5. PAH Associated with Drugs and Toxins
Although several drugs and toxins have been associated with the development of PAH, the strongest causal association has been with anorectic agents such as aminorex and the fenfluramines (34,35). The adjusted odds ratio for fenfluramine use longer than six months and an associated diagnosis of IPAH was 7.5, and the high prevalence of anorectic use in patients with secondary forms of PH raises the possibility that the drugs precipitate PH in patients with underlying conditions (36). Anecdotally, PAH associated with fenfluramines is more aggressive than IPAH and may carry a worse prognosis, although spontaneous regression may occur as well.
2.3.6. PAH Associated with Other Diseases
Other miscellaneous diseases have been associated with PAH, such as the rare condition Type Ia glycogen storage disease. PH commonly complicates sickle cell disease, although this condition is sometimes related to diastolic dysfunction rather than PAH. Patients with hered-itary hemorrhagic telangiectasia may also develop classic PAH or have PH secondary to right-to-left shunting through pulmonary arteri-ovenous malformations.
2.4. PAH Associated with Significant Pulmonary Venular