Introduction
Pulmonary arterial hypertension (PAH) is a disease affecting the pulmonary vascular endothelium of the small pulmonary vessels that causes progressive elevations in pulmonary vascular resistance, leading to right ventricular failure and death. PAH can result from a number of causes or associated risk factors. A clinical classification (Evian classification) was developed in 1993 and subsequently adopted into clinical practice in an effort to group disorders that share similarities in pathophysiology, clinical presentation, and treatment options. This classification was revised recently in 2003 during the Third World Symposium on PAH held in Venice, Italy (see Table 1). From a hemodynamic standpoint, PAH is defined as a mean pulmonary arterial pressure that is >25mmHg at rest or >30mmHg during exercise. The Doppler echocardiographic definition of PAH is based on a tricuspid regurgitation get that is >2.8m/sec. Data regarding the true prevalence of PAH remain somewhat elusive. Idiopathic PAH (IPAH) occurs in one to four cases per million population. The prevalence is 15% to 60% in patients with collagen vascular disease, 2% to 4% in portal hypertension, and 0.5% among patients with HIV infection.
Pathobiology of PAH
The pathobiology of PAH is multifactorial and cannot be explained by a single factor or gene mutation. There is excessive pulmonary vasoconstriction perhaps from inhibition of one of the voltage gated potassium channels (Kv1.5 and 2.1) in the pulmonary vascular smooth muscle cells or from endothelial dysfunction, which in turn leads to impaired production of vasodilators such as nitric oxide and prostacyclin and increased production of vasoconstrictors like endothelin-1 and thromboxane. These abnormalities further increase pulmonary vascular tone and promote vascular remodeling that involves all layers of the vessel wall. Fibroblast proliferation and migration, activation of matrix metalloproteinase (MMP) 2 and 9, and disordered proteolysis of the extracellular matrix plays a key role in vascular remodeling. Inflammatory mechanisms, activation of cytokines and chemokines, serotonin, transforming growth factor (TGF)-α superfamily, and angiopoietin-1 also promote the vascular remodeling process. Finally, platelet dysfunction, enhanced interactions between platelets and the vessel wall, and thrombotic lesions are potentially important in the development of PAH. The initiating process in this cascade of cellular and molecular events is, however, as yet unknown. Mutations in two receptors of the TGF-α superfamily have been identified in patients with familial PAH.
About 50% of familial cases have exonic mutations of the bone morphogenetic protein receptor type-2 (BMPR2), while 10% of the sporadic cases have this mutation. Presence of the BMPR2 mutation confers a 15% to 20% lifetime chance of developing PAH. Mutations of activin-like kinase type-1 (ALK-1) in some patients with hereditary hemorrhagic telangiectasia (HHT) confers susceptibility to PAH. Further studies are needed to understand the interactions between genes and the environment that may either enhance or prevent the development of PAH in persons carrying these mutations.
Histopathology in the different forms of PAH is qualitatively similar but with quantitative differences in the prevalence and distribution of pathological changes in the different areas of the pulmonary vasculature. Medial hypertrophy of the muscular and elastic arteries, and dilation of the elastic arteries are non-specific pathologic findings that occur in all forms of PAH. Complex changes such as plexiform lesions, dilation lesions and arteritis are present in several but not all PAH patients. The plexiform lesions are generally present in 20% to 60% of the pulmonary arteries and extremely rare in PAH associated with collagen vascular disease.
Diagnosis of PAH
Every patient with suspected PAH must undergo a careful diagnostic work-up to clarify the diagnosis and identify the category. The essential testing includes an electrocardiogram, transthoracic echocardiogram, chest X-ray, pulmonary function testing, perfusion/ventilation (V/Q) lung scan, HIV test, connective tissue disease screening, overnight oximetry, assessment of exercise capacity, routine laboratory studies, and a right heart catheterization. In some cases, transesophageal echocardiogram, left heart catheterization, spiral or high resolution computed tomography (CT) scanning, magnetic resonance imaging (MRI), pulmonary angiography, and polysomnography may be necessary. The echocardiogram is the most important screening test in PAH patients. Pulmonary artery systolic pressure can be estimated on an echocardiogram by measuring the systolic regurgitant tricuspid flow Doppler velocity and applying the Bernoulli equation. In experienced hands, quantifiable tricuspid regurgitant flow signals are present in 74% of cases, and the sensitivity of this non-invasive method in estimating the pulmonary artery systolic pressure ranges between 0.79 and 1.00, and the specificity from 0.60 to 0.98. The echocardiographic estimate is, however, inaccurate in the presence of severe right ventricular failure and pulmonary regurgitation.
Perhaps more important than the estimate of pulmonary artery systolic pressure, the echocardiogram provides important information regarding right atrial and right ventricular morphology, left ventricular and mitral valve function and the integrity of the inter-atrial and interventricular septum. This non-invasive test is also used to assess prognosis and response to therapy.
Right heart catheterization is the most important diagnostic test for PAH. It gives an accurate measurement of the pulmonary artery pressure and cardiac output from which the pulmonary vascular resistance can be calculated. It helps to detect intracardiac shunts and rule out left heart disease. Vasodilator testing can be combined with right heart catheterization to ascertain if the PAH is 'vaso-reactive' or fixed. This finding is critical both for treatment decision-making and for determining prognosis. Inhaled nitric oxide, intravenous adenosine or prostacyclin are frequently used to determine vaso-reactivity. The incidence of vaso-reactivity varies between 8.6% and 26.5%, based upon a definition that calls for a reduction in mean pulmonary artery pressure to <35mmHg or a >20% drop in mean pulmonary artery pressure without a decrease in cardiac output. After completion of diagnostic testing, PAH patients are ascribed a functional status, based upon the World Health Organization (WHO) Classification (see Table 2).
Treatment of PAH
The goals of treating PAH are to reduce pulmonary vascular resistance, inhibit the progressive vaso-proliferation and treat right ventricular failure. The end-points of treatment include improved symptoms, quality of life, exercise tolerance, and survival free from hospitalization.
The general treatment measures include diuretics to alleviate congestive symptoms, oxygen to treat resting, exertional or nocturnal hypoxia, digoxin, and oral anticoagulants. The use of digoxin is primarily based on data regarding its efficacy in left heart failure rather than evidence in PAH patients. The evidence for benefit of oral anticoagulants in PAH is based upon retrospective analysis of single center studies. Three-year survival improved with warfarin therapy from 31% to 47% in one series and 21% to 49% in another study.
Calcium channel blockers in high doses improve survival in vaso-reactive IPAH patients when compared with a control group of non-vaso-reactive patients. Doses required are higher than those used for systemic hypertension management and therefore not well tolerated by patients who have severe right ventricular dysfunction and failure. Given the relatively low incidence of vaso-reactivity, these drugs are useful only in a minority of PAH patients.
Prostanoid therapy plays a prominent role in the treatment of PAH. Exogenously administered prostanoids may overcome the endogenous deficiency that exists in PAH patients. Prospective, randomized controlled trials have shown that continuous intravenous prostacyclin therapy (epoprostenol) improves symptoms, quality of life, hemodynamics, and exercise tolerance in patients with IPAH and PAH associated with collagen vascular disease and WHO Class III-IV symptoms. There is less compelling data supporting the efficacy of epoprostenol infusions in PAH associated with congenital systemic-to-pulmonary shunts, portal hypertension, and HIV infection. Long-term epoprostenol therapy in IPAH patients results in sustained benefit and improved survival. Observed survival at one, two, and three years with epoprostenol therapy was 87.8%, 76.3%, and 62.8%, respectively, and was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4%, respectively, based on historical data. The drug has a short half-life (<6 minutes), and is unstable in an acidic pH and at room temperature. It requires a chronic venous access and is expensive. Dosing begins at 2ng/kg/min with gradual uptitration by 1-2ng/kg/min, based upon clinical and side-effects, until a 'plateau' dose is reached. Generally, this is between 30-40ng/kg/min, though there are wide individual variations. Common side-effects of this therapy include flushing, jaw pain, diarrhea, nausea, erythematous rash, and myalgias.
Alternate delivery routes to administer prostanoids have been evaluated. Treprostinil is a prostacyclin analogue with a half-life of three hours that can be delivered subcutaneously. This drug has shown benefits similar to epoprostenol in a randomized controlled trial of patients with IPAH, and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts and WHO class II- IV symptoms. Dosing begins at 0.625–1.25ng/kg/min, with gradual increments by 1.25ng/kg/min, based upon clinical and side-effects to a 'plateau' dose of 18-20ng/kg/min, with individual variations. Side-effects are similar to epoprostenol with the exception of pain at the infusion site which occurs in 85% of treated patients.
Iloprost, which is an inhaled analogue of prostacyclin has a half-life of 20-25 minutes and effects similar to epoprostenol. It is available in Europe and New Zealand and is currently being evaluated in randomized controlled trials in the US. Beraprost is an orally active prostacyclin analogue with a half-life of 35-40 minutes that is available in Japan. In two randomized, double-blind, placebo-controlled trials, this drug increased exercise capacity only in IPAH patients with no sustained benefit beyond six months of therapy.
Endothelin receptor antagonists have emerged as an important treatment strategy for PAH patients. Endothelin is overexpressed in the pulmonary arteries of PAH patients and several investigations have clearly demonstrated that it plays a critical role in the pathogenesis. Endothelin exerts its biologic effects through two receptors - endothelin receptor sub-type A (ETA) located in the vascular smooth muscle cell and ETB located in the endothelial cell. The proportion of these receptors is more or less equal in health, but changes in disease with upregulation of the ETB receptor. Vasoconstriction and cell proliferation are predominantly mediated through ETA receptor, while fibrosis, inflammation, neurohormonal modulation, and clearance of endothelin are mediated primarily through the ETB receptor. Vasodilation through increased production of nitric oxide and prostacyclin are also mediated through the ETB receptor. Bosentan is an antagonist of both the ETA and ETB receptor. In randomized, placebo-controlled clinical trials, bosentan improved symptoms, quality of life, hemodynamics, exercise tolerance, and time to clinical worsening in IPAH and PAH associated with collagen vascular disease with WHO class III or IV symptoms. Three-year survival was 86% in bosentan-treated patients compared with a predicted survival of 48% based upon a validated National Institutes of Health (NIH) survival equation. Dosing begins with 62.5mg twice daily with uptitration to 125mg twice daily in four weeks. Bosentan is primarily eliminated by hepatic metabolism through the P450 enzymes CYP2C9 and CYP3A4. Side-effects include hepatocellular injury at high doses, dose-related decrease in hemoglobin level, headache, and flushing. Greater than three-fold increase in aminotransferases due to inhibition of the bile salt export pump in the hepatocyte occurs in 13% of bosentan-treated patients. This hepatic abnormality is often asymptomatic and resolves with either dose reduction or cessation. Glyburide and cyclosporine A interact with the p450 enzyme system and are contraindicated in patients receiving bosentan.
Selective ETA antagonists sitaxsentan and ambrisentan are currently under investigation. The rationale is to block the vasoconstriction mediated by the ETA receptor while keeping the 'favorable' effects of the ETB receptor intact. A trial comparing sitaxsentan with bosentan is also in progress.
The nitric oxide-cyclic GMP signalling plays a pivotal role in pulmonary vasoregulation. Endothelial nitric oxide synthase activity is reduced in the pulmonary vasculature of PAH patients and correlates negatively with the severity of vascular remodeling. Increasing nitric oxide delivery, directly or indirectly by limiting enzymatic degradation through phosphodiesterases (PDE5), has great therapeutic potential in PAH patients. Sildenafil, a PDE5 inhibitor is a potent pulmonary vasodilator that is currently being investigated in a placebo-controlled trial in PAH patients.
Combining different classes of drugs to maximize therapeutic benefit has not been systematically evaluated in PAH. There is evidence in small, uncontrolled studies indicating incremental benefit to adding endothelin antagonists to prostanoids and PDE5 inhibitors to prostanoids.
For patients with persistent symptoms on medical therapy there are different interventional and surgical approaches available. Balloon atrial septostomy creates a right-to-left inter-atrial shunt to help decompress a severely dysfunctional right ventricle and, by increasing cardiac output, despite a fall in the systemic arterial oxygen saturation, augments systemic oxygen delivery. This procedure carries a mortality risk of 5.6% and should only be undertaken at experienced centers. The effect of balloon atrial septostomy on long-term survival in PAH patients is unknown at this time.
Pulmonary endarterectomy is a potentially curative treatment option for severely symptomatic patients with chronic thromboembolic pulmonary hypertension. Careful patient selection is a key to successful outcome. Mortality rates range between 5% and 24% and there is a distinct learning curve. Although there are no randomized, controlled studies, significant and persistent decreases in pulmonary pressures and resistance are seen accompanied by improved functional status, quality of life and right ventricular function. Five-year survival rates of 75% to 80% have been reported in experienced centers.
Lung and heart-lung transplantation are options for carefully selected PAH patients who are failing other therapies. Appropriate timing of transplant listing is critical since the waiting period for donor organs is unpredictable and often long. Heart-lung transplantation is recommended when severe right ventricular failure is present. One, three, and five-year survival after lung transplantation is 64%, 54%, and 44% respectively for IPAH patients. Results are inferior in patients with PAH associated with systemic-to-pulmonary shunts and Eisenmenger's physiology.